propylthiouracil and Hypothyroidism

Hyperthyroidism affects about 0.2%-2.7% of all pregnancies, and is generally treated with propylthiouracil (PTU). However, previous studies about the effects of propylthiouracil on maternal or foetal are contentious.. This meta-analysis was carried out to investigate the safety and efficacy of propylthiouracil during pregnancy.. PubMed, EBSCO, Embase, Scopus, Web of Science, Cochrane, CNKI, Wanfang and VIP database were searched from inception until August 31, 2021 for all available randomized controlled trials (RCTs) or cohort studies that evaluated the efficacy of propylthiouracil and its effects on pregnancy outcomes. Odds ratio (OR) and 95% confidence interval (CI) were used for binary variables, weighted mean difference (WMD) and 95% confidence interval (CI) were used for continuous variables. RevMan5.4 and Stata 16.0 were used for performing the meta-analysis.. The researchers examined data from 13 randomized controlled trials and cohort studies involving 18948 infants. Congenital anomalies were not significantly associated with PTU in the pooled results (OR = 1.03, 95%CI: 0.84-1.25, P = 0.80, I2 = 40.3%). There were no statistically significant differences in neonatal hypothyroidism (OR = 0.55, 95%CI: 0.06-4.92, P = 0.593, I2 = 57.0%) or hepatotoxicity (OR = 0.34, 95%CI: 0.08-1.48, P = 0.151, I2 = 0.0%) exposed to PTU compared to the control group. The serum levels of FT3, FT4, TT3, and TT4 were significantly lower in the propylthiouracil group compared to the control group.. This meta-analysis confirmed the beneficial effects of propylthiouracil treatment, namely the risks of adverse pregnancy outcomes were not increased, and it also proved PTU's efficacy in the treatment of pregnant women with hyperthyroidism. The findings supported the use of propylthiouracil during pregnancy with hyperthyroidism in order to improve clinical pregnancy outcomes in patients with thyroid dysfunction.

Topics: Antithyroid Agents; Female; Humans; Hyperthyroidism; Hypothyroidism; Infant, Newborn; Methimazole; Pregnancy; Pregnancy Complications; Propylthiouracil

Fetal thyroid disorders while uncommon in general, have significant morbidity and profound effects in the neonate. Pregnancy provides the opportunity not only for the diagnosis of these conditions but also for therapeutic interventions. In careful balance, these disorders range from hypothyroidism to hyperthyroidism, both may manifest with fetal thyroid goiters as well. The intrauterine therapeutic approach of these must also weight the balance in this range as well as the maternal well being which may also express thyroid dysfunction. In this review we explore the different fetal manifestations of thyroid disease, describe the pathophysiology and therapeutic approaches both in practice and in development.

Topics: Antithyroid Agents; Female; Fetal Diseases; Gestational Age; Goiter; Humans; Hyperthyroidism; Hypothyroidism; Infant, Newborn; Neonatal Screening; Pregnancy; Pregnancy Complications; Prenatal Diagnosis; Propylthiouracil; Thyroid Diseases; Thyroxine; Ultrasonography, Prenatal

This review covers the current American Thyroid Association recommendations on diagnosis and management of thyroid disease during pregnancy and the postpartum period. It lists the recommendations in a reader-friendly way, and facilitates rational therapy of thyroid disorders, in relation to obstetric health, at the primary care level.

Topics: Adrenergic beta-Antagonists; Antithyroid Agents; Disease Management; Female; Fluid Therapy; Humans; Hyperthyroidism; Hypothyroidism; Postnatal Care; Practice Guidelines as Topic; Preconception Care; Pregnancy; Pregnancy Complications; Pregnancy Complications, Neoplastic; Prenatal Care; Propylthiouracil; Thyroid Neoplasms; Thyroid Nodule; Thyrotropin; Thyroxine; Time Factors

Functional thyropathies present significant health risks for patients. Advanced functional thyropathies are always treated while indications for therapy of subclinical thyropathies are individual and often controversial. It is widely agreed that these disorders should be diagnosed and individuals should be followed. The drug of choice in substitution therapy of hypothyroidism is levothyroxine, in the treatment of hyperthyroidism it is methimazole. Administration of propylthiouracil should be limited to the first trimester of pregnancy, because its serious hepatotoxicity has been described. Hyperthyroidism based on thyroid nodules and immunogenic hyperthyroidism not reaching long-term remission, need to be treated radically: by surgery or radioiodine treatment. When radiation protection requirements are met, radioiodine can also be administered on an outpatient basis. Exceptionally, small doses of methimazole can be administered over an extended period of time in individual cases.

Topics: Female; Humans; Hyperthyroidism; Hypothyroidism; Iodine Radioisotopes; Methimazole; Pregnancy; Pregnancy Complications; Propylthiouracil; Thyroid Function Tests; Thyroidectomy; Thyroxine

Topics: Amniotic Fluid; Diagnosis, Differential; Female; Fetal Diseases; Goiter; Humans; Hyperthyroidism; Hypothyroidism; Pregnancy; Propylthiouracil; Thyroid Diseases; Thyroxine; Ultrasonography, Prenatal

Glioblastoma multiforme (GBM) is the most malignant and frequent brain tumor, with an aggressive growth pattern and poor prognosis despite best treatment modalities. Long-term survival of patients with GBM is rare. Optic glioma represents 0.6-1.2% of all brain tumors. Unlike low-grade optic gliomas in children, optic gliomas in adults are highly aggressive and death usually occurs in less than a year. Prolonged progression-free survival and survival rates have been reported in association with induced hypothyroidism in two clinical trials for recurrent GBM. We present the clinical, radiological, and pathological findings in a patient with inoperable GBM of the optic chiasm. Following failure of initial, standard radiation and temozolomide therapy, chemical hypothyroidism was induced using the antithyroid thioamide, propylthiouracil, followed by carboplatin chemotherapy. Initial thyroid stimulating hormone, free T4, and free T3 analysis was carried out and then monthly. This patient responded rapidly to treatment (clinically and with tumor regression within 4 weeks) on two separate occasions with an extended remission period (2.5 years) and prolonged overall survival (4.5 years). We report the successful long-term tumor response to medically induced chemical hypothyroidism in conjunction with carboplatinum chemotherapy of an adult patient with grade IV GBM of the optic chiasm. These clinical observations find mechanistic support from the recent identification of potent mitogenic actions of the thyroid hormone, L-thyroxine, in malignant glioma through binding to a cognate thyroid hormone receptor on the αvβ3 integrin. Approaches to block its activity are now explored in preclinical studies.

Topics: Antithyroid Agents; Carboplatin; Combined Modality Therapy; Humans; Hypothyroidism; Male; Middle Aged; Optic Chiasm; Optic Nerve Glioma; Propylthiouracil; Thyroxine; Treatment Outcome; Triiodothyronine

Advances in prenatal imaging techniques and in fetal hormonology now allow for identification of disorders of thyroid function in the fetus. These can potentially be treated in utero by giving drugs to the mother.. This review examines the feasibility of in utero treatment of fetal thyroid disorders, either indirectly by treating the mother or by giving the necessary drugs directly to the fetus.. In women with Graves' disease, autoimmune fetal hyperthyroidism can generally be treated in a noninvasive way by optimizing treatment of the mother, such as by increasing the dose of antithyroid drugs. For goitrous fetal hypothyroidism leading to hydramnios, repeated intra-amniotic injections of thyroxine have been reported to decrease the size of the fetal thyroid.. Experience with such procedures is limited but positive. The risk that direct in utero treatment of the fetus may provoke premature labor or cause infection should be carefully evaluated.. Follow-up of the efficacy and the possible long-term consequences of medical interventions to normalize thyroid function of the fetus are of great importance. Specialized care of the fetus should be provided by skilled teams with extensive experience in prenatal care.

Topics: Adult; Antithyroid Agents; Female; Fetal Diseases; Goiter; Graves Disease; Humans; Hyperthyroidism; Hypothyroidism; Maternal-Fetal Exchange; Pregnancy; Pregnancy Complications; Propylthiouracil; Thyroid Diseases; Thyroxine

To collect and assess clinical reports of a putative relationship between thyroid state and the biology of cancers of various types.. A number of prospective case-control studies reviewed here have suggested that subclinical hyperthyroidism increases risk of certain solid tumors and that spontaneous hypothyroidism may delay onset or reduce aggressiveness of cancers. Small case studies have reached similar conclusions. A controlled prospective trial of induced hypothyroidism beneficially affected the course of glioblastoma. A context in which to interpret such findings is the recent description of a plasma membrane receptor for thyroid hormone on cancer cells and dividing tumor-associated endothelial cells.. Accumulating clinical evidence may justify new, broadly-based controlled studies in cancer patients of the possible contribution of thyroid hormone to tumor behavior.

Topics: Animals; Antithyroid Agents; Cell Proliferation; Female; Humans; Hyperthyroidism; Hypothyroidism; Integrin alphaVbeta3; Neoplasms; Propylthiouracil; Rats; Receptors, Thyroid Hormone; Risk Factors; Thyroid Hormones

Topics: Abortion, Spontaneous; Adult; Antithyroid Agents; Autoantibodies; Diabetes Mellitus, Type 1; Diabetes, Gestational; Female; Fertilization in Vitro; Gestational Age; Graves Disease; Humans; Hyperthyroidism; Hypothyroidism; Infant, Newborn; Infertility, Female; Iodine; Male; Menstrual Cycle; Menstruation Disturbances; Pregnancy; Pregnancy Complications; Prevalence; Propylthiouracil; Puerperal Disorders; Risk Factors; Thyroid Diseases; Thyroid Gland; Thyroid Hormones; Thyroiditis; Thyrotropin; Thyroxine; Ultrasonography

In Graves' patients complicated by pregnancy, both maternal and fetal problems related to the disease can be reduced or avoided by controlling hyperthyroidism. However, optimal treatment for mothers may exert detrimental effects on fetuses. Methimazole may cause "methimazole embryopathy". Antithyroid drug doses that maintain mothers in euthyroid status are sometimes excessive fetuses. Furthermore, successful treatment with surgery or radioiodine occasionally may result in fetal hyperthyroidism due to TSH receptor antibody(TRAb). There are approaches to manage these problems. Propylthiouracil is chosen in treating Graves' disease in early pregnancy. In later pregnancy, maternal free thyroxine is maintained near or somewhat above normal. Ablative therapy is not recommended in women whose TRAb levels are extremely high from the standpoint of fetal thyroid state.

Topics: Antithyroid Agents; Autoantibodies; Congenital Abnormalities; Female; Fetal Diseases; Graves Disease; Humans; Hyperthyroidism; Hypothyroidism; Immunoglobulins, Thyroid-Stimulating; Infant; Infant, Newborn; Lactation; Maternal-Fetal Exchange; Methimazole; Milk, Human; Pregnancy; Pregnancy Complications; Pregnancy Trimesters; Propylthiouracil

The subject of thyroid disease in pregnancy is receiving increasing attention from many scientific disciplines. Thyroid function in pregnancy is characterised by a T4 surge at 12 weeks declining thereafter. Serum thyroid hormone concentrations fall in the second half of pregnancy but there are few data on normal reference ranges. Fetal brain development depends on T4 transport into the fetus which in turn depends on sufficient maternal iodine supply. There is current concern that adequate iodisation is not present in large parts of Europe. There is increasing evidence that thyroid autoimmunity is associated with fetal loss but the mechanism is unclear and therapy requires carefully conducted studies. While hyperthyroidism in pregnancy is uncommon, effects on both mother and child are critical if untreated. The use of propylthiouracil is recommended together with measurement of TSH receptor antibodies at 36 weeks gestation. Women receiving thyroxine therapy for hypothyroidism or as suppressive therapy should have their dose increased by up to 50% during pregnancy. There are now substantial data to show deleterious effects on child IQ resulting from low maternal T4 (or high TSH) during gestation. Major advances in molecular biology have contributed to elucidation of many genetic causes of congenital hypothyroidism. However, the aetiology of the majority of cases is still unclear and further research is required. The presence of TPO antibodies in about 10% of pregnant women in early gestation is a predictor of an increased incidence of subclinical hypothyroidism during pregnancy and also of postpartum thyroid dysfunction. The latter condition occurs in 5-9% of women and 25-30% progress to permanent hypothyroidism. This review suggests that screening for thyroid function in early pregnancy and levothyroxine intervention therapy for maternal subclinical hypothyroidism should be considered but evidence is awaited. Screening for both thyroid dysfunction and thyroid antibodies ideally at a preconception clinic but certainly in early gestation is recommended.

Topics: Antithyroid Agents; Autoantibodies; Congenital Hypothyroidism; Drug Combinations; Female; Humans; Hyperthyroidism; Hypothyroidism; Immunoglobulins, Thyroid-Stimulating; Infant, Newborn; Intelligence Tests; Mass Screening; Maternal-Fetal Exchange; Pregnancy; Pregnancy Complications; Propylthiouracil; Receptors, Thyrotropin; Thyroid Diseases; Thyroid Function Tests; Thyrotropin; Thyroxine

Topics: Animals; Carbimazole; Choanal Atresia; Ectodermal Dysplasia; Female; Goiter; Guinea Pigs; Humans; Hypothyroidism; Methimazole; Mice; Pregnancy; Propylthiouracil; Rabbits; Rats; Teratogens; Thyroid Gland

Pregnancy is accompanied by changes in thyroid function. Due to the increased synthesis of thyroid binding globulin and the thyroid-stimulating effect of human chorionic gonadotrophin (hCG), serum concentrations of thyroid hormones will increase in the first trimester of pregnancy (total T4, T3). Free T4 levels decrease during the latter half of pregnancy. Hyperthyroidism during pregnancy is usually due to Graves' disease. Definitive therapy may be considered for cases prior to pregnancy, although a medical management as would be given during pregnancy is an equally good option. The medical management of hyperthyroidism consists of a monotherapy with thyreostatics in which the recommended dose needs to be adjusted on the basis of free T4 in the high-normal and thyroid stimulating hormone (TSH) in the low-normal area so as to minimise the risk of foetal hypothyroidism. The transplacental passage of maternal TSH receptor stimulating antibodies may cause foetal hyperthyroidism. Another cause of maternal hyperthyroidism during pregnancy is 'gestational transient thyrotoxicosis', which is associated with high hCG levels during the first trimester of pregnancy. It is nearly always accompanied by hyperemesis gravidarum. Hypothyroidism in pregnancy has negative consequences for the foetus. If the hypothyroidism is apparent prior to pregnancy, it should be corrected before conception (target TSH value of 1 mU/l). If discovered during pregnancy, treatment with levothyroxine should be started as soon as possible. In the case of a pre-existing hypothyroidism a 25-50% increase in the levothyroxine dosage is often needed during the first trimester of pregnancy. This is possibly due to an increased requirement. An adequate serum concentration of T4 is necessary for foetal brain development.

Topics: Adult; Antithyroid Agents; Disease Management; Dose-Response Relationship, Drug; Female; Fetal Diseases; Hormone Replacement Therapy; Humans; Hyperthyroidism; Hypothyroidism; Infant, Newborn; Pregnancy; Pregnancy Trimester, First; Pregnancy, High-Risk; Propylthiouracil; Thyroid Function Tests; Thyroxine

Topics: Antithyroid Agents; Congenital Hypothyroidism; Female; Goiter; Graves Disease; Humans; Hypothyroidism; Infant, Newborn; Maternal-Fetal Exchange; Pregnancy; Pregnancy Complications; Propylthiouracil

The development of hyperthyroidism after primary hypothyroidism is unusual. We report such a case in a 37-year old man and review the clinical and immunologic aspects of the previously published cases of 50 female and 19 male patients with a similar condition.

Topics: Adult; Antithyroid Agents; Female; Humans; Hyperthyroidism; Hypothyroidism; Male; Propylthiouracil; Thyrotropin; Thyroxine

Topics: Female; Graves Disease; Humans; Hypothyroidism; Immunosuppressive Agents; Male; Methimazole; Mutation; Propylthiouracil; Receptors, Thyrotropin; Syndrome; Thyroid Gland; Thyroid Hormones

Therapy of thyroid dysfunction needs a close cooperation between endocrinologist and gynecologist. In addition to a number of metabolic changes during pregnancy, the diaplacentar transfer of different substances (thionamides, antibodies) has to be considered. Pregnant women with overt and subclinical hypothyroidism should be treated using L-Thyroxine with the bTSH between 1 and 2 mU/l. Many of the women need an increase of the L-Thyroxine dose during pregnancy. Overt hyperthyroidism (mostly due to Graves' disease) has to be treated immediately after diagnosis using thionamides. Because thionamides cross the placenta, the dose should be as low as possible with the fT4 in upper level and bTSH in the lower level of normal range. Most studies show, that both methimazole (MI) and propylthiouracil (PTU) can be used in pregnancy. Although PTU is preferred especially in the USA, an advantage of PTU over MI is not proven. Surgery is necessary in only few cases of hyperthyroidism during pregnancy with the optimal time for surgery during the second trimester. In case of subclinical hyperthyroidism and HCG induced hyperthyroidism several controls of thyroid function should be performed to decide whether treatment is necessary.

Topics: Abnormalities, Drug-Induced; Antithyroid Agents; Dose-Response Relationship, Drug; Female; Humans; Hyperthyroidism; Hypothyroidism; Infant, Newborn; Methimazole; Pregnancy; Pregnancy Complications; Propylthiouracil; Risk Factors; Thyroid Function Tests; Thyroxine

Topics: Adrenergic beta-Antagonists; Carbimazole; Female; Fetal Diseases; Humans; Hyperthyroidism; Hypothyroidism; Iodine Radioisotopes; Pregnancy; Pregnancy Complications; Propylthiouracil; Referral and Consultation; Thyroid Function Tests; Thyroidectomy; Thyroxine; Treatment Outcome

Recent modifications of the radioimmunoassay systems for TSH have greatly extended the clinical utility of the measurement of this hormone, so that its use is no longer limited to the diagnosis of primary hypothyroidism. The newer assays provide improved sensitivity and specificity, such that it is now possible to distinguish TSH levels that are within the normal range from those that are suppressed, e.g., in thyrotoxicosis. New vistas of clinical applications are being revealed as we improve our understanding of human thyroid physiology and pathophysiology. It is the purpose of this communication to summarize information about the improved TSH radioimmunoassay, to demonstrate the new observations available regarding TSH concentrations in various normal and diseased conditions, and finally, to illustrate the various ways in which the assay provides more accurate guidance in the clinical diagnosis and management of thyroid and nonthyroid disease.

Topics: Adolescent; Adult; Aged; Aging; Child; Child, Preschool; Circadian Rhythm; Female; Goiter; Graves Disease; Humans; Hyperthyroidism; Hypothyroidism; Infant; Infant, Newborn; Male; Mass Screening; Middle Aged; Pregnancy; Propylthiouracil; Radioimmunoassay; Reference Values; Thyroiditis, Autoimmune; Thyrotropin; Thyroxine; Triiodothyronine

Topics: Adult; Calcium; Carbimazole; Congenital Hypothyroidism; Dihydrotachysterol; Female; Humans; Hyperparathyroidism; Hyperthyroidism; Hypoparathyroidism; Hypothyroidism; Infant, Newborn; Parathyroid Diseases; Parathyroid Glands; Pregnancy; Pregnancy Complications; Propylthiouracil; Puerperal Disorders; Thyroid Diseases; Thyroxine

Topics: Adult; Aminoglutethimide; Animals; Antithyroid Agents; Carbimazole; Cobalt; Ethionamide; Female; Fetal Diseases; Goiter; Humans; Hyperthyroidism; Hypothyroidism; Infant, Newborn; Iodides; Lithium; Male; Methimazole; Pregnancy; Pregnancy Complications; Propylthiouracil; Rats; Sulfonamides; Sulfonylurea Compounds; Vegetables

Topics: Aging; Animals; Dexamethasone; Fasting; Humans; Hyperthyroidism; Hypothyroidism; Infant, Newborn; Kinetics; Liver Cirrhosis; Propylthiouracil; Thyroid Gland; Thyrotropin; Thyroxine; Triiodothyronine

There are two biologically active thyroid hormones, thyroxine (T4) and triiodothyronine (T3). Most T3 is produced extrathyroidally, so that alterations in circulating thyroid hormone concentrations may occur as a result of both thyroidal and extrathyroidal abnormalities. Extrathyroidal T4 conversion to T3 is decreased in patients with different acute and chronic illnesses. When T4 conversion to T3 is impaired and serum T3 concentrations decline, serum concentrations of biologically inactive 3,3',5'-triiodothyronine (reverse T3) increase. In this review, we present current information on thyroidal and extrathyroidal T4 and T3 production in normal subjects and patients with various thyroid diseases and other illnesses, consider the physiologic significance of these changes, and discuss the value and interpretation of various iodothyronine measurements.

Topics: Chemical Phenomena; Chemistry; Glucocorticoids; Humans; Hyperthyroidism; Hypothyroidism; Prealbumin; Propylthiouracil; Protein Binding; Thyroid Gland; Thyrotropin; Thyrotropin-Releasing Hormone; Thyroxine; Thyroxine-Binding Proteins; Triiodothyronine

Topics: Animals; Chemical Phenomena; Chemistry; Humans; Hypothyroidism; Propylthiouracil; Rats; Thyroid Gland; Thyroid Hormones; Thyroxine; Triiodothyronine

Topics: Acetaldehyde; Animals; Brain; Ethanol; Fasting; Hyperthyroidism; Hypothyroidism; Liver; Male; Oxygen Consumption; Propylthiouracil; Rats; Triiodothyronine

Topics: Congenital Hypothyroidism; Female; Humans; Hyperthyroidism; Hypothyroidism; Infant, Newborn; Maternal-Fetal Exchange; Pregnancy; Prognosis; Propylthiouracil; Thyroid (USP); Thyroid Diseases; Thyroid Gland; Thyroxine

Topics: Abortion, Spontaneous; Female; Fetal Diseases; Humans; Hyperthyroidism; Hypothyroidism; Maternal-Fetal Exchange; Methimazole; Pregnancy; Pregnancy Complications; Propylthiouracil; Thyroid Diseases; Thyroid Function Tests; Thyroid Gland; Thyroid Hormones; Thyroidectomy; Thyrotropin-Releasing Hormone; Thyroxine

Topics: Biological Transport; Female; Humans; Hyperthyroidism; Hypothyroidism; Iodides; Kinetics; Methimazole; Pregnancy; Propylthiouracil; Thyroid Gland; Thyrotropin; Thyroxine; Thyroxine-Binding Proteins; Triiodothyronine; Umbilical Cord

1. The present study was conducted to examine the effects of α-lipoic acid on hypothyroidism-induced negative growth performance and whether α-lipoic acid alleviates acute heat stress in relation to hypothyroid status. 2. Female broiler chickens (14 d-old) were fed diets supplemented with α-lipoic acid (100 mg/kg) and an antithyroid substance, propylthiouracil (200 mg/kg), for 20 d under thermoneutral conditions (25°C). At 42 d of age, chickens were exposed to a high ambient temperature (36°C, 60% RH) for 4 h. 3. Under the thermoneutral condition, propylthiouracil administration decreased feed efficiency and concomitantly increased adipose tissue and thyroid gland weights. Plasma nonesterified fatty acids and triacylglycerol were also increased by propylthiouracil administration. However, α-lipoic acid supplementation did not affect the hypothyroidism-induced effects. 4. In hypothyroid chickens, the rise in respiratory rate induced by heat exposure was greatly inhibited by α-lipoic acid administration at 1 h, but this effect had disappeared at 4 h. In addition, a similar inhibitory effect on the concentrations of plasma nonesterified fatty acids was subsequently observed at 4 h. 5. Therefore, the present study suggested that α-lipoic acid alleviates acute heat stress if chickens are in a hypothyroid status.

Topics: Animal Feed; Animals; Body Weight; Chickens; Diet; Dietary Supplements; Fatty Acids, Nonesterified; Female; Hot Temperature; Hypothyroidism; Poultry Diseases; Propylthiouracil; Stress, Physiological; Thioctic Acid

A hypothesis was tested that providing the breeder hens with exogenous thyroxine (T(4)) would help their offspring to better survive the ascites-inducing condition during the growing period. In total, 132 broiler breeder hens were randomly assigned to one of 3 treatments: control (CON), hypothyroid [HYPO; 6-N-propyl-2-thiouracil (PTU)-treated], and hyperthyroid (HYPER; T(4)-treated). The hens were artificially inseminated, and the hatching eggs (n = 1,320) were incubated. No eggs in the HYPO group hatched. The 1-d-old male chicks (n = 288) from other groups were reared for 42 d under standard or low ambient temperature to induce ascites. Blood samples were drawn from the hens, embryos, and broilers for determination of T(4) and triiodothyronine (T(3)). The hematocrit was also determined in broilers. The PTU-treated hens had an increased BW along with lower plasma T(3) and T(4) concentrations. Plasma T(4) was higher in the HYPER hens compared with CON hens, but T(3) concentration was not different between these groups. The fertility rate was not affected by either hypo- or hyperthyroidism. The embryos in the HYPO group had lower plasma T(3) and T(4) concentrations at d 18 of embryonic development and internal pipping. Higher plasma T(4) was recorded in the HYPER birds at internal pipping, although plasma T(3) concentration was not affected at this stage. Maternal hyperthyroidism decreased the overall incidence of ascites in the cold-exposed chickens (10.0 vs. 33.4% for HYPER and CON groups, respectively). Although the effect of maternal PTU or T(4) treatment on plasma thyroid hormones and on the right ventricle-to-total ventricular weight ratio in the broilers was not significant, the cold-exposed healthy CON chicks showed higher hematocrit values, compared with the HYPER birds. It was concluded that maternal hyperthyroidism could decrease the incidence of cold-induced ascites in broiler chickens; however, probable causal mechanisms remain to be elucidated.

Topics: Animals; Ascites; Chickens; Cold Temperature; Female; Hyperthyroidism; Hypothyroidism; Male; Poultry Diseases; Propylthiouracil; Thyroxine; Weight Gain

Alterations in thyroid function are associated with changes in body weight, metabolism, and low-grade inflammation. In several studies, plasma levels of visfatin were found to be associated with body mass index, diabetes, and metabolic syndrome. In our study we aimed to evaluate visfatin levels according to thyroid dysfunction. The study cohort comprised 56 Hashimoto thyroiditis patients with hypothyroidism (43.94+/-14.27 yr), 56 Graves patients with hyperthyroidism (45.87+/-13.28 yr), and 56 euthyroid healthy subjects (45.23+/-7.11 yr) as a control group. In addition, we evaluated the effect of therapy on plasma visfatin levels in 16 hypothyroid and in 25 hyperthyroid patients. Markedly low visfatin levels were found in hyperthyroid patients [9.44 (8.07- 10.8) ng/ml] compared with the hypothyroid [49.93 (40.72- 59.1) ng/ml] and control groups [38.6 (30.6-46.6) ng/ml] (p<0.001, p<0.001). Plasma visfatin levels in patients with hypothyroidism decreased significantly following treatment [58.58 (10.21-190.7) ng/ml vs 40.00 (10.01-102.6) ng/ml; p=0.001]. Plasma visfatin levels increased significantly after antithyroid therapy in patients with hyperthyroidism [7.86 (1.02-19.23) ng/ml vs 12.63 (3.48-110.9) ng/ml; p<0.001]. There were negative correlations between visfatin levels with free T3 (r=-0.719, p<0.001), and free T4 (r=-0.716, p<0.001) levels. There was a positive correlation between visfatin and TSH levels (r=0.701, p<0.001). There was a negative correlation between delta visfatin levels with delta free T3, delta free T4 (r=-0.686, p<0.001; r=-0.624, p<0.001). Visfatin thus seems to be regulated by thyroid hormones. While the influence of thyroid dysfunction on adipocytokine production and release is still poorly understood, the results of our study suggest that the effects of hyper- and hypothyroidism on various metabolic parameters may be partly mediated by visfatin.

Topics: Adult; Antithyroid Agents; Cross-Sectional Studies; Cytokines; Female; Hormone Replacement Therapy; Humans; Hyperthyroidism; Hypothyroidism; Male; Middle Aged; Nicotinamide Phosphoribosyltransferase; Osmolar Concentration; Propranolol; Propylthiouracil; Recovery of Function; Thyroid Gland; Thyroxine

Two experiments were conducted during mid-gestation to examine effects in ewes of propylthiouracil (PTU) treatment alone or with melatonin on serum thyroid hormones, postpartum reproduction, and lamb performance. In the first experiment, beginning on day 0 (first day of treatment when all animals were 72.2+/-0.9 days of gestation), ewes received daily treatments (gavage) consisting of either 0mg (n=6) or 40 mg (n=6) PTU/kg body weight/day for 15 days. After 15 days, the 40 mg dosage was decreased to 20mg/kg body weight for an additional 20 days (35 days of PTU). Serum thyroxine (T4) did not differ (P>0.10) between groups through day 4; but on day 5, control females had a serum value of 67 ng/ml compared with 46 (+/-5)ng/ml for PTU-treated ewes (P=0.02). On the last day that 40 mg of PTU was administered, serum T4 averaged 67 and 7 (+/-5)ng/ml (P<0.001) in the two respective groups. Serum T4 remained low and was 80 and 1 ng/ml (P<0.001) in control and treated ewes on day 34. Serum T4 rose gradually after PTU but remained different from that observed in control ewes through day 48. Lambs from control and treated ewes had similar (P=0.46) T4 values at birth but lambs from PTU-treated ewes had lower (P=0.03) birth weights than did those from control ewes. Serum progesterone (P4) after parturition indicated a lack of cyclicity in all ewes. In the second experiment, beginning on day 0 (76.8+/-4.7 days of gestation), ewes received PTU as in Experiment 1. In addition, after 15 days of PTU, melatonin was given (i.m. injections at 5mg/day) for 30 days. Propylthiouracil decreased (P0.60) for lambs born to control and treated ewes. Female offspring of PTU+melatonin-treated dams reached puberty, became anestrus, and returned to cyclicity at similar (P>0.10) times to contemporary ewe lambs. Results indicate that 40/20mg PTU alone or with melatonin does not induce cyclicity after lambing in spring lambing ewes and has little effect on offspring performance.

Topics: Animals; Body Weight; Dose-Response Relationship, Drug; Estrous Cycle; Female; Hypothyroidism; Melatonin; Pregnancy; Progesterone; Propylthiouracil; Reproduction; Seasons; Sheep; Thyroxine; Time Factors; Triiodothyronine

T-cell activation has been implicated in the pathogenesis of psoriasis; adenosine deaminase (ADA) activity has been considered as a marker of T-cell activation. The antithyroid drug propylthiouracil (PTU) has recently been shown to have beneficial effects on psoriatic lesions, probably by acting on the immune system.. To investigate whether ADA activity may be related to psoriasis and whether oral PTU affects ADA activity and gives clinical improvement in psoriatic patients.. ADA activities were measured in plasma, erythrocyte and tissue samples of patients with psoriasis before and after 2 months of treatment with either PTU 100 mg three times daily or PTU plus thyroxine 25 microg once daily (to prevent possible hypothyroidism, which may be induced by PTU) as well as in healthy controls. The severity of the disease was evaluated before and after treatment according to Psoriasis Area and Severity Index (PASI) scores. Routine analyses and thyroid function tests were also carried out during the study.. All patients showed significant clinical improvement in their lesions and decreased PASI scores after the treatments. Elevated baseline ADA activities in skin and plasma were found to be lower, and decreased baseline erythrocyte ADA was higher, after the treatments in all patients, and they were not different from control values. Although thyroid function tests were not affected by the treatments, serum thyroid-stimulating hormone levels were found to be higher after the treatments, and there was a larger increase in patients treated with PTU alone. However, none of the patients had clinical hypothyroidism or cytopenia.. ADA activity may be clinically useful for indicating T-cell activation in psoriasis. Because of its antiproliferative and immunomodulatory effects, antioxidant potential and low toxicity, PTU may be an effective agent in the treatment of psoriasis.

Topics: Adenosine Deaminase; Adolescent; Adult; Aged; Biomarkers; Dermatologic Agents; Erythrocytes; Female; Humans; Hypothyroidism; Male; Middle Aged; Propylthiouracil; Psoriasis; Severity of Illness Index; Thyroid Gland; Thyrotropin; Thyroxine; Triiodothyronine

Although propylthiouracil has previously been shown to reduce the risk of mortality in alcoholic liver disease by 60%, generalized use of propylthiouracil for this condition has not occurred. Additional data are therefore presented on four aspects to provide a better assessment of its therapeutic effectiveness. First, the characteristics and the prognosis of dropouts were virtually identical in both the drug and placebo groups. Also the methodology and analysis employed, were designed to control for dropouts, thus providing an accurate interpretation of the outcome. Secondly, since 97% of the patients continued to drink, abstinence was not a precondition for the beneficial effect of propylthiouracil. However, the beneficial effect was observed most clearly in those patients who continued to drink at lower levels, whereas lower level drinking per se did not afford protection in placebo patients. Thirdly, serious side effects or clinical hypothyroidism occurred extremely rarely in these patients, many of whom have now received propylthiouracil for over 4 years. Fourthly, we discuss why the outcome in long-term clinical trials in alcoholic liver disease cannot be compared with effects observed in clinical trials lasting only a few weeks. Journal of Hepatology.

Topics: Clinical Trials as Topic; Female; Follow-Up Studies; Humans; Hypothyroidism; Liver Diseases, Alcoholic; Male; Middle Aged; Patient Compliance; Propylthiouracil; Time Factors

Sixty-seven patients entered a double-blind, controlled trial to evaluate the efficacy of propylthiouracil treatment in severe alcoholic hepatitis. Twenty-three percent (7 of 31) given propylthiouracil and 19% (7 of 36) given placebo died during the 6-wk study. Propylthiouracil treatment did not reduce the frequency and incidence of complications in alcoholic hepatitis, but induced hypothyroidism in 4 patients. Treatment produced no beneficial effect on any of the hepatic biochemical tests. We were unable to show any beneficial effect of propylthiouracil treatment on morbidity and mortality in patients with severe acute alcoholic hepatitis.

Topics: Adult; Clinical Trials as Topic; Double-Blind Method; Female; Hepatitis, Alcoholic; Humans; Hypothyroidism; Male; Propylthiouracil; Random Allocation

In 28 patients with Graves' disease showing a wide range of thyroid function between the extremes of hypothyroidism and hyperthyroidism, the following parameters of peripheral thyroid function were measured: serum thyroxine concentration, serum-free thyroxine concentration, serum triiodothyronine concentration, and serum-free triiodothyronine concentration. In 25 patients, thyroxine turnover was also measured. Thyroxine turnover was found to be highly correlated with serum-free thyroxine concentration (r equals 0.9405) and serum-free triiodothyronine concentration (r equals 0.9184). Serum-free thyroxine fraction correlated with serum-free triiodothyronine fraction (r equals 0.8445), suggesting that similar factors in serum controlled the intensity of protein binding for both thyroxine and triiodothyronine. Thyroxine turnover calculated by a noncompartmental method agreed closely with values calculated by the compartmental method, suggesting that the former simpler method has general utility.

Topics: Adult; Aged; Clinical Trials as Topic; Female; Graves Disease; Humans; Hyperthyroidism; Hypothyroidism; Male; Methimazole; Middle Aged; Propylthiouracil; Radioimmunoassay; Thyroid Function Tests; Thyrotropin; Thyrotropin-Releasing Hormone; Thyroxine; Thyroxine-Binding Proteins; Triiodothyronine

Topics: Animals; Calcinosis; Calcium; Calcium Chloride; Clinical Trials as Topic; Disease Models, Animal; Hyperthyroidism; Hypothyroidism; Iodine Radioisotopes; Parathyroid Glands; Phosphates; Propylthiouracil; Rats; Skin Diseases; Thyroid Function Tests; Thyroid Gland; Thyroidectomy

Topics: Antithyroid Agents; Clinical Trials as Topic; Graves Disease; Humans; Hyperthyroidism; Hypothyroidism; Iodine Isotopes; Perchlorates; Potassium; Propylthiouracil; Thyroid Function Tests; Thyroxine; Thyroxine-Binding Proteins; Triiodothyronine

Thyroid hormones are critical for healthy brain functions at every stage of life. Hypothyroidism can cause severe cognitive dysfunction in patients who do not receive adequate treatment. Although thyroid hormone replacement alleviates cognitive decline in hypothyroid patients, there are studies showing that there is no complete recovery. The aim of this study was to investigate the effects of high-intensity interval training (HIIT) in hypothyroid rats on spatial and recognition memory, neuroinflammation, amyloid-beta load and compare these effects with T3 replacement. Hypothyroidism was induced and maintained by administration of 6-n-propyl-2-thiouracil (PTU) with their drinking water to 6-weeks-old male Sprague-Dawley rats for 7 weeks. The animals exercised in the treadmill according to the HIIT protocol for four weeks. T3 was injected intraperitoneally daily during the last two weeks of the study. All animals performed in the elevated plus maze test, Morris water maze test, novel object recognition test, and rotarod motor performance test in the last week of the study and then the animals were sacrificed. Amyloid beta (1-42) and TNFα levels were measured in the prefrontal cortex and hippocampus by ELISA. Anxiety-like behaviors did not significantly differ between groups. T3 replacement with or without HIIT increased motor performance in PTU-treated rats. HIIT and/or T3 replacement increased the exercise performance. HIIT and/or T3 replacement alleviated spatial and recognition memory impairments and normalized TNFα and amyloid-beta levels in the hippocampus in hypothyroid rats. In summary, regular physical exercise may have potential benefits in preserving cognitive functions in hypothyroid patients.

Topics: Amyloid beta-Peptides; Animals; High-Intensity Interval Training; Hippocampus; Humans; Hypothyroidism; Male; Propylthiouracil; Rats; Rats, Sprague-Dawley; Tumor Necrosis Factor-alpha

The calcium/calmodulin protein kinase II (CaMKII) signaling cascade is crucial for hippocampus-dependent learning and memory. Hypothyroidism impairs hippocampus- dependent learning and memory in adult rats, which can be prevented by simple replacement therapy with L-thyroxine (thyroxine, T4) treatment. In this study, we compared animal models of hypothyroidism induced by thyroidectomy and treatment with propylthiouracil (PTU) in terms of synaptic plasticity and the effect on underlying molecular mechanisms of spatial and non-spatial types of memory.. Hypothyroidism was induced using thyroidectomy or treatment with propylthiouracil (PTU). L-thyroxin was used as replacement therapy. Synaptic plasticity was evaluated using in vivo electrophysiological recording. Training in the radial arm water maze (RAWM), where rats had to locate a hidden platform, generated spatial and non-spatial learning and memory. Western blotting measured signaling molecules in the hippocampal area CA1 area.. Our findings show that thyroidectomy and PTU models are equally effective, as indicated by the identical plasma levels of thyroid stimulating hormone (TSH) and T4. The two models produced an identical degree of inhibition of synaptic plasticity as indicated by depression of long-term potentiation (LTP). For non-spatial memory, rats were trained to swim to a visible platform in an open swim field. Analysis of hippocampal area CA1 revealed that training, on both mazes, of control and thyroxine-treated hypothyroid rats, produced significant increases in the P-calcium calmodulin kinase II (P-CaMKII), protein kinase-C (PKCγ), calcineurin and calmodulin protein levels, but the training failed to induce such increases in untreated thyroidectomized rats.. Thyroxine therapy prevented the deleterious effects of hypothyroidism at the molecular level.

Topics: Animals; Calcium; Calcium-Calmodulin-Dependent Protein Kinase Type 2; Calmodulin; Hippocampus; Hypothyroidism; Propylthiouracil; Rats; Rats, Wistar; Thyroidectomy; Thyroxine

The plant, Ficus religiosa (L.) from the family Moraceae, has been extensively used in Ayurveda and Unani. Traditionally this plant is known for the treatment of constipation, liver diseases and neurological disorders that are related to hypothyroidism.. This study was primarily designed to evaluate the effect of Ficus religiosa leaf (FL) extract in ameliorating hypothyroidism in rats and to identify the major bioactive compounds in the test extract that might be responsible for the thyroid-altering activity. In addition, the probable mechanism underlying the thyroid regulation of the main FL constituents were analyzed by molecular docking.. Adult female Wistar rats were used. LC-ESI-MS/MS was performed to identify the compounds present in the extract. HPLC analysis of FL extract was also performed. A pilot study was made using 3 doses of FL extract. Out of 50, 100, and 200 mg/kg, 100 mg/kg appeared to be the most effective one as it could increase thyroid hormones and decreased TSH levels. In the final experiment, propyl-thiouracil (PTU)-induced hypothyroid rats were orally treated with FL extract (100 mg/kg) or L-thyroxine (100 μg/kg, i.p.) daily for 28 consecutive days. On 29th day, all rats were sacrificed and the serum levels of triiodothyronine (T. LC-MS-MS analyses of the leaf extract identified 11 compounds including the three major compounds, betulinic acid (BA), chlorogenic acid (CGA), and quinic acid (QA). While the PTU treatment decreased the levels of thyroid hormones and 5'D1 activity, it increased the TSH, ALT, AST, TNF-α, IL-6, TC, and TG levels. Furthermore, hepatic LPO significantly increased with a decrease in reduced GSH, SOD, CAT, and GPx. However, FL treatment in PTU-induced animals nearly reversed these adverse effects and improved liver function by decreasing ALT, AST, hepatic LPO and increasing the levels of antioxidants. FL not only improved the liver histology, but also suppressed the inflammatory cytokines, TNF-α and IL-6 in PTU-induced animals. A molecular docking study towards the understanding of the thyroid stimulatory mechanism of action revealed that BA, CGA, and QA might have augmented thyroid hormones by interacting with the thyroid hormone receptor (TRβ1) and TSH receptor (TSHR).. For the first time, we report the pro-thyroidal potential of Ficus religiosa leaf extract. We postulate that its main bioactive compounds, BA, CGA, and QA involved in this action may serve as novel thyroid agonists in ameliorating hypothyroidism.

Topics: Animals; Antioxidants; Ficus; Hypothyroidism; Interleukin-6; Liver; Molecular Docking Simulation; Phytochemicals; Pilot Projects; Plant Extracts; Polyphenols; Propylthiouracil; Rats; Rats, Wistar; Superoxide Dismutase; Tandem Mass Spectrometry; Thyroid Hormones; Thyrotropin; Thyroxine; Tumor Necrosis Factor-alpha

Sexual dysfunction may indicate severe endocrine diseases. Recent research has suggested a link between hypothyroidism, low testosterone (T) levels, and erectile dysfunction (ED); however, the exact cause is unknown.. We sought to investigate possible beneficial effects of levothyroxine and T alone or in combination on ED in propylthiouracil (PTU)-induced hypothyroid rats.. Adult Wistar rats (n = 35) were divided into 5 groups: control, PTU-induced hypothyroidism, PTU + levothyroxine, PTU + Sustanon (a mixture of 4 types of T: propionate, phenylpropionate, isocaproate, and decanoate) and PTU + levothyroxine + Sustanon. PTU was given in drinking water for 6 weeks. Four weeks after PTU administration, levothyroxine (20 μg microgram kg/day, oral) and Sustanon (10 mg/kg/week, intramuscular) were given for 2 weeks. Serum levels of total T, triiodothyronine (T3), and thyroxine (T4) were determined. In vivo erectile response and in vitro relaxant responses were measured. Localization of neuronal nitric oxide synthase (nNOS), endothelial NOS (eNOS), and phosphodiesterase type 5 (PDE5) were determined using immunohistochemical analysis. The relative area of smooth muscle to collagen was measured using Masson trichrome staining.. Outcome variables included in vivo erectile function, in vitro relaxant and contractile responses of corpus cavernosum (CC) strips; protein localization of eNOS, nNOS, and PDE5; and smooth muscle content in penile tissue.. The rat model of hypothyroidism showed a significant decline in serum levels of total T, T3, and T4. Levothyroxine increased T3 and T4 levels, whereas Sustanon normalized only total T levels. Combined treatment enhanced all hormone levels. Rats with hypothyroidism displayed the lowest erectile response (P < 0.001 vs controls). Combined treatment returned reduced responses, while partial amelioration was observed after levothyroxine and Sustanon treatment alone. Acetylcholine (P < 0.01 vs controls), electrical field stimulation (P < 0.001 vs controls), and sildenafil-induced relaxant responses (P < 0.05 vs controls) were decreased in the CC strips from hypothyroid rats. The combined treatment increased the reduction in relaxation responses. Levothyroxine and Sustanon restored decreases in eNOS and nNOS expression in the hypothyroid group. There was no significant difference in PDE5 expression among groups. Monotreatment partially enhanced reduced smooth muscle mass, while combined therapy completely recovered.. The combination of thyroid hormones and T is likely to be a therapeutic approach for treatment of hypothyroidism-induced ED in men.. Beneficial effects of levothyroxine and Sustanon treatment were shown in vitro and in vivo in PTU-induced hypothyroid rats. The main limitation of the study was the lack of measurement of androgen-sensitive organ weights and luteinizing hormone, follicle-stimulating hormone, and prolactin levels.. These findings demonstrate that neurogenic and endothelium-dependent relaxation responses are reduced by hypothyroidism, which is detrimental to T levels and erectile responses. Levothyroxine and Sustanon combination medication was able to counteract this effect.

Topics: Animals; Erectile Dysfunction; Humans; Hypothyroidism; Male; Propylthiouracil; Rats; Rats, Sprague-Dawley; Rats, Wistar; Testosterone; Thyroxine

Spermatogenesis is significantly influenced by the thyroid gland. Thyroid disorders can be caused by a variety of factors. Traditionally, Ellettaria cardamomum has been used to treat a variety of ailments. The effects of E. cardamomum extract (ECE) on spermatogenesis in hypothyroid mice were investigated in this study.. In this study 42 male mice, weighing (25-35 g) were randomly divided in six groups: control group (taking normal saline, 0.5 mL/day, by oral gavage [P.O.]), hypothyroid group (taking 0.1% propylthiouracil in drinking water for 2 weeks), hypothyroid groups treated by levothyroxine (15 mg/kg/day, P.O.) and hypothyroid groups treated by ECE (100, 200 and 400 mg/kg/day, P.O.). After the end of experiments the mice were anaesthetised and blood samples were collected for hormonal analysis.. The sperm count and microscopic studies of testes were done also. Our results showed that the T. According to our findings, the ECE may stimulates thyroid gland function and increases testosterone and spermatogenesis.

Topics: Animals; Elettaria; Hypothyroidism; Male; Mice; Mice, Inbred BALB C; Propylthiouracil; Seeds; Spermatogenesis; Testosterone

In rats, hypothyroidism during fetal and neonatal development can disrupt neuronal migration and induce the formation of periventricular heterotopia in the brain. However, it remains uncertain if heterotopia also manifest in mice after developmental hypothyroidism and whether they could be used as a toxicological endpoint to detect TH-mediated effects caused by TH system disrupting chemicals. Here, we performed a mouse study where we induced severe hypothyroidism by exposing pregnant mice (n = 3) to a very high dose of propylthiouracil (PTU) (1500 ppm) in the diet. This, to obtain best chances of detecting heterotopia. We found what appears to be very small heterotopia in 4 out of the 8 PTU-exposed pups. Although the incidence rate could suggest some utility for this endpoint, the small size of the ectopic neuronal clusters at maximum hypothyroidism excludes the utility of heterotopia in mouse toxicity studies aimed to detect TH system disrupting chemicals. On the other hand, parvalbumin expression was manifestly lower in the cortex of hypothyroid mouse offspring demonstrating that offspring TH-deficiency caused an effect on the developing brain. Based on overall results, we conclude that heterotopia formation in mice is not a useful toxicological endpoint for examining TH-mediated developmental neurotoxicity.

Topics: Animals; Female; Humans; Hypothyroidism; Maternal Exposure; Mice; Periventricular Nodular Heterotopia; Pregnancy; Prenatal Exposure Delayed Effects; Propylthiouracil; Rats; Thyroid Hormones

The present study aimed to analyse both neurobehavioural and biochemical results of neonates born of mothers exposed to different doses of lithium along with the groups that received lithium at the highest dose with folic acid as a preventive treatment.. Male and female rats were mated in separate cages, and pregnant rats were divided into eight first group as (1) vehicle; (2) propylthiouracil (PTU)-induced hypothyroidism; (3-4) received two different doses of lithium carbonate (15 and 30 mg/kg); (5-7) the highest doses of lithium (30 mg/kg) plus three different doses of folic acid (5, 10 and 15 mg/kg); and (8) received just folic acid (15 mg/kg). All treatments were dissolved in drinking water and continued until delivery, followed by returning to a regular diet without treatment.. Lithium (30 mg/kg) disrupts both behavioural and biochemical markers, including TSH, T3 and T4 as measuring indicators to assess thyroid function, IL-10 and TNF-α as anti-inflammatory and inflammatory agents, respectively, malondialdehyde as an oxidative stress marker, alongside SOD, and catalase activity as antioxidant indicators. Besides, folic acid, almost at the highest dose (15 mg/kg), attenuated memory impairement and anxiety-like behaviour caused by lithium. Moreover, the groups treated with folic acid alone in comparison with vehicles demonstrated higher levels of antioxidant and anti-inflammatory indicators.. According to the results, prenatal exposure to a high dose of lithium (30 mg/kg) leads to foetal neurodevelopmental disorder and growth restriction through various mechanisms more likely attributed to hypothyroidism, which means it should be either prohibited or prescribed cautiously during pregnancy.

Topics: Animals; Anti-Inflammatory Agents; Antioxidants; Cognition; Dietary Supplements; Female; Folic Acid; Hypothyroidism; Lithium; Male; Pregnancy; Propylthiouracil; Rats; Rats, Wistar

Goiter with hypothyroidism occurs in several thyroid diseases. Xiao-Luo-Wan (XLW), which contains Scrophularia ningpoensis Hemsl., Fritillaria thunbergii Miq. and Ostrea gigas Thunberg, has been used as an effective Chinese medicine for the treatment of goiters in China for hundreds of years. Based on clinical observations and experimental studies, XLW also exerts a certain effect on hypothyroidism. However, the therapeutic mechanism of XLW remains unclear.. The present study aimed to investigate the therapeutic effect of XLW on propylthiouracil (PTU)-induced goiter with hypothyroidism in rats and to uncover the underlying molecular mechanism using ultra high-performance liquid chromatography-mass spectrometry (UPLC/MS), network pharmacology, and molecular docking simulations.. After successful modeling, the remaining rats were randomly divided into a model group, an Euthyrox group, an XLW group, and a control group. The corresponding drugs were given by gavage for four consecutive weeks. The growth status was monitored, the relative thyroid weight was calculated, and the total serum T3, T4, and TSH content were detected. Hematoxylin-eosin (H&E) staining was used to observe the pathological changes in the thyroid glands. The chemical components of the XLW were identified by UPLC/MS and the putative targets of XLW were predicted using multiple databases. We performed network pharmacology based on the intersection of goiter/hypothyroidism-related targets and XLW targets. Then, we performed KEGG pathway enrichment analysis, and key targets were further screened using protein-protein interaction (PPI) networks. Finally, molecular docking was used to predict the binding ability of XLW identified components and the key targets.. XLW significantly increased the levels of T3 and T4, and reduced TSH, increased body weight, and decreased swollen thyroid glands in PTU-induced rats. XLW promoted the morphological recovery of thyroid follicles and epithelial cells. Twenty-one main chemical components of XLW were identified using UPLC/MS. 270 potential gene targets of XLW and 717 known targets of goiter/hypothyroidism disease were obtained by searching the Traditional Chinese Medicine Systems Pharmacology Database (TCMSP), Swiss Target Prediction, and UniProt databases. A total of 83 KEGG pathways were enriched with phosphatidylinositol 3-kinase-protein kinase B (PI3K-AKT) and RAS signaling pathways. PPI analysis revealed nine key targets of kinase-protein kinase B (AKT) 1, interleukin (IL) 6, vascular endothelial growth factor A (VEGFA), tumor necrosis factor (TNF), glyceraldehyde 3-phosphate dehydrogenase (GAPDH), epidermal growth factor receptor (EGFR), GTPase HRas (HRAS), matrix metalloproteinase (MMP) 9, and heat shock protein 90 alpha family class A member 1 (HSP90AA1). Molecular docking verified which drug components had good binding ability to key targets (all ≤5 kcal/mol).. For PTU-induced goiter with hypothyroidism in rats, XLW improves thyroid function, reduces goiter, increases body weight, and promotes the recovery of thyroid follicles and epithelial cells. The underlying molecular mechanism suggests that XLW may regulate thyroid hormone signaling by regulating the PI3K-AKT, RAS, and other signaling pathways. This study provides a pharmacological and biological basis for using XLW to treat goiter with hypothyroidism.

Topics: Animals; Chromatography, High Pressure Liquid; Disease Models, Animal; Drugs, Chinese Herbal; Goiter; Hypothyroidism; Male; Mass Spectrometry; Molecular Docking Simulation; Network Pharmacology; Phosphatidylinositol 3-Kinase; Propylthiouracil; Proto-Oncogene Proteins c-akt; ras Proteins; Rats; Rats, Wistar

The present study evaluates the neuroprotective effect of α-lipoic acid (ALA) and/or metformin (MET) on the behavioral and neurochemical changes induced by hypothyroidism.. Rats were divided into control, rat model of hypothyroidism induced by propylthiouracil, and rat model of hypothyroidism treated with ALA, MET, or their combination.. Behaviorally, hypothyroid rats revealed impaired memory and reduced motor activity as indicated from the novel object recognition test and open-field test, respectively. Hypothyroidism induced a significant increase in lipid peroxidation (malondialdehyde [MDA]) and a significant decrease in reduced glutathione (GSH) and nitric oxide (NO) in the cortex and hippocampus. These were associated with a significant increase in tumor necrosis factor-α (TNF-α) and a significant decrease in brain-derived neurotrophic factor (BDNF). Hypothyroidism decreased significantly the levels of serotonin (5-HT), norepinephrine (NE), and dopamine (DA) and reduced the activities of acetylcholinesterase (AchE) and Na+, K+-ATPase in the cortex and hippocampus. Treatment of hypothyroid rats with ALA and/or MET showed an improvement in memory function and motor activity. Moreover, ALA and/or MET prevented the increase in MDA and TNF-α, and the decline in GSH, NO, BDNF, 5-HT, NE, and DA. It also restored AchE and Na+, K+-ATPase activities in the studied brain regions.. ALA and/or MET has a potential neuroprotective effect against the adverse behavioral and neurochemical changes induced by hypothyroidism in rats.

Topics: Acetylcholinesterase; Adenosine Triphosphatases; Animals; Brain-Derived Neurotrophic Factor; Dopamine; Glutathione; Hypothyroidism; Malondialdehyde; Metformin; Neuroprotective Agents; Nitric Oxide; Norepinephrine; Propylthiouracil; Rats; Serotonin; Thioctic Acid; Tumor Necrosis Factor-alpha

Glycyrrhiza and sargassum are among the 18 incompatible medicaments according to traditional Chinese medicine (TCM) theory. Although it contains glycyrrhiza and sargassum, Haizao Yuhu decoction (HYD) is a classic prescription widely used as TCM to treat goiter. According to the Chinese Pharmacopoeia, glycyrrhiza is divided into three varieties: Glycyrrhiza uralensis Fish., Glycyrrhiza glabra L., and Glycyrrhiza inflata Bat. Whether the three varieties of glycyrrhiza have different efficacy or toxicity when applied in the HYD is unknown.. To explore whether the HYDs comprising three varieties of glycyrrhiza have different efficacy or toxicity when used to treat goiter in rats and the underlying mechanisms of these HYDs.. For two weeks, the goiter model was replicated by intragastric propylthiouracil (PTU) administration. Samples were divided into the control group, model group, euthyrox group, HYD with glycyrrhiza uralensis (HYD-U) group, HYD with glycyrrhiza glabra (HYD-G) group, and HYD with glycyrrhiza inflata (HYD-I) group. After four weeks of treatment, body weight, rectal temperature, thyroid/liver/kidney coefficient, thyroid/liver/kidney function, thyroid/liver/kidney histomorphology, and thyroid ultrastructure were evaluated. Then, real-time quantitative reverse-transcription polymerase chain reaction (RTqPCR), Western blot, and immunofluorescence analyses were performed to detect genes and proteins affecting autophagy and apoptosis in thyroid cells in the AMP-activated Protein Kinases (AMPK)/Mammalian target of rapamycin (mTOR) pathway.. All three HYDs increased thyroid hormones (THs) levels, relieved thyroid pathological tissue and ultrastructure, and activated vital proteins and genes in the AMPK/mTOR pathway. Comparisons among the efficacy of the three HYDs indicated that HYD-U restored the THs most effectively; however, no difference in the anti-goiter effect was observed. Moreover, the three HYDs resulted in no toxicity and promoted the recovery of impaired liver and kidney function caused by PTU. Comparisons among the recovery effects of the three HYDs on the liver and kidney were the same.. Our experiments demonstrated that the three HYDs had outstanding anti-goiter effects and protected liver and kidney function. Their anti-goiter effects were attributed to AMPK/mTOR pathway-induced autophagy and apoptosis. HYD-U resulted in the best THs recovery. It was further indicated that in our present study, glycyrrhiza and sargassum were compatible in the three HYDs, thereby suggesting their safety of compounding in HYD and providing a basis for the research of the 18 incompatible medicaments.

Topics: AMP-Activated Protein Kinases; Animals; Autophagy; Drugs, Chinese Herbal; Glycyrrhiza; Glycyrrhiza uralensis; Hypothyroidism; Mammals; Plant Extracts; Propylthiouracil; Rats; Thyroid Hormones; TOR Serine-Threonine Kinases; Triterpenes

Hypothyroidism disturbs redox homeostasis and takes part in cardiovascular system dysfunction. Considering antioxidant and cardio-protective effects of PPAR-γ agonists including pioglitazone (POG) and rosiglitazone (RSG), the present study was aimed to determine the effect of POG or RSG on oxidants and antioxidants indexes in the heart and aorta tissues of Propylthiouracil (PTU)-induced hypothyroid rats.. The animals were divided into six groups: (1) Control; (2) propylthiouracil (PTU), (3) PTU-POG 10, (4) PTU-POG 20, (5) PTU-RSG 2, and (6) PTU-RSG 4. Hypothyroidism was induced in rats by giving 0.05% propylthiouracil (PTU) in drinking water for 42 days. The rats of PTU-POG 10 and PTU-POG 20 groups received 10 and 20 mg/kg POG, respectively, besides PTU, and the rats of PTU-RSG 2 and PTU-RSG 4 groups received 2 and 4 mg/kg RSG, respectively, besides PTU. The animals were sacrificed, and the serum of the rats was collected to measure thyroxine level. The heart and aorta tissues were also removed for the measurement of biochemical oxidative stress markers.. Hypothyroidism was induced by PTU administration, which was indicated by lower serum thyroxine levels. Hypothyroidism also was accompanied by a decrease of catalase (CAT), superoxide dismutase (SOD) activities, and thiol concentration in the heart and aorta tissues while increased level of malondialdehyde (MDA). Interestingly, administration of POG or RSG dramatically reduced oxidative damage in the heart and aorta, as reflected by a decrease in MDA and increased activities of SOD, CAT, and thiol content.. The results of this study showed that administration of POG or RSG decreased oxidative damage in the heart and aorta tissues induced by hypothyroidism in rats.

Topics: Animals; Antioxidants; Heart; Hypothyroidism; Oxidative Stress; Pioglitazone; PPAR gamma; Propylthiouracil; Rats; Rats, Wistar; Sulfhydryl Compounds; Superoxide Dismutase; Thyroxine

In the study investigating the effects of boron on thyroid hormones and some biochemical parameters in hypothyroid rats, 49 Wistar Albino male rats were divided into seven groups; (Control (C), Hypothyroidism (H), boron groups (B10, and B20), hypothyroid + boron groups (HB10 and HB20), and Treatment (T). Four groups (H, HB10, HB20, and T) were administered 10 mg/kg (B10 and HB10), 20 mg/kg (B20 and HB20) boron for 3 weeks, respectively after hypothyroidism was induced using Propycil® containing propylthiouracil (PTU). Thyroid hormone analyses and biochemical measurements were made from the serum and thyroid gland tissue was examined histopathologically. According to the findings, the fT3 level increased in the B10 group compared to the control group (p < 0.05). While AST, ALT, and ALP activities were found to be higher in the hypothyroid group than in the control group, AST and ALP activities in the HB10 and HB20 groups decreased to values close to the control group. Total cholesterol levels were found to be lower in boron-given groups compared to control and hypothyroid groups (p < 0.05). Sodium iodide symporter (NIS) immunoreactivity was found to be high in hypothyroid rat groups. As a result, it was observed that the increased AST and ALP activities in rats decreased with boron administration. The serum hormone levels measured in the study are not sufficient to understand the effect of boron on the thyroid gland, and it was concluded that further studies at the molecular level are needed to understand the effects of boron on the thyroid gland.

Topics: Animals; Boron; Hypothyroidism; Propylthiouracil; Rats; Rats, Wistar; Thyroid Hormones

Propylthiouracil (PTU) is a common drug that is used in medicine for treating hyperthyroidism. Furthermore, hypothyroidism can also be induced with PTU. Considering the antioxidant effects of thymoquinone (TMQ), this study was designed to find out whether TMQ could counteract the oxidative damage in the heart and aorta tissues induced by hypothyroidism in rats.. Animals were arranged into four groups: (1) Control, (2) PTU, (3) PTU-TMQ 5, and (4) PTU-TMQ 10. Hypothyroidism was induced in rats by giving 0.05% PTU in drinking water. PTU and TMQ (5 and 10 mg/kg, ip) treatments were done for 42 days. Finally, the animals were sacrificed and the serum of the rats was collected for thyroxine level assessment. The heart and aorta tissues were also removed for biochemical oxidative stress markers measurement.. A lower serum thyroxine level was observed after PTU treatment compared to the control group. Hypothyroidism also was accompanied by a decrease of thiol content, and superoxide dismutase (SOD), and catalase (CAT) activities in the heart and aorta tissues while increased malondialdehyde (MDA). Furthermore, a significant reduction in oxidative damage was noted in the heart and aorta following the administration of TMQ (5 and 10 mg/kg) which was indicated by the reduction in MDA and improved activities of SOD, CAT, and thiol.. In this study, TMQ was found to improve oxidative damages in the heart and aorta tissues of hypothyroid rats.

Topics: Animals; Antioxidants; Aorta; Benzoquinones; Homeostasis; Hypothyroidism; Oxidation-Reduction; Oxidative Stress; Propylthiouracil; Rats; Rats, Wistar; Sulfhydryl Compounds; Superoxide Dismutase; Thyroxine

Maternal hypothyroidism is associated with pre-eclampsia and intrauterine growth restriction, gestational diseases involving oxidative stress (OS) and endoplasmic reticulum stress (ERS) in the placenta. However, it is not known whether hypothyroidism also causes OS and ERS at the maternal-fetal interface. The aim was to evaluate the fetal-placental development and the expression of mediators of OS and of the unfolded protein response (UPR) in the maternal-fetal interface of hypothyroid rats. Hypothyroidism was induced in Wistar rats with propylthiouracil and the fetal-placental development and placental and decidual expression of antioxidant, hypoxia, and UPR mediators were analyzed at 14 and 18 days of gestation (DG), as well the expression of 8-OHdG and MDA, and reactive oxygen species (ROS) and peroxynitrite levels. Hypothyroidism reduced fetal weight at 14 and 18 DG, in addition to increasing the percentage of fetal death and reducing the weight of the uteroplacental unit at 18 DG. At 14 DG, there was greater decidual and/or placental immunostaining of Hif1α, 8-OHdG, MDA, SOD1, GPx1/2, Grp78 and CHOP in hypothyroid rats, while there was a reduction in placental and/or decidual gene expression of Sod1, Gpx1, Atf6, Perk, Ho1, Xbp1, Grp78 and Chop in the same gestational period. At 18 DG, hypothyroidism increased the placental ROS levels and the decidual and/or placental immunostaining of HIF1α, 8-OHdG, MDA, ATF4, GRP78 and CHOP, while it reduced the immunostaining and enzymatic activity of SOD1, CAT, GST. Hypothyroidism increased the placental mRNA expression of Hifα, Nrf2, Sod2, Gpx1, Cat, Perk, Atf6 and Chop at 18 DG, while decreasing the decidual expression of Sod2, Cat and Atf6. These findings demonstrated that fetal-placental restriction in female rats with hypothyroidism is associated with hypoxia and dysregulation in placental and decidual expression of UPR mediators and antioxidant enzymes, and activation of oxidative stress and endoplasmic reticulum stress at the maternal-fetal interface.

Topics: Animals; Antioxidants; Endoplasmic Reticulum Stress; Female; Humans; Hypothyroidism; Hypoxia; NF-E2-Related Factor 2; Oxidative Stress; Peroxynitrous Acid; Placenta; Pregnancy; Propylthiouracil; Rats; Rats, Wistar; Reactive Oxygen Species; RNA, Messenger; Superoxide Dismutase-1

Nanoselenium (Nan S) is a form of selenium element that acts with high absorption and low toxicity. However, few studies have examined the effects of Nan S on cognitive impairment. On the other hand, hypothyroidism is a common disease that causes cognitive disorders. Therefore, this study aimed to investigate the effect of Nan S on memory impairment in rats due to propylthiouracil (PTU) - induced hypothyroidism. The roles of brain-derived neurotrophic factor (BDNF), nitric oxide (NO), and oxidative stress were also challenged.. The animals were randomly divided into 4 groups: (1) Control group (normal saline), (2) hypothyroid (Hypo) group: where 0.05% PTU was added to drinking water, (3) and (4) Hypo-Nan S 50, Hypo-Nan S 100 in which 50 or 100 µg/ kg of Nan S were injected respectively. After 6 weeks, spatial and avoidance memory was measured by Morris water maze (MWM) and passive avoidance (PA) tests. The animals then underwent deep anesthesia and the serum samples and the hippocampus and cortex were collected to be used for thyroxin and biochemical measurements including malondialdehyde (MDA), NO, thiol, superoxide dismutase (SOD), catalase (CAT), and BDNF.. The rats showed an increase in the escape latency and traveled path in MWM in the Hypo group compare with the Control group and these parameters were decreased in both Hypo-Nan S 50 and Hypo-Nan S 100 groups compared to the Hypo group. The rats of both Hypo-Nan S 50 and Hypo-Nan S 100 groups spent longer time and traveled longer distances in the target area during the probe trial of MWM than the Hypo group. In addition, the latency to enter the dark box in the PA test was lower in the Hypo group than in the Control group, which was significantly improved after Nan S treatment. Furthermore, the hippocampal and cortical lipid peroxide marker (MDA) levels and NO metabolites of the Hypo group were significantly increased and the antioxidant markers (total thiol, SOD, and CAT) were significantly inhibited compared to the Control group. Compared with the Hypo group, Nan S administration could significantly decrease the oxidant factors and increase the activities antioxidant system and concentration of BDNF.. It is concluded that Nan S might be able to enhance endogenous antioxidant proteins due to its antioxidant activity, thereby improving BDNF and spatial and avoidance memory in the hypothyroidism-induced memory impairment model however, more studies are still necessary to elucidate the exact mechanism(s).

Topics: Animals; Antioxidants; Brain; Brain-Derived Neurotrophic Factor; Hippocampus; Hypothyroidism; Maze Learning; Memory Disorders; Nitric Oxide; Oxidative Stress; Propylthiouracil; Rats; Rats, Wistar; Sulfhydryl Compounds; Superoxide Dismutase

The effect of curcumin (Cur) on cognitive impairment and the possible role of brain tissue oxidative stress, nitric oxide (NO) levels, and brain-derived neurotrophic factor (BDNF) were investigated in juvenile hypothyroid rats. The juvenile rats (21 days old) were allocated into the following groups: (1) control; (2) hypothyroid (0.05% propylthiouracil (PTU) in drinking water); (3-5) hypothyroid-Cur 50, 100, and 150, which in these groups 50, 100, or 150 mg/kg, Cur was orally administered by gavage during 6 weeks. In the hypothyroid rats, the time elapsed and the traveled distance to locate the hidden platform in the learning trials of Morris water maze (MWM) increased, and on the probe day, the amount of time spent in the target quadrant and the distance traveled in there was decreased. Hypothyroidism also decreased the latency and increased the time spent in the darkroom of the passive avoidance (PA) test. Compared with the hypothyroid group, Cur enhanced the performance of the rats in both MWM and PA tests. In addition, Cur reduced malondialdehyde concentration and NO metabolites; however, it increased thiol content as well as the activity of catalase (CAT) and superoxide dismutase enzymes in both the cortex and hippocampus. Cur also increased hippocampal synthesis of BDNF in hypothyroid rats. The beneficial effects of Cur cognitive function in juvenile hypothyroid rats might be attributed to its protective effect against oxidative stress and potentiation of BDNF production.

Topics: Animals; Brain-Derived Neurotrophic Factor; Catalase; Curcumin; Drinking Water; Hippocampus; Hypothyroidism; Malondialdehyde; Maze Learning; Memory Disorders; Nitric Oxide; Oxidative Stress; Propylthiouracil; Rats; Rats, Wistar; Sulfhydryl Compounds; Superoxide Dismutase

Adult-onset hypothyroidism is associated with learning and cognitive dysfunctions, which may be related to alterations in synaptic plasticity. Local reduced levels of thyroid hormones (THs) may impair glia morphology and activity, and promote the increase of pro-inflammatory cytokine levels mainly in the hippocampus. Given that neuroinflammation induces memory impairments, hypothyroidism-related glia dysfunction may participate in brain disorders. Thus, we investigated the mechanisms linking hypothyroidism and neuroinflammation, from a protective perspective. We induced hypothyroidism in adult C57BL/6J and wild-derived WSB/EiJ male mice by a seven-week propylthiouracil (PTU) treatment. We previously showed that WSB/EiJ mice were resistant to high-fat diet (HFD)-induced obesity, showing no neuroinflammatory response through adaptive abilities, unlike C57BL/6J. As PTU and HFD treatments are known to induce comparable inflammatory responses, we hypothesized that WSB/EiJ mice might also be protected against hypothyroidism-induced neuroinflammation. We showed that hypothyroid WSB/EiJ mice depicted no hippocampal neuroinflammatory response and were able to maintain their hippocampal thyroid signalling despite low circulatisng TH levels. In contrast, C57BL/6J mice exhibited disturbed hippocampal TH signalling, accompanied by neuroinflammation and memory impairment. Our results reinforce the preponderance of the hippocampal TH regulatory system over TH circulating levels in the hippocampal glial reactivity.

Topics: Animals; Cytokines; Hippocampus; Hypothyroidism; Male; Mice; Mice, Inbred C57BL; Neuroglia; Propylthiouracil; Thyroid Hormones

Hyperlipidemia is a common metabolic disorder in the general population, which may arise in hypothyroidism. Apelin is an endogenous ligand that acts as an adiponectin, and is involved in energy storage and metabolism. This study evaluated the effects of apelin administration per se or in combination with T4 on the serum level of thyroid-stimulating hormone (TSH), body weight, and lipid profile, along with the serum level of apelin, and its mRNA expression in heart, in 6-propyl-2-thiouracil (PTU)-induced hypothyroid rats. Male Wistar rats were assigned to five different groups: control, H (hypothyroid), H+A, H+T, and H+A+T. All groups except the control one received PTU (0.05%) in the drinking water for 6 weeks. In addition to PTU, the H+A, H+T, and H+A+T groups received apelin (200 μg/kg/day, i.p.), l-thyroxin (T4) (20 μg/kg/day, via gavage tube), and apelin+T4 during the last 14 days of the trial, respectively. A combined application of T4 and apelin in the H+A+T group effectively diminished mean TSH level, low-density-lipoprotein cholesterol/high-density-lipoprotein cholesterol ratio, and atherogenic index in these animals when compared with these values for the H group. Coadministration of apelin with T4 may offer valuable therapeutic benefits, specifically lowering blood plasma TSH, lipid disorder, and atherosclerosis biomarkers in PTU-induced hypothyroid rats.

Topics: Animals; Apelin; Humans; Hypothyroidism; Lipids; Male; Propylthiouracil; Rats; Rats, Wistar; Thyrotropin

In this study, we aimed to investigate the laryngeal and parotid histopathological alterations in rats with experimentally induced postnatal hypothyroidism.. 200-300 g weighed Wistar albino rats were included in this study. The rats were randomly divided into four groups: group 1 is control and the other groups are experimental groups. Food and water were supplied ad libitum in group 1, no medication was administered. Propylthiouracil (PTU) was administered intraperitoneally for 15 days in group 2; for 30 days in group 3, for 45 days in group 4. The larynx and parotid glands of the rats were removed and intracardiac blood samples were collected for thyroid-stimulating hormone (TSH) analysis under anesthesia (ketamine hydrochloride, 100 mg/kg) 24 h after the last PTU injection. The same procedures were done for the control group at day 46. Histopathological evaluation was done for all the specimens.. While submucosal vascular dilatation was significantly higher in the experiment groups (p < 0.05), there was not a significant difference in lamina propria edema, inflammation, goblet cell loss, cilia loss between the groups in larynx specimens. In parotid gland specimens, serous asinus atrophy, stromal connective tissue increase were significantly higher in experiment groups (p < 0.05). In addition, there was a significant difference in nuclear morphology between control and experimental groups (p < 0.05).. The results of the study showed that hypothyroidism may have effect on inflammatory procedure by causing vascular dilation in larynx and serous asinus atrophy nucleus changes, connective tissue increase in stroma in parotid gland.

Topics: Animals; Hypothyroidism; Larynx; Parotid Gland; Propylthiouracil; Rats; Rats, Wistar

Thyroid hormones have a wide range of effects on growth, differentiation, evolution, metabolism, and physiological function of all tissues, including the vascular bed. In this study, the effect of fetal hypothyroidism on impairment of aortic vasorelaxation responses in adulthood was investigated with emphasis on possible involvement of hydrogen sulfide (H2S)/nitric oxide interaction. Two groups of female rats were selected. After mating and observation of vaginal plaque, one group received propylthiouracil (200 ppm in drinking water) until the end of pregnancy and another group had no propylthiouracil treatment during the fetal period. In adult rats, aortic relaxation responses to l-arginine and GYY4137 were assessed in the presence or absence of Nω-nitro-L-arginine methyl ester hydrochloride and dl-propargylglycine in addition to the biochemical measurement of thyroid hormones and some related factors. Obtained findings showed a lower vasorelaxation response for GYY4137 and l-arginine in the fetal hypothyroidism group, and preincubation with Nω-nitro-L-arginine methyl ester hydrochloride or dl-propargylglycine did not significantly aggravate this weakened relaxation response. In addition, aortic levels of sirtuin 3, endothelial nitric oxide synthase, cystathionine gamma-lyase, and H2S were significantly lower in the fetal hypothyroidism group. Meanwhile, no significant changes were obtained regarding serum levels of thyroid hormones including free triiodothyronine;, total triiodothyronine, free thyroxine, total thyroxine, and thyroid-stimulating hormone in adult rats. It can be concluded that hypothyroidism in the fetal period has inappropriate effects on the differentiation and development of vascular bed with subsequent functional abnormality that persists into adulthood, and part of this vascular abnormality is mediated through weakened interaction and/or cross talk between H2S and nitric oxide.

Topics: Animals; Aorta; Cell Differentiation; Disease Models, Animal; Female; Fetal Diseases; Gasotransmitters; Gestational Age; Hydrogen Sulfide; Hypothyroidism; Male; Nitric Oxide; Pregnancy; Propylthiouracil; Rats, Wistar; Signal Transduction; Vasodilation

The role that thyroid hormone deficiency plays in depression and synaptic plasticity in adults has only begun to be elucidated. This paper analyzes the possible link between depression and hypothyroidism in cognitive function alterations, using Wistar-Kyoto (WKY-an animal model of depression) rats and control Wistar rats under standard and thyroid hormone deficiency conditions (propylthiouracil administration-PTU). A weakening of memory processes in the WKY rats is shown behaviorally, and in the reduction of long-term potentiation (LTP) in the dentate gyrus (DG) and CA1 hippocampal regions. PTU administration decreased LTP and increased basal excitatory transmission in the DG in Wistar rats. A decrease in short-term synaptic plasticity is shown by the paired-pulse ratio measurement, occurring during hypothyroidism in DG and CA1 in WKY rats. Differences between the strains may result from decreases in the p-CaMKII, p-AKT, and the level of acetylcholine, while in the case of the co-occurrence of depression and hypothyroidism, an increase in the p-ERK1-MAP seemed to be important. Obtained results show that thyroid hormones are less involved in the inhibition of glutamate release and/or excitability of the postsynaptic neurons in WKY rats, which may indicate a lower sensitivity of the hippocampus to the action of thyroid hormones in depression.

Topics: Animals; CA1 Region, Hippocampal; Cognitive Dysfunction; Dentate Gyrus; Depression; Disease Models, Animal; Gene Expression; Hippocampus; Humans; Hypothyroidism; Long-Term Potentiation; Male; Memory; Neuronal Plasticity; Propylthiouracil; Rats; Rats, Inbred WKY; Rats, Wistar; Thyroid Hormones

The aim of this study was to evaluate the potential of syringic acid (SA) against propylthiouracil (PTU)-induced hypothyroidism in rats. SA at a prestandardized dose, 50 mg/kg/day, was orally administered to PTU-induced hypothyroid rats for 30 days, and alterations in the levels of serum triiodothyronine (T

Topics: Animals; Female; Gallic Acid; Hypothyroidism; Propylthiouracil; Rats; Rats, Wistar; Thyroid Hormone Receptors beta

We investigated the effects of melatonin on rats with induced hypothyroidism during gestation as well as its effect on the development of the gonads of their offspring. Fifteen pregnant rats were divided into three groups: GC, rats without induced hypothyroidism; GH, rats with induced hypothyroidism; GHM, rats with induced hypothyroidism plus melatonin. Hypothyroidism was induced by oral administration of 6-propyl-2-thiouracil and melatonin was applied subcutaneously. Treatments were performed during gestation and lactation. For the matrices, we evaluated the number of pups, body weight gain, ovarian weight, thyroid weight, organosomatic index, thyroid stimulating hormone (TSH) dose and thyroid morphometry. For the pups, weight gain, TSH, weight, morphometry of the gonads and organosomatic index were analyzed, as well as the cell proliferation index. TSH was elevated only in the matrices of GH animals. Melatonin prevented reduction of ovarian and thyroid weight, number of pups, follicular diameter and thyroid epithelial proportion of the matrices with hypothyroidism. The offspring of rats of the GH group exhibited less body weight gain, gonad and thyroid weight, and gonad cell proliferation index compared to the offspring born of rats of the GC and GHM groups. Melatonin prevented the effects of maternal hypothyroidism on the offspring of rats.

Topics: Animals; Antioxidants; Antithyroid Agents; Female; Gonads; Hypothyroidism; Melatonin; Pregnancy; Pregnancy Complications; Prenatal Exposure Delayed Effects; Propylthiouracil; Rats; Thyroid Gland

Propylthiouracil (PTU)-induced hypothyroidism is a well-established model for assessing hormonal and morphological changes in thyroid as well as other central and peripheral tissues. Somatostatin (SST) is known to regulate hormonal secretion and synthesis in endocrine tissues; however, nothing is currently known about the distribution of SST and its receptor in hypothyroidism.. In the present study, the comparative immunohistochemical distribution of SST and somatostatin receptors (SSTRs) were analyzed in PTU-induced hypothyroid rats. Rats were treated with PTU for 15 days followed by a co-administration of levothyroxine (LVT) for 15 days. After PTU and LVT treatments (day 30), rats were further administered LVT alone for 15 more days (day 45). The subcellular distribution of SST and SSTR subtypes was determined by peroxidase immunohistochemistry in the thyroid gland collected from control and treated rats.. SST and SSTR subtypes were found to be moderately expressed in control thyroid tissues. SST and SSTR subtypes like immunoreactivity increased significantly in follicular and parafollicular epithelial cells in the thyroid of PTU-treated rats. The PTU-induced changes in the expression of SST and SSTR subtypes were suppressed by the administration of the LVT. In addition to thyroid tissues, SST and SSTRs expression was also changed in non-follicular tissues including blood vessels, smooth muscle cells, and connective tissue following treatments.. The present study revealed a distinct subcellular distribution of SST and SSTR subtypes in the thyroid and provides a new insight for the role of SST and SSTR subtypes in hypothyroidism in addition to its well-established role in negative regulation of hormonal secretion.

Topics: Animals; Hypothyroidism; Propylthiouracil; Rats; Receptors, Somatostatin; Somatostatin

During pregnancy, maternal metabolic disease and hormonal imbalance may alter fetal beta cell development and/or proliferation, thus leading to an increased risk for developing type 2 diabetes in adulthood. Although thyroid hormones play an important role in fetal endocrine pancreas development, the impact of maternal hypothyroidism on glucose homeostasis in adult offspring remains poorly understood.. We investigated this using a mouse model of hypothyroidism, induced by administration of an iodine-deficient diet supplemented with propylthiouracil during gestation.. Here, we show that, when fed normal chow, adult mice born to hypothyroid mothers were more glucose-tolerant due to beta cell hyperproliferation (two- to threefold increase in Ki67-positive beta cells) and increased insulin sensitivity. However, following 8 weeks of high-fat feeding, these offspring gained 20% more body weight, became profoundly hyperinsulinaemic (with a 50% increase in fasting insulin concentration), insulin-resistant and glucose-intolerant compared with controls from euthyroid mothers. Furthermore, altered glucose metabolism was maintained in a second generation of animals.. Therefore, gestational hypothyroidism induces long-term alterations in endocrine pancreas function, which may have implications for type 2 diabetes prevention in affected individuals.

Topics: Animals; Antithyroid Agents; Blood Glucose; Cell Proliferation; Diet, High-Fat; Disease Models, Animal; Female; Glucose Intolerance; Hyperinsulinism; Hypothyroidism; Insulin Resistance; Insulin-Secreting Cells; Iodine; Islets of Langerhans; Mice; Pregnancy; Pregnancy Complications; Prenatal Exposure Delayed Effects; Propylthiouracil; Stress, Physiological

Hypothyroidism frequently manifests with altered mood and disturbed cognition. Kynurenic acid may influence cognition through antagonism of N-methyl-d-aspartate receptors (NMDA) and α7 nicotinic receptors. In here, thyroid hormones effects on kynurenic acid synthesis in rat cortical slices and on kynurenine aminotransferases (KATs) activity in semi-purified cortical homogenates were studied. Furthermore, brain kynurenic acid levels and KATs activities were evaluated in experimental model of hypothyroidism, induced by chronic administration of 0.05% propylthiouracil in drinking water. In vitro, L-thyroxine (T

Topics: Animals; Brain; Disease Models, Animal; Hypothyroidism; Kynurenic Acid; Male; Propylthiouracil; Rats, Wistar; Thyroid Gland; Thyroxine; Transaminases; Triiodothyronine; Up-Regulation

The association between hypothyroidism and renal diseases has been described in many studies.. An experimental model of hypothyroidism was induced in adult male Wistar rats by administration of propylthiouracil (6 mg/kg/body weight). One hypothyroid group was treated with thymoquinone at the dose of 50 mg/kg/body weight and compared to the untreated group. Thyroid function and oxidant/antioxidant status were assessed in the serum. Catalase gene expression was assessed using the real-time polymerase chain reaction. The kidney was assessed both histologically and immunohistochemically.. Administration of propylthiouracil resulted in a significant decrease in the serum levels of nitric oxide, reduced glutathione, and superoxide dismutase activity while the level of malondialdehyde significantly (. Thymoquinone may have a potential protective effect against hypothyroidism-induced renal injury acting through the attenuation of the oxidative stress and upregulation of renal catalase gene expression.

Topics: Animals; Benzoquinones; Biological Products; Gene Expression; Hypothyroidism; Kidney Cortex; Male; Nigella sativa; Propylthiouracil; Rats; Rats, Wistar; Up-Regulation

Studies with 6-n-propyl-2-thiouracil (PTU) in laboratory rodents have shown that transient neonatal hypothyroidism leads to increased Sertoli cell (SC) number, testis size and sperm production. However, scarce and inconclusive data are available for farm animals. In the present study, Piau pigs received PTU in a gel capsule containing 8 mg/kg of body weight for 14 weeks starting from the first week of age, whereas control animals received only the vehicle. Blood samples were collected during the experimental period for hormonal evaluation in the serum. The animals were orchiectomized at adulthood and had their testes used for histomorphometric analysis. Indicating that the PTU concentration used was effective in promoting hypothyroidism, PTU-treated pigs showed a 30% lower body weight and reduced thyroxine levels (p < 0.05) during the treatment period. At adulthood, the body weight was similar in both groups but, surprisingly, PTU-treated pigs showed 30% lower testis weight (p < 0.05). In general, treated pigs presented increased follicle-stimulating hormone levels, whereas testosterone levels tended to be lower from 9 to 23 weeks of age. No significant differences were observed for estradiol, Leydig cell volume and number, tubular diameter, SC number per gram of testis, SC efficiency and meiotic index. However, seminiferous tubule occupancy, total tubular length, SC number per testis, and daily sperm production per testis and per gram of testis (DSP/g/T) were significantly lower (p < 0.05) in PTU-treated pigs. Therefore, in contrast to laboratory rodents, our results showed that SC proliferation and DSP/g/T (spermatogenic efficiency) in Piau pigs is diminished by postnatal PTU treatment.

Topics: Animals; Animals, Newborn; Antimetabolites; Cell Count; Hypothyroidism; Leydig Cells; Male; Propylthiouracil; Seminiferous Tubules; Sertoli Cells; Spermatogenesis; Spermatozoa; Swine

Hypothyroidism-associated learning and memory impairment is reported to be connected to oxidative stress and reduced levels of brain-derived neurotrophic factor (BDNF). The effects of neuronal nitric oxide inhibitor 7-nitroindazole (7NI) on brain tissues oxidative damage, nitric oxide (NO), BDNF and memory impairments in hypothyroid juvenile rats were investigated. Male Wistar juvenile rats (20 days old) were divided into five groups, including Martinez et al. (J Neurochem 78 (5):1054-1063, 2001). Control in which vehicle was injected instead of 7NI, (Jackson in Thyroid 8 (10):951-956, 1998) Propylthiouracil (PTU) where 0.05% PTU was added in drinking water and vehicle was injected instead of 7NI, (Gong et al. in BMC Neurosci 11 (1):50, 2010; Alva-Sánchez et al. in Brain Res 1271:27-35, 2009; Anaeigoudari et al. in Pharmacol Rep 68 (2): 243-249, 2016) PTU-7NI 5, PTU-7NI 10 and PTU-7NI 20 in which 5, 10, or 20 mg/kg7NI was injected intraperitoneally (i.p.). Following 6 weeks, Morris water maze (MMW) and passive avoidance learning (PAL) tests were used to evaluate the memory. Finally, the hippocampus and the cortex of the rats were removed after anesthesia by urethane to be used for future analysis. The escape latency and traveled path in MWM test was increased in PTU group (P < 0.001). PTU also reduced the latency to enter the dark box of PAL and the time spent and the distance in the target quadrant in MWM test (P < 0.001 and P < 0.01). Treatment with 7NI attenuated all adverse effects of PTU (P < 0.05 to P < 0.001). PTU lowered BDNF and thiol content and superoxide dismutase (SOD) and catalase (CAT) activities in the brain but increased malondialdehyde (MDA) and nitric oxide (NO) metabolites. In addition, 7NI improved thiol, SOD, CAT, thiol, and BDNF but attenuated MDA and NO metabolites. The results of the current study showed that 7NI improvement in the learning and memory of the hypothyroid juvenile rats, which was accompanied with improving of BDNF and attenuation of NO and brain tissues oxidative damage.

Topics: Animals; Brain-Derived Neurotrophic Factor; Enzyme Inhibitors; Hippocampus; Hypothyroidism; Indazoles; Learning Disabilities; Male; Maze Learning; Memory; Memory Disorders; Morris Water Maze Test; Nitric Oxide Synthase Type I; Oxidative Stress; Propylthiouracil; Rats, Wistar

Among today's health problems, metabolic diseases are at the forefront. Hypothyroidism (HT) is a disease characterized by increased TSH, decreased T3&T4 concentrations in serum, with overall metabolic slowdown. Although there are many studies in the literature about oxidative status in HT, statements in these studies are contradictory. In our study, the effect of essential oils obtained from the leaves, flowers, and roots of Myrtus communis L. on oxidative metabolism in an HT model induced by propylthiouracil (PTU) in rats was investigated. A total of 36 Wistar albino rats were randomly divided into six groups as follows: (1) Control, (2) PTU, (3) M. communis L. oil 200 (MO 200), (4) M. communis L. oil 400 (MO 400), (5) PTU + MO 200, and (6) PTU + MO 400. In our study, while oxidative status deteriorates in groups given PTU, antioxidant activity increases in groups given M. communis L. oil. PRACTICAL APPLICATIONS: Essential oils are aromatic oily liquids derived from different parts of plants. M. communis L. is one of the best-known herbs in the class of aromatic and medicinal plants. This paper emphasizes the effect of M. communis L. oil on the negative oxidative state that occurs in HT conditions. The present study provides a positive effect of essential oils obtained from the M. communis L. on the oxidative state seen in HT. In light of this information, it may be beneficial to use M. communis L. oil due to its antioxidative effect in HT conditions.

Topics: Animals; Antioxidants; Hypothyroidism; Myrtus; Oils, Volatile; Oxidants; Propylthiouracil; Rats; Rats, Wistar

Thyroid hormones have important roles in normal development and energy regulating mechanisms as well as signaling mechanisms that affect energy consumption through central and peripheral pathways. The aim of this study was to determine the effects of thyroid dysfunction on adropin, asprosin and preptin levels in rat.. The study was performed on the 38 male Wistar-albino rats. Experiment groups were designed as follows. 1-Control, 2-Hypothyroidism; To induce hypothyroidism PTU was applied by intraperitoneal as 10 mg/kg/day for 2 weeks. 3-Hypothyroidism + Thyroxine; Previously animals were made with hypothyroidism by 1 week PTU application and then 1 week l-thyroxine was given by intraperitoneal as 1.5 mg/kg/day. 4-Hyperthyroidism; Rats were made with hyperthyroidism by 3 weeks l-thyroxine (0.3 mg/kg/day). 5-Hyperthyroidism + PTU; Animals were made hyperthyroisim by l-thyroxine as groups 4, then 1 week PTU was applied to treatment of hiperthyrodism. At the end of supplementation animals were sacrificed and blood samples were collected for FT3, FT4, adropin, asprosin, preptin analysis.. FT3 ve FT4 levels were reduced significantly in hypothyroidism while increased in hyperthyroidism (p<0.001). Hipothyrodism led to reduces adropin, asprosin and preptin levels. And also hyperthyroidism reduced adropin and preptin levels (p<0.001).. The results of study show that experimental hypothyroidism and hyperthyroidism lead to significantly change to adropin, asprosin and preptin levels. However, correction of thyroid function caused to normals levels in asprosin and preptin.

Topics: Animals; Blood Proteins; Fibrillin-1; Hyperthyroidism; Hypothyroidism; Insulin-Like Growth Factor II; Peptide Fragments; Peptide Hormones; Peptides; Propylthiouracil; Rats; Thyroxine; Triiodothyronine

Arecoline is known to cause endocrine dysfunction. In the current article role of arecoline on pineal-testis activity was investigated in hypothyroid rats induced by propylthiouracil (PTU). PTU treatment caused thyroid dysfunction ultrastructurally with a fall in T

Topics: Animals; Antithyroid Agents; Arecoline; Endoplasmic Reticulum; Fructose; Hypothyroidism; Leydig Cells; Male; Melatonin; N-Acetylneuraminic Acid; Pineal Gland; Propylthiouracil; Rats; Serotonin; Testis; Testosterone; Thyroid Gland; Thyrotropin; Thyroxine; Triiodothyronine

Hypothyroidism is a condition that becomes more prevalent with age. Patients with untreated hypothyroidism have consistently reported symptoms of severe cognitive impairments. In patients suffering hypothyroidism, thyroid hormone supplementation offers the prospect to alleviate the cognitive consequences of hypothyroidism; however, the therapeutic value of TH supplementation remains at present uncertain and the link between cellular modifications associated with hypothyroidism and neurodegeneration remains to be elucidated. In the present study, we therefore evaluated the molecular and behavioral consequences of T3 hormone replacement in an animal model of hypothyroidism. We have previously reported that the antithyroid molecule propylthiouracil (PTU) given in the drinking water favors cerebral atrophy, brain neuroinflammation, Aβ production, Tau hyperphosphorylation, and altered plasticity-related cell-signaling pathways in the hippocampus in association with hippocampal-dependent spatial memory deficits. In the present study, our aim was to explore, in this model, the effect of hippocampal T3 signaling normalization on various molecular mechanisms involved in learning and memory that goes awry under conditions of hypothyroidism and to evaluate its potential for recovery of hippocampal-dependent memory deficits. We report that T3 supplementation can alleviate hippocampal-dependent memory impairments displayed by hypothyroid rats and normalize key markers of thyroid status in the hippocampus, of neuroinflammation, Aβ production, and of cell-signaling pathways known to be involved in synaptic plasticity and memory function. Together, these findings suggest that normalization of hippocampal T3 signaling is sufficient to reverse molecular and cognitive dysfunctions associated with hypothyroidism.

Topics: Amyloid beta-Peptides; Animals; Anxiety; Behavior, Animal; Biomarkers; Hippocampus; Hypothyroidism; Male; Neuronal Plasticity; Propylthiouracil; Rats, Wistar; RNA, Messenger; Signal Transduction; Spatial Memory; Thyroid Gland; Thyroid Hormones

6-n-propyl-2-thiouracil (PTU), a thioamide drug, is used as an effective anti-thyroid agent to treat hyperthyroidism and Graves' disease. However, acute liver oxidative damage is an important side effect of the drug. In the present study, we report that PTU administration to rat induces hepatic epigenetic changes by upregulating expression of DNMT1, DNMT3a, DNMT3b, MBD4, MeCP2, p53 and Gadd45a and down-regulation of PCNA and C/EBP-β. This is accompanied by decrease in the cell population and augmentation of cellular lipid peroxidation, an index of oxidative stress, in liver. On the other hand, co-administration of curcumin, a polyphenol extract from the rhizome of Curcuma longa L, along with PTU ameliorates PTU- induced oxidative stress and epigenetic parameters except for the expression of MBD4. Also, co-administration of curcumin with PTU resulted in restoration of hepatic cell population and histoarchitecture. The protective effect of curcumin to PTU-induced hepatotoxicity is attributed to its antioxidative properties.

Topics: Animals; CCAAT-Enhancer-Binding Protein-beta; Cell Cycle Proteins; Curcuma; Curcumin; DNA (Cytosine-5-)-Methyltransferases; Endodeoxyribonucleases; Epigenesis, Genetic; Humans; Hypothyroidism; Liver; Male; Nuclear Proteins; Proliferating Cell Nuclear Antigen; Propylthiouracil; Rats

Thyroid hormone (TH) is a key regulator of transcriptional homeostasis in the heart. While hypothyroidism is known to result in adverse cardiac effects, the molecular mechanisms that modulate TH signaling are not completely understood. Mediator is a multiprotein complex that coordinates signal-dependent transcription factors with the basal transcriptional machinery to regulate gene expression. Mediator complex protein, Med13, represses numerous thyroid receptor (TR) response genes in the heart. Further, cardiac-specific overexpression of Med13 in mice that were treated with propylthiouracil (PTU), an inhibitor of the biosynthesis of the active TH, triiodothyronine (T3), resulted in resistance to PTU-dependent decreases in cardiac contractility. Therefore, these studies aimed to determine if Med13 is necessary for the cardiac response to hypothyroidism. Here we demonstrate that Med13 expression is induced in the hearts of mice with hypothyroidism. To elucidate the role of Med13 in regulating gene transcription in response to TH signaling in cardiac tissue, we utilized an unbiased RNA sequencing approach to define the TH-dependent alterations in gene expression in wild-type mice or those with a cardiac-specific deletion in Med13 (Med13cKO). Mice were fed a diet of PTU to induce a hypothyroid state or normal chow for either 4 or 16 weeks, and an additional group of mice on a PTU diet were treated acutely with T3 to re-establish a euthyroid state. Echocardiography revealed that wild-type mice had a decreased heart rate in response to PTU with a trend toward a reduced cardiac ejection fraction. Notably, cardiomyocyte-specific deletion of Med13 exacerbated cardiac dysfunction. Collectively, these studies reveal cardiac transcriptional pathways regulated in response to hypothyroidism and re-establishment of a euthyroid state and define molecular pathways that are regulated by Med13 in response to TH signaling.

Topics: Animals; Electrocardiography; Gene Deletion; Gene Expression Regulation; Hypothyroidism; Mediator Complex; Mice, Inbred C57BL; Mice, Knockout; Myocardium; Organ Specificity; Propylthiouracil; Signal Transduction; Thyroid Hormones; Transcription, Genetic

To characterize the influence of hypothyroidism on the endocrine activity of mesenteric and omental adipose tissue (MOAT) and the peripheral regulation of energy balance (EB) in rats, we analyzed food intake (FI); basal metabolic rate (BMR); locomotor activity; body weight (BW); serum hormone concentrations and the expression of their receptors in MOAT. We evaluated the morphology and differentiation of adipocytes. Hypothyroidism decreased FI, BMR and BW. The percentage of visceral white adipose tissue (WAT) depots and the morphology of adipocytes were similar to euthyroid rats. Serum leptin and adiponectin expression in MOAT were altered by hypothyroidism. The expression of Perilipin 1, HSL, UCP1 and PRDM16 was significantly lower in MOAT of hypothyroid animals. Hypothyroidism in rats leads to a compensated EB by inducing a white adipocyte dysfunction and a decrease in BW, BMR, FI and adipokine secretions without changing the percentage of WAT depots and the morphology of the MOAT.

Topics: Adipocytes; Adipokines; Adipose Tissue; Adipose Tissue, White; Animals; Basal Metabolism; Biomarkers; Body Weight; Corticosterone; Eating; Fatty Acids; Female; Glucose; Hypothyroidism; Insulin; Mesentery; Motor Activity; Omentum; Ovary; Propylthiouracil; Rats, Sprague-Dawley; RNA, Messenger

Developmental hypothyroidism as a model of autism spectrum disorders disrupts hippocampal neurogenesis through the adult stage. The present study investigated the ameliorating effect of postweaning exposure to antioxidant on the hypothyroidism-induced disruptive neurogenesis. Mated female Sprague-Dawley rats were treated with 0 or 10 ppm 6-propyl-2-thiouracil (PTU) as an anti-thyroid agent in drinking water from gestational day 6 to postnatal day (PND) 21 on weaning. PTU-exposed male offspring were fed either basal diet, diet containing α-glycosyl isoquercitrin (AGIQ) at 5,000 ppm or α-lipoic acid (ALA) at 1,000 ppm as an antioxidant from PND 21 to PND 77. PTU-exposure decreased DCX

Topics: Animals; Antioxidants; Apoptosis; Doublecortin Protein; Female; Gene Expression Regulation, Developmental; Hippocampus; Hypothyroidism; Male; Neurogenesis; Pregnancy; Propylthiouracil; Quercetin; Rats, Sprague-Dawley; Thioctic Acid

The expression of homosynaptic long-term depression (LTD) governs the subsequent induction of long-term potentiation (LTP) at hippocampal synapses. This process, called metaplasticity, is associated with a transient increase in the levels of several kinases, such as extracellular signal-regulated protein kinases 1/2 (ERK1/2), c-Jun N-terminal kinase (JNK), and Akt kinase. It has been increasingly realized that the chemical changes in the hippocampus caused by hypothyroidism may be the key underlying causes of the learning deficits, memory loss, and impaired LTP associated with this disease. However, the functional role of thyroid hormones in the "plasticity of synaptic plasticity" has only begun to be elucidated. To address this issue, we sought to determine whether the administration of 6-n-propyl-2-thiouracil (PTU) alters the relationship between priming and the induction of subsequent LTP and related signaling molecules. The activation of ERK1/2, JNK, and Akt was measured in the hippocampus at least 95 min after priming onset. We found that priming stimulation at 5 Hz for 3 s negatively impacted the induction of LTP by subsequent tetanic stimulation in hypothyroid animals, as manifested by a more rapid decrease in the fEPSP slope and population spike amplitude. This phenomenon was accompanied by lower levels of phosphorylated Akt in the surgically removed hippocampus of the hypothyroid rats compared to the euthyroid rats. The metaplastic response and the expression of these proteins in the 1-Hz-primed hippocampus were not different between the two groups. These observations suggest that decreased PI3K/Akt signaling may be involved in the compromised metaplastic regulation of LTP observed in hypothyroidism, which may account for the learning difficulties/cognitive impairments associated with this condition.

Topics: Animals; Excitatory Postsynaptic Potentials; Hippocampus; Hypothyroidism; Male; MAP Kinase Kinase 4; MAP Kinase Signaling System; Mitogen-Activated Protein Kinase 1; Mitogen-Activated Protein Kinase 3; Neuronal Plasticity; Propylthiouracil; Proto-Oncogene Proteins c-akt; Rats; Rats, Wistar

Recent studies have demonstrated that hypothyroidism is associated with infertility. This work was undertaken to evaluate the protective effects of Aframomum melegueta on testicular functions and fertility of hypothyroid male rats. Male rats were orally treated with propylthiouracil (PTU: 10 mg/kg) in combination with plant aqueous or methanol seed extract (20 and 100 mg/kg) for 56 days. Vitamin E and clomiphene citrate served as positive controls. On day 47 of treatment, each male was mated with two adult females for fertilization potential evaluation. At the end of the treatment, genital sex organ weights, sperm characteristics, testicular histology, oxidative status, plasmatic hormones and fertility potential were evaluated. Results indicated that PTU created hypothyroidism characterised by a significant increase in TSH with reduction of T3 and T4. PTU also lowered genital sex organ weights, sperm count, viability and motility, plasmatic levels of luteinising hormone, follicle-stimulating hormone and testosterone, and increased prolactin, cholesterol and testicular oxidative stress. Alteration in sperm morphology, testis and epididymis histology, and fertilization potential was also noticed. Co-administration with A. melegueta extracts successfully reversed PTU-induced infertility without any effect on thyroid hormones. These results provide evidence that A. melegueta has a protective effect on fertility in hypothyroid condition.

Topics: Animals; Disease Models, Animal; Epididymis; Female; Fertility; Humans; Hypothyroidism; Infertility; Male; Organ Size; Plant Extracts; Propylthiouracil; Rats; Reproduction; Sperm Motility; Spermatogenesis; Testis; Thyroid Hormones; Zingiberaceae

Hypothyroidism has been claimed to generate sexual dysfunctions such as ejaculatory disorders. Aframomum melegueta is an aphrodisiac plant with pro-ejaculatory properties. We investigated the protective effects of aqueous extract (AE) and methanolic extract (ME) of A. melegueta on the ejaculatory function of hypothyroid male rats.. Forty sexually experienced male rats were partitioned into 8 groups (5 rats per group) and treated for 28 d as follows: Group 1, Control; Group 2, propylthiouracil (PTU, 10 mg/kg) + distilled water (DW, 10 mL/kg); Group 3, PTU + 5% Tween 80 (10 mL/kg); Group 4, PTU + bromocriptine (6 mg/kg); Group 5, PTU + AE (20 mg/kg); Group 6, PTU + AE (100 mg/kg); Group 7, PTU + ME (20 mg/kg), and Group 8, PTU + ME (100 mg/kg). On days 0, 7, 14 and 28 of treatment, each male rat was paired with primed receptive female for measurement of ejaculatory latency time (ELT) and post-ejaculatory interval (PEI) for 1.5 h. On day 29, each male rat was urethane-anesthetized and the spinal cord was transected. Thereafter, following urethral/penile stimulations and intravenous injection of dopamine, contractions of the bulbospongiosus muscles and the intraseminal pressure were registered. After these recordings, blood was collected through the catheterization of abdominal artery and plasma was used for thyroid-stimulating hormone (TSH), prolactin and testosterone assays.. PTU-induced hypothyroidism was characterized by a significant elevation (P < 0.001) of plasmatic TSH and prolactin levels, but a decline (P < 0.001) in plasmatic testosterone, compared to untreated group. ELT, PEI, contractions of the bulbospongiosus muscles and the intraseminal pressure were also altered by PTU treatment. On the contrary, A. melegueta extracts elevated testosterone (AE, 100 mg/kg, P < 0.01; ME, 100 mg/kg, P < 0.05) and decreased prolactin (AE, 100 mg/kg, P < 0.05; ME, 20 mg/kg, P < 0.05) levels, compared to corresponding controls. With regard to DW + PTU group, prolactin concentration was lowered (P < 0.05) in rats administered with bromocriptine. Treatment with A. melegueta extracts significantly prevented the lengthening of ELT (P < 0.05) and PEI (P < 0.001). Hypothyroid state also altered the fictive ejaculation by increasing the latency and decreasing the number and frequency of bulbospongiosus muscle contractions. There was also a decrease in the intraseminal pressure. These alterations were significantly (P < 0.05) alleviated in plant extract-treated groups.. This study highlighted the ejaculatory disturbance of hypothyroidism in male rats and its prevention with A. melegueta extracts.

Topics: Animals; Disease Models, Animal; Ejaculation; Female; Hypothyroidism; Male; Plant Extracts; Propylthiouracil; Rats; Rats, Wistar; Zingiberaceae

The number of Sertoli cells (SCs) ultimately determines the upper limit of sperm production in the testis. Previous studies have shown that thyroid hormones (TH) receptors are abundantly expressed in developing SCs; therefore, it was highly significant to discover that transient neonatal hypothyroidism induced by the goitrogen 6-n-propyl-2-thiouracil (PTU) can extend SCs proliferation beyond the first 2 weeks postnatal and increase testis weight and sperm production. Further studies concluded that treatment must begin before day 8 post birth in rats. Recent studies, however, showed that SCs present in the transition region at the rete testis exhibit a more immature phenotype and have prolonged mitotic activity, which led to the hypothesis that SCs in this region will retain the capacity to respond to PTU treatment over a longer period of time. In the present study, male Wistar rats were treated with PTU from days 21 to 40 and were evaluated at 40 and 160 days of age. Similar to neonatal rat SCs, it was demonstrated that prepubertal SCs in the transition region have a high mitotic activity and are highly sensitive to TH levels. This delayed, transient hypothyroidism resulted in significantly increased testis weight, SCs number and daily sperm production. The results demonstrate for the first time that Sertoli cells showing plasticity in the transition region can be stimulated to increase proliferation and contribute to a late stage surge in testis weight and sperm output.

Topics: Animals; Antithyroid Agents; Female; Hypothyroidism; Male; Pregnancy; Pregnancy Complications; Propylthiouracil; Rats, Wistar; Sertoli Cells; Spermatogenesis; Testis; Thyroid Gland

Adult-onset hypothyroidism induces cognitive impairments in learning and memory. Thyroxin (T4) replacement therapy appears to be effective in biochemically restoring euthyroidism, as evidenced by serum T4 and triiodothyronine concentrations within the normal range, although some the patients still exhibit cognitive dysfunctions. Here, we investigated the cognitive functions of propylthiouracil-induced hypothyroid mice in C57BL/6j and 129/Sv strains using the passive avoidance task and the novel object recognition test. Cognitive dysfunctions in hypothyroid mice were found only in the C57BL/6j strain, not in the 129/Sv strain. Further, we found that cholinergic neurons in the basal forebrain increased the membrane potential and input resistance with decreased capacitance, and that they decreased the amplitude and width of action potential in hypothyroid mice in the C57BL/6j strain but not in those in the 129/Sv strain, compared with the controls for each strain. Additionally, the excitability of cholinergic neurons in the basal forebrain was reduced in the hypothyroid mice in the C57BL/6j strain. These results indicated that transgenic mice with the C57BL/6j genetic background are more suitable for revealing the mechanism underlying hypothyroidism-induced cognitive dysfunction, and that the cholinergic basal forebrain may be the appropriate target for treating cognitive dysfunction in adult-onset hypothyroidism.

Topics: Animals; Basal Forebrain; Cholinergic Neurons; Cognitive Dysfunction; Disease Models, Animal; Hypothyroidism; Learning; Male; Membrane Potentials; Memory; Mice, 129 Strain; Mice, Inbred C57BL; Mice, Transgenic; Propylthiouracil; Thyroid Hormones

Protective effects of a mixed hot water extracts of Astragalus membranaceus (AWE) and Laminaria japonica (LWE), AWE: LWE 85:15 (g/g; AL mix), were investigated against propylthiouracil (PTU)-induced hypothyroidism in rats. Rats were challenged with PTU, resulting in, increased thyroid gland weight, decreased liver weight and antioxidant activities, reduced serum tri-iodothyronine and thyroxine levels with increased thyroid stimulating hormone levels, and elevated serum aspartate aminotransferase level. However, orally administered AL mix with 100, 200, and 400 mg kg

Topics: Animals; Antioxidants; Antithyroid Agents; Astragalus propinquus; Chemical and Drug Induced Liver Injury; Coumaric Acids; Hypothyroidism; Iodine; Laminaria; Plant Extracts; Propylthiouracil; Rats; Thyroid Gland

Hypothyroidism causes an imbalance in antioxidant and pro-oxidants criteria in the brain and enhances the concentration of reactive oxygen species (ROS), and neuronal damage has been observed following an excessive ROS. The main purpose of this study was to examine the preventive effect of vitamin C on hypothyroidism associated neuronal damage in the hippocampus of neonatal and juvenile rats. Pregnant rats after delivery of their pups were randomly divided into four groups and treated with (1) normal drinking water as a control group, (2) Propylthiouracil (PTU) 0.005% added to drinking water, (3-, 4) PTU + Vit C 10 mg/ kg and PTU + Vit C 100 mg/ kg to drinking water. Treatment was carried out during rat's lactation period until to the postnatal day (PND) 60. To assess the histological and stereological changes that occur in this study, brains of 5 male pups were extracted. The number of dark neurons and apoptotic cells in the hippocampal sub-regions of PTU group was significantly greater than the control group's hippocampal sub-regions. In addition, hypothyroidism induced a reduction in the hippocampal volume and increased the numerical density and the total amount of dark neurons. The vitamin C only dose of 100 mg/kg significantly reduced the number of dark neurons and apoptotic cells (P < 0.01) and considerably weakened the influence of hypothyroidism on the volume reduction of the hippocampus (P < 0.05). The current study suggested that vitamin C administration has a possibility to prevent hippocampal neuronal damage caused by neonatal and juvenile hypothyroidism in rats.

Topics: Animals; Animals, Newborn; Antioxidants; Antithyroid Agents; Apoptosis; Ascorbic Acid; Cell Count; Female; Hippocampus; Hypothyroidism; Imaging, Three-Dimensional; Male; Neurons; Neuroprotective Agents; Pregnancy; Propylthiouracil; Rats; Rats, Wistar; Thyroxine

Dysregulated DNA methylation in lymphocytes has been linked to autoimmune disorders. The aims of this study were to identify global DNA methylation patterns in patients with autoimmune thyroid diseases and to observe methylation changes after treatment for these conditions.. A cross-sectional study was conducted, including the following patients: 51 with newly diagnosed Graves' disease (GD), 28 with autoimmune hypothyroidism (AIT), 29 with positive thyroid autoantibodies, and 39 matched healthy volunteers. Forty GD patients treated with radioiodine or antithyroid drugs and 28 AIT patients treated with L-thyroxine were followed for three months. Serum free triiodothyronine, free thyroxine, thyrotropin, thyroid peroxidase antibodies, thyroglobulin antibodies, and thyrotropin receptor antibodies were assayed using electrochemiluminescent immunoassays. CD3. Hypomethylation and down-regulated DNMT1 expression in T and B lymphocytes were observed in the newly diagnosed GD patients. Neither the AIT patients nor the positive thyroid autoantibodies patients exhibited differences in their global DNA methylation status or DNMT mRNA levels compared with healthy controls. Antithyroid drugs restored global methylation and DNMT1 expression in both T and B lymphocytes, whereas radioiodine therapy affected only T cells. L-thyroxine replacement did not alter the methylation or DNMT expression levels in lymphocytes. The global methylation levels of B cells were negatively correlated with the serum thyroid peroxidase antibodies in patients with autoimmune thyroid diseases.. Hyperthyroid patients with newly diagnosed GD had global hypomethylation and lower DNMT1 expression in T and B lymphocytes. The results provide the first demonstration that antithyroid drugs or radioiodine treatment restore global DNA methylation and DNMT1 expression with concurrent relief of hyperthyroidism.

Topics: Adult; B-Lymphocytes; Cross-Sectional Studies; DNA (Cytosine-5-)-Methyltransferase 1; DNA Methylation; Female; Graves Disease; Hashimoto Disease; Humans; Hypothyroidism; Iodine Radioisotopes; Male; Methimazole; Middle Aged; Propylthiouracil; T-Lymphocytes; Thyroiditis, Autoimmune; Thyroxine; Triiodothyronine

In this study, the effect of thymoquinone (TQ) on propylthiouracil (PTU)-induced memory impairment was investigated in juvenile rats. The rats were grouped into control, Hypo, Hypo-TQ5 and Hypo-TQ10. Propylthiouracil increased latency time in the Morris water maze test and decreased delay in entering the dark compartment in the passive avoidance test. Both 5 mg/kg and 10 mg/kg doses of TQ decreased latency time in the Morris water maze test and increased delay in entering the dark compartment in a passive avoidance test. The PTU also increased malondialdehyde and nitric oxide metabolites in the brain while reduced the thiol content and superoxide dismutase and catalase activities and serum T4 level. Both doses of TQ decreased malondialdehyde and nitric oxide metabolites in the brain while enhanced the thiol content and superoxide dismutase and catalase activities and serum T4 level. The results of the present study showed that TQ protected against PTU-induced memory impairments in rats.

Topics: Animals; Antioxidants; Antithyroid Agents; Avoidance Learning; Benzoquinones; Brain Injuries; Catalase; Disease Models, Animal; Hippocampus; Hypothyroidism; Learning Disabilities; Male; Malondialdehyde; Maze Learning; Memory Disorders; Nitric Oxide; Oxidative Stress; Propylthiouracil; Rats, Wistar; Superoxide Dismutase

Thyroid hormones (THs) are essential for brain development, but few rodent models exist that link TH inefficiency to apical neurodevelopmental endpoints. We have previously described a structural anomaly, a heterotopia, in the brains of rats treated in utero with propylthiouracil (PTU). However, how the timing of an exposure relates to this birth defect is unknown. This study seeks to understand how various temporal treatments of the mother relates to TH insufficiency and adverse neurodevelopment of the offspring. Pregnant rats were exposed to PTU (0 or 3 ppm) through the drinking water from gestational day 6 until postnatal day (PN) 14. On PN2 a subset of pups was cross-fostered to a dam of the opposite treatment, to create 4 conditions: pups exposed to PTU prenatally, postnatally, during both periods, or not at all (control). Both PTU and TH concentrations were characterized in the mother and offspring over time, to capture the dynamics of a developmental xenobiotic exposure. Brains of offspring were examined for heterotopia presence and severity, and adult littermates were assessed for memory impairments. Heterotopia were observed under conditions of prenatal exposure, and its severity increased in animals in the most prolonged exposure group. This malformation was also permanent, but not sex biased. In contrast, behavioral impairments were limited to males, and only in animals exposed to PTU during both the gestational and postnatal periods. This suggests a distinct TH-dependent etiology for both phenotypes, and illustrates how timing of hypothyroxinemia can induce abnormal brain structure and function.

Topics: Animals; Animals, Newborn; Behavior, Animal; Cross-Over Studies; Female; Hypothyroidism; Learning Disabilities; Male; Malformations of Cortical Development; Maternal Exposure; Pregnancy; Prenatal Exposure Delayed Effects; Propylthiouracil; Thyroid Hormones

Mild perinatal hypothyroidism may result from inadequate iodine intake, insufficient treatment of congenital hypothyroidism, or exposure to endocrine-disrupting chemicals. Because thyroid hormones are critical for brain development, severe hypothyroidism that is untreated in infancy causes irreversible cretinism. Milder hypothyroidism may also affect cognitive development; however, the effects of mild and/or moderate hypothyroidism on brain development are not fully understood. In this study, we examined the behavior of adult male mice rendered mildly hypothyroid during the perinatal period using low-dose propylthiouracil (PTU). PTU was administered through drinking water (5 or 50 ppm) from gestational day 14 to postnatal day 21. Cognitive performance, studied by an object in-location test (OLT), was impaired in PTU-treated mice at postnatal week 8. These results suggest that, although the hypothyroidism was mild, it partially impaired cognitive function. We next measured the concentration of neurotransmitters (glutamate, γ-aminobutyric acid, and glycine) in the hippocampus using in vivo microdialysis during OLT. The concentrations of neurotransmitters, particularly glutamate and glycine, decreased in PTU-treated mice. The expression levels of N-methyl-d-aspartate receptor subunits, which are profound regulators of glutamate neurotransmission and memory function, also were decreased in PTU-treated mice. These data indicate that mild perinatal hypothyroidism causes cognitive disorders in adult offspring. Such disorders may be partially induced secondary to decreased concentrations of neurotransmitters and receptor expression.

Topics: Animals; Animals, Newborn; Cognition; Disease Models, Animal; Hippocampus; Hypothyroidism; Male; Mice; Propylthiouracil; Rats; Synapses

High fat diet consumes and thyroid hormones (THs) disorders may affect nutrients metabolism, but their impact on the absorptive epithelium, the first place of nutrients access, remains unknown. Our aim was to evaluate the intestinal morphology and nutrients transporters content in mice fed standard (LFD) or high fat (HFD) diets in hypo or hyperthyroidism-induced condition.. C57BL/6 male mice fed LFD or HFD diets for 12 weeks, followed by saline, PTU (antithyroid drug) or T3 treatment up to 30 days. The mice were euthanized and proximal intestine was removed to study GLUT2, GLUT5, PEPT1, FAT-CD36, FATP4, NPC1L1 and NHE3 distribution by Western blotting. Since PPAR-a is activated by fatty acids, which is abundant in the HFD, we also evaluated whether PPAR-a affects nutrients transporters. Thus, mice were treated with fenofibrate, a PPAR-a agonist.. HFD decreased GLUT2, PEPT1, FAT-CD6 and NPC1L1, but increased NHE3, while GLUT5 and FATP4 remained unaltered. THs did not alter distribution of nutrients transporters neither in LFD nor in HFD groups, but they increased villi length and depth crypt in LFD and HFD, respectively. Fenofibrate did not affect content of nutrients transporters, excluding PPAR-a involvement on the HFD-induced changes.. We assume that chronic HFD consumption reduced most of the nutrients transporters content in the small intestine of mice, which might limit the entrance of nutrients and gain weight. Since NHE3 promotes sodium absorption, and it was increased in HFD group, this finding could contribute to explain the hypertension observed in obesity.

Topics: Animals; Antithyroid Agents; Diet, High-Fat; Fenofibrate; Glucose Tolerance Test; Hyperthyroidism; Hypolipidemic Agents; Hypothyroidism; Intestinal Mucosa; Intestine, Small; Intestines; Male; Membrane Transport Proteins; Mice; Mice, Inbred C57BL; PPAR alpha; Propylthiouracil; Sodium-Hydrogen Exchanger 3; Thyroid Hormones; Triiodothyronine

Thyroid hormones (THs) play a critical role in the development of ovarian cells. Although the\ effects of THs on female reproduction are of great interest, the mechanism remains unclear. We\ investigated the effects of TH dysregulation on reproductive hormones in rats. Propylthiouracil (PTU)\ and L-thyroxine were administered to rats to induce hypo- and hyperthyroidism, respectively, and the\ reproductive hormone profiles were analyzed by radioimmunoassay (RIA). Ovarian histology was\ evaluated with hematoxylin and eosin (H&E) staining, and gene protein level or mRNA content was\ analyzed by western blotting or reverse transcription polymerase chain reaction (RT-PCR). The serum\ levels of gonadotropin releasing hormone (GnRH) and follicle stimulating hormone (FSH) in both rat\ models were significantly decreased on day 21, although there were no significant changes at earlier\ time points. There were no significant differences in luteinizing hormone (LH) or progesterone (P4)\ levels between the treatment and the control groups. Both PTU and L-thyroxine treatments downregulated\ estradiol (E2) concentrations; however, the serum testosterone (T) level was increased only in\ hypothyroid rats at day 21. In addition, the expression levels of FSH receptor, cholesterol side-chain\ cleavage enzyme (P450scc), and steroidogenic acute regulatory protein (StAR) were decreased in both\ rat models. Moreover, the onset of puberty was significantly delayed in the hypothyroid group. These\ results provide evidence that TH dysregulation alters reproductive hormone profiles, and that the\ initiation of the estrous cycle is postponed in hypothyroidism.

Topics: Animals; Biomarkers; Cholesterol Side-Chain Cleavage Enzyme; Disease Models, Animal; Estradiol; Estrous Cycle; Female; Follicle Stimulating Hormone; Gonadotropin-Releasing Hormone; Hyperthyroidism; Hypothyroidism; Luteinizing Hormone; Ovary; Phosphoproteins; Progesterone; Propylthiouracil; Rats, Sprague-Dawley; Sexual Maturation; Testosterone; Thyroid Gland; Thyroid Hormones; Thyroxine; Time Factors

In this study, we used an experimental model of congenital hypothyroidism to show that deficient thyroid hormones (TH) disrupt different neurochemical, morphological and functional aspects in the cerebral cortex of 15-day-old offspring. Our results showing decreased glutamine synthetase (GS) activity and Ca

Topics: Acetylcholinesterase; Animals; Animals, Newborn; Antigens, Nuclear; Behavior, Animal; Biological Transport; Body Composition; Cells, Cultured; Cerebral Cortex; Female; Glial Fibrillary Acidic Protein; Glucose; Glutamate-Ammonia Ligase; Glutamic Acid; Hypothyroidism; L-Lactate Dehydrogenase; Molecular Docking Simulation; Motor Activity; Nerve Tissue Proteins; Oxidation-Reduction; Phosphorylation; Propylthiouracil; Rats, Wistar; Receptors, Cytoplasmic and Nuclear; Sensorimotor Cortex; Thyroid Gland; Thyroid Hormones

Purpose The aim of the study was to evaluate the effects of prenatal hypothyroidism on neonatal rats by the way of activity-dependent neuroprotective factor (ADNF) expression. Methods Twenty-one Wistar albino neonatal rats were divided into two subgroups; a control group and neonatal rats with experimental maternal hypothyroidism. Hypothyroidism was induced by using propylthiouracil (PTU). Neonatal rats obtained PTU from breast milk continuously for 1 week after birth. The rats from the control group were fed only normal feed and water. After birth, body weight and blood thyroid hormone levels were tested. Glial fibrillary acidic protein (GFAP), Slug, Numb, Notch-1 and ADNF antibodies were used for immunohistochemical analysis. Real-time polymerase chain reaction (RT-PCR) and Western blotting analyses were used to evaluate ADNF gene expression levels from 1-week-old rat's brain. Results There was no difference between the two groups for birth weights. The thyroxine (T4) level from the experimental group was <0.4 ng/mL, and it was 0.8 ng/mL for the control group. It was shown that, the results from the experimental group samples had significantly lower ADNF mRNA levels than control group (p < 0.05). The increase from GFAP and Numb expression and decrease from Slug expression were shown in the experimental group. Local differences were identified for ADNF and a decrease was shown in both sides of brain. There was no difference for Notch-1 expression for both groups. Conclusion In this study, decreasing ADNF expression might contribute to developing neurological problems in congenital hypothyroidism.

Topics: Animals; Brain; Female; Hypothyroidism; Oligopeptides; Pregnancy; Prenatal Exposure Delayed Effects; Propylthiouracil; Rats; Rats, Wistar

Thyroid pathologies have deleterious effects on lactation. Especially hypothyroidism (HypoT) induces premature mammary involution at the end of lactation and decreases milk production and quality in mid lactation. Milk synthesis is controlled by JAK2/STAT5 signaling pathway and prolactin (PRL), which activates the pathway. In this work we analyzed the effect of chronic 6-propyl-2-thiouracil (PTU)-induced HypoT on PRL signaling pathway on mammary glands from rats on lactation (L) days 2, 7 and 14. HypoT decreased prolactin receptor expression, and expression and activation of Stat5a/b protein. Expression of members of the SOCS-CIS family, inhibitors of the JAK-STAT pathway, decreased in L2 and L7, possibly as a compensatory response of the mammary cells to maintain PRL responsiveness. However, on L14, the level of these inhibitors was normal and the transcription of α-lactoalbumin (lalba), a target gene of the PRL pathway, decreased by half. HypoT altered the transcriptional capacity of the cell and decreased mRNA levels of Prlr and Stat5b on L14. Stat5b gene has functional thyroid hormone response elements in the regulatory regions, that bind thyroid hormone receptor β (TRβ) differentially and in a thyroid hormone dependent manner. The overall decrease in the PRL signaling pathway and consequently in target gene (lalba) mRNA transcription explain the profound negative impact of HypoT on mammary function through lactation.

Topics: Animals; Chromatin Immunoprecipitation; Computational Biology; Female; Humans; Hypothyroidism; Janus Kinases; Lactation; Mammary Glands, Animal; MCF-7 Cells; Prolactin; Promoter Regions, Genetic; Propylthiouracil; Rats, Wistar; RNA, Messenger; Signal Transduction; STAT Transcription Factors; Thyrotropin

Topics: Animals; Animals, Newborn; Cell Proliferation; Female; Hypothyroidism; Lactation; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Nitric Oxide Synthase Type II; Organ Size; Propylthiouracil; Seminiferous Tubules; Sertoli Cells; Spermatogenesis; Testis

Thyroid hormones (THs) play an important role in maintaining the link between metabolism and reproduction and the altered THs status is associated with induction of oxidative stress in various organs like brain, heart, liver and testis. Further, reactive oxygen species play a pivotal role in regulation of glucose homeostasis in several organs, and glucose utilization by Leydig cells is essential for testosterone biosynthesis and thus is largely dependent on glucose transporter 8 (GLUT8). Glucose uptake by Sertoli cells is mediated through glucose transporter 3 (GLUT3) under the influence of THs to meet energy requirement of developing germ cells. THs also modulate level of gap junctional protein such as connexin 43 (Cx43), a potential regulator of cell proliferation and apoptosis in the seminiferous epithelium. Although the role of transient neonatal hypothyroidism in adult testis in terms of testosterone production is well documented, the effect of THs deficiency in early developmental period and its role in testicular glucose homeostasis and oxidative stress with reference to Cx43 in immature mice remain unknown. Therefore, the present study was conducted to evaluate the effect of neonatal hypothyroidism on testicular glucose homeostasis and oxidative stress at postnatal days (PND) 21 and 28 in relation to GLUT3, GLUT8 and Cx43. Hypothyroidism induced by 6-propyl-2-thiouracil (PTU) markedly decreased testicular glucose level with considerable reduction in expression level of GLUT3 and GLUT8. Likewise, lactate dehydrogenase (LDH) activity and intratesticular concentration of lactate were also decreased in hypothyroid mice. There was also a rise in germ cell apoptosis with increased expression of caspase-3 in PTU-treated mice. Further, neonatal hypothyroidism affected germ cell proliferation with decreased expression of proliferating cell nuclear antigen (PCNA) and Cx43. In conclusion, our results suggest that neonatal hypothyroidism alters testicular glucose homeostasis via increased oxidative stress in prepubertal mice, thereby affecting germ cell survival and proliferation.

Topics: Age Factors; Animals; Animals, Newborn; Antioxidants; Apoptosis; Cell Proliferation; Connexin 43; Disease Models, Animal; Down-Regulation; Glucose; Glucose Transport Proteins, Facilitative; Glucose Transporter Type 3; Homeostasis; Hypothyroidism; L-Lactate Dehydrogenase; Lactic Acid; Lipid Peroxidation; Male; Mice; Oxidative Stress; Proliferating Cell Nuclear Antigen; Propylthiouracil; Testis; Time Factors

This study aimed to examine the neuroprotective effects of Nigella sativa (N. sativa) in the hippocampus of propylthiouracil (PTU)-induced hypothyroid rats during neonatal and juvenile growth. Twenty- five pregnant rats from early gestation (GD 0) were divided into five groups: (1) control (received drinking water), (2) PTU (received 0.005% PTU in drinking water), (3-5) PTU + NS 0.05%, PTU + NS 0.1%, PTU + NS 0.2% (along with PTU, received 0.05%, 0.1% and 0.2% W/V of N. sativa respectively) and treatment continued until postnatal day 60 (PN 60). The brains of male pups were removed for histological and stereological assessments. N. sativa extract significantly reduced the production of dark neurons and apoptotic cells in different areas of the hippocampus compared to the PTU group. Moreover, it significantly attenuated the effect of hypothyroidism on the volume reduction of the hippocampus. The results of the present study suggested that N. sativa extract has a potential ability to prevent the hippocampal neural damage after inducing hypothyroidism during neonatal and juvenile growth in rats.

Topics: Animals; Animals, Newborn; Antithyroid Agents; Apoptosis; Body Weight; Cell Count; Female; Hippocampus; Hypothyroidism; Male; Neurons; Neuroprotective Agents; Nigella sativa; Plant Extracts; Pregnancy; Propylthiouracil; Rats; Rats, Wistar

We investigated the effects of hydroalcoholic extract of Nigella sativa (NS) on renal tissue oxidative damage associated with propylthiouracil (PTU)-induced hypothyroidism during neonatal and juvenile growth in rats.. Pregnant rats were divided into five groups designated as: 1) control; 2) propylthiouracil (PTU); 3) PTU-NS100; 4) PTU-NS200, and 5) PTU-NS400. All mothers except the control group received 0.005% PTU in their drinking water during lactation. Besides PTU, mothers in groups 3-5 received 100, 200, and 400 mg/kg of NS extract. After lactation period, the off spring continued to receive the same experimental treatment for the first 8 weeks of their life. Ten male off springs of each group were randomly selected, blood samples collected, and the kidney tissues removed.. The serum thyroxin concentration in PTU group was lower than control group and improved by extract. PTU increased the renal malondialdehyde (MDA), while reduced the total thiols concentrations and catalase (CAT) and superoxide dismutase (SOD) activity compared to control group. Administration of 200 and 400 mg/kg of NS extract decreased MDA level, while it increased the total thiols and 400 mg/kg increased CAT and SOD activity in renal tissues compared to PTU group. Serum creatinine and blood urea nitrogen (BUN) in PTU group was higher than in comparison with the control group. 400 mg/kg decreased creatinine, but both 200 and 400 mg/kg improved BUN concentration compared to PTU group.. The results of this study demonstrate that the hydroalcoholic extract of NS has a protective effect on the renal tissue oxidative damage associated with PTU-induced hypothyroidism during neonatal and juvenile growth in rats.

Topics: Animals; Animals, Newborn; Antithyroid Agents; Blood Urea Nitrogen; Catalase; Creatinine; Female; Hypothyroidism; Kidney; Male; Malondialdehyde; Nigella sativa; Oxidative Stress; Plant Extracts; Pregnancy; Pregnancy Complications; Prenatal Exposure Delayed Effects; Propylthiouracil; Rats; Rats, Wistar; Sulfhydryl Compounds; Superoxide Dismutase; Thyroxine

Fetal goitrous hypothyroidism is mainly caused by maternal treatment of Graves' disease. Fetal goiter sometimes compresses the trachea and esophagus and may cause polyhydramnios, preterm labor, complications of labor and delivery, and neonatal respiratory disorder.. We report a case of fetal goitrous hypothyroidism in which the mother had Graves' disease, which was treated with propylthiouracil. Intra-amniotic levothyroxine (L-T4) administration was performed, and the fetal goiter decreased in size. A female infant was delivered without goiter and complications. Thyroid function was within the normal range.. Previous reports on fetal goitrous hypothyroidism that was treated with intra-amniotic L-T4 showed that patients who had intra-amniotic L-T4 administration were likely to have a good outcome compared with patients who did not have L-T4. Thyroid function of the mother and fetus should be carefully monitored and treated appropriately.

Topics: Adult; Antithyroid Agents; Female; Fetal Diseases; Goiter; Graves Disease; Humans; Hypothyroidism; Pregnancy; Pregnancy Complications; Propylthiouracil; Thyroxine; Treatment Outcome; Ultrasonography, Prenatal

The mechanisms of vascular alterations resulting from early thyroid hormones deficiency are poorly understood. We tested the hypothesis that antenatal/early postnatal hypothyroidism would alter the activity of endothelial NO pathway and Rho-kinase pathway, which are specific for developing vasculature. Dams were treated with propylthiouracil (PTU, 7 ppm) in drinking water during gestation and 2 weeks after delivery, and their progeny had normal body weight but markedly reduced blood levels of thyroid hormones (ELISA). Small arteries from 2-week-old male pups were studied using wire myography, qPCR and Western blotting. Mesenteric arteries of PTU pups, compared to controls, demonstrated smaller maximum response to α

Topics: Animals; Blood Glucose; Female; Gene Expression Regulation; Hypothyroidism; Iodide Peroxidase; Iodothyronine Deiodinase Type II; Pregnancy; Prenatal Exposure Delayed Effects; Propylthiouracil; Random Allocation; Rats; RNA, Messenger; Thyroid Hormone Receptors alpha; Thyroid Hormones; Vascular Resistance

Thyroid hormones (THs) are important for growth and development of many tissues, and altered thyroid status affects various organs and systems. Testis also is considered as a thyroid hormone responsive organ. Though THs play an important role in regulation of testicular steroidogenesis and spermatogenesis, the exact mechanism of this regulation remains poorly understood. The present study, therefore, is designed to examine the effect of neonatal hypothyroidism on prepubertal Parkes (P) strain mice testis in relation to thyroid hormone receptor alpha 1 (THRα1). Hypothyroidism was induced by administration of 6-propyl-2-thiouracil (PTU) in mother's drinking water from birth to day 28; on postnatal day (PND) 21 only pups, and on PND 28, both pups and lactating dams were euthanized. Serum T

Topics: Animals; Animals, Newborn; Body Weight; Female; Hypothyroidism; Immunoblotting; Male; Mice; Organ Size; Propylthiouracil; Reproducibility of Results; RNA, Messenger; Sexual Maturation; Steroids; Testis; Thyroid Hormone Receptors alpha; Thyroid Hormones

In the present study, we investigated oxidative stress parameters and antioxidant defence status in perinatal hypothyroid rat liver and heart. We found that the proteincarbonyl content did not differ significantly between the three groups both in the pup liver and in the heart. The OH˙ level was significantly decreased in the hypothyroid heart but not in the liver compared with controls. A slight but not significant decrease in SOD activity was observed in both perinatal hypothyroid liver and heart. A significantly increased activity of CAT was observed in the liver but not in the heart of hypothyroid pups. The GPx activity was considerably increased compared with controls in the perinatal hypothyroid heart and was unaltered in the liver of hypothyroid pups. We also found that vitamin E levels in the liver decreased significantly in hypothyroidism and were unaltered in the heart of perinatal hypothyroid rats. The GSH content was elevated significantly in both hypothyroid liver and heart. The total antioxidant capacity was higher in the liver of the hypothyroid group but not in the hypothyroid heart. Thyroxine replacement could not repair the above changes to normal. In conclusion, perinatal hypothyroidism modulates the oxidative stress status of the perinatal liver and heart.

Topics: Animals; Antioxidants; Catalase; Female; Glutathione; Glutathione Peroxidase; Hydroxides; Hypothyroidism; Liver; Male; Myocardium; Pregnancy; Propylthiouracil; Protein Carbonylation; Rats; Superoxide Dismutase; Thyroxine; Triiodothyronine; Vitamin E

The hippocampus maintains a capacity for neurogenesis throughout life, a capacity that is reduced in models of adult onset hypothyroidism. The effects of developmental thyroid hormone (TH) insufficiency on neurogenesis in the adult hippocampus, however, has not been examined. Graded degrees of TH insufficiency were induced in pregnant rat dams by administration of 0, 3 or 10ppm of 6-propylthiouracil (PTU) in drinking water from gestational day (GD) 6 until weaning. Body, brain, and hippocampal weight were reduced on postnatal day (PN) 14, 21, 78 and hippocampal volume was smaller at the 10 but not 3ppm dose level. A second experiment examined adult hippocampal neurogenesis following developmental or adult onset hypothyroidism. Two male offspring from 0 and 3ppm exposed dams were either maintained on control water or exposed to 3ppm PTU to create 4 distinct treatment conditions (Control-Control; Control-PTU, PTU-Control, PTU-PTU) based on developmental and adult exposures. Beginning on the 28th day of adult exposure to 0 or 3ppm PTU, bromodeoxyuridine (BrdU, 50mg/kg, ip) was administered twice daily for 5days, and one male from each treatment was sacrificed 24h and 28days after the last BrdU dose and brains processed for immunohistochemistry. Although no volume changes were seen in the hippocampus of the neonate at 3ppm, thinning of the granule cell layer emerged in adulthood. Developmental TH insufficiency produced a reduction in newly born cells, reducing BrdU+ve cells at 1 with no further reduction at 28-days post-BrdU. Similar findings were obtained using the proliferative cell marker Ki67. Neuronal differentiations was also altered with fewer doublecortin (Dcx) expressing cells and a higher proportion of immature Dcx phenotypes seen after developmental but not adult TH insufficiency. An impaired capacity for neurogenesis may contribute to impairments in synaptic plasticity and cognitive deficits previously reported by our laboratory and others following moderate degrees of developmental TH insufficiency induced by this PTU model.

Topics: Analysis of Variance; Animals; Animals, Newborn; Antimetabolites; Bromodeoxyuridine; Cell Count; Cell Differentiation; Disease Models, Animal; Dose-Response Relationship, Drug; Doublecortin Domain Proteins; Doublecortin Protein; Female; Hippocampus; Hypothyroidism; Ki-67 Antigen; Microtubule-Associated Proteins; Neurogenesis; Neuropeptides; Pregnancy; Prenatal Exposure Delayed Effects; Propylthiouracil; Rats; Rats, Long-Evans; Thyroid Hormones

Topics: Animals; Cognition; Glucose; Hippocampus; Hypothyroidism; Male; Memory; Neuronal Plasticity; Propylthiouracil; Rats; Rats, Sprague-Dawley

Experimental hypothyroidism retards mammary carcinogenesis promoting apoptosis of tumor cells. β-catenin plays a critical role in cell adhesion and intracellular signaling pathways conditioning the prognosis of breast cancer. However, the mechanistic connections associated with the expression of β-catenin in thyroid status and breast cancer are not known. Therefore, we studied the relationship between the expression and localization of β-catenin and apoptosis in mammary tumors induced by 7,12-dimethylbenz(a)anthracene (DMBA) in hypothyroid (Hypot) and euthyroid (EUT) rats. Female Sprague Dawley rats were treated with a dose of DMBA (15 mg/rat) at 55 days of age and were then divided into two groups: HypoT (0.01% 6-N-propyl-2-thiouracil in drinking water, n = 54) and EUT (untreated control, n = 43). Latency, incidence and progression of tumors were determined. At sacrifice, tumors were obtained for immunohistological studies and Western Blot. The latency was longer (p < 0.05), the incidence was lower (p < 0.0001) and tumor growth was slower (p < 0.01) in HypoT rats compared to EUT. The expression of Bax, cleaved caspase-9 and caspase-3 was significantly higher in tumors of HypoT than in EUT (p < 0.05) indicating the activation of the intrinsic pathway. In this group, β-catenin was expressed in the plasma membrane and with less intensity, while its expression was nuclear and with greater intensity in the EUT (p < 0.05). Moreover, the expression of survivin was reduced in tumors of HypoT rats (p < 0.05). In conclusion, decreased expression of β-catenin and its normal location in membrane of mammary tumors are associated with augmented apoptosis via activation of the intrinsic pathway in HypoT rats.

Topics: Animals; Apoptosis; beta Catenin; Disease Progression; Female; Hypothyroidism; Mammary Neoplasms, Animal; Propylthiouracil; Rats; Rats, Sprague-Dawley

Thyroid diseases have deleterious effects on lactation, litter growth and survival, and hinder the suckling-induced hormone release, leading in the case of hyperthyroidism, to premature mammary involution. To determine the effects of hypothyroidism (HypoT) on late lactation, we analyzed the effect of chronic 6-propyl-2-thiouracil (PTU)-induced HypoT on mammary histology and the expression of members of the JAK/STAT/SOCS signaling pathway, milk proteins, prolactin (PRLR), estrogen (ER), progesterone (PR) and thyroid hormone (TR) receptors, markers of involution (such as stat3, lif, bcl2, BAX and PARP) on lactation (L) day 21. HypoT mothers showed increased histological markers of involution compared with control rats, such as adipose/epithelial ratio, inactive alveoli, picnotic nuclei and numerous detached apoptotic cells within the alveolar lumina. We also found decreased PRLR, β-casein and α-lactoalbumin mRNAs, but increased SOCS1, SOCS3, STAT3 and LIF mRNAs, suggesting a decrease in PRL signaling and induction of involution markers. Furthermore, Caspase-3 and 8 and PARP labeled cells and the expression of structural proteins such as β-Actin, α-Tubulin and Lamin B were increased, indicating the activation of apoptotic pathways and tissue remodelation. HypoT also increased PRA (mRNA and protein) and erβ and decreased erα mRNAs, and increased strongly TRα1, TRβ1, PRA and ERα protein levels. These results show that lactating HypoT rats have premature mammary involution, most probably induced by the inhibition of prolactin signaling along with the activation of the LIF-STAT3 pathway.

Topics: Animals; Female; Gene Expression Regulation; Hypothyroidism; Lactation; Leukemia Inhibitory Factor; Mammary Glands, Animal; Milk Proteins; Prolactin; Propylthiouracil; Rats; Signal Transduction; STAT3 Transcription Factor

Pancreatic progenitors derived from human embryonic stem cells (hESCs) are a potential source of transplantable cells for treating diabetes and are currently being tested in clinical trials. Yet, how the milieu of pancreatic progenitor cells, including exposure to different factors after transplant, may influence their maturation remains unclear. Here, we examined the effect of thyroid dysregulation on the development of hESC-derived progenitor cells in vivo. Hypothyroidism was generated in SCID-beige mice using an iodine-deficient diet containing 0.15% propyl-2-thiouracil, and hyperthyroidism was generated by addition of L-thyroxine (T4) to drinking water. All mice received macroencapsulated hESC-derived progenitor cells, and thyroid dysfunction was maintained for the duration of the study ("chronic") or for 4 weeks posttransplant ("acute"). Acute hyperthyroidism did not affect graft function, but acute hypothyroidism transiently impaired human C-peptide secretion at 16 weeks posttransplant. Chronic hypothyroidism resulted in severely blunted basal human C-peptide secretion, impaired glucose-stimulated insulin secretion, and elevated plasma glucagon levels. Grafts from chronic hypothyroid mice contained fewer β-cells, heterogenous MAFA expression, and increased glucagon(+) and ghrelin(+) cells compared to grafts from euthyroid mice. Taken together, these data suggest that long-term thyroid hormone deficiency may drive the differentiation of human pancreatic progenitor cells toward α- and ε-cell lineages at the expense of β-cell formation.

Topics: Animals; Antithyroid Agents; Biomarkers; Cell Differentiation; Cell Line; Cells, Immobilized; Diabetes Mellitus, Type 1; Disease Models, Animal; Heterografts; Human Embryonic Stem Cells; Humans; Hyperthyroidism; Hypothyroidism; Insulin-Secreting Cells; Iodine; Male; Mice, SCID; Propylthiouracil; Random Allocation; Thyroxine; Transplantation, Heterologous; Transplantation, Heterotopic

The goal of this study was to evaluate whether sodium selenite could afford protection against the effects of hypothyroidism on long-term potentiation (LTP), which is thought to be the cellular basis for learning and memory. Hypothyroidism was induced in young-adult rats by the administration of 6-n-propyl-2-thiouracil (PTU) in tap water for 21 days. Half of these hypothyroid and euthroid rats were given 10ppM selenium with their drinking water. Field potentials were recorded from the dentate gyrus in response to stimulation of the medial perforant pathway in vivo. PTU treatment resulted in a significant reduction in both free T3 and free T4 levels, whereas selenium administration to PTU-treated rats restored only the levels of free T3 to their control values. Thyroid hormone levels were not affected by selenium in euthyroid rats. PTU-treated rats exhibited an attenuation of population spike (PS) - LTP, but a comparable potentiation of excitatory postsynaptic potential (EPSP) was found among these rats. The administration of selenium to PTU-treated rats was partially able to attenuate impairment of LTP, but not of potentiation during the LTP induction protocol in hypothyroid rats. Interestingly, the hypothyroid rats that were supplemented with selenium had a lower EPSP potentiation during induction protocol than the control rats. The present study suggests a possible importance of T3 in Se-induced rescue of impaired PS-LTP in hypothyroidism.

Topics: Animals; Excitatory Postsynaptic Potentials; Hypothyroidism; Long-Term Potentiation; Male; Propylthiouracil; Rats, Wistar; Selenium; Thyroid Hormones

The present study is aimed at bringing out the information on the effect of berberine chloride in hyper and hypo thyroidal model with two dose levels.. The research article also reviewed details of various existing patents associated with comprehensive compilation regarding the therapeutic application of berberine and related forms.. Sixty female wistar rats weighing between 150-250 gm were divided in to 10 groups. The animals were grouped in to solvent control; hypothyroid; hyperthyroid; prophylactic with two different doses of berberine chloride (50 and 100 mg/kg); treatment groups similar to that of the prophylactic and therapeutic group. To substantiate the dose dependent effect of berberine chloride in 6-n-propyL-2-thiouracil (PTU) induced hypothyroidism, lipid profile, thyroid profile, enzymes profiles and blood profiles, in addition to histopathological studies were also carried out. There was no any significant difference in the lipid profile among solvent control, treatment and prophylactic groups. However, there was a significant difference (***p<0.001) in serum triglycerides, LDL and VLDL of hypothyroid group when compound to that of the rest.. As far as thyroid profile is concerned, T3 level of berberine chloride (50 mg/kg) treated groups (prophylactic+ treatment) showed a significant rise compared to hypothyroid group. TSH level in prophylactic groups was far higher than the rest of the groups (3.002±0.0192, 1.051±0.0008 against the solvent control, 0.308±0.008). SGOT, SGPT levels were significantly higher with the therapeutic group than that of the normal and hypo-thyroidal group. Blood profile of berberine chloride (100 mg/kg) treated therapeutic group was comparable to that of the solvent control than all other groups. The probable mechanism underlying may be that inactivation of type I 5.-iodothyronine deiodinase (5.DI) enzyme by NF-kB pathway.. From the findings of the current study it can be concluded that berberine chloride possesses both thyroid stimulating and suppressing activities depending on its dose, especially berberine chloride 50 mg/kg supports thyroid stimulating property.

Topics: Animals; Antithyroid Agents; Berberine; Biomarkers; Chlorides; Disease Models, Animal; Dose-Response Relationship, Drug; Female; Hyperthyroidism; Hypothyroidism; Lipids; Patents as Topic; Propylthiouracil; Rats, Wistar; Thyroid Gland; Thyroid Hormones; Time Factors

Hypothyroidism during early development leads to numerous morphological, biochemical and functional changes in developing brain. In this study, we investigated the effects of voluntary and treadmill exercise on learning, memory and hippocampal BDNF levels in both hypothyroid male and female rat pups. To induce hypothyroidism in the mothers, 6-propyl-2-thiouracil (PTU) was added to their drinking water (100mg/L) from their embryonic day 6 to their postnatal day (PND) 21. For 14days, from PNDs 31 to 44, the rat pups were trained with one of the two different exercise protocols, namely the mild treadmill exercise and the voluntary wheel exercise. On PNDs 45-52, a water maze was used for testing their learning and memory ability. The rats were sacrificed one day later and their BDNF levels were then measured in the hippocampus. The findings of the present study indicate that hypothyroidism during the fetal period and the early postnatal period is associated with the impairment of spatial learning and memory and reduced hippocampal BDNF levels in both male and female rat offspring. Both the short-term treadmill exercise and the voluntary wheel exercise performed during the postnatal period reverse the behavioral and neurochemical deficits induced by developmental thyroid hormone insufficiency in both male and female rat offspring. The findings of this study thus demonstrate a marked reversibility of both behavioral and neurochemical disorders induced by developmental thyroid hormone insufficiency through the performance of exercise.

Topics: Animals; Brain-Derived Neurotrophic Factor; Disease Models, Animal; Female; Hippocampus; Hypothyroidism; Learning Disabilities; Male; Maze Learning; Memory Disorders; Motor Activity; Pregnancy; Prenatal Exposure Delayed Effects; Propylthiouracil; Random Allocation; Rats, Wistar; Running; Spatial Memory

Preclinical Research The aim of the present study was to evaluate the effects of thyroid dysfunction on markers of oxidative stress in rat pancreas. Hypothyroidism and hyperthyroidism were, respectively, induced in rats via administration of propylthiouracil (PTU) and L-thyroxine sodium salt in drinking water for 45 days. The activities of superoxide dismutase (SOD), catalase (CAT), glutathioen peroxidase (GPx), glutathione reductase (GR), glucose-6-phosphate dehydrogenase (G6PD), xanthine oxidase (XO), and nonenzymatic markers of oxidative stress including malondialdehyde (MDA), protein carbonyl (PC), reduced glutathione (GSH), and total thiols (T-SH) were determined in the rat pancreas. In hyperthyroid rats, pancreatic CAT, SOD, GPx, GR, XO, G6PD activities were increased compared with those in hypothyroid and control groups. There were no differences in activities of antioxidant enzymes between hypothyroid and control rats. Pancreatic MDA and PC in hyperthyroid rats increased compared with hypothyroid and the control animals. Whereas, hyperthyroid rats had decreased levels of tissue GSH and T-SH compared with hypothyroid and the control groups. The findings showed that only GSH level has decreased significantly in the hypothyroid group compared with control groups. In conclusion, our results showed that experimental hyperthyroidism induces oxidative stress in pancreas of rats, but hypothyroidism has no major impact on oxidative stress markers. Drug Dev Res 77 : 199-205, 2016.   © 2016 Wiley Periodicals, Inc.

Topics: Animals; Antioxidants; Biomarkers; Disease Models, Animal; Glutathione; Hyperthyroidism; Hypothyroidism; Male; Oxidative Stress; Pancreas; Propylthiouracil; Rats; Rats, Wistar; Sulfhydryl Compounds; Thyroxine

Thyroid hormones (TH) are one of the key factors for normal prenatal development in mammals. Previously, we showed that subclinical maternal hypothyroidism leads to premature atresia of ovarian follicles in female rat offspring in the pre-pubertal and pubertal periods. The influence of decreased concentration of TH on primordial follicles pool formation during neonatal and early infantile period of rat pups was not investigated previously. Maternal hypothyroidism during pregnancy has irreversible negative influence on primordial follicles pool formation and population of resting oocytes in female rat offspring. The study was done on neonatal and early infantile control (n-10) and hypothyroid (n-10) female rat pups derived from control (n-6) and propylthiouracil (PTU) treated pregnant dams (n-6), respectively. Ovaries of all pups were removed and processed for light and transmission electron microscopy (TEM). Number of nests, oogonia and oocytes per nest, primordial, primary, secondary and preantral follicles were determined. Screening for overall calcium presence in ovarian tissue was done using Alizarin red staining. Morphology and volume density of nucleus, mitochondria and smooth endoplasmic reticulum (sER) in the oocytes in primordial follicles was also assessed. Caspase-3 and terminal deoxynucleotidyl transferase dUTP nick end labelling (TUNEL), both markers for apoptosis, and proliferating cell nuclear antigen (PCNA) for proliferation were determined in oocytes and granulosa cells in different type of follicles. In neonatal period, ovaries of hypothyroid pups had a decreased number of oogonia, oocytes and nests, an increased number of primordial follicles and a decreased number of primary and secondary follicles, while in early infantile period, increased number of primary, secondary and preantral follicles were found. Alizarin red staining was intense in hypothyroid neonatal rats that also had the highest content of dilated sER. Number of mitochondria with altered morphology in both groups of hypothyroid pups was increased. Apoptosis markers have not shown significant difference between groups but PCNA had an increased expression in the oocytes and granulosa cells in primordial follicles of hypothyroid rats. Light and electron microscopy analysis indicate that previously detected premature ovarian follicular atresia in pre-pubertal and pubertal hypothyroid rats is preceded with premature formation of primordial follicles followed by slight changes

Topics: Animals; Animals, Newborn; Apoptosis; Caspase 3; Congenital Hypothyroidism; Endoplasmic Reticulum, Smooth; Female; Hypothyroidism; In Situ Nick-End Labeling; Microscopy; Microscopy, Electron, Transmission; Mitochondria; Oocytes; Ovarian Follicle; Ovary; Pregnancy; Pregnancy Complications; Proliferating Cell Nuclear Antigen; Propylthiouracil; Rats

The most important conditions associated with hypothyroidism is the cardiac dysfunction. Apelin is an endogenous ligand, involved in energy storage and metabolism which improves cardiac contractility. This study was done to evaluate the effects of apelin, l-Thyroxin (T4) or a combination of both, on cardiac function and mRNA expression of two contractile proteins, α and β myosin heavy chain (α-MHC and β-MHC), in 6-propyl-2-thiouracil (PTU)-induced hypothyroid rats. Forty male Wistar rats were randomly assigned into five groups: Ctrl (Control), and 4 hypothyroid groups (H, HA, HT, and HAT). The Hypothyroid (H) group received 0.05% PTU in the drinking water for six weeks; the next 3 groups, along with PTU, received apelin (HA, 200μg/kg/day, ip), T4 (HT, 20μg/kg/day, gavage), or a combination of both drugs (HAT) for the last 2weeks (weeks 5 and 6). TSH and T4 were measured using ELISA kit. Isolated hearts of animals were perfused in Langendorff apparatus and left ventricular developed pressure, cardiac contractility, heart rate, rate pressure product and perfusion pressure were assessed using PowerLab ADInstruments. In addition α-MHC and β-MHC mRNA expression were evaluated by RT-PCR method in heart tissue. Apelin alone or accompanied by T4 significantly increased cardiac contractility and performance as compared to hypothyroid group. Apelin also significantly increased the alpha-MHC mRNA expression and in the presence of T4 significantly decreased beta-MHC mRNA expression. It seems that apelin alone may improve cardiac function in hypothyroid rats via genomic pathways.

Topics: Animals; Apelin; Gene Expression Regulation; Hypothyroidism; Intercellular Signaling Peptides and Proteins; Male; Myocardial Contraction; Myocardium; Myosin Heavy Chains; Propylthiouracil; Rats; Rats, Wistar; RNA, Messenger; Thyroxine; Ventricular Myosins

Thyroid hormone insufficiency during neurodevelopment can result into significant structural and functional changes within the developing central nervous system (CNS), and is associated with the establishment of serious cognitive impairment and neuropsychiatric symptomatology. The aim of the present study was to shed more light on the effects of gestational and/or lactational maternal exposure to propylthiouracil (PTU)-induced hypothyroidism as a multilevel experimental approach to the study of hypothyroidism-induced changes on crucial brain enzyme activities of 21-day-old Wistar rat offspring in a brain region-specific manner. This experimental approach has been recently developed and characterized by the authors based on neurochemical analyses performed on newborn and 21-day-old rat offspring whole brain homogenates; as a continuum to this effort, the current study focused on two CNS regions of major significance for cognitive development: the frontal cortex and the hippocampus. Maternal exposure to PTU in the drinking water during gestation and/or lactation resulted into changes in the activities of acetylcholinesterase and two important adenosinetriphosphatases (Na(+),K(+)- and Mg(2+)-ATPase), that seemed to take place in a CNS-region-specific manner and that were dependent upon the PTU-exposure timeframe followed. As these findings are analyzed and compared to the available literature, they: (i) highlight the variability involved in the changes of the aforementioned enzymatic parameters in the studied CNS regions (attributed to both the different neuroanatomical composition and the thyroid-hormone-dependent neurodevelopmental growth/differentiation patterns of the latter), (ii) reveal important information with regards to the neurochemical mechanisms that could be involved in the way clinical hypothyroidism could affect optimal neurodevelopment and, ultimately, cognitive function, as well as (iii) underline the need for the adoption of more consistent approaches towards the experimental simulation of congenital and early-age-occurring hypothyroidism.

Topics: Acetylcholinesterase; Animals; Ca(2+) Mg(2+)-ATPase; Female; Frontal Lobe; Gestational Age; Hippocampus; Hypothyroidism; Lactation; Male; Nerve Tissue Proteins; Organ Specificity; Pregnancy; Pregnancy Complications; Prenatal Exposure Delayed Effects; Propylthiouracil; Rats; Rats, Wistar; Sodium-Potassium-Exchanging ATPase

Neurodevelopment is known to be particularly susceptible to thyroid hormone insufficiency and can result in extensive structural and functional deficits within the central nervous system (CNS), subsequently leading to the establishment of cognitive impairment and neuropsychiatric symptomatology. The current study evaluated the effects of gestational and/or lactational maternal exposure to propylthiouracil (PTU)-induced hypothyroidism (as a suggestive multilevel experimental approach to the study of hypothyroidism-induced changes that has been developed and characterized by the authors) on crucial brain enzyme activities of 21-day-old Wistar rat offspring in a CNS region-specific manner. The activities of acetylcholinesterase (AChE), Na(+),K(+)-ATPase and Mg(2+)-ATPase in the offspring hypothalamus, cerebellum and pons were assessed. The study demonstrated that maternal exposure to PTU (0.05% w/v in the drinking water) during the critical periods of neurodevelopment can result in an inhibition of hypothalamic, pontine and cerebellar Na(+),K(+)-ATPase; a major marker of neuronal excitability and metabolic energy production as well as an important regulator of important systems of neurotransmission. On the other hand, no significant changes in the activities of the herein offspring CNS regions' AChE and Mg(2+)-ATPase were recorded. The observed Na(+),K(+)-ATPase inhibition: (i) is region-specific (and non-detectable in whole brain homogenetes), (ii) could constitute a central event in the pathophysiology of clinically-relevant hypothyroidism-associated developmental neurotoxicity, (iii) occurs under all examined experimental schemes, and (iv) certainly deserves further clarification at a molecular and histopathological level. As these findings are analyzed and compared to the available literature, they also underline the need for the adoption and further study of Na(+),K(+)-ATPase activity as a consistent neurochemical marker within the context of a systematic comparative study of existing (and novel) simulation approaches to congenital and early age hypothyroidism.

Topics: Acetylcholinesterase; Animals; Brain; Ca(2+) Mg(2+)-ATPase; Cerebellum; Congenital Hypothyroidism; Female; Hypothalamus; Hypothyroidism; Lactation; Male; Pons; Pregnancy; Pregnancy Complications; Prenatal Exposure Delayed Effects; Propylthiouracil; Rats; Rats, Wistar; Sodium-Potassium-Exchanging ATPase

Thyroid hormone (TH) is essential for a number of physiological processes and is particularly critical during nervous system development. The hippocampus is strongly implicated in cognition and is sensitive to developmental hypothyroidism. The impact of TH insufficiency in the foetus and neonate on hippocampal synaptic function has been fairly well characterised. Although adult onset hypothyroidism has also been associated with impairments in cognitive function, studies of hippocampal synaptic function with late onset hypothyroidism have yielded inconsistent results. In the present study, we report hypothyroidism induced by the synthesis inhibitor propylthiouracil (10 p.p.m., 0.001%, minimum of 4 weeks), resulted in marginal alterations in excitatory postsynaptic potential (EPSP) and population spike (PS) amplitude in the dentate gyrus measured in vivo. No effects were seen in tests of short-term plasticity, and a minor enhancement of long-term potentiation of the EPSP slope was observed. The most robust synaptic alteration evident in hypothyroid animals was an increase in synaptic response latency, which was paralleled by a failure to maintain normal body temperature under anaesthesia, despite warming on a heating pad. Latency shifts could be reversed in hypothyroid animals by increasing the external heat source and, conversely, synaptic delays could be induced in control animals by removing the heat source, with a consequent drop in body and brain temperature. Thermoregulation is TH- dependent, and anaesthesia necessary for surgical procedures posed a thermoregulatory challenge that was differentially met in control and hypothyroid animals. Minor increases in field potential EPSP slope, decreases in PS amplitudes and increased latencies are consistent with previous reports of hypothermia in naive control rats. We conclude that failures in thyroid-dependent temperature regulation rather than direct action of TH in synaptic physiology are responsible for the observed effects. These findings stand in contrast to the synaptic impairments observed in adult offspring following developmental TH insufficiency, and emphasise the need to control for the potential unintended consequences of hypothermia in the interpretation of hypothyroid-induced changes in physiological systems, most notably synaptic transmission.

Topics: Age of Onset; Anesthesia; Animals; Dentate Gyrus; Excitatory Postsynaptic Potentials; Hippocampus; Hypothermia; Hypothyroidism; Male; Propylthiouracil; Rats; Rats, Long-Evans

A growing number of studies have revealed that neurocognitive impairment, induced by adult-onset hypothyroidism, may not be fully restored by traditional hormone substitution therapies, including thyroxine (T4). The present study has investigated the effect of T4 and donepezil (DON; an acetylcholinesterase (AChE) inhibitor) treatment on the hypothyroidism-induced alterations of acetylcholine (ACh) content and AChE activity. Furthermore, we examined synaptotagmin-1 (syt-1) and SNAP-25 expression in the hippocampus of adult rats. Adding 0.05% propylthiouracil to their drinking water for five weeks induced hypothyroidism in the rat models. From the fourth week, the rats were treated with T4, DON or a combination of both. Concentration of ACh and the activity of AChE was determined colorimetrically. The results demonstrated that hypothyroidism induced a significant decrease of Ach content and AChE activity (by 17 and 34%, respectively), which were restored to control values by T4 administration. DON treatment also restored Ach to the normal level. Protein levels of syt-1 and SNAP-25 were determined by immunohistochemistry. The results demonstrated that syt-1 was expressed at significantly lower levels in hypothyroid rats, while SNAP-25 levels were notably higher compared with the controls. Two-week treatment with T4 alone failed to normalize the expression levels of these two proteins, while co-administration of T4 and DON was able to induce this effect. These data suggested that the thyroid hormone, T4, may have a direct effect on the metabolism of hippocampal ACh in adult rats, and that the DON treatment may facilitate the recovery of synaptic protein impairments induced by hypothyroidism.

Topics: Acetylcholine; Acetylcholinesterase; Animals; Antithyroid Agents; Cholinesterase Inhibitors; Donepezil; Hippocampus; Hypothyroidism; Immunohistochemistry; Indans; Luminescent Measurements; Male; Piperidines; Propylthiouracil; Rats; Rats, Sprague-Dawley; Synaptosomal-Associated Protein 25; Synaptotagmin I; Thyrotropin; Thyroxine; Triiodothyronine

Sickness behavior is an expression of a motivational state triggered by activation of the peripheral innate immune system, whereby an organism reprioritizes its functions to fight infection. The relationship between thyroid hormone and immune cells is complex, and additional insights are needed about the involvement of the cross-talk between thyroid hormone, the central nervous system and immune function, as demonstrated by the consequences to sickness behavior. The aim of this work was to evaluate sickness behavior in hypothyroid mice. Control mice and mice treated with propylthiouracil (PTU) for 30days (0.05%; added to drinking water) received a single dose of LPS (200μg/kg; i.p.) or saline, and the behavioral response was assessed for 24h. We provide evidence that thyroid status acts a modulator for the development of depressive-like and exploratory behaviors in mice that are subjected to an immunological challenge because the PTU pretreatment delayed the LPS-induced behavioral changes observed in an open field test and in a forced swimming test. This response was observed concomitantly with a lower thermal index until 4h after the LPS administration. This result demonstrates that thyroid status modifies behavioral responses to immune challenge and suggests that thyroid hormones are essential for the manifestation of sickness behavior during endotoxemia.

Topics: Animals; Anorexia; Antithyroid Agents; Endotoxemia; Exploratory Behavior; Fever; Hypothyroidism; Illness Behavior; Lipopolysaccharides; Male; Mice; Motor Activity; Propylthiouracil

Uveal melanoma is highly metastatic, prognosis is poor and there are no effective treatments to extend survival. Accumulating evidence suggests that thyroid hormones have a mitogenic effect via binding to αvβ3 integrin. We aimed to examine the impact of thyroid status on survival in a murine B16F10 model for ocular melanoma, highly expressing the integrin. In two independent experiments oral propylthiouracil (PTU) was used to induce hypothyroidism (n=9), thyroxine to induce hyperthyroidism (n=11) and mice given plain water served as control (n=8). At day 21, the subretinal space was inoculated with 10(2) B16F10 cells. In non-inoculated mice (n=6 of each group) serum free T4 (FT4) levels were measured and additional non-inoculated mice (3 given PTU and 4 given thyroxine or water) served as internal control to demonstrate the impact of the dissolved substance. The PTU-inoculated mice showed clinical evidence of intraocular tumor growth significantly later than the thyroxine mice (P=0.003) and survival time was significantly longer (P<0.001). FT4 levels differed significantly between groups (P<0.001) and with no signs of illness in the internal control group. Our findings suggest that hyperthyroidism shortens survival, whereas relative hypothyroidism may have a protective role in metastatic ocular melanoma.

Topics: Animals; Antithyroid Agents; Disease Models, Animal; Eye Neoplasms; Hyperthyroidism; Hypothyroidism; Lung Neoplasms; Male; Melanoma; Mice; Mice, Inbred C57BL; Propylthiouracil; Survival Rate; Thyroxine

Thyroid hormones (TH) regulate mammary function. Hypothyroidism (HypoT) has deleterious effects on lactation, litter growth and survival. We analyzed the effect of chronic 6-propyl-2-thiouracil (PTU)-induced HypoT in the expression of nuclear receptors, co-regulators and oxytocin receptor (OTR) on lactation (L) days 2, 7 and 14. TH receptors (TRs) were increased on L7 at mRNA and protein levels, except TRα protein, that fell on L14. HypoT decreased TRα2 mRNA on L7 and TRα1 protein on L2, while TRβ1 protein increased on L14. HypoT increased estrogen receptor β (ERβ) mRNA on L7 but decreased its protein levels on L14. Progesterone receptor A (PRA) mRNA decreased from L2 to L14 while PRB increased, and at protein levels PRA levels showed a nadir on L7, while PRB peaked. HypoT decreased PRA mRNA and protein and increased PRB mRNA at L14. Nuclear receptor co-activator (NCOA) 1 and RXRα mRNA showed an opposite pattern to the TRs, while NCOA2 increased at L14; HypoT blocked the variations in NCOA1 and NCOA2. HypoT increased NCOR1 on L2 and decreased OTR at L2 and circulating estradiol and NCOR2 at L14. In controls the most notable changes occurred on L7, suggesting it is a key inflection point in mammary metabolism. The low levels of TRα1, NCOA1 and OTR, and increased NCOR1 produced by HypoT on L2 may hinder the mammary ability to achieve normal milk synthesis and ejection, leading to defective lactation. Later on, altered ER and PR expression may impair further mammary function.

Topics: Animals; Female; Gene Expression; Hypothyroidism; Lactation; Mammary Glands, Animal; Nuclear Receptor Co-Repressor 1; Nuclear Receptor Coactivator 1; Nuclear Receptor Coactivator 2; Propylthiouracil; Protein Isoforms; Rats, Wistar; Receptors, Estrogen; Receptors, Oxytocin; Receptors, Progesterone; Receptors, Thyroid Hormone; Retinoid X Receptor alpha

Clotting abnormalities are discussed both in the context with thyroid dysfunctions and obesity caused by a high fat diet. This study aimed to investigate the impact of hypo-, or hyperthyroidism on the endogenous thrombin potential (ETP), a master indicator of clotting activation, on Sprague Dawley rats fed a normal or high fat diet. Female Sprague Dawley rats (n = 66) were grouped into normal diet (ND; n = 30) and high-fat diet (HFD; n = 36) groups and subdivided into controls, hypothyroid and hyperthyroid groups, induced through propylthiouracil or triiodothyronine (T3) treatment, respectively. After 12 weeks of treatment ETP, body weight and food intake were analyzed. Successfully induced thyroid dysfunction was shown by T3 levels, both under normal and high fat diet. Thyroid dysfunction was accompanied by changes in calorie intake and body weight. In detail, compared to euthyroid controls, hypothyroid rats showed significantly increased-and hyperthyroid animals significantly decreased-ETP levels. High fat diet potentiated these effects in both directions. In summary, we are the first to show that hypothyroidism and high fat diet potentiate the thrombotic capacity of the clotting system in Sprague Dawley rats. This effect may be relevant for cardiovascular disease where thyroid function is poorly understood as a pathological contributor in the context of clotting activity and obesogenic nutrition.

Topics: Animals; Body Weight; Diet, High-Fat; Eating; Female; Hyperthyroidism; Hypothyroidism; Propylthiouracil; Rats; Rats, Sprague-Dawley; Thrombophilia; Triiodothyronine

Hypothyroidism affects cardiopulmonary regulation and function of dopaminergic receptors. Here we evaluated effects of 5 months of hypothyroidism on dopamine D1 receptor modulation of breathing in female hamsters using a D1 receptor antagonist SCH 23390. Euthyroid hamsters (EH) served as controls. Results indicated that hypothyroid female hamsters (HH) exhibited decreased body weights and minute ventilation (VE) following hypoxia due to decreased frequency of breathing (F). Moreover, SCH 23390 administration in HH increased VE by increasing tidal volume during exposure to air, hypoxia and following hypoxia. Relative to vehicle, SCH 23390 treatment decreased body temperature and hypoxic VE responsiveness in both groups. In EH, SCH 23390 decreased F in air, hypoxia and post hypoxia, and VE during hypoxia trended to decrease (P=0.053). Finally, expression of D1 receptor protein was not different between the two groups in any region evaluated. Thus, hypothyroidism in older female hamsters affected D1 receptor modulation of ventilation differently relative to euthyroid animals, but not expression of D1 receptors.

Topics: Animals; Benzazepines; Blotting, Western; Body Temperature; Body Weight; Carbon Dioxide; Disease Models, Animal; Dopamine Antagonists; Female; Hypothyroidism; Mesocricetus; Oxygen Consumption; Propylthiouracil; Receptors, Dopamine D1; Respiration; Tidal Volume

One of the most important thyroid hormone targets is the cardiovascular system. Hemodynamic changes, such as decreased resting heart rate (HR), myocardial contractility, and cardiac output, and increased diastolic pressure and systemic vascular resistance, have been observed in hypothyroid patients. Moreover, in these patients, ECG changes include sinus bradycardia and low voltage complexes (P waves or QRS complexes).. This study aimed at evaluating the prophylactic effect of apelin on HR changes and QRS voltage that occur in propylthiouracil (PTU)-induced hypothyroid rats.. In this study, 48 adult male Wistar rats weighing 170-235g were randomly divided into 6 groups: Control group (normal saline ip injection + tap water gavage); P group (PTU 0.05%, in drinking water); A group (apelin 200 µg.kg-1.day-1, ip); PA group [co-administration of PTU and apelin]; PT group [co-administration of PTU + T4 (0.2 mg/g per day, gavage)]; and PAT group (co-administration of PTU, apelin and T4). All experiments were performed for 28 consecutive days, and then the animals were anesthetized with an ip injection of ketamine (80 mg/kg) and xylazine (12 mg/kg). Lead II electrocardiogram was recorded to calculate HR and QRS voltage.. Heart rate and QRS voltage increased more significantly in the hypothyroid group that consumed both apelin and T4 (201 ± 4 beat/min, 0.71 ± 0.02 mv vs. hypothyroid 145 ± 9 beat/min, 0.563 ± 0.015 mv; respectively).. The co-administration of apelin and T4 showed a protective effect on QRS voltage and HR in PTU‑induced hypothyroid rats.

Topics: Animals; Antithyroid Agents; Apelin; Body Weight; Cardiotonic Agents; Drug Combinations; Electrocardiography; Heart Rate; Hypothyroidism; Intercellular Signaling Peptides and Proteins; Male; Myocardial Contraction; Propylthiouracil; Random Allocation; Rats, Wistar; Reproducibility of Results; Thyrotropin; Thyroxine

Previous studies have recently shown that maternal hypothyroidism leads to impaired glucose metabolism and reduced insulin secretion in adult offspring in rats. The aim of this study was to locate the defect in the insulin secretion pathway induced by maternal hypothyroidism. Pregnant Wistar rats were divided into two groups; the control group consumed water, while the hypothyroid (FH) group received water containing 0.025% 6-propyl-2-thiouracil during gestation. An intravenous glucose tolerance test was carried out on 5-month-old male offspring. In in vitro studies, the effects of various secretagogues and inhibitors acting at different levels of the insulin secretion cascade were investigated, and insulin content, insulin secretion and glucokinase activity of the islets were compared. Although insulin content of the FH islets did not differ from that of control islets, insulin secretion from FH islets was reduced when it was challenged by glucose or arginine. Compared with control islets, activities of both hexokinase and glucokinase were also significantly decreased in the FH islets. Although, in both groups, increasing glibenclamide and nifedipine concentrations in the presence of 16.7 mmol l(-1) glucose increased and decreased insulin secretion, respectively, the percentage of changes in secretion of FH islets was significantly lower compared with control islets. The response of FH islets to high extracellular potassium concentration and diazoxide was also significantly lower than that of the control islets. These findings demonstrate that impaired insulin secretion in the FH group is probably related to alterations in different steps of the insulin secretion pathway and not in the insulin pool of β-cells.

Topics: Age Factors; Animals; Blood Glucose; Disease Models, Animal; Female; Glucokinase; Glucose Tolerance Test; Hexokinase; Hypothyroidism; Insulin; Insulin Secretion; Islets of Langerhans; Male; Pregnancy; Prenatal Exposure Delayed Effects; Propylthiouracil; Rats, Wistar; Time Factors

Bromocriptine depressed ventilation in air and D2 receptor expression in the nucleus tractus solitaries (NTS) in male hypothyroid hamsters. Here we postulated that in age-matched hypothyroid female hamsters, the pattern of D2 receptor modulation of breathing and D2 receptor expression would differ from those reported in hypothyroid males. In females hypothyroidism did not affect D2 receptor protein levels in the NTS, carotid bodies or striatum. Bromocriptine, but not carmoxirole (a peripheral D2 receptor agonist), increased oxygen consumption and body temperature in awake air-exposed hypothyroid female hamsters and stimulated their ventilation before and following exposure to hypoxia. Carmoxirole depressed frequency of breathing in euthyroid hamsters prior to, during and following hypoxia exposures and stimulated it in the hypothyroid hamsters following hypoxia. Although hypothyroidism did not affect expression of D2 receptors, it influenced central D2 modulation of breathing in a disparate manner relative to euthyroid hamsters.

Topics: Air; Animals; Body Temperature; Bromocriptine; Carotid Body; Corpus Striatum; Cricetinae; Dopamine Agonists; Female; Hypothyroidism; Hypoxia; Indoles; Male; Oxygen Consumption; Propylthiouracil; Pyridines; Receptors, Dopamine D2; Respiration; Sex Factors; Solitary Nucleus; Thyroxine; Wakefulness

The present investigation was carried out to evaluate alterations in oxidative stress parameter [lipid peroxidation (LPx)] and antioxidant enzyme activities [superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GPx)] in rat brainstem in response to neonatal hypothyroidism during development (from birth to 7, 15 and 30 days old) and adulthood (90 days old). Hypothyroidism in rats was induced by feeding the lactating mothers (from the day of parturition till weaning, 25 days old) or directly to the pups with 0.05 % [6-n-propyl 2-thiouracil (PTU)] in drinking water. Increased level of LPx was observed in brainstem of 7 days old hypothyroid rats, accompanied by augmented activities of SOD and GPx. In 15 and 30 days old hypothyroid rat brainstem, a significant decline in LPx was observed. Significantly increased activities of CAT and GPx were observed in 15 and 30 days PTU-treated rats. Decreased level of LPx was observed in brainstem of rats treated with PTU from birth to 30 days followed by withdrawal up to 90 days of age (transient hypothyroidism) as compared to control and persistent treatment of PTU up to 90 days of age. Activities of CAT and GPx were decreased in persistent hypothyroid rats of 90 days old with respect to control and transient hypothyroid rats. On the other hand, SOD activity was decreased in both persistent and transient hypothyroid rats with respect to control rats. These results suggest that the PTU-induced neonatal hypothyroidism modulates the antioxidant defence system during postnatal development and adulthood in brainstem of rats.

Topics: Animals; Animals, Suckling; Antioxidants; Brain Stem; Catalase; Glutathione Peroxidase; Hypothyroidism; Lipid Peroxidation; Male; Nerve Tissue Proteins; Oxidation-Reduction; Oxidative Stress; Propylthiouracil; Rats; Rats, Wistar; Superoxide Dismutase

Endothelial dysfunction is an initial and vascular smooth muscle cell (VSMC) apoptosis, a later step of atherosclerosis. Hypothyroidism accelerates atherosclerosis. However, the early events responsible for this pro-atherosclerotic effect are unclear.. Rats were resistant to induction of atherosclerosis by high cholesterol diet alone, but became susceptible in hypothyroid state achieved by administration of propylthiouracil (PTU) for 6 weeks. VSMC dysfunction and apoptosis were obvious within 1 week after PTU treatment, without signs of endothelial dysfunction. This early VSMC damage was caused by hypothyroidism but not the high cholesterol diet. In ApoE knockout mice, PTU-induced hypothyroidism triggered early VSMC apoptosis, increased oxidative stress, and accelerated atherosclerosis development. Thyroid hormone supplementation (T4, 10, or 50 μg/kg) prevented atherogenic phenotypes in hypothyroid rats and mice. In rats, thyroidectomy caused severe hypothyroidism 5 days after operation, which also led to rapid VSMC dysfunction and apoptosis. In vitro studies did not show a direct toxic effect of PTU on VSMCs. In contrast, thyroid hormone (T3, 0.75 μg/L plus T4, 50 nmol/L) exerted a direct protection against VSMC apoptosis, which was reduced by knockdown of TRα1, rather than TRβ1 and TRβ2 receptors. TRα1-mediated inhibition of apoptotic signalling of JNKs and caspase-3 contributed to the anti-apoptotic action of thyroid hormone.. These findings provide an in vivo example for VSMC apoptosis as an early trigger of hypothyroidism-associated atherosclerosis, and reveal activation of TRα1 receptors to prevent VSMC apoptosis as a therapeutic strategy in this disease.

Topics: Animals; Apolipoproteins E; Apoptosis; Atherosclerosis; Cells, Cultured; Hypothyroidism; Mice; Mice, Inbred C57BL; Mice, Knockout; Muscle, Smooth, Vascular; Myocytes, Smooth Muscle; Propylthiouracil; Rats; Rats, Sprague-Dawley; Thyroid Hormone Receptors alpha; Thyroid Hormone Receptors beta; Thyroid Hormones

Data available on thyroid dysfunction and insulin secretion are inconsistent. The aim of this study was to assess the effect of hypothyroidism on insulin secretion, in vivo and in vitro, in rats. Adult Wistar male rats were divided into 4 groups, the control, the propylthiouracyl (PTU)-treated hypothyroid, the surgically thyroidectomized, and the sham-operated thyroidectomized. After 5 weeks, intravenous glucose tolerance test (IVGTT) was performed and 3 weeks later pancreatic islets were isolated to assess glucose induced insulin secretion and insulin content. Fasting serum glucose and insulin levels did not differ between the groups, but serum glucose concentration during IVGTT in the PTU-induced hypothyroid group was significantly higher as compared to controls, throughout 5-60 min. The serum glucose concentration during IVGTT in the thyroidectomized rats was also significantly higher than in the sham-operated ones, except at 10 and 60 min. The area under the curve of the serum insulin was significantly lower during IVGTT in the PTU-treated (10,010 ± 1,380 pmol/l/60 min) and thyroidectomized (13,930 ± 2,786) groups vs. their comparable groups (19,150 ± 2,110), p<0.01 and (20,650 ± 1,601), p<0.05, respectively. In the PTU-treated, but not in thyroidectomized animals, insulin secretion in response to glucose 8.3 and 16.7 mM was significantly lower than their comparable group. The results show that PTU- and thyroidectomy-induced hypothyroidism leads to impaired glucose tolerance due to reduced glucose stimulated insulin secretion. Islets insulin secretion is positively correlated with serum T3 and T4 concentrations.

Topics: Animals; Glucose; Humans; Hypothyroidism; In Vitro Techniques; Insulin; Insulin Secretion; Islets of Langerhans; Male; Propylthiouracil; Rats; Rats, Wistar; Thyroidectomy; Thyroxine; Triiodothyronine

Hypothyroidism is known to exert significant structural and functional changes to the developing central nervous system, and can lead to the establishment of serious mental retardation and neurological problems. The aim of the present study was to shed more light on the effects of gestational and/or lactational maternal exposure to propylthiouracil-induced experimental hypothyroidism on crucial brain enzyme activities of Wistar rat offspring, at two time-points of their lives: at birth (day-1) and at 21 days of age (end of lactation). Under all studied experimental conditions, offspring brain acetylcholinesterase (AChE) activity was found to be significantly decreased due to maternal hypothyroidism, in contrast to the two studied adenosinetriphosphatase (Na(+),K(+)-ATPase and Mg(2+)-ATPase) activities that were only found to be significantly altered right after birth (increased and decreased, respectively, following an exposure to gestational maternal hypothyroidism) and were restored to control levels by the end of lactation. As our findings regarding the pattern of effects that maternal hypothyroidism has on the above-mentioned crucial offspring brain enzyme activities are compared to those reported in the literature, several differences are revealed that could be attributed to both the mode of the experimental simulation approach followed as well as to the time-frames examined. These findings could provide the basis for a debate on the need of a more consistent experimental approach to hypothyroidism during neurodevelopment as well as for a further evaluation of the herein presented and discussed neurochemical (and, ultimately, neurodevelopmental) effects of experimentally-induced maternal hypothyroidism, in a brain region-specific manner.

Topics: Acetylcholinesterase; Adenosine Triphosphatases; Aging; Animals; Brain; Disease Models, Animal; Enzyme Activation; Female; Hypothyroidism; Male; Pregnancy; Pregnancy Complications; Prenatal Exposure Delayed Effects; Propylthiouracil; Rats; Rats, Wistar

The present study was performed to determine target gene profiles associated with pathological mechanisms of developmental neurotoxicity. For this purpose, we selected a rat developmental hypothyroidism model because thyroid hormones play an essential role in both neuronal and glial development. Region-specific global gene expression analysis was performed at postnatal day (PND) 21 on four brain regions representing different structures and functions, i.e., the cerebral cortex, corpus callosum, dentate gyrus and cerebellar vermis of rats exposed to 6-propyl-2-thiouracil in the drinking water at 3 and 10ppm from gestational day 6 to PND 21. Expression changes of gene clusters of neuron differentiation and development, cell migration, synaptic function, and axonogenesis were detected in all four regions. Characteristically, gene expression profiles suggestive of affection of ephrin signaling and glutamate transmission were obtained in multiple brain regions. Gene clusters suggestive of suppression of myelination and glial development were specifically detected in the corpus callosum and cerebral cortex. Immunohistochemically, immature astrocytes immunoreactive for vimentin and glial fibrillary acidic protein were increased, and oligodendrocytes immunoreactive for oligodendrocyte lineage transcription factor 2 were decreased in the corpus callosum. Immunoreactive intensity of myelin basic protein was also decreased in the corpus callosum and cerebral cortex. The hippocampal dentate gyrus showed downregulation of Ptgs2, which is related to synaptic activity and neurogenesis, as well as a decrease of cyclooxygenase-2-immunoreactive granule cells, suggesting an impaired synaptic function related to neurogenesis. These results suggest that multifocal brain region-specific microarray analysis can determine the affection of neuronal or glial development.

Topics: Age Factors; Animals; Brain; Cluster Analysis; Disease Models, Animal; Female; Gene Expression Profiling; Gene Expression Regulation, Developmental; Hypothyroidism; Male; Neurogenesis; Neuroglia; Neurons; Oligonucleotide Array Sequence Analysis; Pregnancy; Prenatal Exposure Delayed Effects; Propylthiouracil; Rats; Rats, Sprague-Dawley; RNA, Messenger; Thyroid Hormones

Thyroid hormones (TH) play crucial roles in brain maturation and are important for neuronal migration and neocortical lamination. Subcortical band heterotopia (SBH) represent a class of neuronal migration errors in humans that are often associated with childhood epilepsy. We have previously reported the presence of SBH in a rodent model of low level hypothyroidism induced by maternal exposure to the goitrogen, propylthiouracil (PTU). In the present study, we report the dose-response characteristics of this developmental malformation and the connectivity of heterotopic neurones with other brain regions, as well as their functionality. Pregnant rats were exposed to varying concentrations of PTU through the drinking water (0-10 p.p.m.) beginning on gestational day 6 to produce graded levels of TH insufficiency. Dose-dependent increases in the volume of the SBH present in the corpus callosum were documented in the adult offspring, with a clear presence at concentrations of PTU that resulted in minor (< 15%) reductions in maternal serum thyroxine as measured when pups were weaned. SBH contain neurones, oligodendrocytes, astrocytes and microglia. Monoaminergic and cholinergic processes were prevalent and many of the axons were myelinated. Anatomical connectivity of SBH neurones to cortical neurones and the synaptic functionality of these anatomical connections was verified by ex vivo field potential recordings. SBH persisted in adult offspring despite a return to euthyroid status on termination of exposure and these offspring displayed an increased sensitivity to seizures. Features of this model are attractive with respect to the investigation of the molecular mechanisms of cortical development, the effectiveness of therapeutic intervention in hypothyroxinaemia during pregnancy and the impact of the very modest TH imbalance that accompanies exposure to environmental contaminants.

Topics: Animals; Brain; Classical Lissencephalies and Subcortical Band Heterotopias; Dose-Response Relationship, Drug; Female; Hypothyroidism; Maternal Exposure; Membrane Potentials; Neuroanatomical Tract-Tracing Techniques; Neuroglia; Neurons; Pentylenetetrazole; Pregnancy; Prenatal Exposure Delayed Effects; Propylthiouracil; Rats; Seizures; Thyrotropin; Thyroxine; Triiodothyronine

Hypothyroidism leads to somatic, neuropsychological, and psychiatric changes that are similar to depression. The mechanisms underlying the behavioral abnormalities in adult onset hypothyroidism remain ambiguous. Hypothyroidism was induced in adult male Wistar rats by the maintenance of 0.05% propylthiouracil (PTU) in drinking water for 5 weeks (hypothyroid group; HP group); control rats (CON group) received an equivalent amount of water. The open field and sucrose preference tests were employed, and the link between behavioral changes and brain glucose metabolism was evaluated using micro positron emission tomography imaging. The open field test revealed slightly decreased locomotor activity and significantly reduced rearing and defecation in the hypothyroid group. Hypothyroid rats were also characterized by decreased body weight, sucrose preference, and relative sucrose intake compared to control rats. Hypothyroidism induced reduced brain glucose metabolism in the bilateral motor cortex, the caudate putamen, the cortex cingulate, the nucleus accumbens, and the frontal association cortex. A decreased sucrose preference was positively correlated with metabolic glucose changes in the caudate putamen and the nucleus accumbens. The results indicate that the activity pattern in adult onset hypothyroidism is different from the activity pattern when hypothyroidism is induced in the developmental period of the central nervous system. Decreased sucrose preference in hypothyroid rats may be attributed to anhedonia. Furthermore, these findings suggest there may be a common mechanism underlying adult onset hypothyroidism and depression.

Topics: Animals; Antithyroid Agents; Body Weight; Brain; Disease Models, Animal; Drinking Water; Food Preferences; Glucose; Hypothyroidism; Locomotion; Male; Motor Activity; Positron-Emission Tomography; Propylthiouracil; Rats; Rats, Wistar; Sucrose

Myoglobin acts as an oxygen store and a reactive oxygen species acceptor in muscles. We examined myoglobin mRNA in rat cardiac ventricle and skeletal muscles during the first 42 days of life and the impact of transient neonatal hypo- and hyperthyroidism on the myoglobin gene expression pattern. Cardiac ventricle and skeletal muscles of Wistar rats at 7-42 days of life were quickly removed, and myoglobin mRNA was determined by Northern blot analysis. Rats were treated with propylthiouracil (5-10 mg/100 g) and triiodothyronine (0.5-50 µg/100 g) for 5, 15, or 30 days after birth to induce hypo- and hyperthyroidism and euthanized either just after treatment or at 90 days. During postnatal (P) days 7-28, the ventricle myoglobin mRNA remained unchanged, but it gradually increased in skeletal muscle (12-fold). Triiodothyronine treatment, from days P0-P5, increased the skeletal muscle myoglobin mRNA 1.5- to 4.5-fold; a 2.5-fold increase was observed in ventricle muscle, but only when triiodothyronine treatment was extended to day P15. Conversely, hypothyroidism at P5 markedly decreased (60%) ventricular myoglobin mRNA. Moreover, transient hyperthyroidism in the neonatal period increased ventricle myoglobin mRNA (2-fold), and decreased heart rate (5%), fast muscle myoglobin mRNA (30%) and body weight (20%) in adulthood. Transient hypothyroidism in the neonatal period also permanently decreased fast muscle myoglobin mRNA (30%) and body weight (14%). These results indicated that changes in triiodothyronine supply in the neonatal period alter the myoglobin expression program in ventricle and skeletal muscle, leading to specific physiological repercussions and alterations in other parameters in adulthood.

Topics: Animals; Animals, Newborn; Antithyroid Agents; Blood Pressure; Blotting, Northern; Gene Expression; Heart Rate; Heart Ventricles; Hyperthyroidism; Hypothyroidism; Male; Muscle, Skeletal; Myocardium; Myoglobin; Organ Size; Propylthiouracil; Random Allocation; Rats, Wistar; Reactive Oxygen Species; RNA, Messenger; Triiodothyronine

The female C3H-A mice with agouty fur color were used to model hyper- and hypothyroidism in the long lasting experiment. The study was carried out for 44 weeks. Hyperthyroidism was induced by the administration of the L-thyroxine injections on alternate days during the whole period of the investigation. Hypothyroidism was achieved by adding propylthiouracil to the drinking water. The change of thyroid state was characterized by biphasic change in body weight. At the beginning of the experiment the hypothyroid animals were retarding by their weight. Otherwise the hyperthyroid animals were advancing by their weight. But since the 18th-21st week the initial trends changed, i. e. the hypothyroid mice body weight started ahead the hyperthyroid one. In the open field test both hypo- and hyperthyroid animals demonstrated the higher level of the investigating activity in comparison with the euthyroid mice. In the hyperthyroid mice the frequency of side-activity acts (grooming) increased significantly. Thus, the hyperthyroid animals appeared to be more anxious. To the 18th week of the experiment the animals of study groups started to demonstrate the apparent visual difference in their fur color. The hyperthyroid mice fur color became darker than one of the hypothyroid and the euthyroid mice. It is worthy of note that the hyperthyroid mice fur color was getting lighter than one of the euthyroid animals. The results are discussed in the context of hypothalamic-pituitary-thyroid axis functioning. The possible mechanisms of hormonal regulation of the fur color in mice are considered to include the hypothalamic-pituitary-thyroid axis hormones activities.

Topics: Animals; Female; Grooming; Hyperthyroidism; Hypothalamo-Hypophyseal System; Hypothyroidism; Mice; Mice, Inbred C3H; Pigmentation; Propylthiouracil; Thyroxine; Time Factors

The main clinical manifestations of autoimmune thyroid diseases are Graves' disease (GD) and Hashimoto's thyroiditis (HT). Graves' disease is the cause of most cases of hyperthyroidism in childhood. Indications for radical therapy (surgery or 131I treatment) in children are still a matter of discussion, as sustained (sometimes very long) remission of GD is possible, while the radical therapy almost always leads to hypothyroidism. Spontaneous evolution from GD with hyperthyroidism to HT with hypothyroidism may also be observed.. The aim of the study was to analyze the clinical course of 6 cases of hyperthyroid girls with GD in whom a normalization of previously increased autoantibodies against thyrotropin (TSH) receptor (anti-TSHR) was observed together with a significant increase in autoantibodies against thyroid peroxidase (anti-TPO) and thyroglobulin (anti-Tg), with concomitant hypo- or euthyroidism but no recurrence of hyperthyroidism.. Patients' age at diagnosis ranged from 5.0 to 16.5 years. Two (2) patients had Turner syndrome, another one (1), diabetic, was on insulin therapy.. In all the girls, antithyroid drugs were administered and euthyroid state was achieved during the first 2.0-3.5 months of the treatment. Mild side effects were observed in only one case. The therapy was continued up to 1.5-4.0 years. Relapses during the therapy were observed in 2 cases. Up to now, no relapses have been observed for 0.5-7.5 years since the therapy withdrawal in 5 patients (1 patient was lost to follow-up), 2 patients are currently treated with levothyroxine due to hypothyroidism.. It seems that the prolonged pharmacotherapy with antithyroid drugs, followed by observation after remission of hyperthyroidism, may be an appropriate therapeutic option at least in some children with GD as they can be cured without radical therapy and the potential risks of such treatment.

Topics: Adolescent; Antithyroid Agents; Autoantibodies; Child; Child, Preschool; Female; Graves Disease; Hashimoto Disease; Humans; Hypothyroidism; Male; Methimazole; Propylthiouracil; Receptors, Thyrotropin; Remission Induction; Thyrotropin

The cardiovascular effects of mild and overt thyroid disease include a vast array of pathological changes. As well, thyroid replacement therapy has been suggested for preserving cardiac function. However, the influence of thyroid hormones on cardiac remodeling has not been thoroughly investigated at the molecular and cellular levels. The purpose of this paper is to study the effect of hypothyroidism and thyroid replacement therapy on cardiac alterations. Thirty Wistar rats were divided into 2 groups: a control (n = 10) group and a group treated with 6-propyl-2-thiouracil (PTU) (n = 20) to induce hypothyroidism. Ten of the 20 rats in the PTU group were then treated with L-thyroxine to quickly re-establish euthyroidism. The serum levels of inflammatory markers, such as C-reactive protein (CRP), tumor necrosis factor alpha (TNF-α), interleukin 6 (IL6) and pro-fibrotic transforming growth factor beta 1 (TGF-β1), were significantly increased in hypothyroid rats; elevations in cardiac stress markers, brain natriuretic peptide (BNP) and cardiac troponin T (cTnT) were also noted. The expressions of cardiac remodeling genes were induced in hypothyroid rats in parallel with the development of fibrosis, and a decline in cardiac function with chamber dilation was measured by echocardiography. Rapidly reversing the hypothyroidism and restoring the euthyroid state improved cardiac function with a decrease in the levels of cardiac remodeling markers. However, this change further increased the levels of inflammatory and fibrotic markers in the plasma and heart and led to myocardial cellular infiltration. In conclusion, we showed that hypothyroidism is related to cardiac function decline, fibrosis and inflammation; most importantly, the rapid correction of hypothyroidism led to cardiac injuries. Our results might offer new insights for the management of hypothyroidism-induced heart disease.

Topics: Animals; Atrial Remodeling; Cytokines; Fibrosis; Heart; Hypothyroidism; Male; Myocardium; Propylthiouracil; Rats; Rats, Wistar; Thyroxine

The role of thyroid hormones in gonad development remains incompletely understood. We examined the dose-related effects of perinatal hypothyroidism induced by a reversible goitrogen, 6-propyl-2-thiouracil (PTU), on reproductive development in male rat offspring. Timed-pregnant Sprague-Dawley rats were orally administered PTU (0, 0.5, 1.0, or 2.0 mg/kg/day) by gavage from gestational day 15 through postnatal day 20. We observed a significant dose-dependent decrease in body weight in offspring with PTU exposure up to 13 weeks of age, but body weight became comparable among groups by 26 weeks of age. Testicular weight tended to be lower up to 7 weeks but was higher after 13 weeks of age. Epididymis weight was not different among the groups at any age. Plasma concentrations of thyroxine and triiodothyronine in the PTU groups were significantly lower at 3 weeks of age but recovered to normal levels by 26 weeks of age. No dose-related trend in plasma testosterone concentrations was found. Seminiferous tubules were larger at 13 and 26 weeks of age with PTU exposure. The number of Sertoli cells was significantly higher from 3 through 26 weeks of age. The number of Leydig cells was significantly lower up to 7 weeks of age but was comparable among groups from 13 weeks of age onwards. Thus, transient gestational and lactational thyroid hormone suppression induced small testes in early life but led to paradoxical dose-dependent testicular enlargement in adults as indicated partly by larger seminiferous tubules with numerous Sertoli cells in male rat offspring.

Topics: Administration, Oral; Animals; Animals, Newborn; Antithyroid Agents; Body Weight; Dose-Response Relationship, Drug; Female; Gestational Age; Hypothyroidism; Leydig Cells; Male; Maternal-Fetal Exchange; Pregnancy; Propylthiouracil; Rats, Sprague-Dawley; Seminiferous Tubules; Sertoli Cells; Testis

We evaluated the role of p35 in the maturation of hippocampal granule neurons in offspring caused by developmental iodine deficiency. Two developmental rat models were established with either an iodine-deficient diet, or propylthiouracil-adulterated water (5 ppm) to impair thyroid function, in pregnant rats from gestational day 6 until postnatal day 28. The protein levels of p35, cyclin-dependent kinase 5, β-catenin, and N-cadherin were assessed on postnatal day 14, 21, and 28. Dendritic morphogenesis of newborn granule neurons in dentate gyrus was examined. Developmental hypothyroidism induced by iodine deficiency and PTU treatment delayed the maturation of hippocampal granule neurons in the offspring and decreased the percentage of Dcx-positive neurons that expressed β-catenin on postnatal day 21 and 28. In addition, downregulation of p35 was observed in dentate gyrus of hypothyroid groups. Developmental hypothyroidism induced by iodine deficiency and PTU treatment could delay the maturation of newborn granule neurons in dentate gyrus, and this deficit may be attributed to the downregulation of p35.

Topics: Animals; Animals, Newborn; Dentate Gyrus; Doublecortin Protein; Down-Regulation; Female; Hippocampus; Hypothyroidism; Iodine; Maternal Exposure; Neurons; Phosphotransferases; Pregnancy; Prenatal Exposure Delayed Effects; Propylthiouracil; Rats; Rats, Wistar

Thyroid hormone deficiency during perinatal development results in significant alterations in neurological functions. The relationship between such events and brain metabolism is not completely understood. The aim of this study was to investigate the effects of hypothyroidism on leucine, mannose, glucose and lactate metabolism in rat cerebellar slices. Experimental hypothyroidism was induced by exposing mothers and pups to propylthiouracil (PTU) until weaning - postnatal day 21. Metabolic analyses were performed in postnatal day 10 (PND10) and 21 (PND21) animals. A matching group of animals received the same oral treatment also after weaning until adulthood PND60 with T3 supplement during lactation (P1-P21). In PND21 animals, PTU treatment significantly increased the rate of leucine oxidation to CO2, although glucose and lactate oxidations were not affected. PTU treatment also increased the oxidation of leucine to CO2 at PND60 (adult animals). PND10 hypothyroidism animals showed a decrease in conversion of mannose to glycolipids and glycoprotein compared with the control group. However, PTU treatment increased the conversion of mannose to glycolipids and glycoprotein in PND21 animals. The replacement of T3 normalized mannose and leucine metabolism in adult rats. These results indicate that deficits in thyroid hormones during lactation could delay or alter brain development and metabolism.

Topics: Animals; Carbon Dioxide; Cerebellum; Disease Models, Animal; Female; Glucose; Hypothyroidism; Lactation; Lactic Acid; Leucine; Mannose; Oxidation-Reduction; Pregnancy; Propylthiouracil; Rats; Rats, Wistar

The atherogenic effects of hypothyroidism on lipid metabolism could result, in part, from the reduced clearance of remnant lipoproteins. In this study, we investigated the expression of hepatic low-density lipoprotein receptor-related protein 1 (LRP1), a receptor for remnant lipoproteins, in hypothyroidism and the effect of 3,3',5-triiodo-L-thyronine (T3) treatment on hepatic LRP1 expression.. C57BL/6 mice were fed a normal diet (control group) or a low-iodine diet supplemented with 0.15% propylthiouracil (PTU/LI group) for 4 weeks. Mice in the PTU/LI group were injected intraperitoneally with T3 (0, 30, and 150 μg/kg of body weight) for 7 days. HepG2 cells were incubated in fetal bovine serum or charcoal-stripped fetal bovine serum with various concentrations of T3. The expression and function of LRP1 in liver samples and cells were analyzed.. Hypothyroidism was successfully induced in PTU/LI mice. Hepatic LRP1 protein expression was lower in the PTU/LI group than in the control group. T3 treatment upregulated hepatic LRP1 protein expression in PTU/LI mice. LRP1 expression in HepG2 cells was reduced after incubation in the medium containing charcoal-stripped fetal bovine serum, which mimics hypothyroidism in vitro, and was recovered by T3 treatment. The protein expression of LRP1 in HepG2 cells was increased by T3 treatment in a dose-dependent manner up to 2.0 nM T3. However, LRP1 mRNA transcription was not affected by hypothyroidism conditions or T3 treatment, either in liver samples or in HepG2 cells. T3 treatment on HepG2 cells increased cellular uptake of lipid-conjugated apolipoprotein E through LRP1.. Our data demonstrate that hepatic LRP1 expression and function decrease in hypothyroidism and are regulated by the thyroid hormone. These results suggest that in hypothyroidism, decreased expression of hepatic LRP1 may be associated with reduced clearance of circulating remnant lipoproteins.

Topics: Animals; Apolipoproteins E; Atherosclerosis; Disease Models, Animal; Down-Regulation; Dyslipidemias; Hep G2 Cells; Humans; Hypothyroidism; Liver; Low Density Lipoprotein Receptor-Related Protein-1; Male; Mice, Inbred C57BL; Propylthiouracil; Receptors, LDL; RNA, Messenger; Triiodothyronine; Tumor Suppressor Proteins

As a potential means of comparing hypothyroidism in humans, this work intended to establish a defined hypothyroid state in immature miniature swine and evaluate specific molecular, cellular, and extracellular responses of their growth plates. Two male, 11-week-old Sinclair miniature swine were given 6-propyl-2-thiouracil (PTU) in their water and two other like animals (controls) were provided water without PTU. Blood levels of thyroid stimulating hormone (TSH), triiodothyronine (T3), and thyroxin (T4) were monitored weekly. At 25 weeks of age, the hind limb proximal femoral physes were harvested and divided into portions for histology and reverse transcription-quantitative polymerase chain reaction (RT-qPCR) analysis. Compared to controls, swine administered PTU exhibited increased TSH and decreased T3 and T4 serum levels during the study period, features consistent with a hypothyroid state. Compared to controls, hypothyroid swine exhibited structurally altered physes and demonstrated significantly decreased gene expression of aggrecan (p < 0.05) and type X collagen (p ≤ 0.1). This is the first hypothyroid model established in miniature swine and represents a potentially important advance for understanding the condition in humans, in which, like this swine model, there are changes critical to growth plate molecular biology, biochemistry and structure.

Topics: Aggrecans; Animals; Collagen Type X; Femur; Gene Expression; Growth Plate; Hypothyroidism; Male; Propylthiouracil; Swine; Swine, Miniature

Recent advances suggest that the cellular redox state may play a significant role in the progression of fibrosis in systemic sclerosis (SSc). Another, and as yet poorly accounted for, feature of SSc is its overlap with thyroid abnormalities. Previous reports demonstrate that hypothyroidism reduces oxidant stress. The aim of this study was therefore to evaluate the effect of propylthiouracil (PTU), and of the hypothyroidism induced by it, on the development of cutaneous and pulmonary fibrosis in the oxidant stress murine model of SSc.. Chronic oxidant stress SSc was induced in BALB/c mice by daily subcutaneous injections of hypochlorous acid (HOCl) for 6 weeks. Mice (n = 25) were randomized into three arms: HOCl (n = 10), HOCl plus PTU (n = 10) or vehicle alone (n = 5). PTU administration was initiated 30 minutes after HOCl subcutaneous injection and continued daily for 6 weeks. Skin and lung fibrosis were evaluated by histologic methods. Immunohistochemical staining for alpha-smooth muscle actin (α-SMA) in cutaneous and pulmonary tissues was performed to evaluate myofibroblast differentiation. Lung and skin concentrations of vascular endothelial growth factor (VEGF), extracellular signal-related kinase (ERK), rat sarcoma protein (Ras), Ras homolog gene family (Rho), and transforming growth factor (TGF) β were analyzed by Western blot.. Injections of HOCl induced cutaneous and lung fibrosis in BALB/c mice. PTU treatment prevented both dermal and pulmonary fibrosis. Myofibroblast differentiation was also inhibited by PTU in the skin and lung. The increase in cutaneous and pulmonary expression of VEGF, ERK, Ras, and Rho in mice treated with HOCl was significantly prevented in mice co-administered with PTU.. PTU, probably through its direct effect on reactive oxygen species or indirectly through thyroid function inhibition, prevents the development of cutaneous and pulmonary fibrosis by blocking the activation of the Ras-ERK pathway in the oxidant-stress animal model of SSc.

Topics: Actins; Animals; Antithyroid Agents; Blotting, Western; Disease Models, Animal; Extracellular Signal-Regulated MAP Kinases; Female; Fibrosis; Hypochlorous Acid; Hypothyroidism; Immunohistochemistry; Mice; Mice, Inbred BALB C; Muscle, Smooth; Oxidants; Propylthiouracil; Pulmonary Fibrosis; Random Allocation; ras Proteins; Scleroderma, Systemic; Skin; Thyrotropin; Thyroxine; Triiodothyronine; Vascular Endothelial Growth Factor A

Thyroid hormones (THs) are essential for growth and development of the kidney. Also TH influences glomerular filtration and tubular functions. Hypothyroidism negative influences kidney function indirectly by affecting the cardiovascular system and the renal blood flow, and directly by affecting glomerular filtration, tubular functions and the structure of the kidney. The purpose of this study was to evaluate changes in biochemical markers, oxidative stress parameter and histological changes in kidney of hypothyroid rats before and after treatment with folic acid. Hypothyroidism was induced for 6 weeks by the administration of propylthiouracil in drinking water. Urea and creatinine were measured to evaluate the changes in kidney function. Also malondialdehyde, nitrite, nitrate and other oxidative stress parameter were measured in serum and kidney tissue as indicators of oxidative damage. Kidney function and oxidative stress parameters in hypothyroid rats were significantly changed compared to those in control rats. Treatment with folic acid helps in improving the adverse effect of hypothyroidism; the histological study also confirms this finding.

Topics: Analysis of Variance; Animals; Antioxidants; Creatinine; Folic Acid; Hypothyroidism; Kidney; Male; Oxidative Stress; Propylthiouracil; Rats; Triiodothyronine; Urea; Weight Gain

This study aimed to elucidate the effect of 6-n-propylthiouracil (PTU)-induced hypothyroidism on oxidative stress parameters and expression of antioxidant enzymes in cerebral cortex of rat brain during postnatal development. A significant decrease in levels of lipid peroxidation and H(2)O(2) were seen in 7 and 30 days old PTU-treated rats with respect to their controls. Significantly decreased activities of superoxide dismutase (SOD) and catalase (CAT) along with the translated products of SOD1 and SOD2 were observed in 7, 15 and 30 days old PTU-treated rats as compared to their respective controls. However, increase in translated product of CAT was seen in all age groups of PTU-treated rats. Glutathione peroxidase activity was decreased in 7 days and increased in 15 days old PTU-treated rats with respect to their control groups. Histological sections clearly show a decline in neuronal migration with neurons packed together in the hypothyroid group as compared to the control.

Topics: Aging; Animals; Animals, Newborn; Antioxidants; Antithyroid Agents; Blotting, Western; Catalase; Cell Movement; Cerebral Cortex; Glutathione Peroxidase; Hydrogen Peroxide; Hypothyroidism; Lipid Peroxidation; Propylthiouracil; Rats; Superoxide Dismutase; Thiobarbituric Acid Reactive Substances

Hypothyroidism has a variety of adverse effects on cognitive function. The treatment of levothyroxine alone cannot restore cognitive defects of hypothyroid patients. Antioxidant vitamin E supplementation could be useful in disturbances which are associated with oxidative stress and could effectively slow the progression of Alzheimer disease. Thus, the purpose of this study was to evaluate oxidative stress status of the serum and hippocampus in hypothyroidism and to examine the effects of levothyroxine replacement therapy with vitamin E supplementation on cognitive deficit. Sprague-Dawley rats were randomly divided into five groups: control group, PTU group, PTU + Vit E group, PTU + L-T4 group, and PTU + L-T4 + Vit E group. Serum and hippocampus malondialdehyde (MDA) levels were determined using the thiobarbituric-acid reactive substances method. Serum and hippocampus superoxide dismutase (SOD) levels were determined by measuring its ability to inhibit the photoreduction of nitroblue tetrazolium. Learning and memory was assessed by Morris water maze test. In the present study, we found that the rats of PTU + Vit E group spent less time to find the platform on days 2, 3, 4, and 5 than the PTU group. Moreover, the rats of PTU + L-T4 + Vit E group spent less time to find the platform on days 4 and 5 than the PTU + L-T4 group. The time spent in the target quadrants was measured in the probe test and no difference was observed in all groups. Oxidative damage has been observed in the serum and hippocampus of hypothyroidism rat. SOD levels of serum and hippocampus tissue were significantly increased and MDA levels were significantly decreased in the PTU + Vit E and PTU + L-T4 + Vit E groups than the PTU and PTU + L-T4 groups. Therefore, these findings indicate that levothyroxine replacement therapy with vitamin E supplementation may ameliorate cognitive deficit in PTU-induced hypothyroidism through the decrease of oxidative stress status.

Topics: Animals; Cognition Disorders; Dietary Supplements; Disease Models, Animal; Hippocampus; Hormone Replacement Therapy; Hypothyroidism; Male; Malondialdehyde; Maze Learning; Oxidative Stress; Propylthiouracil; Rats; Rats, Sprague-Dawley; Superoxide Dismutase; Thyroxine; Vitamin E

A serum metabonomic profiling method based on ultra-performance liquid chromatography/time-of-flight mass spectrometry (UHPLC/TOF-MS) was applied to investigate the metabolic changes in hypothyroid rats induced by propylthiouracil (PTU). With Significance Analysis of Microarray (SAM) for classification and selection of biomarkers, 13 potential biomarkers in rat serum were screened out. Furthermore, Ingenuity Pathway Analysis (IPA) was introduced to deeply analyze unique pathways of hypothyroidism that were primarily involved in sphingolipid metabolism, fatty acid transportation, phospholipid metabolism and phenylalanine metabolism. Our results demonstrated that the metabonomic approach integrating with IPA was a promising tool for providing a novel methodological clue to systemically dissect the underlying molecular mechanism of hypothyroidism.

Topics: Animals; Body Weight; Chromatography, High Pressure Liquid; Fatty Acids; Hypothyroidism; Male; Mass Spectrometry; Metabolomics; Phenylalanine; Phospholipids; Propylthiouracil; Rats; Rats, Wistar; Sphingolipids

Protein kinase Cα (PKCα) has been implicated in the regulation of a variety of cellular functions, such as proliferation, differentiation, and apoptosis, in response to a diverse range of stimuli. Activated PKCα mediates oxidative stress, apoptosis, and inflammatory reaction. Thyroid hormone (TH) is essential for the proper development of the mammalian central nervous system. TH deficiency during critical periods of brain development results in permanent cognitive and neurological impairments. In the present study, we attempted to explore whether PKCα is involved in impaired brain function in developing hypothyroid rat brain. Severe perinatal hypothyroidism was obtained by administration of 30 mg/day propylthiouracil to dams. Brain PKC activity in hypothyroid pups was increased significantly in cytosol and membrane fractions. The change of membrane PKC activity was more marked than that of cytosol, and hypothyroidism led to a higher ratio of membrane PKC activity to that in cytosol, which means abnormal activation of PKC in developing hypothyroid rat brain. Thyroxine replacement partially corrected these changes. After being treated with bisindolmaleimide XI, a mainly selective inhibitor for PKCα, the hypothyroid pups showed improved place navigation test results, and further Western blot analysis showed that PKCα expression in cytosol fractions was increased in hypothyroid rat brain with or without bisindolmaleimide XI treatment, but, after treatment with bisindolmaleimide XI, PKCα content in membrane fractions decreased almost to normal. Therefore, we conclude that PKCα appears to be involved in the impaired brain development observed in perinatal hypothyroid rat brain.

Topics: Animals; Animals, Newborn; Antithyroid Agents; Body Weight; Brain; Enzyme Inhibitors; Female; Gene Expression Regulation, Developmental; Hypothyroidism; Indoles; Male; Maleimides; Maze Learning; Pregnancy; Prenatal Exposure Delayed Effects; Propylthiouracil; Protein Kinase C-alpha; Rats; Rats, Sprague-Dawley; Thyroxine; Time Factors

Although thyroid dysfunction occurs frequently in humans and some animal species, the mechanisms by which hypo- and hyperthyroidism affect the corpus luteum have not been thoroughly elucidated. This study evaluated the levels of proliferative activity, angiogenesis, apoptosis and expression of cyclooxygenase-2 in the corpus luteum of female rats with thyroid dysfunction. These processes may be important in understanding the reproductive changes caused by thyroid dysfunction. A total of 18 adult female rats were divided into three groups (control, hypothyroid and hyperthyroid) with six animals per group. Three months after treatment to induce thyroid dysfunction, the rats were euthanized in the dioestrus phase. The ovaries were collected and immunohistochemically analysed for expression of the cell proliferation marker CDC-47, vascular endothelial growth factor (VEGF), VEGF receptor Flk-1 and cyclooxygenase-2 (COX-2). Apoptosis was evaluated using the TUNEL assay. Hypothyroidism reduced the intensity and area of COX-2 expression in the corpus luteum (p < 0.05), while hyperthyroidism did not alter COX-2 expression in the dioestrus phase. Hypothyroidism significantly reduced the expression of CDC-47 in endothelial cells and pericytes in the corpus luteum, whereas hyperthyroidism did not induce a detectable change in CDC-47 expression (p > 0.05). Hypothyroidism reduced the level of apoptosis in luteal cells (p < 0.05) and increased VEGF expression in the corpus luteum. In contrast, hyperthyroidism increased the level of apoptosis in the corpus luteum (p < 0.05). In conclusion, thyroid dysfunction differentially affects the levels of proliferative activity, angiogenesis and apoptosis and COX-2 expression in the corpus luteum of female rats.

Topics: Animals; Apoptosis; Cell Proliferation; Corpus Luteum; Cyclooxygenase 2; Female; Hyperthyroidism; Hypothyroidism; Immunohistochemistry; In Situ Nick-End Labeling; Minichromosome Maintenance Complex Component 7; Neovascularization, Physiologic; Propylthiouracil; Rats; Rats, Wistar; Thyroxine; Vascular Endothelial Growth Factor A; Vascular Endothelial Growth Factor Receptor-2

Thyroid hormones are recognized as the key metabolic hormones that play a critical role in the development of central nervous system (CNS) throughout life. The present study was designed to determine the changes in brain monoamine concentrations in 6-n-propyl thiouracil (PTU)-induced hypothyroid rats, in addition to the ameliorating role of folic acid treatment. Fifty male albino rats were equally divided into five groups; first and second groups were the control and folic acid groups, respectively, while the third group was the hypothyroid group in which the rats received PTU in drinking water for 6 weeks. The fourth and fifth groups were co- and post-treated folic acid groups with hypothyroid rats, respectively. Our results revealed that serotonin and norepinephrine concentrations were significantly decreased in the hypothalamus and cortex, while it significantly increased in the hippocampus of hypothyroid rats when compared with control group. Serotonin and norepinephrine concentrations were decreased in hypothalamus and cortex in co- and post-treated folic acid groups with hypothyroid rats, while the concentration of dopamine were significantly increased in the hypothalamus and hippocampus of the hypothyroid rats and co-treated folic acid group with hypothyroid rats. In cortex, the dopamine concentration was significantly increased in hypothyroid rats and post-treated folic acid group with hypothyroid rats, while it significantly decreased in co-treated folic acid group with hypothyroid rats when compared with the control group. Also, our results revealed that, folic acid treatment was better if it is administered as an adjuvant after returning to the euthyroid state by withdrawing PTU from the drinking water.

Topics: Animals; Brain; Brain Chemistry; Cerebral Cortex; Chromatography, High Pressure Liquid; Disease Models, Animal; Drug Therapy, Combination; Folic Acid; Hypothalamus; Hypothyroidism; Male; Norepinephrine; Propylthiouracil; Rats; Serotonin; Thyrotropin; Triiodothyronine; Vitamin B Complex

The present study was undertaken to investigate the effect of vitamin E and curcumin on the expression of antioxidant genes in 6-propyl-2-thiouracil (PTU)-induced hypothyroid rat renal cortex. The levels of lipid peroxidation and protein carbonylation were increased in hypothyroid rat kidney. Co-administration of vitamin E and curcumin to hypothyroid rats resulted in amelioration of lipid peroxidation level, whereas curcumin alone alleviated the protein carbonylation level. The mRNA levels of SOD1 and SOD2 were decreased in hypothyroid rats. Decreased level of SOD1 transcripts was observed in hypothyroid rats supplemented with curcumin alone or co-administrated with vitamin E. Translated products of SOD1 and SOD2 in hypothyroid rats was elevated in response to supplementation of both the antioxidants. Decreased SOD1 and SOD2 activities in hypothyroid rats compared to control were either unaltered or further decreased in response to the antioxidants. Expressions of CAT at transcript and translate level along with its activity were down regulated in hypothyroid rats. Administration of vitamin E to hypothyroid rats resulted in elevated CAT mRNA level. In contrast, expression of CAT protein was elevated in response to both the antioxidants. However, CAT activity was unaltered in response to vitamin E and curcumin. GPx1 and GR mRNA level and the activity of glutathione peroxidase (GPx) were not affected in response to induced hypothyroidism. The activity of GPx was increased in response to vitamin E treatment, whereas decreased GR activity in hypothyroid rats was further declined by the administration of antioxidants. The over all results suggest that vitamin E and curcumin differentially modulate the altered antioxidant defence mechanism of rat kidney cortex under experimental hypothyroidism.

Topics: Analysis of Variance; Animals; Base Sequence; Blood Urea Nitrogen; Blotting, Western; Catalase; Creatine; Curcumin; Densitometry; DNA Primers; Gene Expression Regulation, Enzymologic; Glutathione Peroxidase; Glutathione Peroxidase GPX1; Hypothyroidism; Kidney Cortex; Lipid Peroxidation; Molecular Sequence Data; Propylthiouracil; Protein Carbonylation; Rats; Real-Time Polymerase Chain Reaction; Sequence Analysis, DNA; Superoxide Dismutase; Superoxide Dismutase-1; Vitamin E

Thyroid hormones are recognized as key metabolic hormones that play a critical role in the central nervous system development throughout life. In the present study, we studied the biochemical changes of hypothalamus of hypothyroid rats at post-pubertal stage, and the possible ameliorating effect of folic acid. A total of 50 male albino rats were equally divided into five groups; the first and second groups were the control and folic acid groups, respectively, while the third group was the hypothyroid group in which rats received daily 6-n-propyl-2-thiouracil (PTU) in drinking water for 6 weeks to induce hypothyroidism. The fourth and fifth groups were hypothyroid rats treated with folic acid for 4 weeks during and after receiving PTU, respectively, and were dissected after 6 and 10 weeks, respectively. There was a significant increase in plasma total homocysteine, malondialdehyde (MDA), oxidized glutathione\\reduced glutathione and total nitric oxide and hypothalamic MDA, serotonin and norepinephrine in the hypothyroid rats group as compared to the control group. This reflects hyperhomocysteinaemia and oxidative stress associated with hypothyroid state. On the other hand, hypothalamic total nitric oxide and dopamine in the hypothyroid rats group were significantly decreased when compared to the control group. Treatment of hypothyroid rats with folic acid improves the oxidative stress and hypothalamic monoamines. Our results revealed that, folic acid treatment was better if it is administered as an adjuvant after returning to the euthyroid state.

Topics: Analysis of Variance; Animals; Antioxidants; Biogenic Monoamines; Folic Acid; Hypothalamus; Hypothyroidism; Male; Propylthiouracil; Rats; Thyrotropin; Triiodothyronine

Hypothyroidism is an underactive thyroid gland that cannot  make enough thyroid hormone to keep the body running normally. Here we studied the histopathological, immunohistochemical, and ultrastructural changes in the hypothyroid rat testes at the postpubertal stage, in addition to the ameliorating role of folic acid in enhancing spermatogenesis, boosting sperm concentration and building up the antioxidant status against the oxidants. A total of 50 male albino rats were equally divided into 5 groups; the first and second groups comprised the control and folic acid groups, respectively; while the third group comprised the hypothyroid group in which rats received 6-n-propyl-2-thiouracil in drinking water for 6 weeks to induce hypothyroidism. The fourth and fifth groups comprised hypothyroid rats treated with folic acid for 4 weeks and dissected after 6 and 10 weeks, respectively. Testes in the hypothyroid rats showed marked morphological and histological changes in the seminiferous tubules with a reduction in sperm count. Our results indicate that hypothyroidism adversely affects spermatogenesis, suggesting that thyroid hormone might play an important role not only in controlling normal testicular development but also in maintaining normal testicular function and spermatogenesis. Further, we suggested an ameliorating role of folic acid in the relief of testicular tissue from changes due to hypothyroidism. However, we found that the best results were found in cases where folic acid was used as an adjuvant therapy for returning to the euthyroid state.

Topics: Analysis of Variance; Animals; Antioxidants; Folic Acid; Histocytochemistry; Hypothyroidism; Male; Microscopy, Electron; Propylthiouracil; Rats; Sperm Count; Spermatozoa; Testis; Thyrotropin; Triiodothyronine

The present study was carried out to elucidate the effectiveness of curcumin in ameliorating the expression of superoxide dismutase (SOD) in cerebral cortex and cerebellum of rat brain under 6-propyl-2-thiouracil (PTU)-induced hypothyroidism. Induction of hypothyroidism in adult rats by PTU resulted in augmentation of lipid peroxidation (LPx), an index of oxidative stress in cerebellum but not in cerebral cortex. Curcumin-supplementation to PTU-treated (hypothyroid) rats showed significant reduction in the level of LPx in both the regions of brain. The decreased translated products (SOD1 and SOD2) and the unchanged activity of SOD in cerebral cortex of PTU-treated rats were increased on supplementation of curcumin to the hypothyroid rats. Declined translated products of SOD1 and SOD2 in cerebellum of PTU-treated rats were alleviated on administration of curcumin to hypothyroid rats. On the other hand, the decreased activity of SOD in cerebellum of PTU-treated rats was further declined on administration of curcumin to the hypothyroid rats. Results of the present investigation indicate that curcumin differentially modulates the expression of superoxide dismutase in rat brain cortex and cerebellum under PTU-induced hypothyroidism.

Topics: Analysis of Variance; Animals; Anti-Inflammatory Agents, Non-Steroidal; Antithyroid Agents; Cerebellum; Cerebral Cortex; Curcumin; Disease Models, Animal; Hypothyroidism; Lipid Peroxidation; Male; Oxidative Stress; Propylthiouracil; Rats; Rats, Wistar; Superoxide Dismutase; Superoxide Dismutase-1; Thiobarbituric Acid Reactive Substances

Postnatal development of fast skeletal muscle is characterized by a transition in expression of myosin heavy chain (MHC) isoforms, from primarily neonatal MHC at birth to primarily IIb MHC in adults, in a tightly coordinated manner. These isoforms are encoded by distinct genes, which are separated by ∼17 kb on rat chromosome 10. The neonatal-to-IIb MHC transition is inhibited by a hypothyroid state. We examined RNA products [mRNA, pre-mRNA, and natural antisense transcript (NAT)] of developmental and adult-expressed MHC genes (embryonic, neonatal, I, IIa, IIx, and IIb) at 2, 10, 20, and 40 days after birth in normal and thyroid-deficient rat neonates treated with propylthiouracil. We found that a long noncoding antisense-oriented RNA transcript, termed bII NAT, is transcribed from a site within the IIb-Neo intergenic region and across most of the IIb MHC gene. NATs have previously been shown to mediate transcriptional repression of sense-oriented counterparts. The bII NAT is transcriptionally regulated during postnatal development and in response to hypothyroidism. Evidence for a regulatory mechanism is suggested by an inverse relationship between IIb MHC and bII NAT in normal and hypothyroid-treated muscle. Neonatal MHC transcription is coordinately expressed with bII NAT. A comparative phylogenetic analysis also suggests that bII NAT-mediated regulation has been a conserved trait of placental mammals for most of the eutherian evolutionary history. The evidence in support of the regulatory model implicates long noncoding antisense RNA as a mechanism to coordinate the transition between neonatal and IIb MHC during postnatal development.

Topics: Animals; Female; Gene Expression Regulation, Developmental; Hypothyroidism; Muscle, Skeletal; Myosin Heavy Chains; Nonmuscle Myosin Type IIB; Propylthiouracil; Rats; RNA, Antisense; Transcription, Genetic

Mounting evidence suggests a potential link between cocaine abuse, disruptions in hypothalamic-pituitary-thyroid axis signaling, and neuroplasticity, but molecular mechanisms remain unknown. Neurogranin (Ng) is a gene containing a thyroid hormone-responsive element within its first intron that is involved in synaptic plasticity. Transcriptional activation requires heterodimerization of thyroid hormone receptor (TR) and retinoid X receptor (RXR) bound by their respective ligands, tri-iodothryonine and 9-cis-retinoic acid (9-cis-RA), and subsequent binding of this complex to the thyroid hormone-responsive element of the Ng gene. In this study, the effects of chronic cocaine abuse on Ng expression in euthyroid and hypothyroid mice were assessed. In cocaine-treated mice, decreased Ng expression was observed in the absence of changes in levels of thyroid hormones or other hypothalamic-pituitary-thyroid signaling factors. Therefore, we hypothesized that cocaine decreases Ng expression via alterations in 9-cis-RA availability and TR/RXR signaling. In support of this hypothesis, RXR-γ was significantly decreased in brains of cocaine-treated mice while CYP26A1, the main enzyme responsible for neuronal RA degradation, was significantly increased. Results from this study provide the first evidence for a direct effect of cocaine abuse on TR/RXR signaling, RA metabolism, and transcriptional regulation of Ng, a gene essential for adult neuroplasticity.

Topics: Animals; Antithyroid Agents; Blotting, Western; Cocaine; Cytochrome P-450 Enzyme System; Depression, Chemical; Enzyme-Linked Immunosorbent Assay; Fluorescent Antibody Technique; Hypothyroidism; Iodide Peroxidase; Male; Mice; Mice, Inbred C57BL; Neurogranin; Propylthiouracil; Real-Time Polymerase Chain Reaction; Receptors, Thyroid Hormone; Retinoic Acid 4-Hydroxylase; Retinoid X Receptors; RNA; Signal Transduction; Stereotyped Behavior; Thyroid Hormones; Tretinoin

Thyroid hormones have marked effects on the growth, development, and metabolic function of virtually all organs and tissues. Thyroid status is an important determinant of cardiovascular function. The present work studied the histopathological and ultrastructural changes in the hypothyroid rat left ventricle at post-pubertal stage, in addition to the ameliorating role of folic acid. A total of 50 male albino rats were randomly divided into 5 groups (group I, control; group II, folic acid; group III, propylthiouracil-induced hypothyroid rats; group IV, co-treatment with folic acid; group V, post-treatment). In order to ensure the hypothyroid state, the level of serum triiodothyronine (T(3)) and thyroid stimulating hormone (TSH) through the dose period was regularly determined. The TSH levels were significantly higher while T(3) levels were significantly lower in hypothyroid rats when compared to control group. The high-performance liquid chromatography analysis showed an increase in homocysteine (Hcy) in the hypothyroid rats group when compared to the control group. The histopathological studies of the ventricle in hypothyroid rats revealed hydrophobic changes in myofibrillar structure with striations, myocardial atrophy, nuclear pyknosis, cytoplasmic vacuoles, and cytoplasmic eosinophilia. Transmission electron micrographs in the myocardium of hypothyroid rats revealed a marked reduction in muscle fibre mass, a marked degeneration of muscle fibres, swollen mitochondria, dilated sarcoplasmic reticulum and more prominent perinuclear oedema observed in the cardiac myocytes. In co-treated hypothyroid rats with folic acid, a regular arrangement of muscle fibres, mild swelling of myofibrillar structure with striations and no continuity with adjacent myofibrils were observed while the post-treated hypothyroid rat with folic acid showed normal architecture of myofibrillar structure with striations and continuity with adjacent myofibrils. In conclusion, our results indicated that folic acid had ameliorative effect against cardiac damage induced by 6-n-propyl-2-thiouracil and the best results were found in case of using the folic acid as an adjuvant therapy after returning to the euthyroid state.

Topics: Animals; Folic Acid; Heart Ventricles; Histocytochemistry; Hypothyroidism; Male; Myocardium; Myocytes, Cardiac; Propylthiouracil; Protective Agents; Rats

Evaluating the activity of the complement system under conditions of altered thyroid hormone levels might help elucidate the role of complement in triggering autoimmune processes. Here, we investigated alternative pathway (AP) activity in male Wistar rats (180 ± 10 g) after altering their thyroid hormone levels by treatment with triiodothyronine (T3), propylthiouracil (PTU) or thyroidectomy. T3 and thyroxine (T4) levels were determined by chemiluminescence assays. Hemolytic assays were performed to evaluate the lytic activity of the AP. Factor B activity was evaluated using factor B-deficient serum. An anti-human factor B antibody was used to measure factor B levels in serum by radial immunodiffusion. T3 measurements in thyroidectomized animals or animals treated with PTU demonstrated a significant reduction in hormone levels compared to control. The results showed a reduction in AP lytic activity in rats treated with increasing amounts of T3 (1, 10, or 50 µg). Factor B activity was also decreased in the sera of hyperthyroid rats treated with 1 to 50 µg T3. Additionally, treating rats with 25 µg T3 significantly increased factor B levels in their sera (P < 0.01). In contrast, increased factor B concentration and activity (32%) were observed in hypothyroid rats. We conclude that alterations in thyroid hormone levels affect the activity of the AP and factor B, which may in turn affect the roles of AP and factor B in antibody production.

Topics: Animals; Antithyroid Agents; Complement Factor B; Complement Pathway, Alternative; Hyperthyroidism; Hypothyroidism; Luminescent Measurements; Male; Propylthiouracil; Rats; Rats, Wistar; Thyroidectomy; Thyroxine; Triiodothyronine

A deficiency of maternal thyroid hormones (THs) during pregnancy may have severe impacts on fetal brain development. However, the cellular targets of THs and their underlying mechanisms are still unclear. In this study, we found that maternal hypothyroidism during pregnancy in mice inhibited neurogenesis in the embryonic telencephalon and caused learning and memory impairment in the offspring. To explore the underlying mechanisms, we treated cultured mouse embryonic neural stem cells (eNSCs) with a physiological level of 3, 5, 3'-triiodo-L-thyronine (T3). We found that T3 promoted the neuronal differentiation of eNSCs, while inhibiting astrocytic differentiation. In addition, the proliferation and maintenance of eNSCs were inhibited by T3. Furthermore, the TH receptor alpha 1 (TRα1) was detected in the eNSCs both in vivo and in vitro. Silencing TRα1 protein expression with specific siRNA eliminated the effects of T3 on eNSCs. We also found that T3 decreased STAT3 phosphorylation and STAT3-DNA binding activity through TRα1. The over expression of STAT3 attenuated the promotive effects of T3 on neuronal differentiation of eNSCs. Taken together, these results suggest that T3 promotes the neuronal differentiation of eNSCs by inhibiting STAT3 signaling activity through TRα1 and contributes to early neurogenesis in the embryonic telencephalon. Our studies reveal the physiological effects of TH in regulating eNSCs differentiation and suggest that eNSCs are one of the major cellular targets in the central nervous system by which TH influences early brain development. These findings also provide new insights into the mechanisms of neurological deficits caused by TH deficiency during embryogenesis.

Topics: Animals; Astrocytes; Cell Proliferation; Embryonic Stem Cells; Female; Hypothyroidism; Maze Learning; Memory; Mice; Mice, Inbred BALB C; Neural Stem Cells; Neurogenesis; Phosphorylation; Pregnancy; Propylthiouracil; RNA, Small Interfering; Signal Transduction; STAT3 Transcription Factor; Telencephalon; Thyroid Hormone Receptors alpha; Triiodothyronine

To elucidate target molecules of white matter development responding to hypothyroidism, global gene expression profiling of cerebral white matter from male rat offspring was performed after maternal exposure to anti-thyroid agents, 6-propyl-2-thiouracil and methimazole, on postnatal day 20. Genes involved in central nervous system development commonly up- or down-regulated among groups treated with anti-thyroid agents. Immunohistochemical distributions of vimentin, Ret proto-oncogene (Ret), deleted in colorectal cancer protein (DCC), and Claudin11 (Cld11) were examined based on the gene expression profile. Immunoreactive cells for vimentin and Ret in the cingulum, and the immunoreactive intensity of Cld11 and DCC in whole white matter were increased by treatment with anti-thyroid agents. Immunoreactive cells for vimentin and Ret were immature astrocytes and oligodendrocytes, respectively. Thus, immunoreactive cells for vimentin and Ret may be quantitatively measurable targets of developmental hypothyroidism in white matter.

Topics: Animals; Antithyroid Agents; Brain; Cell Movement; Female; Gene Expression Profiling; Hypothyroidism; Male; Maternal-Fetal Exchange; Methimazole; Neurons; Pregnancy; Propylthiouracil; Proto-Oncogene Proteins c-ret; Rats; Real-Time Polymerase Chain Reaction; Tissue Array Analysis; Vimentin

The protective effect of hypothyroidism against ischemic or toxic conditions has been shown in various tissues. We investigated the effect of propylthiouracil (PTU)/methimazole (MMI)-induced hypothyroidism and acute local effect of MMI on the outcome of lethal ischemia in random-pattern skin flaps.. Dorsal flaps with caudal pedicles were elevated at midline and flap survival was measured at the seventh day after surgery. The first group, as control, received 1 mL of 0.9% saline solution in the flap before flap elevation. In groups 2 and 3, hypothyroidism was induced by administration of either PTU 0.05% or MMI 0.04% in drinking water. The next four groups received local injections of MMI (10, 20, 50, or 100 μg/flap) before flap elevation. Local PTU injection was ignored due to insolubility of the agent.. Hypothyroidism was induced in chronic PTU- and MMI-treated groups, and animals in these groups showed significant increase in their flap survival, compared to control euthyroid rats (79.47% ± 10.49% and 75.48% ± 12.93% versus 52.26% ± 5.75%, respectively, P < 0.01). Acute local treatment of skin flaps with MMI failed to significantly affect the flap survival.. This study demonstrates for the first time that hypothyroidism improves survival of random-pattern skin flaps in rats.

Topics: Animals; Antithyroid Agents; Dermatologic Surgical Procedures; Disease Models, Animal; Hypothyroidism; Ischemia; Male; Methimazole; Plastic Surgery Procedures; Propylthiouracil; Rats; Rats, Sprague-Dawley; Skin; Surgical Flaps; Thyroid Gland

Testis tissue xenografting is a powerful approach for the study of testis development and spermatogenesis, and for fertility preservation in immature individuals. In bovine testis xenografts, maturation and spermatogenesis are inefficient when compared to other species. To evaluate if exogenous modulation of the endocrine milieu in recipient mice will affect spermatogenic efficiency in xenografts from newborn calves, recipient mice were treated with the GnRH antagonist acyline (5 mg/kg s.c. every 2 weeks) to reduce testosterone production in xenografts, or with 6-N-propyl-2-thiouracil (PTU, 0.1% in drinking water for 4 weeks), to induce transient hypothyroidism in recipient mice respectively. Both treatments altered developmental parameters of testis xenografts and reduced germ cell differentiation. While the effects of acyline treatment can be attributed to inhibition of GnRH and gonadotropin action, lower Sertoli cell numbers and decreased seminiferous tubule length observed after PTU treatment were opposite to effects reported previously in rats. Regardless of treatment, Sertoli cells underwent only partial maturation in xenografts as Müllerian inhibiting substance and androgen receptor expression were lower than in donor and adult tissue controls respectively. In conclusion, although treatments did not result in improvement of maturation of bovine testis xenografts, the current study demonstrates that exogenous modulation of the endocrine milieu to affect xenograft development in recipient mice provides an accessible model to study endocrine control of spermatogenesis in large donor species.

Topics: Animals; Animals, Newborn; Antithyroid Agents; Cattle; Gonadotropin-Releasing Hormone; Hypothyroidism; Male; Mice; Oligopeptides; Propylthiouracil; Sertoli Cells; Spermatogenesis; Testis; Testosterone; Thyroid Hormones; Transplantation, Heterologous

Adequate thyroid hormone is critical for cerebellar development. Developmental hypothyroidism induced by iodine deficiency during the perinatal period results in permanent impairments of cerebellar development with an unclear mechanism. In the present study we investigated effects of perinatal iodine deficiency and hypothyroidism on cerebellar cell apoptosis, doublecortin (Dcx) and reelin. Apoptosis is an essential part of neural development. Dcx and reelin are two important molecules involved in neuronal migration, structure, and development in cerebellum.. Two developmental rat models were created by administering dam rats with either iodine-deficient diet or propylthiouracil (PTU, 5 ppm or 15 ppm)-added drinking water from gestational day (GD) 6 until postnatal day (PND) 28. TUNEL assay and protein levels of Dcx and reelin in cerebella were assessed on PND14, 21 and 28.. Apoptotic cells were increased in the iodine-deficient and PTU-treated rats. Dcx protein levels in the cerebella of iodine-deficient and PTU-treated rats were significantly downregulated on PND14. Interestingly, iodine deficiency and PTU treatment upregulated the levels of Dcx protein on PND21 and 28. Reelin expressions in iodine-deficient and PTU-treated rats were significantly decreased on PND14 and 21. On PND28, reelin expressions of three treated groups were still lower than control group, although without significant difference.. These findings may implicate alterations in cell apoptosis and levels of Dcx and reelin in the impairments of cerebellar development induced by developmental iodine deficiency and hypothyroidism.

Topics: Animals; Animals, Newborn; Apoptosis; Cell Adhesion Molecules, Neuronal; Cerebellum; Doublecortin Domain Proteins; Doublecortin Protein; Extracellular Matrix Proteins; Female; Gene Expression Regulation, Developmental; Hypothyroidism; Iodine; Male; Microtubule-Associated Proteins; Nerve Tissue Proteins; Neuropeptides; Pregnancy; Pregnancy Complications; Propylthiouracil; Rats; Rats, Wistar; Reelin Protein; Serine Endopeptidases; Thyroid Hormones

Thyroid hormones are important regulators of lipid metabolism. Polymorphonuclear leukocytes (PMN) are essential components of innate immune response. Our goal was to determine whether hypothyroidism affects lipid metabolism in PMN cells. Wistar rats were made hypothyroid by administrating 0.1 g/L 6-propyl-2-thiouracil (PTU) in drinking water during 30 days. Triacylglycerides (TG), cholesterol and phospholipids were determined in PMN and serum by conventional methods. The mRNA expression of LDL receptor (LDL-R), 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCoAR), sterol regulatory element binding protein 2 (SREBP-2), and diacylglycerol acyltransferase 2 (DGAT-2) were quantified by Real-Time PCR. Cellular neutral lipids were identified by Nile red staining. We found hypothyroidism decreases serum TG whereas it increases them in PMN. This result agrees with those observed in Nile red preparations, however DAGT-2 expression was not modified. Cholesterol synthesizing enzyme HMGCoAR mRNA and protein was reduced in PMN of hypothyroid rats. As expected, cholesterol content decreased in the cells although it increased in serum. Hypothyroidism also reduced relative contents of palmitic, stearic, and arachidonic acids, whereas increased the myristic, linoleic acids, and the unsaturation index in PMN. Thus, hypothyroidism modifies PMN lipid composition. These findings would emphasize the importance of new research to elucidate lipid-induced alterations in specific function(s) of PMN.

Topics: Animals; Base Sequence; Chromatography, Gas; DNA Primers; Fatty Acids; Female; Hydroxymethylglutaryl CoA Reductases; Hypothyroidism; Lipids; Neutrophils; Propylthiouracil; Rats; Rats, Wistar; Reverse Transcriptase Polymerase Chain Reaction; Thyroid Hormones; Thyrotropin

Study of physiological angiogenesis and associated signalling mechanisms in adult heart has been limited by the lack of a robust animal model. We investigated thyroid hormone-induced sprouting angiogenesis and the underlying mechanism. Hypothyroidism was induced in C57BL/6J mice by feeding with propylthiouracil (PTU). One year of PTU treatment induced heart failure. Both 12 weeks- (young) and 1 year-PTU (middle age) treatment caused a remarkable capillary rarefaction observed in capillary density. Three-day Triiodothyronine (T3) treatment significantly induced cardiac capillary growth in hypothyroid mice. In cultured left ventricle (LV) tissues from PTU-treated mice, T3 also induced robust sprouting angiogenesis where pericyte-wrapped endothelial cells formed tubes. The in vitro T3 angiogenic response was similar in mice pre-treated with PTU for periods ranging from 1.5 to 12 months. Besides bFGF and VEGF(164) , PDGF-BB was the most robust angiogenic growth factor, which stimulated notable sprouting angiogenesis in cultured hypothyroid LV tissues with increasing potency, but had little effect on tissues from euthyroid mice. T3 treatment significantly increased PDGF receptor beta (PDGFR-β) protein levels in hypothyroid heart. PDGFR inhibitors blocked the action of T3 both on sprouting angiogenesis in cultured LV tissue and on capillary growth in vivo. In addition, activation of Akt signalling mediated in T3-induced angiogenesis was blocked by PDGFR inhibitor and neutralizing antibody. Our results suggest that hypothyroidism leads to cardiac microvascular impairment and rarefaction with increased sensitivity to angiogenic growth factors. T3-induced cardiac sprouting angiogenesis in adult hypothyroid mice was associated with PDGF-BB, PDGFR-β and downstream activation of Akt.

Topics: Age Factors; Angiogenesis Inducing Agents; Animals; Becaplermin; Coronary Vessels; Disease Models, Animal; Female; Heart; Heart Ventricles; Hypothyroidism; Mice; Mice, Inbred C57BL; Myocardium; Neovascularization, Physiologic; Platelet-Derived Growth Factor; Propylthiouracil; Proto-Oncogene Proteins c-akt; Proto-Oncogene Proteins c-sis; Receptor, Platelet-Derived Growth Factor beta; Signal Transduction; Tissue Culture Techniques; Triiodothyronine

In the present study, regulatory role of vitamin E and curcumin on antioxidant gene (AOG) expression in hypothyroid rat liver is reported. Adult male rats were rendered hypothyroid by administration of 0.05 % 6-propyl-thiouracil in their drinking water, while vitamin E (200 mg/kg body weight) and curcumin (30 mg/kg body weight) were supplemented orally for 30 days. Expression of antioxidant genes (Cu/Zn-superoxide dismutase; SOD1, Mn superoxide dismutase; SOD2, catalase; CAT, glutathione peroxidase; GPx1 and glutathione reductase; GR) was evaluated using RT-PCR and Western blot analyses. The activities of antioxidant enzymes were measured in mitochondrial fraction (MF) and post-mitochondrial fraction (PMF) of rat liver. In addition measurement of glutathione redox status was also carried out in both the fractions. The enhanced transcripts of CAT, GPx1 and GR in hypothyroid rat liver were alleviated by administration of vitamin E and curcumin. Elevated levels of translated product of all AOGs in hypothyroid group were remained unchanged after antioxidant administration. However, enhanced SOD1, GPx1 and decreased GR activities in PMF were normalized by vitamin E and curcumin. Similarly the increased SOD2, GPx1 and decreased CAT activities in MF were also normalized by vitamin E and curcumin supplementation. Administration of vitamin E and curcumin enhanced mitochondrial GSH level; whereas the enhanced GSH level in PMF of hypothyroid rats was alleviated by vitamin E. Thus it can be concluded that besides the antioxidant role of vitamin E and curcumin, they also regulate hepatic antioxidant gene expression in hypothyroid rats.

Topics: Animals; Antioxidants; Antithyroid Agents; Curcumin; Gene Expression; Glutathione; Glutathione Peroxidase; Glutathione Peroxidase GPX1; Hypothyroidism; Liver; Male; Mitochondria; Oxidative Stress; Propylthiouracil; Rats; Superoxide Dismutase; Vitamin E

Adult hypothyroidism is a highly prevalent condition that impairs processes, such as learning and memory. Even though tetra-iodothyronine (T(4)) treatment can overcome the hypothyroidism in the majority of cases, it cannot fully recover the patient's learning capacity and memory. In this work, we analyzed the cellular and molecular changes in the adult brain occurring with the development of experimental hypothyroidism.. Adult male Sprague-Dawley rats were treated with 6-propyl-2-thiouracil (PTU) for 20 days to induce hypothyroidism. Neuronal and astrocyte apoptosis were analyzed in the hippocampus of control and hypothyroid adult rats by confocal microscopy. The content of brain-derived neurotrophic factor (BDNF) was analyzed using enzyme-linked immunosorbent assay (ELISA) and in situ hybridization. The glutamatergic synapse and the postsynaptic density (PSD) were analyzed by electron microscopy. The content of PSD proteins like tyrosine receptor kinase B (TrkB), p75, and N-methyl-D-aspartate receptor (NMDAr) were analyzed by immunoblot.. We observed that the hippocampus of hypothyroid adult rats displayed increased apoptosis levels in neurons and astrocyte and reactive gliosis compared with controls. Moreover, we found that the amount of BDNF mRNA was higher in the hippocampus of hypothyroid rats and the content of TrkB, the receptor for BDNF, was reduced at the PSD of the CA3 region of hypothyroid rats, compared with controls. We also observed that the glutamatergic synapses from the stratum radiatum of CA3 from hypothyroid rats, contained thinner PSDs than control rats. This observation was in agreement with a reduced content of NMDAr subunits at the PSD in hypothyroid animals.. Our data suggest that adult hypothyroidism affects the hippocampus by a mechanism that alters the composition of PSD, reduces neuronal and astrocyte survival, and alters the content of the signaling neurotrophic factors, such as BDNF.

Topics: Animals; Antithyroid Agents; Apoptosis; Astrocytes; Brain-Derived Neurotrophic Factor; Gliosis; Hippocampus; Hypothyroidism; Male; Neurons; Post-Synaptic Density; Propylthiouracil; Rats; Rats, Sprague-Dawley; Receptor, trkB; Receptors, N-Methyl-D-Aspartate

The objective of this study was to evaluate fetal weight, histomorphometric changes and proliferative activity, apoptosis and angiogenesis of the placenta in rats with hypothyroidism. Thirty-six adult female rats were divided into two groups with 18 animals each: control and hypothyroidism. Hypothyroidism was induced by daily administration of propylthiouracil (1 mg/animal). The administration began five days before becoming pregnant and the animals were sacrificed at 14 or 19 days of gestation. The control group received a placebo. The number and weight of fetuses and the rate of fetal death was determined, as well as the morphometric characteristics, the immunohistochemical expression of cell division control protein 47 (CDC)-47 and vascular endothelial growth factor (VEGF) and the number of apoptotic cells in the placental disk. The data were analysed by Mann-Whitney U test. Hypothyroidism reduced the weight of fetuses and of the uterus and placenta (P<0.05), altered the thickness of the placental labyrinth and spongiotrophoblast (P<0.05), increased the population of glycogen cells in the spongiotrophoblast (P<0.05), interfered with the vascular development of the placental labyrinth and decreased VEGF expression (P<0.05), reduced the expression of CDC-47 and cellularity and increased the apoptotic rate in the placental disk (P<0.05). We conclude that hypothyroidism affects fetal weight by altering the proliferative activity, apoptosis and vascularisation of the placenta.

Topics: Adenosine Triphosphatases; Animals; Apoptosis; Biomarkers; Cell Proliferation; Disease Models, Animal; DNA-Binding Proteins; Down-Regulation; Female; Fetal Death; Fetal Growth Retardation; Fetal Weight; Gestational Age; Glycogen; Hypothyroidism; Immunohistochemistry; Minichromosome Maintenance Complex Component 7; Neovascularization, Physiologic; Placenta; Pregnancy; Propylthiouracil; Rats; Trophoblasts; Vascular Endothelial Growth Factor A

The plasticity and vulnerability of the rat spinal cord (SC) during postnatal development has been less investigated compared to other CNS structures. In this study, we determined the effects of thyroid hormonal (TH) deficiency and excess on postnatal growth and neurochemical development of the rat SC. The growth as well as the specific and total activity of acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) enzymes of the SC were determined in hypo- and hyperthyroid rat pups at postnatal (P) days P1, P5, P10 and P21 (weaning), and were compared to age-matched untreated normal controls. AChE is a cholinergic synaptic enzyme while BuChE is a metabolic enzyme mainly found in glial cells and neurovascular cells. The SC is rich in somatic motor, autonomic cholinergic neurons and associated interneurons. Daily subcutaneous injection of pups with thyroxine (T4) and administration of antithyroid goitrogen propylthiouracil (PTU) in the litter's drinking water were used to induce hyper- and hypothyroidism, respectively. Enzyme assays were carried out spectrophotometrically at the above-mentioned ages, using SC homogenates with acetylthiocholine-chloride as the substrate, together with specific cholinesterase inhibitors, which specifically target AChE and BuChE. SC weights were significantly lower at P10 and P21 in hypothyroid pups but unchanged in the hyperthyroid ones. Hypothyroidism significantly reduced both specific and total AChE activity in SC of P10 and P21 rat pups, while having no effects on the BuChE activity, although total BuChE activity was decreased due to reduced total tissue weight. In contrast both specific and total AChE activities were markedly and significantly increased (>100%) in the P10 and P21 hyperthyroid pups. However, BuChE specific activity was unaffected by this treatment. The results indicate that hypothyroid condition significantly reduces, while hyperthyroidism increases, the postnatal development of cholinergic synapses, thereby influencing the functional development of this major sensory and motor structure. However, the neurochemical development of glia and other non-neuronal cells, where BuChE is mainly localized, is comparatively unaffected in these abnormal developmental conditions.

Topics: Acetylcholinesterase; Animals; Animals, Newborn; Antithyroid Agents; Body Weight; Butyrylcholinesterase; Female; Hyperthyroidism; Hypothyroidism; Pregnancy; Propylthiouracil; Rats; Rats, Sprague-Dawley; Spinal Cord; Thyroxine

Exposure to 6-propyl-2-thio-uracil (PTU), a neonatal goitrogen, leads to increased testis size and sperm production in rodents. Akt1, a gene involved in cell survival and proliferation is also phosphorylated by thyroxine (T(4)). Therefore, we examined the requirement for Akt1 in germ cell survival following PTU-induced hypothyroidism. Experiments were performed using Akt1+/+, Akt1+/-, and Akt1-/- mice. PTU was administered (0.01% w/v) via the drinking water of dams from birth to PND21. At PND15, T(4) serum levels were similar in all control groups, and significantly lower in all exposed groups with a dramatic decrease in Akt1-/- mice. PTU-exposed Akt1-/- testes displayed smaller tubules, increased apoptosis, delayed lumen formation, and increased inhibin B and AMH mRNA. Relative adult testis weights were similar in all exposure groups; however, no increase in daily sperm production was observed in PTU-exposed Akt1-/- mice. In conclusion, Akt1 contributes to the effects of thyroid hormone on postnatal testis development.

Topics: Animals; Animals, Newborn; Anti-Mullerian Hormone; Antithyroid Agents; Apoptosis; Female; Gene Expression Regulation, Developmental; Hypothyroidism; Inhibins; Lactation; Litter Size; Male; Maternal Exposure; Mice; Mice, Knockout; Organ Size; Pregnancy; Propylthiouracil; Proto-Oncogene Proteins c-akt; RNA, Messenger; Sertoli Cells; Spermatozoa; Testis; Triiodothyronine

The toxicity of perfluorooctane sulfonate (PFOS), a persistent organic compound, is of great concern. Several studies have reported that PFOS decreases circulating thyroid hormone (TH) concentrations. However, the mechanisms involved remain to be determined. Female rats were exposed to (1) vehicle; (2) PFOS (0.2, 1.0, and 3.0 mg/kg); (3) propylthiouracil (PTU, 10 mg/kg); or (4) PTU (10 mg/kg) + PFOS (3.0 mg/kg) by gavage once a day for 5 consecutive days. Parameters including contents of total T4 (TT4) and total T3 (TT3) in both serum and bile, serum concentrations of transthyretin and thyroglobulin, as well as transcripts of transporters involved in hepatic uptake and efflux of T4 were determined in control and PFOS-exposed groups. TT4 and TT3 were also analyzed in PTU and PTU + PFOS groups in order to reflect the different hormone effects between PFOS, PTU, and PFOS + PTU. Results showed that serum TT4 and TT3 decreased, while bile TT4 and TT3 remained stable following PFOS exposure. Exposure to 3.0 mg/kg of PFOS significantly enhanced hepatic organic anion transporter OATP2 mRNA expression (1.43 times of control). Treatment with PFOS increased hepatic expression of multidrug resistance--associated protein MRP2, approximately 1.80 and 1.69 times of control in 1.0 and 3.0 mg/kg groups, respectively. Spearman's correlation coefficients revealed that MRP2 mRNA expression correlated well with serum TT4 level (r = -0.528, P = 0.012). Serum thyroglobulin and transthyretin levels remained stable. Serum TT3, bile TT4, and bile TT3 were significantly different between PFOS and PTU groups. No significant differences of TT4 and TT3 in both serum and bile were observed between PTU and PTU + PFOS (P > 0.05). In conclusion, PFOS increased hepatic expression of OAPT2, which could possibly enhance hepatic uptake and metabolism of T4 in rats. PFOS-induced TT4 deficiency is mainly due to the extrathyroidal metabolism of T4, which is probably different from the classic goitrogen, PTU.

Topics: Alkanesulfonic Acids; Animals; Antithyroid Agents; ATP-Binding Cassette Transporters; Bile; Dose-Response Relationship, Drug; Environmental Pollutants; Female; Fluorocarbons; Hypothyroidism; Liver; Organic Anion Transporters; Propylthiouracil; Random Allocation; Rats; Rats, Wistar; RNA, Messenger; Thyroxine; Triiodothyronine; Up-Regulation

Treatment of Graves' disease during pregnancy with antithyroid drugs (ATDs) poses a risk of inducing hypothyroidism and, thus, development of a goiter to the fetus.. We report two patients referred to our department after discovery of a fetal goiter by ultrasound examination in the second trimester of pregnancy. The women receiving 400 mg/day propylthiouracil and 10 mg/day thiamizole, respectively, had thyrotropin and total thyroxine values within the normal reference range but a lowered free thyroxine level. Fetal blood sampling by cordocentesis revealed severe fetal hypothyroidism as the cause of goiter development. Reduction of maternal ATD dose and injection of levothyroxine intra-amniotically quickly reduced the goiter size, and both babies were born euthyroid and without goiters.. Two pregnant women with Graves' disease were overtreated with ATDs inducing iatrogenic goiter in the fetuses. Successful treatment with intra-amniotic levothyroxine injections rendered the babies euthyroid and nongoitrous at birth.. Correct interpretation of thyroid function tests during pregnancy in general--and during ATD therapy of Graves' disease in particular--is difficult. Awareness of pregnancy-related changes in maternal thyroid status, and a close teamwork among endocrinologists, obstetricians, and experts in fetal medicine, is pivotal in ensuring normal growth and development of the unborn child of these patients.

Topics: Adult; Antithyroid Agents; Female; Fetal Diseases; Goiter; Graves Disease; Humans; Hypothyroidism; Infant, Newborn; Male; Methimazole; Pregnancy; Pregnancy Complications; Pregnancy Trimester, Second; Propylthiouracil; Thyrotropin; Thyroxine

Thyroid hormone (TH) is essential for the proper development of mammalian central nervous system. TH deficiency during critical period of brain development results in permanent cognitive and neurological impairments. Hippocampus is a structure involved in various memory processes that are essential for creating new memories, and lesions to hippocampus result in impaired learning and memory. Protein kinase C (PKC) isoforms play an important role in many types of learning and memory, and deletion of specific PKC genes results in deficits in learning. In the present study, we used real-time PCR and Western blot to investigate the conventional PKC expression in developing rat hippocampus with different thyroid status, trying to establish a correlation between TH deficiency and conventional PKC expression in developing rat hippocampus. We found that PKCβI and PKCγ expression decreased significantly both in mRNA and protein levels in hypothyroid group compared with the normal controls, and thyroxine replacement could restore it. As for PKCα, we did not find any difference between different thyroid status. Though the expression of PKCβII also decreased in the TH deficiency group, the change was not significant. Taken together, our data indicate TH deficiency can cause hippocampal PKCβ1 and PKCγ downregulation during rat brain development. Since there are other PKC isoforms in the rat brain, whether these change is related to impaired learning and memory of perinatal hypothyroid rats requires further researches.

Topics: Animals; Blotting, Western; Female; Gene Expression; Hippocampus; Hormone Replacement Therapy; Hypothyroidism; Male; Pregnancy; Pregnancy Complications; Propylthiouracil; Protein Kinase C; Protein Kinase C beta; Protein Kinase C-alpha; Rats; Rats, Sprague-Dawley; Reverse Transcriptase Polymerase Chain Reaction; Thyroxine

To date, there has been only one in vitro study of the relationship between neuropeptide EI (NEI) and the hypothalamic-pituitary-thyroid (HPT) axis. To investigate the possible relationship between NEI and the HPT axis, we developed a rat model of hypothyroidism and hyperthyroidism that allows us to determine whether NEI content is altered in selected brain areas after treatment, as well as whether such alterations are related to the time of day. Hypothyroidism and hyperthyroidism, induced in male rats, with 6-propyl-1-thiouracil and l-thyroxine, respectively, were confirmed by determination of triiodothyronine, total thyroxine, and thyrotropin levels. All groups were studied at the morning and the afternoon. In rats with hypothyroidism, NEI concentration, evaluated on postinduction days 7 and 24, was unchanged or slightly elevated on day 7 but was decreased on day 24. In rats with hyperthyroidism, NEI content, which was evaluated after 4 days of l-thyroxine administration, was slightly elevated, principally in the preoptic area in the morning and in the median eminence-arcuate nucleus and pineal gland in the afternoon, the morning and afternoon NEI contents being similar in the controls. These results provide the bases to pursue the study of the interaction between NEI and the HPT axis.

Topics: Animals; Brain; Hyperthyroidism; Hypothyroidism; Male; Median Eminence; Oligopeptides; Pituitary Gland; Propylthiouracil; Rats; Rats, Sprague-Dawley; RNA, Messenger; Thyroid Gland; Thyrotropin; Thyroxine; Triiodothyronine

Adequate thyroid hormone is critical for cerebellar development. Developmental hypothyroidism induced by iodine deficiency during gestation and postnatal period results in permanent impairments of cerebellar development with an unclear mechanism. In the present study, we implicate cerebellar caveolin-1 and synaptotagmin-1, the two important molecules involved in neuronal development, in developmental iodine deficiency, and in developmental hypothyroidism. Two developmental rat models were created by administrating dam rats with either iodine-deficient diet or propylthiouracil (PTU, 5 or 15 ppm)-added drinking water from gestational day 6 till postnatal day (PN) 28. Nissl staining and the levels of caveolin-1 and synaptotagmin-1 in cerebella were assessed on PN28 and PN42. The results show that the numbers of Purkinje cells were reduced in the iodine-deficient and PTU-treated rats. The upregulation of caveolin-1 and the downregulation of synaptotagmin-1 were observed in both iodine-deficient and PTU-treated rats. These findings may implicate decreases in the number of Purkinje cells and the alterations in the levels of caveolin-1 and synaptotagmin-1 in the impairments of cerebellar development induced by developmental iodine deficiency and hypothyroidism.

Topics: Animals; Antithyroid Agents; Blotting, Western; Caveolin 1; Cerebellum; Hypothyroidism; Iodine; Nerve Tissue Proteins; Propylthiouracil; Rats; Rats, Wistar; Synaptotagmin I

Pitx2 is a homeodomain transcription factor required in a dose-dependent manner for the development of multiple organs. Pitx2-null homozygotes (Pitx2(-/-)) have severe pituitary hypoplasia, whereas mice with reduced-function alleles (Pitx2(neo/neo)) exhibit modest hypoplasia and reduction in the developing gonadotroph and Pou1f1 lineages. PITX2 is expressed broadly in Rathke's pouch and the fetal pituitary gland. It predominates in adult thyrotrophs and gonadotrophs, although it is not necessary for gonadotroph function. To test the role of PITX2 in thyrotroph function, we developed thyrotroph-specific cre transgenic mice, Tg(Tshb-cre) with a recombineered Tshb bacterial artificial chromosome that ablates floxed genes in differentiated pituitary thyrotrophs. We used the best Tg(Tshb-Cre) strain to generate thyrotroph-specific Pitx2-deficient offspring, Pitx2(flox/-;)Tg(Tshb-cre). Double immunohistochemistry confirmed Pitx2 deletion. Pitx2(flox/-);Tg(Tshb-cre) mice have a modest weight decrease. The thyroid glands are smaller, although circulating T(4) and TSH levels are in the normal range. The pituitary levels of Pitx1 transcripts are significantly increased, suggesting a compensatory mechanism. Hypothyroidism induced by low-iodine diet and oral propylthiouracil revealed a blunted TSH response in Pitx2(flox/-);Tg(Tshb-cre) mice. Pitx1 transcripts increased significantly in control mice with induced hypothyroidism, but they remained unchanged in Pitx2(flox/-);Tg(Tshb-cre) mice, possibly because Pitx1 levels were already maximally elevated in untreated mutants. These results suggest that PITX2 and PITX1 have overlapping roles in thyrotroph function and response to hypothyroidism. The novel cre transgene that we report will be useful for studying the function of other genes in thyrotrophs.

Topics: Animals; Chromosomes, Artificial, Bacterial; Female; Homeobox Protein PITX2; Homeodomain Proteins; Hypothyroidism; Immunohistochemistry; Male; Mice; Mice, Transgenic; Paired Box Transcription Factors; Propylthiouracil; Thyrotrophs; Thyrotropin, beta Subunit; Transcription Factors

Mammalian germ cell apoptosis plays a key role in controlling the correct number of germ cells supported by Sertoli cells during the first wave of spermatogenesis in mammalian puberty. However, little is known about hormonal factors that could influence the rate of germ cell apoptosis during puberty or adulthood. In this work we evaluate germ cell apoptosis under hypothyroidism induced by goitrogen propylthiouracil (PTU) during the first wave of spermatogenesis. Neonatally administered PTU promoted a delay in the differentiation of Sertoli cells as evaluated by the expression of clusterin using immunohistochemistry and RT-PCR. Clusterin had different expression levels in control and PTU-treated animals, but under both conditions the highest levels were found in 35-day-old rats. In addition, clusterin displayed a cytoplasmic localization in control testes, but appeared located in the nucleus in PTU-treated animals. The wave of apoptosis (determined by caspase activity and quantification of apoptotic cells) characteristic of the first round of spermatogenesis was delayed by at least 10 days in these animals. The expression levels of proapoptotic genes like BAX or BAD were different between control and PTU-treated rats; although in both groups the highest level was found at the same age (days). Thus our results indicate that the characteristic pubertal apoptotic wave during rat spermatogenesis is delayed in neonatal hypothyroid rats.

Topics: Animals; Animals, Newborn; Antithyroid Agents; Apoptosis; Hypothyroidism; Immunohistochemistry; Male; Organ Size; Propylthiouracil; Rats; Rats, Sprague-Dawley; Reverse Transcriptase Polymerase Chain Reaction; Seminiferous Tubules; Sertoli Cells; Spermatogenesis; Testis; Thyroxine; Time Factors; Triiodothyronine

Thyroid hormone is critical for the proper development of the central nervous system. However, the specific role of thyroid hormone on brain angiogenesis remains poorly understood. Treatment of rats from birth to postnatal day 21 (P21) with propylthiouracil (PTU), a reversible blocker of triiodothyronine (T3) synthesis, resulted in decreased brain angiogenesis, as indicated by reduced complexity and density of microvessels. However, when PTU was withdrawn at P22, these parameters were fully recovered by P90. These changes were paralleled by an altered expression of vascular endothelial growth factor A (Vegfa) and basic fibroblast growth factor (Fgf2). Physiologic concentrations of T3 and thyroxine (T4) stimulated proliferation and tubulogenesis of rat brain-derived endothelial (RBE4) cells in vitro. Protein and mRNA levels of VEGF-A and FGF-2 increased after T3 stimulation of RBE4 cells. The thyroid hormone receptor blocker NH-3 abolished T3-induced Fgf2 and Vegfa upregulation, indicating a receptor-mediated effect. Thyroid hormone inhibited the apoptosis in RBE4 cells and altered mRNA levels of apoptosis-related genes, namely Bcl2 and Bad. The present results show that thyroid hormone has a substantial impact on vasculature development in the brain. Pathologically altered vascularization could, therefore, be a contributing factor to the neurologic deficits induced by thyroid hormone deficiency.

Topics: Animals; Antithyroid Agents; Brain; Fluorescent Antibody Technique; Hypothyroidism; Immunohistochemistry; Microscopy, Electron, Transmission; Microvessels; Neovascularization, Physiologic; Propylthiouracil; Rats; Rats, Wistar; Reverse Transcriptase Polymerase Chain Reaction; Thyroxine; Triiodothyronine

Developmental iodine deficiency leads to inadequate thyroid hormone, which damages the hippocampus. In the present study, we implicate hippocampal caveolin-1 and synaptophysin in developmental iodine deficiency and hypothyroidism. Two developmental rat models were established: pregnant rats were administered either an iodine-deficient diet or propylthiouracil (PTU)-adulterated (5 p.p.m. or 15 p.p.m.) drinking water from gestational day 6 until postnatal day (PN) 28. Nissl staining and the levels of caveolin-1 and synaptophysin in several hippocampal subregions were assessed on PN14, PN21, PN28 and PN42. The results obtained show that surviving cells in the iodine-deficient and PTU-treated rats were lower than in controls. Up-regulation of caveolin-1 and down-regulation of synaptophysin were observed in the iodine-deficient and PTU-treated rats. Our findings implicate decreases in the number of surviving cells and alterations in the levels of caveolin-1 and synaptophysin in the impairments in neural development induced by developmental iodine deficiency and hypothyroidism.

Topics: Animals; Caveolin 1; Cell Count; Cell Survival; Diet; Disease Models, Animal; Female; Hippocampus; Hypothyroidism; Iodine; Male; Neurons; Propylthiouracil; Pyramidal Cells; Random Allocation; Rats; Rats, Wistar; Synaptophysin; Time Factors

The mechano growth factor (MGF), a splice variant of the IGF-I gene, was first discovered in mechanically overloaded skeletal muscle and was shown to play an important role in proliferation of muscle stem cells. Since then, the presence and effects of MGF have been demonstrated in other tissues. MGF has been shown to act neuroprotectively during brain ischemia, and pretreatment with MGF before myocardial infarction improves cardiac function. Because MGF plays a permissive role in exercise-induced skeletal muscle hypertrophy, we hypothesize that MGF is commonly involved in cardiac hypertrophy. To investigate the regulation of MGF expression in heart, mice were treated with thyroid hormone (T(3)) for 12 d to induce physiological cardiac hypertrophy. MGF mRNA expression was specifically increased in midregions of the septum and left ventricular wall. Interestingly, MGF expression strongly correlated with the increased or decreased beating frequency of hyperthyroid and hypothyroid hearts. To further investigate the mechanically dependent induction of MGF, neonatal rat cardiomyocytes were isolated and exposed to T(3). Upon T(3) treatment, cardiomyocytes increased both contractile activity measured as beats per minute and MGF as well as IGF-IEa mRNA expression. Importantly, when cardiomyocytes were contractile arrested by KCl, simultaneous exposure to T(3) prevented the up-regulation of MGF, whereas IGF-IEa was still induced. These studies demonstrated that MGF but not IGF-IEa expression is dependent on beating activity. These findings suggest that MGF is specifically stimulated by mechanical loading of the heart to mediate the hypertrophic response to thyroid hormone.

Topics: Alternative Splicing; Animals; Animals, Newborn; Genetic Variation; Hyperthyroidism; Hypothyroidism; Insulin-Like Growth Factor I; Mice; Mice, Inbred C57BL; Muscle, Skeletal; Myocytes, Cardiac; Physical Conditioning, Animal; Polymerase Chain Reaction; Propylthiouracil; Rats; Rats, Wistar; RNA; RNA, Messenger; Thyroid Gland; Triiodothyronine

Thyroid hormone is essential for normal brain development, although the degree to which the developing brain is sensitive to small perturbations in serum thyroxin is not clear. An important concept related to this is that the developing brain possesses potent mechanisms to compensate for low serum thyroid hormone, and this concept is routinely employed in discussions concerning clinical treatments or public health. However, experimental studies have not directly tested whether (or the degree to which) putative compensatory mechanisms can ameliorate the consequences of small reductions in serum thyroxin (T(4)). To formally test this concept, we employed a model of graded T(4) reductions using doses of propylthiouracil (PTU) that were 200- to 67-fold lower than the dose traditionally used to produce hypothyroidism in rats. PTU produced a stepwise decrease in serum total T(4), and a stepwise increase in serum thyroid-stimulating hormone (TSH), in type 2 deiodinase mRNA expression and enzyme activity in the brain, and in the expression of the mRNA encoding the tri-iodothyronine (T(3)) transporter MCT8 in the postnatal day (P) 15 cortex. However, the mRNA encoding RC3/neurogranin, a direct target of T(3) action, exhibited a strong negative linear correlation with serum total T(4) despite these adaptive responses. In addition, single-cell analysis of RC3 mRNA levels in cortical neurones demonstrated that the co-expression of MCT8 did not alter the relationship between RC3 mRNA and serum T(4). These findings do not support the currently envisioned concept of the developing brain being capable of compensating for low T(4).

Topics: Animals; Antithyroid Agents; Brain; Female; Hypothyroidism; Iodide Peroxidase; Male; Methimazole; Monocarboxylic Acid Transporters; Neurogranin; Perchlorates; Propylthiouracil; Rats; Rats, Long-Evans; Rats, Sprague-Dawley; Thyrotropin; Thyroxine

The objective of the present study was to evaluate the effect of 6-n-propylthiouracil (PTU)-induced hypothyroidism on oxidative stress parameters, expression of antioxidant defence enzymes, cell proliferation and apoptosis in the developing cerebellum. PTU challenged neonates showed significant decrease in serum T(3) and T(4) levels and marked increase in TSH levels. Significantly elevated levels of cerebellar H(2)O(2) and lipid peroxidation were observed in 7 days old hypothyroid rats, along with increased activities of superoxide dismutase and glutathione peroxidase and decline in catalase activity. In 30 days old hypothyroid rats, a significant decline in cerebellar lipid peroxidation, superoxide dismutase and glutathione peroxidase activity and expression was observed along with an up-regulation in catalase activity and expression. Expression of antioxidant enzymes was studied by Western blot and semi-quantitative rt-PCR. A distinct increase in cell proliferation as indicated by proliferating cell nuclear antigen (PCNA) immunoreactivity was observed in the internal granular layer of cerebellum of 7 days old hypothyroid rats and significant drop in PCNA positive cells in the cerebellar molecular layer and internal granular layer of 30 days old PTU treated rats as compared to controls. In situ end labeling by TUNEL assay showed increased apoptosis in cerebellum of hypothyroid rats in comparison to controls. These results suggest that the antioxidant defence system of the developing cerebellum is sensitive to thyroid hormone deficiency and consequent alterations in oxidative stress status may play a role in regulation of cell proliferation of the cerebellum during neonatal brain development.

Topics: Animals; Antioxidants; Antithyroid Agents; Catalase; Cerebellum; Female; Humans; Hydrogen Peroxide; Hypothyroidism; Lipid Peroxidation; Oxidants; Oxidative Stress; Pregnancy; Proliferating Cell Nuclear Antigen; Propylthiouracil; Rats; Rats, Wistar; Superoxide Dismutase; Thiobarbituric Acid Reactive Substances; Thyroid Hormones

Rats made hypothyroid with propilthyouracil start showing abnormal cycling on the second cycle after the start of the treatment, with a high proportion of spontaneous pseudopregnancies and reduced fertility.. To investigate some of the mechanisms involved in these reproductive abnormalities, hypothyroidism was induced in virgin rats by propilthyouracil (0.1 g/L in the drinking water) and we determined circulating hormones by radioimmunoassay and whole ovary expression of ovarian hormone receptors, growth factors and steroidogenic enzymes using semi-quantitative RT-PCR.The study was performed on days 6 to 9 of treatment, corresponding to diestrus I (at 20.00-22.00 h), diestrus II (at 20.00-22.00 h), proestrus and estrus (both at 8.00-10.00 h and 20.00-22.00 h) of the second estrous cycle after beginning propilthyouracil treatment. Another group of rats was mated on day 8 and the treatment continued through the entire pregnancy to evaluate reproductive performance.. Hypothyroidism increased circulating prolactin and estradiol on estrus 5 to 7-fold and 1.2 to 1.4-fold respectively. Growth hormone and insulin-like growth factor 1 diminished 60 and 20% respectively on proestrus morning. Hypothyroidism doubled the ovarian mRNA contents of estrogen receptor-beta on proestrus and estrus evenings, cyp19A1 aromatase mRNA on estrus evening and of growth hormone receptor on proestrus evening. Hypothyroidism did not influence ovulation rate or the number of corpora lutea at term, but a diminished number of implantation sites and pups per litter were observed (Hypothyroid: 11.7 +/- 0.8 vs.. 13.9 +/- 0.7).. Short term hypothyroidism alters normal hormone profile in the cycling rat increasing the expression of estrogen receptor-beta and cyp19A1 aromatase on estrus, which in turn may stimulate estradiol and prolactin secretion, favouring corpus luteum survival and the subsequent instauration of pseudopregnancy.

Topics: Animals; Embryo Implantation; Estrous Cycle; Female; Gonadal Steroid Hormones; Growth Hormone; Hypothyroidism; Insulin-Like Growth Factor I; Male; Ovary; Ovulation; Pregnancy; Prolactin; Propylthiouracil; Rats; Rats, Wistar; Thyroid Hormones; Time Factors

This study was performed to investigate the effects of L-thyroxine treatment on plasma vasopressin (AVP) levels in rats with hypothyroidism induced by propylthiouracil (PTU). Animals were separated into three groups each having 6 rats: control, PTU, PTU+L-thyroxine groups. Then, the groups were further divided into 3 sub-groups including 6 rats (a; basal, b; hypertonic stimulated and c; hypovolemic stimulated). At the end of the experiments all rats were decapitated in order to obtain plasma samples for analysis in terms of Hct, osmolality, TT 3 , TT 4 and vasopressin. Haematocrit (Hct) levels were the highest in hypovolemic stimulated sub-group (P < 0.001). Osmolality levels were higher in hypertonic stimulated sub-groups (P < 0.001). Total T 3 and T 4 values were the lowest in the PTU group and the highest in the L-thyroxine treated group (P < 0.001). Plasma AVP levels were reduced by hypothyroidism. However, L-thyroxine treatment after the hypothyroidism prevented this reduction (P < 0.001). Vasopressin responses to basal, hypovolemic and hypertonic stimulations were the lowest in the PTU group (P < 0.001). The results of the present study show that basal and stimulated plasma vasopressin levels are reduced in PTU-induced hypothyroidism. However, L-thyroxine treatment following hypothyroidism prevents this reduction.

Topics: Animals; Antithyroid Agents; Body Weight; Dietary Supplements; Hypertonic Solutions; Hypothyroidism; Hypovolemia; Male; Propylthiouracil; Rats; Rats, Wistar; Thyroxine; Vasopressins

The role of thyroid hormones in testis structure and function has been fairly well studied in laboratory rodents. However, there are no comprehensive data in the literature for mice regarding the effects of transiently induced neonatal hypo- and hyperthyroidism on testis and spermatogonial cell development from birth to adulthood. Our goals were to evaluate the effects of propylthiouracil (PTU) and triidothyronine (T3) on Sertoli cell proliferation/differentiation and to correlate these events with the evolution of the spermatogenic process, tubular lumen formation, blood vessel volume density, and size and number of different spermatogonial types. Although Sertoli cell maturation was accelerated or delayed, respectively, in T3- and PTU-treated mice, the pace of the germ cell maturation was only slightly altered before puberty and the period of Sertoli cell proliferation was apparently not affected by the treatments. However, compared with controls, the total number of Sertoli cells per testis from 10 days of age to adulthood was significantly increased and decreased in PTU- and T3-treated mice, respectively. In comparison to all other spermatogonia, type A(2) was the largest cell in all ages and groups investigated. The PTU-treated mice had a significantly increased total number of undifferentiated spermatogonia as well as volume and percentage of vessels/capillaries, probably due to the higher number of Sertoli cells, particularly at 10 days of age. Taken together, our results suggest that neonatal hypothyroidism may be a valuable tool for studying spermatogonial biology as well as a means for providing more spermatogonial stem cells that could potentially be used for spermatogonial transplantation, thereby optimizing the efficiency of this technique when young mice are used as donors.

Topics: Analysis of Variance; Animals; Animals, Newborn; Antithyroid Agents; Cell Differentiation; Cell Proliferation; Hyperthyroidism; Hypothyroidism; Male; Mice; Mice, Inbred C57BL; Propylthiouracil; Sertoli Cells; Spermatogenesis; Testis; Time Factors; Triiodothyronine

Topics: Adult; Antithyroid Agents; Cordocentesis; Female; Fetal Diseases; Goiter; Graves Disease; Hormone Replacement Therapy; Humans; Hypothyroidism; Injections, Intramuscular; Pregnancy; Pregnancy Complications; Propylthiouracil; Thyroxine; Ultrasonography

Thyroid hormones have long been known to play important roles in the development and functions of the central nervous system, however, the precise molecular mechanisms that regulate thyroid hormone-responsive gene expression are not well understood. The present study investigated the role of DNA methylaion and histone acetylation in the effects of perinatal hypothyroidism on regulation of reelin and brain-derived neurotrophic factor (BDNF) gene expression in rat hippocampus. The findings indicated that the activities of DNA methyltransferase (DNMT), methylated reelin and BDNF genes were up-regulated, whereas, the activities of histone acetylases (HAT), the levels of global acetylated histone 3 (H3) and global acetylated histone 4 (H4), and acetylated H3, acetylated H4 at reelin promoter and at BDNF gene promoter for exon II were down-regulated in the hippocampus at the developmental stage of the hypothyroid animals. These results suggest that epigenetic modification of chromatin might underlie the mechanisms of hypothyroidism-induced down-regulation of reelin and BDNF gene expression in developmental rat hippocampus.

Topics: Acetylation; Animals; Animals, Newborn; Brain-Derived Neurotrophic Factor; Cell Adhesion Molecules, Neuronal; DNA Methylation; Down-Regulation; Exons; Extracellular Matrix Proteins; Female; Gene Expression Regulation, Developmental; Hippocampus; Histones; Hypothyroidism; Nerve Tissue Proteins; Pregnancy; Propylthiouracil; Rats; Reelin Protein; RNA, Messenger; Serine Endopeptidases; Thyroid Hormones; Transcription, Genetic; Up-Regulation

The antithetical regulation of cardiac α- and β-myosin heavy chain (MHC) genes by thyroid hormone (T(3)) is not well understood but appears to involve thyroid hormone interaction with its nuclear receptor and MHC promoters as well as cis-acting noncoding regulatory RNA (ncRNA). Both of these phenomena involve epigenetic regulations. This study investigated the extent that altered thyroid state induces histone modifications in the chromatin associated with the cardiac MHC genes. We hypothesized that specific epigenetic events could be identified and linked to cardiac MHC gene switching in response to a hypothyroid or hyperthyroid state. A hypothyroid state was induced in rats by propylthiouracil treatment (PTU), whereas a hyperthyroid (T(3)) was induced by T(3) treatment. The left ventricle was analyzed after 7 days for MHC pre-mRNA expression, and the chromatin was assessed for enrichment in specific histone modifications using chromatin immunoprecipitation quantitative PCR assays. At both the α-MHC promoter and the intergenic region, the enrichment in acetyl histone H3 at K9/14 (H3K9/14ac) and trimethyl histone H3 at K4 (H3K4me3) changed in a similar fashion. They were both decreased with PTU treatment but did not change under T(3), except at a location situated 5' to the antisense intergenic transcription start site. These same marks varied differently on the β-MHC promoter. For example, H3K4me3 enrichment correlated with the β-promoter activity in PTU and T(3) groups, whereas H3K9/14ac was repressed in the T(3) group but did not change under PTU. Histone H3K9me was enriched in chromatin of both the intergenic and α-MHC promoters in the PTU group, whereas histone H4K20me1 was enriched in chromatin of β-MHC promoter in the normal control and T(3) groups. Collectively, these findings provide evidence that specific epigenetic phenomena modulate MHC gene expression in altered thyroid states.

Topics: Acetylation; Animals; Binding Sites; Chromatin Assembly and Disassembly; Chromatin Immunoprecipitation; Disease Models, Animal; DNA, Intergenic; Epigenesis, Genetic; Female; Gene Expression Regulation; Histones; Hyperthyroidism; Hypothyroidism; Methylation; Myocardium; Myosin Heavy Chains; Polymerase Chain Reaction; Promoter Regions, Genetic; Propylthiouracil; Protein Processing, Post-Translational; Rats; Rats, Sprague-Dawley; RNA Precursors; RNA, Messenger; Time Factors; Transcription, Genetic; Triiodothyronine; Ventricular Myosins

An investigation was made to evaluate the pharmacological importance of fruit peel extracts of Mangifera indica (MI), Citrullus vulgaris (CV) and Cucumis melo (CM) with respect to the possible regulation of tissue lipid peroxidation (LPO), thyroid dysfunctions, lipid and glucose metabolism. Pre-standardized doses (200mg/kg of MI and 100mg/kg both of CV and CM), based on the maximum inhibition in hepatic LPO, were administered to Wistar albino male rats for 10 consecutive days and the changes in tissue (heart, liver and kidney) LPO and in the concentrations of serum triiodothyronine (T(3)), thyroxin (T(4)), insulin, glucose, alpha-amylase and different lipids were examined. Administration of three test peel extracts significantly increased both the thyroid hormones (T(3) and T(4)) with a concomitant decrease in tissue LPO, suggesting their thyroid stimulatory and antiperoxidative role. This thyroid stimulatory nature was also exhibited in propylthiouracil (PTU) induced hypothyroid animals. However, only minor influence was observed in serum lipid profile in which CM reduced the concentrations of total cholesterol and low-density lipoprotein-cholesterol (LDL-C), while CV decreased triglycerides and very low-density lipoprotein-cholesterol (VLDL-C). When the combined effects of either two (MI+CV) or three (MI+CV+CM) peel extracts were evaluated in euthyroid animals, serum T(3) concentration was increased in response to MI+CV and MI+CV+CM treatments, while T(4) level was elevated by the combinations of first two peels only. Interestingly, both the categories of combinations increased T(4) levels, but not T(3) in PTU treated hypothyroid animals. Moreover, a parallel increase in hepatic and renal LPO was observed in these animals, suggesting their unsafe nature in combination. In conclusion the three test peel extracts appear to be stimulatory to thyroid functions and inhibitory to tissue LPO but only when treated individually.

Topics: Animals; Antithyroid Agents; Citrullus; Cucumis melo; Hypothyroidism; Lipid Peroxidation; Male; Mangifera; Plant Extracts; Propylthiouracil; Rats; Rats, Wistar

Human populations are simultaneously exposed to a variety of anthropogenic contaminants. However, despite extensive literature on animal exposure to single compounds, data on the toxicity of complex mixtures are scarce. The Northern Contaminant Mixture (NCM) was formulated to contain the 27 most abundant contaminants in the same relative proportions found in the blood of Canadian Arctic populations. Sprague-Dawley rat dams were dosed from the first day of gestation until weaning with methylmercury (MeHg), polychlorinated biphenyls (PCBs) or organochlorines pesticides (OCs) administered either separately or together in the NCM. An additional control group for hypothyroxinemia was included by dosing dams with the goitrogen 6-propyl-2-thiouracil (PTU). Offspring growth, survival, serum thyroxine and Thyroid Stimulating Hormone (TSH) levels, thyroid gland morphology, brain taurine content and cerebellum and hippocampus protein expression patterns resulting from such exposures were monitored. Pups' increased mortality rate and impaired growth observed in the NCM treatment group were attributed to MeHg, while decreased circulating thyroxine levels and perturbations of thyroid gland morphology were mostly attributable to PCBs. Interestingly, despite comparable reduction in serum thyroxine levels, PCBs and PTU exposures produced markedly different effects on pup's growth, serum TSH level and brain taurine content. Analysis of cerebellum and hippocampus protein expression patterns corroborated previous cerebellum gene expression data, as contaminant co-exposure in the NCM significantly masked the effects of individual components on protein two-dimensional electrophoresis patterns. Identification by MALDI-TOF/TOF MS of differentially expressed proteins involved notably in neuronal and mitochondrial functions provided clues on the cellular and molecular processes affected by these contaminant mixtures.

Topics: Age Factors; Animals; Arctic Regions; Body Weight; Brain; Canada; Cerebellum; Complex Mixtures; Disease Models, Animal; Electrophoresis, Gel, Two-Dimensional; Female; Gestational Age; Hippocampus; Hydrocarbons, Chlorinated; Hypothyroidism; Male; Methylmercury Compounds; Mitochondrial Proteins; Nerve Tissue Proteins; Pesticides; Polychlorinated Biphenyls; Propylthiouracil; Rats; Rats, Sprague-Dawley; Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; Taurine; Thyroid Gland; Thyroid Hormones; Water Pollutants, Chemical

Years of effort have failed to establish a generally-accepted mechanism of thyroid hormone (TH) action in the mature brain. Recently, both morphological and pharmacological evidence have supported a direct neuroactive role for the hormone and its triiodinated metabolites. However, no direct physiological validation has been available. We now describe electrophysiological studies in vivo in which we observed that local thyroxine (T4) administration promptly inhibited field excitatory postsynaptic potentials recorded in the dentate gyrus (DG) with stimulation of the medial perforant pathway, a result that was found to be especially pronounced in hypothyroid rats. In separate in vitro experiments, we observed more subtle but statistically significant responses of hippocampal slices to treatment with the hormone. The results demonstrate that baseline firing rates of CA1 pyramidal cells were modestly reduced by pulse-perfusion with T4. By contrast, administration of triiodothyronine (T3) was often noted to have modest enhancing effects on CA1 cell firing rates in hippocampal slices from euthyroid animals. Moreover, and more reliably, robust firing rate increases induced by norepinephrine were amplified when preceded by treatment with T3, whereas they were diminished by pretreatment with T4. These studies provide the first direct evidence for functional, nongenomic actions of TH leading to rapid changes in neuronal excitability in adult rat DG studied in vivo and highlight the opposing effects of T4 and T3 on norepinephrine-induced responses of CA1 cells studied in vitro.

Topics: Action Potentials; Adrenergic alpha-Agonists; Animals; Antithyroid Agents; Dentate Gyrus; Dose-Response Relationship, Drug; Electrophysiology; Excitatory Postsynaptic Potentials; Hippocampus; Hypothyroidism; Male; Neurons; Norepinephrine; Propylthiouracil; Rats; Rats, Sprague-Dawley; Rats, Wistar; Thyroid Gland; Thyroxine; Triiodothyronine

Environmental chemicals have a potential impact on neuronal development and children's health. The current developmental neurotoxicity (DNT) guideline studies to assess their underlying risk are costly and time-consuming; therefore the more efficient protocol for DNT test is needed. Hypothyroidism in rats induced by perinatal exposure to propylthiouracil (PTU), a thyroid hormone synthesis inhibitor, offers an advantageous model of developmental neurotoxicity (DNT). Understanding the associated alterations in gene expression in brain is a key to elucidate mechanisms and find appropriate molecular markers. The purpose of the present study was to identify PTU treatment-affected transcriptomes in the rat cerebral cortex and the hippocampus using DNA microarrays, and to specify candidate genes linked to DNT. We used an approximately 9000 probe microarray to examine differentially expressed genes between PTU-dosed and vehicle-dosed rats at postnatal days 4, 14, 22 and 70. Expression of immediate early genes (IEGs) such as activity-regulated cytoskeleton-associated protein (Arc), Homer 1, early growth response 1 (Egr 1), myelin-associated genes such as myelin-associated oligodendrocytic basic protein (MOBP), myelin basic protein (MBP) and proteolipid protein (PLP) and Kcna1 was apparently affected by perinatal administration of PTU. The results suggest that the alterations may be responsible for the detrimental effects caused by PTU treatment on the nervous system.

Topics: Animals; Animals, Newborn; Antithyroid Agents; Apoptosis Regulatory Proteins; Carrier Proteins; Cerebral Cortex; Disease Models, Animal; Early Growth Response Protein 1; Gene Expression Regulation; Genes, Immediate-Early; Hippocampus; Homer Scaffolding Proteins; Hypothyroidism; Kv1.1 Potassium Channel; Male; Muscle Proteins; Myelin Basic Protein; Myelin Proteins; Myelin Proteolipid Protein; Myelin-Associated Glycoprotein; Myelin-Oligodendrocyte Glycoprotein; Nerve Tissue Proteins; Oligonucleotide Array Sequence Analysis; Propylthiouracil; Rats; RNA, Messenger; Transcription Factors

This study addressed the influence of propylthiouracil (PTU)-induced hypothyroidism on postnatal and adult neurogenesis. PTU was administered from birth to postnatal day 10 (P10) or P21, leading to decreased neural stem cell/progenitor proliferation in the dentate gyrus, as well as significantly fewer granule cells and reduced hippocampal volume. Upon P22 PTU withdrawal, plasma thyroid hormone levels were normal by P90, there was no difference in the number of dentate gyrus or subventricular proliferating cells, but brain weight was smaller. In addition, dentate gyrus density of surviving BrdU-labeled cells increased, with no changes to the olfactory bulb. Quantitative PCR revealed decreased FGF-2, NGF, Wnt3a, and VEGF-A hippocampal expression during PTU treatment, with recovery in adulthood. Pro-apoptotic Bax was up-regulated, and anti-apoptotic Bcl-2 was down-regulated, during PTU treatment, both of which were normalized in the adult brain. In contrast, apoptosis-inducing factor (AIF) was down-regulated in the adult. These results suggest that mechanisms in the adult brain attempt to compensate for decreased neurogenesis due to postnatal hypothyroidism.

Topics: Aging; Animals; Animals, Newborn; Antithyroid Agents; Apoptosis Regulatory Proteins; Atrophy; Brain; Cell Count; Cognition Disorders; Dentate Gyrus; Disease Models, Animal; Down-Regulation; Hypothyroidism; Neurogenesis; Neurons; Organ Size; Propylthiouracil; Rats; Rats, Wistar; Thyroid Hormones

C cells are primarily known for producing calcitonin, a hypocalcemic and hypophosphatemic hormone. Nevertheless, besides their role in calcium homeostasis, C cells may be involved in the intrathyroidal regulation of follicular cells, suggesting a possible interrelationship between the two endocrine populations. If this premise is true, massive changes induced by different agents in the activity of follicular cells may also affect calcitonin-producing cells. To investigate the behaviour of C cells in those circumstances, we have experimentally induced two opposite functional thyroid states. We hyperstimulated the follicular cells using a goitrogen (propylthiouracil), and we suppressed thyroid hormone synthesis by oral administration of thyroxine. In both scenarios, we measured T(4), TSH, calcitonin, and calcium serum levels. We also completely sectioned the thyroid gland, specifically immunostained the C cells, and rigorously quantified this endocrine population. In hypothyroid rats, not only follicular cells but also C cells displayed hyperplastic and hypertrophic changes as well as increased calcitonin levels. When exogenous thyroxine was administered to the rats, the opposite effect was noted as a decrease in the number and size of C cells, as well as decreased calcitonin levels. Additionally, we noted that the two cell types maintain the same numerical relation (10 +/- 2.5 follicular cells per C cell), independent of the functional activity of the thyroid gland. Considering that TSH serum levels are increased in hypothyroid rats and decreased in thyroxine-treated rats, we discuss the potential involvement of thyrotropin in the observed results.

Topics: Animals; Body Weight; Calcitonin; Calcium; Cell Size; Goiter; Hypothyroidism; Male; Paracrine Communication; Propylthiouracil; Rats; Rats, Wistar; Thyrotropin; Thyroxine

To clarify the developmental effects of hypothyroidism and to establish a detection system of resultant brain retardation, pregnant rats were administered 3 or 12 ppm of 6-propyl-2-thiouracil (PTU) or 200 ppm of methimazole (MMI) in the drinking water from gestation day 10 to postnatal day 20 and maintained after weaning until 11 weeks of age (adult stage). Offspring displayed evidence of growth retardation lasting into the adult stage, which was particularly prominent in males. Except for hypothyroidism-related thyroid follicular cell hypertrophy, most histopathological changes that appeared at the end of chemical exposure were related to growth retardation and reversed by the adult stage. A delayed onset of puberty and an adult stage gonadal enlargement occurred by exposure to anti-thyroid agents, both being especially evident in males, and this effect might be related to gonadal growth suppression during exposure. At the adult stage, the distribution variability of hippocampal CA1 pyramidal neurons reflecting mismigration could be detected in animals receiving both thyrotoxins, with a dose-dependent effect by PTU. Similarly, a reduction in the area of the corpus callosum and oligodendroglial cell numbers in the cerebral deep cortex, both reflecting impaired oligodendroglial development, were detected in rats administered both chemicals. Thus, all effects, except for impaired brain development, might be linked to systemic growth retardation, and the brain morphometric methods employed in this study may be useful to evaluate the potency of chemicals to induce hypothyroidism-related brain retardation.

Topics: Animals; Animals, Newborn; Antithyroid Agents; Body Weight; Cell Movement; Disease Models, Animal; Embryo, Mammalian; Female; Fetal Growth Retardation; Genitalia; Hypothyroidism; Male; Oligodendroglia; Organ Size; Pregnancy; Prenatal Exposure Delayed Effects; Propylthiouracil; Pyramidal Cells; Rats; Thyroid Gland; Thyroid Hormones

Propylthiouracil (PTU) is presently considered to be the treatment of choice for hyperthyroidism in pregnancy. It is known to cross the human placenta, and therefore may affect the fetus. The major aims of this study were to evaluate the rate of major anomalies and to report the rate of fetal goitre, accompanied by hypothyroidism, in fetuses/ newborns of mothers after in utero exposure to PTU.. Prospective observational controlled cohort study of PTU-exposed pregnancies of women counselled by the Israeli Teratology Information Service between the years 1994 and 2004 compared with women exposed to nonteratogens.. We followed up 115 PTU-exposed pregnancies and 1141 controls. The rate of major anomalies was comparable between the groups [PTU 1/80 (1.3%), control 34/1066 (3.2%), P= 0.507]. Hypothyroidism was found in 9.5% of fetuses/neonates (56.8% of whom with goitre). Hyperthyroidism, possibly resulting from maternal disease, was found in 10.3%. Goitres prenatally diagnosed by ultrasound were successfully treated in utero by maternal dose adjustment. In most cases neonatal thyroid functions normalized during the first month of life without any treatment. Median neonatal birth weight was lower [PTU 3145 g (2655-3537) vs. control 3300 g (2968-3600), P= 0.018].. PTU does not seem to be a major human teratogen. However, it could cause fetal/neonatal hypothyroidism with or without goitre. Fetal thyroid size monitoring and neonatal thyroid function tests are important for appropriate prevention and treatment.

Topics: Abnormalities, Drug-Induced; Adult; Antithyroid Agents; Birth Weight; Case-Control Studies; Cohort Studies; Female; Goiter; Humans; Hyperthyroidism; Hypothyroidism; Infant, Newborn; Maternal-Fetal Exchange; Pregnancy; Pregnancy Complications; Pregnancy Outcome; Prenatal Exposure Delayed Effects; Propylthiouracil; Ultrasonography, Prenatal

There is accumulating evidence showing that ischemic preconditioning (PC) may lose its cardioprotective effect in the diseased states. The present study investigated whether PC can be effective in hypothyroidism, a clinical condition which is common and often accompanies cardiac diseases such as heart failure and myocardial infarction. Hypothyroidism was induced in rats by 3-week administration of 6n-propyl-2-thiouracil in water (0.05 %). Normal and hypothyroid hearts (HYPO) were perfused in Langendorff mode and subjected to 20 min of zero-flow global ischemia and 45 min of reperfusion. A preconditioning protocol (PC) was also applied prior to ischemia. HYPO hearts had significantly improved post-ischemic recovery of left ventricular developed pressure, end-diastolic pressure and reduced lactate dehydrogenase release. Furthermore, phospho-JNK and p38 MAPK levels after ischemia and reperfusion were 4.0 and 3.0 fold lower in HYPO as compared to normal hearts (P<0.05). A different response to PC was observed in normal than in HYPO hearts. PC improved the post-ischemic recovery of function and reduced the extent of injury in normal hearts but had no additional effect on the hypothyroid hearts. This response, in the preconditioned normal hearts, resulted in 2.5 and 1.8 fold smaller expression of the phospho-JNK and phospho-p38 MAPK levels at the end of reperfusion, as compared to non-PC hearts (P<0.05), while in HYPO hearts, no additional reduction in the phosphorylation of these kinases was observed after PC. Hypothyroid hearts appear to be tolerant to ischemia-reperfusion injury. This response may be, at least in part, due to the down-regulation of ischemia-reperfusion induced activation of JNKs and p38 MAPK kinases. PC is not associated with further reduction in the activation of these kinases in the hypothyroid hearts and fails to confer added protection in those hearts.

Topics: Animals; Cardiac Myosins; Disease Models, Animal; Hypothyroidism; Ischemic Preconditioning, Myocardial; JNK Mitogen-Activated Protein Kinases; L-Lactate Dehydrogenase; Male; Myocardial Contraction; Myocardial Reperfusion Injury; Myocardium; p38 Mitogen-Activated Protein Kinases; Perfusion; Phosphorylation; Propylthiouracil; Rats; Rats, Wistar; Recovery of Function; Sarcoplasmic Reticulum Calcium-Transporting ATPases; Treatment Failure; Ventricular Function, Left; Ventricular Pressure

Markedly lowered thyroid hormone levels during development may influence a child's behaviour, intellect, and auditory function. Recent studies, indicating that even small changes in the mother's thyroid hormone status early in pregnancy may cause adverse effects on her child, have lead to increased concern for thyroid hormone disrupting chemicals in the environment. The overall aim of the study was therefore to provide a detailed knowledge on the relationship between thyroid hormone levels during development and long-lasting effects on behaviour and hearing. Groups of 16-17 pregnant rats (HanTac:WH) were dosed with PTU (0, 0.8, 1.6 or 2.4 mg/kg/day) from gestation day (GD) 7 to postnatal day (PND) 17, and the physiological and behavioural development of rat offspring was assessed. Both dams and pups in the higher dose groups had markedly decreased thyroxine (T(4)) levels during the dosing period, and the weight and histology of the thyroid glands were severely affected. PTU exposure caused motor activity levels to decrease on PND 14, and to increase on PND 23 and in adulthood. In the adult offspring, learning and memory was impaired in the two highest dose groups when tested in the radial arm maze, and auditory function was impaired in the highest dose group. Generally, the results showed that PTU-induced hypothyroxinemia influenced the developing rat brain, and that all effects on behaviour and loss of hearing in the adult offspring were significantly correlated to reductions in T(4) during development. This supports the hypothesis that decreased T(4) may be a relevant predictor for long-lasting developmental neurotoxicity.

Topics: Age Factors; Animals; Animals, Newborn; Antithyroid Agents; Auditory Threshold; Behavior, Animal; Body Weight; Disease Models, Animal; Dose-Response Relationship, Drug; Female; Gestational Age; Hearing; Hypothyroidism; Male; Maze Learning; Motor Activity; Nervous System; Neurotoxicity Syndromes; Organ Size; Pregnancy; Prenatal Exposure Delayed Effects; Propylthiouracil; Rats; Rats, Wistar; Thyroid Gland; Thyroxine

Adult-onset hypothyroidism is associated with neurological changes such as cognitive dysfunction and impaired learning, which may be related to alterations of synaptic plasticity. We investigate the consequence of adult-onset hypothyroidism on thyroid-mediated transcription events in striatal synaptic plasticity, and the effect of triiodothyronine (T3) replacement. We used hypothyroid mice, treated with propylthiouracil (PTU) and methimazole (MMI), with or without subsequent administration of T3. We evaluated the amount of T3 nuclear receptors (TRalpha1, TRbeta) and striatal plasticity indicators: neurogranin (RC3), Ras homolog enriched in striatum (Rhes), Ca2+/calmodulin-dependent protein kinase (CaMKII), and dopamine- and cAMP-regulated phosphoprotein (DARPP-32). In addition, we assessed hypothyroid mice motor behavior as related to striatum synaptic functions. Hypothyroid mice exhibited significantly reduced TRbeta, RC3 and Rhes expression. T3 administration reversed the expression of TRbeta, RC3, and up-regulated CaMKII levels as well as motor behavior, and decreased DARPP-32 protein phosphorylation. We suggest that thyroid hormone modulation had a major impact on striatal synaptic plasticity of adult mice which produced in turn motor behavior modifications.

Topics: Age Factors; Animals; Behavior, Animal; Biomarkers; Calcium-Calmodulin-Dependent Protein Kinase Type 2; Corpus Striatum; Disease Models, Animal; Dopamine and cAMP-Regulated Phosphoprotein 32; GTP-Binding Proteins; Hypothyroidism; Male; Methimazole; Mice; Motor Activity; Movement Disorders; Neurogranin; Neuronal Plasticity; Phosphorylation; Presynaptic Terminals; Propylthiouracil; Receptors, Thyroid Hormone; Synaptic Transmission; Thyroid Gland; Triiodothyronine; Up-Regulation

Free radical-mediated oxidative stress has been implicated in the etiopathogenesis of several autoimmune disorders. Also, there is growing evidence supporting the role of reactive oxygen species in the pathogenesis of thyroid disorders. The aim of this study was to investigate the influence of hypothyroidism, hyperthyroidism, and their treatments on the metabolic state of oxidative stress, and antioxidant status markers.. A total of 20 newly diagnosed patients with overt hypothyroidism due to Hashimoto's thyroiditis, 20 patients with overt hyperthyroidism due to Graves' disease, and 20 healthy subjects as the control group were enrolled in the study. Fasting blood samples (12 h), taken at the initiation, after the 30th and 60th day of therapy were analyzed for malondialdehyde, nitrite, vitamin E, vitamin A, beta-carotene, ascorbate, and myeloperoxidase and superoxide dismutase activity. No patient presented additional risk factors for increased reactive oxygen species levels.. Malondialdehyde, nitrite, vitamin E, and myeloperoxidase activity increased in patients with hypothyroidism. After 2 months, the levels of nitrite and vitamin E were reduced to control levels by treatment. The patients with hyperthyroidism had increased levels of malondialdehyde and myeloperoxidase activity in comparison with the controls. Treatment with propylthiouracil attenuated these increments after 1 month.. Our results reveal an increased generation of reactive oxygen species and impairment of the antioxidant system in patients with hyperthyroidism, and particularly in patients with hypothyroidism. These findings indicate that thyroid hormones have a strong impact on oxidative stress and the antioxidant system.

Topics: Adult; Antioxidants; Antithyroid Agents; beta Carotene; Female; Humans; Hyperthyroidism; Hypothyroidism; Male; Malondialdehyde; Middle Aged; Nitrites; Oxidative Stress; Peroxidase; Propylthiouracil; Reactive Oxygen Species; Superoxide Dismutase; Thyroxine; Vitamin A; Vitamin E

Expression of all of the isoforms of the subunits of AMP-activated protein kinase (AMPK) and AMPK activity is increased in skeletal muscle of hyperthyroid rats. Activity of AMPK in skeletal muscle is regulated principally by the upstream kinase, LKB1. This experiment was designed to determine whether the increase in AMPK activity is accompanied by increased expression of the LKB1, along with binding partner proteins. LKB1, MO25, and downstream targets were determined in muscle extracts in control rats, in rats given 3 mg of thyroxine and 1 mg of triiodothyronine per kilogram chow for 4 wk, and in rats given 0.01% propylthiouracil (PTU; an inhibitor of thyroid hormone synthesis) in drinking water for 4 wk (hypothyroid group). LKB1 and MO25 increased in the soleus of thyroid hormone-treated rats vs. the controls. In other muscle types, LKB1 responses were variable, but MO25 increased in all. In soleus, MO25 mRNA increased with thyroid hormone treatment, and STRAD mRNA increased with PTU treatment. Phospho-AMPK and phospho-ACC were elevated in soleus and gastrocnemius of hyperthyroid rats. Thyroid hormone treatment also increased the amount of phospho-cAMP response element binding protein (CREB) in the soleus, heart, and red quadriceps. Four proteins having CREB response elements (CRE) in promoter regions of their genes (peroxisome proliferator-activated receptor-gamma coactivator-1alpha, uncoupling protein 3, cytochrome c, and hexokinase II) were all increased in soleus in response to thyroid hormones. These data provide evidence that thyroid hormones increase soleus muscle LKB1 and MO25 content with subsequent activation of AMPK, phosphorylation of CREB, and expression of mitochondrial protein genes having CRE in their promoters.

Topics: Adaptor Proteins, Signal Transducing; Adaptor Proteins, Vesicular Transport; AMP-Activated Protein Kinase Kinases; AMP-Activated Protein Kinases; Animals; Antithyroid Agents; Blotting, Western; Calcium-Binding Proteins; Cyclic AMP Response Element-Binding Protein; Disease Models, Animal; Electric Stimulation; Hyperthyroidism; Hypothyroidism; Male; Mitochondrial Proteins; Multienzyme Complexes; Muscle, Skeletal; Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; Phosphoprotein Phosphatases; Phosphorylation; Promoter Regions, Genetic; Propylthiouracil; Protein Phosphatase 2C; Protein Serine-Threonine Kinases; Rats; Rats, Sprague-Dawley; RNA-Binding Proteins; RNA, Messenger; Signal Transduction; Thyroxine; Transcription Factors; Triiodothyronine

This study examined the deleterious effects of di(n-butyl) phthalate (DBP) on the male reproductive organs in hypothyroid rats. Hypothyroidism was induced in prepubertal male rats (28 days of age) by an intraperitonial (i.p.) injection of 10 mg/kg/day propylthiouracil (PTU) for 30 days. DBP (100 and 500 mg/kg/day) was administered by oral gavages to the intact or hypothyroid rats for 30 days. The body weight of the PTU-treated rats was significantly lower than the control group. The total triiodothyronine (T3) and thyroxine (T4) serum level was lower, and the thyroid-stimulating hormone (TSH) level was higher in the hypothyroid rats than in the control rats. The DBP treatment rats showed significantly lower testes, epididymides, seminal vesicles, and ventral prostate weights than the untreated rats. The hypothyroid rats had significantly higher thyroid weights and lower adrenal glands weights than the control rats. The histomorphological examination showed diffused Leydig cells hyperplasias and germ cells loss in the DBP (500 mg/kg)-treated rats, whereas these effects were mild in the DBP-treated hypothyroid rats. The serum levels of monobutyl phthalate (MBP) were significantly lower in PTU-induced hypothyroid rats than in the DBP-treated rats. This data suggests that the hypothyroid status might offer some protection from male reproductive organ toxicity caused by a disturbance in the metabolic activation of the parent compound, DBP.

Topics: Animals; Body Weight; Dibutyl Phthalate; Hypothyroidism; Male; Organ Size; Phthalic Acids; Propylthiouracil; Rats; Rats, Sprague-Dawley; Testis; Thyroid Hormones; Thyrotropin

Apoptosis, proliferation and histomorphometry of spleen were investigated in ovariectomized and non-ovariectomized adult Wistar rats maintained in hypothyroidism induced by daily administration of propylthiouracil (PTU) during 120 days. Two groups ovariectomized euthyroid and non-ovariectomized euthyroid were used as controls. Plasma was collected for free T4 dosage and the spleen for histomorphometry analysis, apoptosis index and the immunohistochemistry expression of caspase 3 and CDC47. Values of free T4 were lower in rats treated with PTU (p<0.05). In the hypothyroid groups there was some decrease in the spleen weight as well as the number and size of lymphoid follicles and there was some increase in the apoptotic index and the caspase 3 expression (p<0.05). However, the increase in the apoptosis index and the expression of caspase 3 in ovariectomized hypothyroid rats spleen was less accentuated than non-ovariectomized hypothyroid ones (p<0.05). The ovariectomized euthyroid group presented white pulp hyperplasia in comparison to the non-ovariectomized euthyroid group. There was no difference in the CDC47 expression between groups. It was concluded that the thyroid and ovarian hypofunction have distinct effects on the spleen and that in the hypothyroidism-hypogonadism association, the increase in the apoptosis index and in the expression of splenic caspase 3 is not as much as in isolated hypothyroidism.

Topics: Adenosine Triphosphatases; Animals; Antithyroid Agents; Apoptosis; Caspase 3; Cell Proliferation; Disease Models, Animal; DNA-Binding Proteins; Female; Hypogonadism; Hypothyroidism; Lymphoid Tissue; Minichromosome Maintenance Complex Component 7; Ovariectomy; Propylthiouracil; Rats; Rats, Wistar; Spleen; Thyroid Gland; Thyroxine

To retrospectively review health records in two general practices in Hamilton, New Zealand (NZ) linking three data sources to estimate the prevalence of diagnosed thyroid dysfunction (TD).. A record-linkage study using computerised searches to find cases of diagnosed TD by diagnostic codes, prescribing data, and laboratory data. Data was verified against computerised and written records.. The prevalence of diagnosed TD was 3.1%. Overt hypothyroidism was diagnosed in 2.5%, overt hyperthyroidism in 0.2% and 'other' conditions such as goitres, nodules and thyroiditis in 0.4% of the study population.. This study provides a representation of TD in the community prior to mandatory iodine fortification. Our prevalence data is similar to national and international literature with the burden of TD being greater in women and in the older population.. A national study with a sufficient sample of Māori and Pacific patients is needed before supplementation with iodine is introduced.

Topics: Adult; Aged; Aged, 80 and over; Antithyroid Agents; Carbimazole; Family Practice; Female; Food, Fortified; Humans; Hyperthyroidism; Hypothyroidism; International Classification of Diseases; Iodine; Male; Medical Records, Problem-Oriented; Middle Aged; New Zealand; Prevalence; Propylthiouracil; Sex Distribution; Thyroid Diseases; Thyroxine; Young Adult

Hypothyroidism during pregnancy and the early postnatal period has severe neurological consequences for the developing offspring. The impact of milder degrees of perturbation of the thyroid axis as encompassed in conditions of subclinical hypothyroidism and hypothyroxinemia, however, has not been established. The present investigation examined the effects of graded levels of hypothyroidism, from subclinical to severe, on global gene expression in the developing rodent brain. Thyroid hormone insufficiency was induced by administration of propylthiouracil (PTU) to pregnant rats via drinking water from gestational day 6 until sacrifice of pups prior to weaning. In the first study a specialised microarray, the Affymetrix Rat Neurobiology array RN_U34, was used to contrast gene expression in the hippocampus of animals exposed to 0 or 10 ppm (10 mg/l) PTU, a treatment producing severe hypothyroidism. In the second study, a more complete genome array (Affymetrix Rat 230A) was used to compare gene expression in the neocortex and hippocampus of postnatal day (PN) 14 animals experiencing graded degrees of thyroid hormone insufficiency induced by delivery of 0, 1, 2 or 3 ppm PTU to the dam. Dose-dependent up- and down-regulation were observed for gene transcripts known to play critical roles in brain development and brain function. Expression levels of a subset of approximately 25 genes in each brain region were altered at a dose of PTU (1 ppm) that induced mild hypothyroxinemia in dams and pups. These data indicate that genes driving important developmental processes are sensitive to relatively modest perturbations of the thyroid axis, and that the level of gene expression is related to the degree of hormone reduction. Altered patterns of gene expression during critical windows of brain development indicate that thyroid disease must be viewed as a continuum and that conditions typically considered 'subclinical' may induce structural and functional abnormalities in the developing central nervous system.

Topics: Animals; Body Weight; Female; Gene Expression Profiling; Gene Expression Regulation, Developmental; Hippocampus; Hypothyroidism; Molecular Sequence Data; Neocortex; Oligonucleotide Array Sequence Analysis; Pregnancy; Propylthiouracil; Rats; Rats, Long-Evans; Thyroid Hormones

Cardiac myosin heavy chain (MHC) gene expression undergoes a rapid transition from beta- to alpha-MHC during early rodent neonatal development (0-21 days of age). Thyroid hormone (3,5,3'-triiodothyronine, T(3)) is a major player in this developmental shift; however, the exact mechanism underlying this transition is poorly understood. The goal of this study was to conduct a more thorough analysis of transcriptional activity of the cardiac MHC gene locus during the early postnatal period in the rodent, in order to gain further insight on the regulation of cardiac MHC genes. We analyzed the expression of alpha- and beta-MHC at protein, mRNA, and pre-mRNA levels at birth and 7, 10, 15, and 21 days after birth in euthyroid and hypothyroid rodents. Using novel technology, we also analyzed RNA expression across the cardiac gene locus, and we discovered that the intergenic (IG) region between the two cardiac genes possesses bidirectional transcriptional activity. This IG transcription results in an antisense RNA product as described previously, which is thought to exert an inhibitory effect on beta-MHC gene transcription. On the second half of the IG region, sense transcription occurs, resulting in expression of a sense IG RNA that merges with the alpha-MHC pre-mRNA. This sense IG RNA transcription was detected in the alpha-MHC gene promoter, approximately -1.8 kb relative to the alpha-MHC transcription start site. Both sense and antisense IG RNAs were developmentally regulated and responsive to a hypothyroid state (11, 14). This novel observation provides more complexity to the cooperative regulation of the two genes, suggesting the involvement of epigenetic processes in the regulation of cardiac MHC gene locus.

Topics: Aging; Animals; Animals, Newborn; Base Sequence; Body Weight; Disease Models, Animal; DNA, Intergenic; Epigenesis, Genetic; Gene Expression Regulation, Developmental; Gene Transfer Techniques; Genes, Reporter; Heart Ventricles; Hypothyroidism; Molecular Sequence Data; Myocardium; Myosin Heavy Chains; Promoter Regions, Genetic; Propylthiouracil; Rats; Reverse Transcriptase Polymerase Chain Reaction; RNA, Antisense; RNA, Messenger; Time Factors; Transcription Initiation Site; Transcription, Genetic; Triiodothyronine; Ventricular Myosins

Topics: Aging; Animals; Disease Models, Animal; DNA, Intergenic; Epigenesis, Genetic; Gene Expression Regulation, Developmental; Heart Ventricles; Hypothyroidism; Myocardium; Myosin Heavy Chains; Promoter Regions, Genetic; Propylthiouracil; Rats; RNA, Antisense; RNA, Messenger; Time Factors; Transcription Initiation Site; Transcription, Genetic; Triiodothyronine; Ventricular Myosins

Differentiation of adult Leydig cells (ALC) in the prepubertal rat testis is stimulated by thyroid hormone (Thy) and inhibited by the Anti-Mullerian Hormone (AMH) produced by the immature Sertoli cell (SC). As Thy induces SC maturation in the prepubertal rat testis, we hypothesized that Thy stimulation of ALC differentiation is mediated via inhibition of AMH production by the SC with their maturation. If this hypothesis is true, AMH production by the prepubertal Sertoli cells in hypothyroid rats should not decline immediately after birth as in euthyroid rats, but should be maintained throughout the hypothyroid period at a similar or higher level to that of day 1 rats. This concept was tested using control rats of postnatal days (pd) 1, 7 and 14 and hypothyroid (fed 0.1% propyl thiouracil/PTU to lactating mothers) rats of pd7 and pd14. Presence of AMH in SC was examined by immunocytochemistry for AMH. Results demonstrated that testes of pd1 rats had intense AMH positive labeling exclusively in cytoplasm of SC. In testes of pd7 and pd14 control and PTU rats, a positive but weak labeling was also observed in cytoplasm of some SC; Germ cells and testicular interstitial cells were negative for AMH at all tested ages in both experimental groups. These findings suggest that AMH production by the prepubertal SC is independent of Sertoli cell maturation and not regulated by Thy. Therefore, Thy regulation of ALC differentiation in the prepubertal rat testis is unlikely to be mediated via inhibition of AMH produced by the SC with their maturation.

Topics: Animals; Animals, Newborn; Animals, Suckling; Anti-Mullerian Hormone; Antithyroid Agents; Cell Differentiation; Cytoplasm; Disease Models, Animal; Female; Hypothyroidism; Immunohistochemistry; Lactation; Leydig Cells; Male; Propylthiouracil; Rats; Rats, Sprague-Dawley; Sertoli Cells; Sexual Maturation; Testis

In the present study, effects of transient hypothyroidism (from birth to 30 days) and persistent hypothyroidism (from birth to 90 days) on testicular antioxidant defence system of mature rats were compared in order to know the role of hypothyroidism induced oxidative stress in testicular development and maturation. Rats were made hypothyroid by feeding lactating mothers and adult rats with 0.05% 6-n-propyl thiouracil (PTU) in drinking water. PTU treatment for 30 days or for 90 days to rats from birth resulted in a decrease in body weight at the age of 90 days in comparison to the controls. The testicular germ cell counts were significantly decreased in persistent hypothyroid rats whereas they were increased in the transient hypothyroid rats. However, a significant reduction in the number of live sperms in epididymis of both 30 day and 90-day PTU treated rats was noticed on 90 days of age. Mitochondrial lipid peroxidation (LPx) levels were decreased in transient hypothyroidism whereas LPx and protein carbonylation were elevated during persistent hypothyroidism in the testis. Reduced testicular superoxide dismutase (SOD), catalase and glutathione reductase (GR) and glutathione peroxidase (GPx) activities were marked during transient hypothyroidism. In contrast, an elevation in SOD (PMF) and catalase activities with a significant decline in GPx and GR activities was found following persistent hypothyroidism. Marked histological changes were observed in the testis of both experimental groups. These results suggest a direct regulatory role of thyroid hormone on testicular physiology and antioxidant defence system during development and maturation.

Topics: Animals; Antimetabolites; Antioxidants; Body Weight; Catalase; Glutathione Peroxidase; Glutathione Reductase; Hypothyroidism; Lipid Peroxidation; Male; Oxidative Stress; Propylthiouracil; Rats; Rats, Wistar; Sexual Maturation; Spermatozoa; Superoxide Dismutase; Testis; Thyroid Hormones

Catch-up growth is defined as a linear growth rate greater than expected for age after a period of growth inhibition. We hypothesized that catch-up growth occurs because growth-inhibiting conditions conserve the limited proliferative capacity of growth plate chondrocytes, thus slowing the normal process of growth plate senescence. When the growth-inhibiting condition resolves, the growth plates are less senescent and therefore grow more rapidly than normal for age. To test this hypothesis, we administered propylthiouracil to newborn rats for 8 wk to induce hypothyroidism and then stopped the propylthiouracil to allow catch-up growth. In untreated controls, the growth plates underwent progressive, senescent changes in multiple functional and structural characteristics. We also identified genes that showed large changes in mRNA expression in growth plate and used these changes as molecular markers of senescence. In treated animals, after stopping propylthiouracil, these functional, structural, and molecular senescent changes were delayed, compared with controls. This delayed senescence included a delayed decline in longitudinal growth rate, resulting in catch-up growth. The findings demonstrate that growth inhibition due to hypothyroidism slows the developmental program of growth plate senescence, including the normal decline in the rate of longitudinal bone growth, thus accounting for catch-up growth.

Topics: Aging; Animals; Female; Growth; Growth Plate; Hypothyroidism; Propylthiouracil; Rats; Rats, Sprague-Dawley; RNA, Messenger

The secretory activity of the Harderian gland (HG) is influenced by both exogenous (such as light and temperature) and endogenous (such as prolactin, thyroid hormones and steroid hormones) factors, which vary among species. In the present study, the effects of hypothyroidism on the rat HG were examined at morphological and biochemical levels. The decrease in cytoplasmic lipoproteic vacuoles and the increase in mucosubstance secretion in the acinar lumina were the most notable histological effects elicited by hypothyroidism. The release of all granules with nuclei and cellular debris suggested the occurrence of holocrine secretion. Electron microscopy revealed in the glandular cells of hypothyroid rat an increased condensation of chromatin in the nuclei, mitochondria with decreased cristae and vacuolisation, decreased glycogen granules, autophagic vacuoles, and lipofuscins in the cytoplasm. TUNEL reaction indicated DNA fragmentation in hypothyroid HG, indicative of an underlying apoptotic process. Translocation of cytochrome c from mitochondria to cytosol strongly supported this hypothesis. In conclusion, these findings indicate that thyroid hormones play a pivotal role in preserving the structural integrity of the rat HG and, hence, its secretory activity.

Topics: Animals; Antithyroid Agents; Cytochromes c; Cytosol; Gene Expression Regulation; Harderian Gland; Hypothyroidism; Iopanoic Acid; Male; Mitochondria; Propylthiouracil; Rats; Rats, Wistar

The developing central nervous system of the fetus and neonate is recognized as very sensitive to maternal or gestational hypothyroidism. Despite this recognition, there is still a lack of data concerning the relationship between thyroid-related biomarkers and neurological outcomes. We used propylthiouracil administered at 0, 3, or 10 ppm in drinking water from gestational d 2 until weaning to create hypothyroid conditions to study the relationship between hypothalamic-pituitary-thyroid axis compensation and impaired neurodevelopment. In addition to serum T(3), T(4), free T(4), and TSH concentrations, cerebrocortical T(3) concentration (cT(3)), hepatic type I and cerebrocortical type II (D2) 5'-deiodinase activity, and thyroidal mRNA for thyroglobulin and sodium iodide symporter were measured. Extracellular recordings from the CA1 region in hippocampal slices were obtained from both postnatal d 21-32 (pups) and postnatal d 90-110 (adults) rats to assess neurophysiological effects. Thyroidal mRNA for thyroglobulin and sodium iodide symporter were increased in pups but not in dams. Both propylthiouracil doses increased cerebrocortical D2 activity approximately 5-fold in pups but only 10 ppm increased D2 activity in dams. In dams, cT(3) concentrations were maintained at 3 ppm but fell 75% at 10 ppm. cT(3) concentration in pups fell 50% at 3 ppm and more than 90% at 10 ppm. In both 3 and 10 ppm pups, hippocampal baseline synaptic activity correlated negatively with cerebrocortical D2 activity. In 3 ppm adults, impaired long-term potentiation was evident. In summary, during depletion of serum T(4), D2 activity served as a sensitive marker of tissue thyroid status, an indicator of the brain's compensatory response to maintain cT(3), and correlated with a neurophysiological outcome.

Topics: Animals; Animals, Newborn; Biomarkers; Electrophysiology; Female; Hippocampus; Hypothyroidism; In Vitro Techniques; Iodide Peroxidase; Iodothyronine Deiodinase Type II; Liver; Male; Neurophysiology; Pregnancy; Propylthiouracil; Rats; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Symporters; Thyroglobulin; Thyroid Gland; Thyrotropin; Thyroxine; Triiodothyronine

We characterized the enzymes that catalyze the deiodination of T(4) to T(3) in the male reproductive tract. Testis, epididymis (EPI), seminal vesicles, prostate, bulbourethral glands, spermatozoa, and semen were taken from sexually mature rats (300 g). Iodothyronine 5'-deiodinase (5'-D) activity was quantified by the radiolabeled-iodide-release method. 5'-D activity was 10-fold higher in EPI and semen than in the rest of the tissues. In EPI, semen, and prostate, the enzymatic activity was completely inhibited by 1 mm 6-n-propyl-2-thiouracil, whereas in the other tissues the inhibition was partial (50%). The high susceptibility to 6-n-propyl-2-thiouracil inhibition, a ping-pong kinetic pattern, and low cofactor (Michaelis Menten constant for dithiothreitol=0.7 mm) and high substrate (Michaelis Menten constant for reverse T(3)=0.4 microm) requirements indicate that EPI 5'-D corresponds to type 1 deiodinase (D1). Real-time RT-PCR amplification of D1 mRNA in this tissue confirms this conclusion. The highest EPI D1 expression occurred at the onset of puberty and sexual maturity, and in the adult, this activity was more abundant in corpus and caput than in the caudal region. EPI D1 expression was elevated under conditions of hyperthyroidism and with addition of 17beta-estradiol. Our data also showed a direct association between D1 and a functional epididymis marker, the neutral alpha-glucosidase enzyme, suggesting that local generation of T(3) could be associated with the development and function of EPI and/or spermatozoa maturation. Further studies are necessary to analyze the possible physiological relevance of 5'-D in the male reproductive system.

Topics: Animals; Antithyroid Agents; Epididymis; Gene Expression Regulation, Enzymologic; Genitalia, Male; Gonadal Steroid Hormones; Hyperthyroidism; Hypothyroidism; Iodide Peroxidase; Male; Propylthiouracil; Rats; Rats, Wistar; Sexual Maturation

Thyroid hormones are necessary for brain development. gamma-Amino-butyric acid (GABA)ergic interneurons comprise the bulk of local inhibitory circuitry in brain, many of which contain the calcium binding protein, parvalbumin (PV). A previous report indicated that severe postnatal hypothyroidism reduces PV immunoreactivity (IR) in rat neocortex. We examined PV-IR and GABA-mediated synaptic inhibition in the hippocampus of rats deprived of thyroid hormone from gestational d 6 until weaning on postnatal d 30. Pregnant dams were exposed to propylthiouracil (0, 3, 10 ppm) via the drinking water, which decreased maternal serum T(4) by approximately 50-75% and increased TSH. At weaning, T(4) was reduced by approximately 70% in offspring in the low-dose group and fell below detectable levels in high-dose animals. PV-IR was diminished in the hippocampus and neocortex of offspring killed on postnatal d 21, an effect that could be reversed by postnatal administration of T(4). Dose-dependent decreases in the density of PV-IR neurons were observed in neocortex and hippocampus, with the dentate gyrus showing the most severe reductions (50-75% below control counts). Altered staining persisted to adulthood despite the return of thyroid hormones to control levels. Developmental cross-fostering and adult-onset deprivation studies revealed that early postnatal hormone insufficiency was required for an alteration in PV-IR. Synaptic inhibition of the perforant path-dentate gyrus synapse evaluated in adult offspring, in vivo, revealed dose-dependent reductions in paired pulse depression indicative of a suppression of GABA-mediated inhibition. These data demonstrate that moderate degrees of thyroid hormone insufficiency during the early postnatal period permanently alters interneuron expression of PV and compromises inhibitory function in the hippocampus.

Topics: Age Factors; Animals; Antithyroid Agents; Dentate Gyrus; Female; Hypothyroidism; Immunohistochemistry; Interneurons; Neocortex; Neural Inhibition; Parvalbumins; Pregnancy; Prenatal Exposure Delayed Effects; Propylthiouracil; Rats; Rats, Long-Evans; Synaptic Transmission; Thyroid Hormones

We previously identified a cold shock domain (CSD)-containing protein (PIPPin), expressed at high level in brain cells. PIPPin has the potential to undergo different posttranslational modifications and might be a good candidate to regulate the synthesis of specific proteins in response to extracellular stimuli. Here we report the effects of T(3) on PIPPin expression in developing rat brain. We found that a significant difference among euthyroid and hypothyroid newborn rats concerns sumoylation of nuclear PIPPin, which is abolished by hypothyroidism. Moreover, T(3) dependence of PIPPin sumoylation has been confirmed in cortical neurons purified from brain cortices and cultured in a chemically defined medium (Maat medium), with or without T(3). We also report that about one half of unmodified as well as all the sumoylated form of PIPPin could be extracted from nuclei with HCl, together with histones. Moreover, this HCl-soluble fraction remains in the nucleus even after treatment with 0.6 M KCl, thus suggesting strong interaction of PIPPin with nuclear structures and perhaps chromatin.

Topics: Animals; Animals, Newborn; Antithyroid Agents; Cell Nucleus; Cells, Cultured; Cerebral Cortex; Female; Hypothyroidism; Nerve Tissue Proteins; Neurons; Pregnancy; Prenatal Exposure Delayed Effects; Propylthiouracil; Protein Structure, Tertiary; Rabbits; Rats; Rats, Wistar; RNA-Binding Proteins; SUMO-1 Protein; Triiodothyronine

Effects of postnatal hypothyroidism and recovery from this condition on regional growth of the rat hippocampus (HC) were studied using two-dimensional (2D) foldout, morphometric maps of HC and its constituent CA1-CA4 regions. The maps were derived from unfolding serial coronal sections of the rat forebrain, consisting of the entire rostrocaudal extent of HC pyramidal cell layer in the normal control and hypothyroid weanling (P25, postnatal day 25) and young adult (P90) male rats, as well as animals allowed to recover from hypothyroid-induced growth retardation at weaning. The maps revealed novel views of HC regions for assessment of topological relationships and measurement of surface areas of the HC cortical sheet (pyramidal cell layer). In normal control P90 rats, the unfolded HC on each side extended 4 times more laterally than rostrocaudally; total HC surface area was about 40 mm(2), compared to 30 mm(2) in the weanling, indicating 35% growth from P25 to P90; CA1 took up 52% of the total HC surface area, followed by CA3 (31%) and CA2 and CA4, 8% each. Hypothyroidism resulted in significant (p<0.01) 11% and 20% reductions in the HC surface area in P25 and P90 rats, respectively; CA1 and CA4 regions suffered the most reductions while CA3 and CA2 regions the least. Recovering rats examined at P90 exhibited remarkable growth plasticity and recovery in HC regions, as evident by their near normal HC cortical surface area values, compared to age-matched controls. The 2D maps also revealed growth deficits in all HC regions of the hypothyroid rats; recovery in these parameters occurred across all dimensions, although the anterior-posterior growth was more severely affected than the mediolateral one. These results are confirmed and extended by volumetric analysis of laminar volumes of HC regions presented in a companion paper [Farahvar, A., Darwish, N., Sladek, S., Meisami, E., in press. Marked recovery of functional metabolic activity and laminar volumes in the rat hippocampus and dentate gyrus following postnatal hypothyroid growth retardation: a quantitative cytochrome oxidase study. Exp. Neurol.]. These results imply that HC regions, in contrast to whole brain, possess exceptional growth plasticity, as shown by ability to dramatically recover from early hypothyroid retardation; also 2D morphometric maps are useful tools to visualize complex and convoluted regional sheet of HC cortex and depict quantitative aspects of growth in normal and experimental condit

Topics: Age Factors; Analysis of Variance; Animals; Animals, Newborn; Body Weight; Brain Mapping; Computer-Aided Design; Disease Models, Animal; Female; Hippocampus; Hypothyroidism; Male; Pregnancy; Propylthiouracil; Rats; Rats, Sprague-Dawley; Recovery of Function; Thyroxine; Triiodothyronine

Thyroid hormones play an important role in brain development. In the present study, we examined the influence of transient postnatal hypothyroidism on reproductive neuroendocrine and behavioral outcomes in the male Syrian (golden) hamster. Hamster pups were rendered hypothyroid following exposure to the goitrogen, 6-n-propyl-2-thiouracil (PTU), between postnatal (PN) day 0 (birth) and PN25 (weaning). By 15 days after cessation of PTU, exposure (PN40) serum thyroxine levels had returned to control levels. The testes of treated males were approximately 30% heavier than controls and daily sperm production was increased by 73%. Immunocytochemistry for GnRH revealed that the total number of GnRH neurons did not vary between groups; however, a shift in the distribution of GnRH neurons was observed in treated males such that more GnRH immunoreactive neurons were found in the caudal portion of their normal distribution. The shift in GnRH distribution was associated with a significant reduction (40-50%) in pituitary gonadotropin secretion. Behaviorally, treated males took significantly longer to investigate the anogenital region and then mount a receptive female. A corresponding reduction in the total number of anogenital investigations and mounts was observed. This difference between treated males and controls was reduced, but not eliminated, over successive trials and by the third trial the number of intromission was similar between treated and control males. We conclude that the full complement of adult reproductive functions observed in the male golden hamster requires thyroid hormones during the early postnatal period. The severity of the effects induced by early hypothyroidism in this species varies from transient to permanent, depending on the endpoint.

Topics: Age Factors; Analysis of Variance; Animals; Animals, Newborn; Antimetabolites; Brain; Cricetinae; Gonadotropin-Releasing Hormone; Hypothyroidism; Immunohistochemistry; Male; Mesocricetus; Neurons; Neurosecretory Systems; Organ Size; Propylthiouracil; Reproduction; Sexual Behavior, Animal; Testis; Thyroxine

Similar to cretinism in human children, absence or deficiency of thyroid hormones in rats and mice during early postnatal development results in marked retardation of brain development along with behavioral and cognitive deficits. Less is known about brain recovery from postnatal hypothyroidism. [Farahvar, A., Meisami, E., 2007. Novel two-dimensional morphometric maps and quantitative analysis reveal marked growth and structural recovery of the rat hippocampal regions from early hypothyroid retardation. Experimental Neurology.] found, by means of morphometric maps, that surface areas of hippocampal cortex and its CA1-CA4 regions which were significantly reduced in developing hypothyroid rats, show nearly complete growth recovery upon restoration of thyroid function. Here we explore the ability of hippocampal synapse-rich neuronal fiber layers to show recovery from early hypothyroid growth retardation. Rat pups were made hypothyroid from birth to day 25 (weaning) or up to young adulthood (day 90) by a treatment with the reversible goitrogen, PTU (n-propylthiouracil), in the drinking water. Recovery was induced by withdrawal of PTU at weaning and analysis of cytochrome oxidase (CytOx)-stained serial sections of the hippocampus and dentate gyrus at the ages of 25 and 90 days. CytOx stains the synapse-rich fiber layers of the hippocampal formation (HCF). Volumetric growth of molecular layer, stratum oriens and radiatum and dentate hilar region showed complete or nearly complete recovery from marked and significant growth retardation induced by early postnatal hypothyroidism. Also the reduced CytOx staining intensity in the hypothyroid rat HCF layers showed marked recovery following hormonal restoration. Results indicate remarkable growth plasticity of the HCF and ability of the synapse-rich fiber layers to show complete recovery of metabolic and functional neural activity from deleterious effects of early hypothyroidism. Mitochondrial CytOx is highly localized to the synapse-rich fiber layers of the HCF and its activity and histochemical staining intensity correlates positively with functional metabolic activity of neural tissue. Thus hippocampus and dentate gyrus neuronal fiber layers and their oxidative activity show remarkable ability to recover from the postnatal hypothyroid growth retardation. The results indicate that some brain regions are less vulnerable to early developmental insults and can recover.

Topics: Age Factors; Animals; Animals, Newborn; Diagnostic Imaging; Disease Models, Animal; Electron Transport Complex IV; Female; Gene Expression Regulation, Developmental; Hippocampus; Hypothyroidism; Male; Pregnancy; Propylthiouracil; Rats; Rats, Sprague-Dawley; Recovery of Function; Thyroid Gland; Thyroid Hormones

Two genes encoding cardiac myosin heavy chain (MHC) isoforms, beta and alpha, are arranged in tandem 4.5 kb apart. We examined pre-mRNA and mature mRNA levels of beta and alpha genes in control, diabetic (streptozotocin), hypothyroid (propylthiouracil), and hyperthyroid rat hearts and analyzed the naturally occurring antisense (AS) beta RNA species that starts in the middle of the 4.5-kb intergenic region and extends upstream to the beta-gene promoter. The beta and alpha genes are expressed antithetically in control, diabetic, hypothyroid, and hyperthyroid hearts. Expression of AS beta-RNA was positively correlated with alpha-mRNA and negatively correlated with sense beta mRNA. These results support the novel idea of common promoter-regulatory elements situated in the intergenic region that likely control transcription of both sense alpha and AS beta genes and that AS beta transcription negatively regulates beta-MHC gene expression. To test whether an intergenic promoter drives transcription of AS beta RNA, a 1340-bp sequence of the intergenic region was inserted into a luciferase plasmid in the 3'-to-5' AS direction and was injected into rat ventricle. This promoter was activated in control heart and decreased greatly in response to propylthiouracil and streptozotocin and increased in hyperthyroid rats, similar in pattern to the endogenous AS beta RNA. When a putative retinoic acid receptor (RAR) site (a known thyroid hormone receptor cofactor) in this promoter was mutated, the reporter activity was almost abolished in control, propylthiouracil, and streptozotocin hearts. We conclude that there is an intergenic promoter that is active in the AS direction and that the putative RAR element is a vital regulatory site.

Topics: Animals; Diabetes Mellitus, Experimental; DNA, Intergenic; Female; Genes, Reporter; Heart Ventricles; Hyperthyroidism; Hypothyroidism; Luciferases; Mutation; Myosin Heavy Chains; Promoter Regions, Genetic; Propylthiouracil; Rats; Rats, Sprague-Dawley; Receptors, Retinoic Acid; Response Elements; RNA; RNA Precursors; RNA, Antisense; RNA, Messenger; Transcription, Genetic; Triiodothyronine; Ventricular Myosins

The effects of sarcomere length (SL) on sarcomeric loaded shortening velocity, power output and rates of force development were examined in rat skinned cardiac myocytes that contained either alpha-myosin heavy chain (alpha-MyHC) or beta-MyHC at 12 +/- 1 degrees C. When SL was decreased from 2.3 microm to 2.0 microm submaximal isometric force decreased approximately 40% in both alpha-MyHC and beta-MyHC myocytes while peak absolute power output decreased 55% in alpha-MyHC myocytes and 70% in beta-MyHC myocytes. After normalization for the fall in force, peak power output decreased about twice as much in beta-MyHC as in alpha-MyHC myocytes (41% versus 20%). To determine whether the fall in normalized power was due to the lower force levels, [Ca(2+)] was increased at short SL to match force at long SL. Surprisingly, this led to a 32% greater peak normalized power output at short SL compared to long SL in alpha-MyHC myocytes, whereas in beta-MyHC myocytes peak normalized power output remained depressed at short SL. The role that interfilament spacing plays in determining SL dependence of power was tested by myocyte compression at short SL. Addition of 2% dextran at short SL decreased myocyte width and increased force to levels obtained at long SL, and increased peak normalized power output to values greater than at long SL in both alpha-MyHC and beta-MyHC myocytes. The rate constant of force development (k(tr)) was also measured and was not different between long and short SL at the same [Ca(2+)] in alpha-MyHC myocytes but was greater at short SL in beta-MyHC myocytes. At short SL with matched force by either dextran or [Ca(2+)], k(tr) was greater than at long SL in both alpha-MyHC and beta-MyHC myocytes. Overall, these results are consistent with the idea that an intrinsic length component increases loaded crossbridge cycling rates at short SL and beta-MyHC myocytes exhibit a greater sarcomere length dependence of power output.

Topics: Animals; Calcium; Cell Size; Dextrans; Disease Models, Animal; Hypothyroidism; Isometric Contraction; Male; Muscle Strength; Myocardial Contraction; Myocytes, Cardiac; Myofibrils; Myosin Heavy Chains; Osmosis; Propylthiouracil; Rats; Rats, Sprague-Dawley; Sarcomeres; Thyroidectomy

The memory impairment induced by adult-onset hypothyroidism is a common symptom. However, the exact onset time that will influence on memory function is still an issue of debate. The purpose of this study is to determine the onset effect of hypothyroidism on the memory during adulthood. Three age groups of Kunming (KM) mice were used, including 2, 8, and 15-month-old mice. Adult-onset hypothyroidism was made by adding PTU to drinking water and hypothyroid states were documented by the measurement of serum thyroid hormones level. A battery of tasks, i.e. novel-object recognition, olfactory discrimination, Morris water maze, was used to test mice's memory. The results showed that adult-onset hypothyroidism induced the impairment of odor and spatial memory consolidation whereas it did not affect visual memory encoding or consolidated spatial memory retention. Age at onset of hypothyroidism was an important factor for the memory impairment induced by hypothyroidism. The 2-month-old hypothyroid mice had significantly impaired abilities in both the olfactory discrimination and the spatial cognitive tasks relative to the 2-month-old controls. The 8-month-old hypothyroid mice had only impaired ability in the spatial cognitive task relative to the same age controls. The 15-month-old hypothyroid mice retained these cognitive abilities relative to the same age controls. These results suggested that adult-onset hypothyroidism could induce an age- and task-dependent impairment of memory in female KM mice.

Topics: Age of Onset; Aging; Analysis of Variance; Animals; Discrimination Learning; Female; Hypothyroidism; Maze Learning; Memory Disorders; Mice; Propylthiouracil; Random Allocation; Recognition, Psychology; Smell; Thyroid Hormones

The molecular mechanisms involved in the response of developing mice to disruptions in maternal thyroid hormone (TH) homeostasis are poorly characterized. We used DNA microarrays to examine a broad spectrum of genes from the livers of mice rendered hypothyroid by treating pregnant mice from gestational d 13 to postnatal d 15 with 6-propyl-2-thiouracil in drinking water. Twenty-four individuals (one male and one female pup from six litters of control or 6-propyl-2-thiouracil treatment groups, respectively) were profiled using Agilent oligonucleotide microarrays. MAANOVA identified 96 differentially expressed genes (false discovery rate adjusted P < 0.1 and fold change > 2 in at least one gender). Of these, 72 genes encode proteins of known function, 15 of which had previously been identified as regulated by TH. Pathway analysis revealed these genes are involved in metabolism, development, cell proliferation, apoptosis, and signal transduction. An immediate-early response gene, Nr4a1 (nuclear receptor subfamily 4, group A, member 1), was up-regulated by 3-fold in hypothyroid juvenile mouse liver; treatment of HepG2 cells with T(3) resulted in down-regulation of Nr4a1. A potential thyroid response element -1218 to -1188 bp upstream of the promoter region of Nr4a1 was identified and demonstrated to bind TH receptor (TR)-alpha and TRbeta. Point mutation or deletion of the sequence containing the potential Nr4a1-thyroid response element in transient gene expression studies resulted in both higher basal expression and loss of T(3) regulatory capacity, suggesting that this site is responsible for the negative regulation of gene expression by TR and TH.

Topics: Age Factors; Animals; Antithyroid Agents; DNA-Binding Proteins; Female; Gene Expression; Gene Expression Profiling; Hypothyroidism; Liver; Male; Mice; Mice, Inbred C57BL; Nuclear Receptor Subfamily 4, Group A, Member 1; Oligonucleotide Array Sequence Analysis; Pregnancy; Promoter Regions, Genetic; Propylthiouracil; Receptors, Cytoplasmic and Nuclear; Receptors, Steroid; Reproducibility of Results; Response Elements; Thyroid Hormones; Transcription Factors

Methods for the isolation and quantitation of cholesterol involve time-consuming chromatographic procedures coupled with the development and measurement of color complexes. The intensity of most color complexes varies with time. This study was undertaken to develop a UV spectrophotometric method to measure cholesterol concentration in plasma lipoprotein fractions. The developed method compared favorably with other methods (chemical and enzymatic) and was then used to investigate the effects of diabetes and hypothyroidism on the lipoprotein cholesterol in rats. Lipoprotein fractions from fasted rats were obtained by gradient ultracentrifugation. Aliquots of the very low-density lipoprotein (VLDL), low-density lipoprotein (LDL) and high-density lipoprotein (HDL) layers were extracted into chloroform-methanol-water. Following hydrolysis of lipid extracts, the solvent was evaporated and the residue was dissolved in ethanol and read in the UV recording spectrophotometer. At 203 nm, a linear relationship between optical density and concentration of cholesterol was obtained. The results obtained with the new method were compared with those obtained using chemical and enzymatic methods and the statistical difference among the methods was insignificant (p>0.05). From the results of our comparative studies of the methods, it was concluded that the UV method is valid for measuring cholesterol in lipoprotein fractions. The method has the advantage being rapid, nondestructive and cost-effective.

Topics: Animals; Cholesterol; Diabetes Complications; Diabetes Mellitus, Experimental; Hypothyroidism; Lipoproteins; Propylthiouracil; Rats; Reference Standards; Spectrophotometry, Ultraviolet

Our previous study has shown the alteration of C cells activity in rats with experimental model of hyperthyroidism. The aim of the present study was the evaluation of parafollicular cells activity in rats with hypothyroidism evoked by propylthiouracil (PTU) given in drinking water over 21 days. Histological, ultrastructural and immunocytochemical studies using specific antibodies against calcitonin and CGRP were performed on thyroid glands taken from experimental and control groups of rats. Moreover, in all animals the calcitonin plasma levels were evaluated by radioimmunoassay. After chronic administration of PTU, thyroid image showed predominant microfollicular hyperplasia and attenuated density of parafollicular cells. The intensity of immunocytochemical reactions for CT and CGRP were weaker in the majority of C cells in comparison to the control rats, in which strong immunocytochemical reaction was observed. Examination in the electron microscope reveals the features of hypoactivity both in follicular and parafollicular cells, in which the quantity and electron density of secretory granules were smaller in comparison to the control group. These microscopic changes were accompanied by a significant decrease of calcitonin plasma concentration. Alteration of C cells activity in the experimental model of hypothyroidism, accompanied by microfollicular hypertrophy, may point to the mutual cooperation between parafollicular and follicular cells.

Topics: Animals; Calcitonin; Calcitonin Gene-Related Peptide; Hypothyroidism; Male; Propylthiouracil; Radioimmunoassay; Rats; Rats, Wistar; Thyroid Gland

The thyroid hormones (THs) are crucial determinants of normal development and metabolism, especially in the central nervous system. The metabolic rate is known to increase in hyperthyroidism and decrease in hypothyroidism. The aim of this work was to investigate how changes in metabolism induced by THs could affect the activities of acetylcholinesterase (AChE), (Na+,K+)- and Mg2+-adenosinetriphosphatase (ATPase) in the frontal cortex and the hippocampus of adult rats. Hyperthyroidism was induced by subcutaneous administration of thyroxine (25 microg/100 g body weight) once daily for 14 days, and hypothyroidism was induced by oral administration of propylthiouracil (0.05%) for 21 days. All enzyme activities were evaluated spectrophotometrically in the homogenated brain regions of 10 three-animal pools. A region-specific behavior was observed concerning the examined enzyme activities in hyper- and hypothyroidism. In hyperthyroidism, AChE activity was significantly increased only in the hippocampus (+22%), whereas Na+,K+-ATPase activity was significantly decreased in the hyperthyroid rat hippocampus (-47%) and remained unchanged in the frontal cortex. In hypothyroidism, AChE activity was significantly decreased in the frontal cortex (-23%) and increased in the hippocampus (+21%). Na+,K+-ATPase activity was significantly decreased in both the frontal cortex (-35%) and the hippocampus (-43%) of hypothyroid rats. Mg2+-ATPase remained unchanged in the regions of both hyper- and hypothyroid rat brains. Our data revealed that THs affect the examined adult rat brain parameters in a region- and state-specific way. The TH-reduced Na+,K+-ATPase activity may increase the synaptic acetylcholine release and, thus, modulate AChE activity. Moreover, the above TH-induced changes may affect the monoamine neurotransmitter systems in the examined brain regions.

Topics: Acetylcholinesterase; Animals; Antithyroid Agents; Ca(2+) Mg(2+)-ATPase; Hippocampus; Hyperthyroidism; Hypothyroidism; Male; Prefrontal Cortex; Propylthiouracil; Rats; Sodium-Potassium-Exchanging ATPase; Thyroxine

Changes in thyroid status are associated with profound alterations in biochemical and physiological functioning of cardiac muscle, although its impact on cardiac energy metabolism is still debated. Similarities between the changes in cardiac gene expression in pathological hypertrophy leading to heart failure and hypothyroidism prompted scientists to suggest a role for thyroid hormone status in the development of metabolic and functional alterations in this disease. We thus investigated the effects of hypothyroidism on cardiac energy metabolism. Hypothyroid state (HYPO) was induced by thyroidectomy and propyl-thio-uracyl in male rats for 3 weeks. We examined the effects of hypothyroid state on oxidative capacity and mitochondrial substrate utilization by measuring oxygen consumption of saponin permeabilized cardiac fibers, mitochondrial biogenesis by reverse transcription polymerase chain reaction and energy metabolism, and energy transfer enzymes by spectrophotometry. The results show that maximal oxidative capacity of the myocardium was decreased from 24.9 +/- 0.9 in control (CT) to 19.3 +/- 0.7 micromol O(2) min(-1) g dry weight(-1) in HYPO. However, protein content and messenger RNA (mRNA) of PGC-1alpha and mRNA of its transcription cascade that is thought to control mitochondrial content in normal myocardium and heart failure, were unchanged in HYPO. Mitochondrial utilization of glycerol-3P (-70%), malate (-45%), and octanoate (-24%) but not pyruvate was decreased in HYPO. Moreover, the creatine kinase system and energy transfer were hardly affected in HYPO. Besides, hypothyroidism decreased the activation of other signaling pathways like p38 mitogen-activated protein kinases, AMP-activated protein kinase, and calcineurin. These results show that cellular hypothyroidism can hardly account for the specific energetic alterations of heart failure.

Topics: AMP-Activated Protein Kinases; Animals; Calcineurin; Electron Transport Complex IV; Energy Metabolism; Energy Transfer; Heart Failure; Hypothyroidism; Intracellular Signaling Peptides and Proteins; Male; Mitochondria, Heart; Multienzyme Complexes; Myocardium; p38 Mitogen-Activated Protein Kinases; Phenotype; Propylthiouracil; Protein Serine-Threonine Kinases; Rats; Rats, Wistar; Signal Transduction; Thyroid Hormones; Transcription Factors

1. Hypothyroidism is accompanied by hyperlipidaemia and oxidative stress and is associated with several complications, such as atherosclerosis. Paraoxonase activity has been reported to decrease in several situations associated with atherosclerosis and oxidative stress. In the present study, the effects of different doses of taurine on serum paraoxonase and arylesterase activities, as well as on the serum lipid profile, were investigated in hypothyroid rats. 2. Forty male Sprague-Dawley rats were randomly divided into five groups as follows: Group 1, rats received normal rat chow and tap water; Group 2, rats received standard rat chow + 0.05% propylthiouracil (PTU) in the drinking water; and Groups 3-5, taurine-supplemented PTU groups (standard rat chow + 0.5, 2 or 3% taurine in the drinking water, respectively, in addition to PTU). Paraoxon or phenylacetate were used as substrates to measure paraoxonase and arylesterase activity, respectively. Plasma and tissue malondialdehyde (MDA) levels, indicators of lipid peroxidation, were determined using the thiobarbituric-acid reactive substances method. Serum triglyceride, total cholesterol and high-density lipoprotein-cholesterol (following precipitation with dextran sulphate-magnesium chloride) were determined using enzymatic methods. 3. Serum paraoxonase and arylesterase activities were increased and plasma and tissue MDA levels and serum triglyceride levels were reduced in a dose-dependent manner in taurine-treated hypothyroid rats. Taurine concentrations were positively correlated with enzyme activities and negatively correlated with MDA and triglyceride levels. 4. Further studies are needed to investigate the role of taurine supplementation in hypothyroidism in human subjects.

Topics: Animals; Antioxidants; Aryldialkylphosphatase; Carboxylic Ester Hydrolases; Cholesterol; Cholesterol, HDL; Dietary Supplements; Disease Models, Animal; Dose-Response Relationship, Drug; Hypothyroidism; Lipid Peroxidation; Male; Malondialdehyde; Paraoxon; Phenylacetates; Propylthiouracil; Rats; Rats, Sprague-Dawley; Taurine; Triglycerides; Up-Regulation

The effect of the hormones triiodothyronine (T3) and melatonin on antioxidant defense system was studied in 6-propyl thiouracil (6-PTU)-treated or photoperiod-exposed teleost Anabas testudineus. 6-PTU (2 microg/g) treatment or photoperiod exposure (24 h) increased malondialdehyde (MDA) and conjugated dienes (CD) concentrations, indicating increased lipid peroxidation (LPO) in the experimental conditions. T3 or melatonin (10(-6) M) treatment for 15 min in vitro in PTU-treated fish reversed the activity of superoxide dismutase (SOD), catalase and glutathione content. T3-treated group showed no change in glutathione peroxidase (GPx) activity, whereas melatonin treatment decreased its activity. T3 inhibited glutathione reductase (GR) activity. Photoperiod exposure (physiological pinealotomy) induced a stressful situation in this teleost, as evidenced by LPO products and antioxidant enzyme activities. Melatonin and T3 treatment for 15 min in vitro also reversed the effect of photoperiod on peroxidation products and the SOD and catalase activities. GR activity decreased in photoperiod-exposed group and melatonin and T3 treatment reversed the activities. The antioxidant enzymes responded to the stress situation after 6-PTU treatment and photoperiod exposure by altering their activities. The study suggested an independent effect of T3 and melatonin on antioxidant defence mechanism in different physiological situations in fish.

Topics: Animals; Antioxidants; Fishes; Free Radicals; Glutathione Peroxidase; Hypothyroidism; Light; Lipid Peroxidation; Liver; Melatonin; Pineal Gland; Propylthiouracil; Thyroid Gland; Triiodothyronine

A twin pregnancy with a coexisting complete hydatiform mole and a healthy fetus is rare. Associated with this condition are potentially serious maternal and fetal complications. We describe a case of a woman, 23/40 pregnant, who was diagnosed with a twin pregnancy complicated by a hydatiform mole, vaginal bleeding, hyperthyroidism and preterm labour at 26/40. Her hyperthyroidism was successfully treated with propylthiouracil. The preterm labour resulted in the livebirth of a healthy male infant. The baby developed biochemical hypothyroidism post-natally. The baby's thyroid function tests were unexpected, revealing a low T4 and a low-normal thyroid stimulating hormone. This is the first case reported in the literature to describe an infant's clinical and biochemical thyroid status after gestational trophoblastic disease complicated by hyperthyroidism.

Topics: Adrenergic beta-Antagonists; Adult; Antithyroid Agents; Female; Humans; Hydatidiform Mole; Hyperthyroidism; Hypothyroidism; Infant, Newborn; Live Birth; Male; Pregnancy; Propranolol; Propylthiouracil; Thyroid Function Tests; Treatment Outcome; Twins

Involvement of thyroid gland in the hepatotoxic manifestations of arsenic trioxide (As(III)) has been studied in rat. The effects of n-propylthiouracil (PTU) (a thyrotoxic compound) and L-thyroxine (a thyroid hormone) have been studied with reference to T(3) and T(4) values in the serum, arsenic concentration in the liver, Ca(2+) accumulation in the liver, aspartate transaminase, alanine transaminase and bilirubin values as the indicators of liver function, histopathological observations and finally the ultrastructural studies. It is concluded that hypothyroid condition protects against As(III) toxicity. Scavenging of reactive oxygen species (ROS) that significantly contribute in As(III) toxicity, by high intracellular concentration of reduced glutathione, as a consequence of PTU treatment is proposed as the plausible protective mechanism.

Topics: Animals; Arsenic Poisoning; Arsenic Trioxide; Arsenicals; Calcium; Hyperthyroidism; Hypothyroidism; Liver; Male; Oxides; Propylthiouracil; Rats; Rats, Wistar; Thyroid Gland; Thyroxine; Triiodothyronine

During adult-onset peripheral hypothyroidism, the brain maintains normal levels of thyroid hormone for some time through a mechanism of 'central homeostasis'. Although onset, duration, and termination of such a homeostatic phenomenon have been recently evaluated in rat models, the mechanism behind remains unknown. During our investigation to understand the mechanism further, we injected the protein synthesis blockers actinomycin D and cycloheximide along with propylthiouracil to adult male rats during the days of onset (day 2) and termination (day 20) of the homeostatic mechanism. We evaluated synaptosomal T(3) level and neuronal Na(+)-K(+)-ATPase and acetylcholinesterase activities along with deiodinase II activity and cyclic adenosine monophosphate level in the cerebral cortex. The results indicated prevalence of unchanged or lower levels of synaptosomal T(3) on the 2nd and on the 20th day, respectively. Such a condition has been parallely supported by reflections in cerebrocortical deiodinase II activity and cyclic adenosine monophosphate levels. The activities of cerebrocortical synaptosomal Na(+)-K(+)-ATPase and acetylcholinesterase, which are the two important physiological parameters for neuronal function, have been found to be supportive of the involvement of a neuronal protein-mediated factor in the 'on' and 'off' reactions in central homeostasis during peripheral hypothyroidism. The results of our study indicate that the expression of 'central thyroid hormone homeostasis' is a genomic nuclear-mediated mechanism.

Topics: Acetylcholinesterase; Age Factors; Animals; Antithyroid Agents; Cell Nucleus; Cerebral Cortex; Cyclic AMP; Cycloheximide; Dactinomycin; Homeostasis; Hypothyroidism; Iodide Peroxidase; Iodothyronine Deiodinase Type II; Male; Propylthiouracil; Protein Synthesis Inhibitors; Rats; Rats, Sprague-Dawley; Sodium-Potassium-Exchanging ATPase; Synaptosomes; Thyroxine; Triiodothyronine

Methimazole (MMI) and propylthiouracil (PTU) are popularly used antithyroid drugs (ATDs) for the treatment of Graves' hyperthyroidism. The aim of the present study was to determine the effects of ATDs on the developing immune system of the rats. Maternal Sprague-Dawley rats were given drinking water containing 200 ppm of MMI, 12 ppm of PTU (high-dose PTU), or 3 ppm of PTU (low-dose PTU) between gestational day (GD) 10 and postnatal week (PNW) 3. Exposure to the ATDs was ceased upon weaning at PNW3, and the male offspring were sampled at PNWs 3 or 11. The serum thyroid-related hormone levels and the hematological components in the offspring were then determined. The expressions of surface markers in the spleen, thymus and peripheral blood were determined using flowcytometry. The weights of the body, spleen and thymus and the splenic and thymic cell numbers were decreased in the MMI-treated and the high-dose PTU-treated animals at PNWs 3 and 11. The serum levels of thyroid-related hormones were depressed in the MMI and high-dose PTU groups. FACS analysis revealed that the ATDs caused proportional changes in the lymphoid cell subpopulations. The proportion of B cells among the total lymphocytes was significantly decreased at PNW3, whereas that of T cells, especially of inactive T cells, was dramatically increased. Moreover, the proportion of CD4(+)CD25(+) regulatory T cells was significantly increased in the spleen and peripheral blood at PNW3. Most of the above-described changes had recovered to normal levels at PNW11. These results suggest that ATDs might have temporal immunomodulatory effects on the developing immune system.

Topics: Animals; Antigens, CD; Antigens, Surface; Female; Fetus; Flow Cytometry; Hypothyroidism; Immune System; Lectins, C-Type; Lymphocyte Subsets; Methimazole; NK Cell Lectin-Like Receptor Subfamily B; Organ Size; Pregnancy; Propylthiouracil; Rats; Rats, Sprague-Dawley; Receptors, Transferrin; Spleen; Thymus Gland

Subclinical form of hypothyroidism was not associated with considerable changes in Ca(2+) content in osteoblasts and blood plasma and in the content of ATP and prostaglandin E2. Activation of prostaglandin E2 synthesis in response to binding of extracellular Ca(2+) in osteoblasts in the absence of ATP was less pronounced (by 11%) compared to the control. Progression of hypothyroidism and development of clinical signs of the disease were accompanied by a decrease in Ca(2+) content in osteoblasts and plasma by 45 and 12%, respectively, and ATP content in osteoblasts by 30%, and by activation of prostaglandin E2 synthesis by 117%. Moreover, the synthesis of prostaglandins in response to binding of extra- and intracellular Ca(2+) also considerably changed. Hyperthyroidism (2 months) was characterized by a moderate decrease in plasma content of Ca(2+) by 15% and ATP by 25%, together with an increase in prostaglandin E2 level by 55.5%. The release of prostaglandin E2 in response to chelation of extracellular Ca(2+) increased even more markedly, but somewhat decreased in response to addition of 5 mM ATP due to compensation of metabolic acidosis.

Topics: Animals; Calcium; Dinoprostone; Female; Femur; Homeostasis; Hyperthyroidism; Hypothyroidism; Male; Osteoblasts; Propylthiouracil; Rats; Thyroxine

Thyroid hormones are critical for the development and maturation of the central nervous system. Although somatic and neurological effects are well documented following severe thyroid hormone deprivation, much less is known of the functional consequences of moderate levels of hormone insufficiency. We have previously demonstrated that severe thyroid hormone reductions in the postnatal period are associated with impairments in synaptic transmission in the dentate gyrus. The present study was performed to examine the dose-response relationships of moderate levels of hormone disruption on synaptic function in the dentate gyrus in an in vivo preparation and to determine the effects on spatial learning. Pre- and postnatal thyroid hormone insufficiency was induced by administration of 3 or 10 ppm propylthiouracil (PTU) to pregnant and lactating dams via the drinking water from gestation day (GD) 6 until postnatal day (PN) 30. This regimen produced a 47% and 65% reduction in serum T4, in the dams of the low and high-dose groups, respectively. At the time of testing of adult offspring, hormone status had returned to control levels. In littermates, field potentials evoked in the dentate gyrus in response to stimulation of the perforant path were assessed under urethane anesthesia. The data reveal dose-dependent reductions in synaptic transmission and impairments in long-term potentiation (LTP) of the EPSP component of the compound field potential. In contrast, LTP of the population spike measure was paradoxically enhanced. Spatial learning in the Morris water maze was profoundly impaired in high-dose animals. Although the majority of subjects in the low-dose group eventually acquired the task, their acquisition rate lagged behind control values. Reversal learning was assessed in all animals reaching criterion performance and found to be impaired in PTU-exposed animals relative to controls. These data support previous findings in area CA1 in vitro, extend observations associated with dentate gyrus synaptic function to a lower dose range, and provide correlative evidence of behavioral disruption in a hippocampal-dependent learning task following developmental thyroid hormone insufficiency.

Topics: Age Factors; Analysis of Variance; Animals; Animals, Newborn; Cues; Dentate Gyrus; Dose-Response Relationship, Drug; Dose-Response Relationship, Radiation; Electric Stimulation; Embryo, Mammalian; Excitatory Postsynaptic Potentials; Female; Hypothyroidism; Long-Term Potentiation; Maze Learning; Pregnancy; Prenatal Exposure Delayed Effects; Propylthiouracil; Rats; Reversal Learning; Spatial Behavior; Synaptic Transmission; Thyroid Hormones; Time Factors

In this study, we examined changes in the biochemical and inotropic events of the alpha(1)-adrenoceptor signaling pathway in hypothyroid rat hearts. Hypothyroidism was induced by treating experimental animals with 0.05% 6-n-propyl-2-thiouracil (PTU) in drinking water for 7 weeks. A significant decrease of beta- and an increase in alpha(1)-adrenoceptor density as well as an increase in the basal activity of the phosphoinositide (4,5) bisphosphate hydrolyzing phospholipase C was observed in sarcolemmal membranes purified from hypothyroid hearts as compared to age-matched euthyroid controls. Following stimulation with 10 microM phenylephrine (in the presence of 10 microM atenolol), the increase of contractile parameters over baseline values was significantly higher in hypo- than euthyroid hearts, while the opposite occurred under beta-stimulation with 0.1 microM isoproterenol. Interestingly, the increase in phenylephrine-mediated positive inotropy was accompanied by a significant increase in the sarcolemmal phospholipase C activity and in the inositol 1,4,5-trisphosphate content in hypothyroid as compared to euthyroid controls. Our results suggest that cardiac alpha(1)-adrenoceptor and its associated phosphoinositide signaling pathway may act as a reserve for catecholamine inotropic response in hypothyroidism, where the beta-adrenoceptors are compromised.

Topics: Animals; Antithyroid Agents; Cell Membrane; Heart; Hypothyroidism; Inositol 1,4,5-Trisphosphate; Male; Phosphatidylinositol 4,5-Diphosphate; Propylthiouracil; Rats; Rats, Sprague-Dawley; Receptors, Adrenergic, alpha-1; Sarcolemma; Signal Transduction; Stimulation, Chemical; Type C Phospholipases; Up-Regulation

The objective of this study was to examine the potential radioprotective properties of propylthiouracil (PTU)-induced hypothyroidism against oxidative organ damage induced by irradiation. Sprague-Dawley rats were pre-treated with saline or PTU (10 mg/kg i.p.) for 15 days, and were then exposed to whole-body irradiation (800 cGy). A group of rats were decapitated at 6 h after exposure to irradiation, while another group was followed for 72 h after irradiation, during which saline or PTU injections were repeated once daily. Lung, liver, kidney and ileum samples were obtained for the determination of malondialdehyde (MDA; an index of lipid peroxidation) and glutathione (GSH, an antioxidant) levels, myeloperoxidase activity (MPO; an index of tissue neutrophil accumulation) and collagen contents, while oxidant-induced DNA fragmentation was evaluated in the ileal tissues. All tissues were also examined microscopically and assayed for the production of reactive oxidants using chemiluminescence (CL). Lactate dehydrogenase (LDH), an indicator of tissue damage, and tumour necrosis factor-alpha (TNFalpha) were assayed in serum samples. Irradiation caused a significant decrease in GSH level, which was accompanied by significant increases in MDA levels, MPO activity, CL levels and collagen content of the tissues studied (P<0.05-0.001). Similarly, serum TNFalpha and LDH were elevated in the irradiated rats as compared with the control group. On the other hand, PTU treatment reversed all these biochemical indices, as well as histopathological alterations induced by irradiation. Our results suggested that PTU-induced hypothyroidism reduces oxidative damage in the lung, hepatic, renal and ileal tissues probably due to hypometabolism, which is associated with decreased production of reactive oxygen metabolites and enhancement of antioxidant mechanisms.

Topics: Animals; Antioxidants; Antithyroid Agents; Collagen; DNA Fragmentation; Glutathione; Hypothyroidism; Ileum; Intestinal Mucosa; Kidney; L-Lactate Dehydrogenase; Lipid Peroxidation; Liver; Lung; Male; Malondialdehyde; Oxidative Stress; Peroxidase; Propylthiouracil; Radiation Protection; Radiation, Ionizing; Rats; Rats, Sprague-Dawley; Tumor Necrosis Factor-alpha; Whole-Body Irradiation

Thyroid hormones are essential for normal functioning of adult mammalian brain. The present investigation deals with the understanding of the time course of thyroid hormone homeostasis in adult rat brain. Animals were rendered hypothyroid by PTU injections (2 mg/100 g bw) for 30 consecutive days. Serum and synaptosomal T3/T4 content, synaptosomal AChE and Na+-K+-ATPase activities were determined on alternate days. While serum T4 level initially increased on the second day compared to control, serum T3 declined in a triphasic pattern; the first phase lasting from the second day to the 6th day, the second phase ended on the 14th day and last phase continued till the 30th day. Cerebro-cortical synaptosomal T3 level increased on the 2nd day from the control, attained a peak on the 4th day, remained stable until the 18th day, and abruptly declined on the 20th day. Synaptosomal T4 content remained negligible or undetected throughout. Synaptosomal membrane Na+-K+-ATPase and AChE activity exhibited an inverse relationship during the experimental regime, being much more prominent on the 2nd, 18th and 20th day coinciding with the variations in brain T3 level. Thus, the study identifies the onset of central homeostasis between the first and second day, its continuation for about 16-18 days and its termination between the 18th and 20th day.

Topics: Acetylcholinesterase; Animals; Antithyroid Agents; Brain; Brain Chemistry; Dextrothyroxine; Homeostasis; Hypothyroidism; Male; Propylthiouracil; Rats; Rats, Sprague-Dawley; Sodium-Potassium-Exchanging ATPase; Synaptic Membranes; Synaptosomes; Triiodothyronine

The effect of hyper or hypoactive thyroid on the renal toxicity of arsenic trioxide has been studied in rats. It was observed that pre-treatment of rats with thyroxine stimulates arsenic excretion in urine. The anti-thyroid drug n-propylthiouracil (PTU), inhibits the accumulation of arsenic in renal tissue. Both treatments affect the renal pathology. Histopathological lesions are less severe in PTU and arsenic-treated rats in comparison to thyroxine and arsenic-treated rats. Ultrastructural studies support light microscopical observations. An adaptive response was noticed against arsenic in PTU pre-treated rats. We attribute this response to decreased glutathione-S-transferase (GSH) activity and increased GSH synthesis in the kidney. A relationship between thyroidal activity and arsenic toxicity is suggested by present observations.

Topics: Animals; Antithyroid Agents; Apoptosis; Arsenic Trioxide; Arsenicals; Creatinine; Glomerulonephritis; Glutathione; Glutathione Transferase; Hyperthyroidism; Hypothyroidism; Kidney; Male; Necrosis; Oxides; Propylthiouracil; Rats; Rats, Wistar; Thyroxine; Triiodothyronine

Thyroid hormones are critical for the maturation and function of the central nervous system. Insufficiency of thyroid hormones in the adulthood causes a wide range of cognitive dysfunctions, including deficits in learning and memory. The present study investigated whether adult-onset hypothyroidism would alter synaptic functions in the dorsal hippocampo-medial prefrontal cortex (mPFC) pathway, a neural pathway important for learning and memory. Adult hypothyroidism was induced by oral administration of 1% (g/l) antithyroid acting drug 6-n-propyl-2-thiouracil (PTU) to adult male Sprague-Dawley rats for 4 weeks. Postsynaptic potentials (PSP) were recorded in the mPFC by stimulating the dorsal hippocampal CA1 region in vivo. Basal synaptic transmission was evaluated by comparing input-output relationships. Paired-pulse facilitation and long-term potentiation were recorded to examine short- and long-term synaptic plasticity. Adult-onset hypothyroidism did not change the basal synaptic transmission, but significantly reduced paired-pulse facilitation and long-term potentiation of PSP. These inhibitions can be restored by thyroid hormone replacement. The results suggest that such alterations in synaptic plasticity of the dorsal hippocampo-mPFC pathway might contribute to understanding basic mechanisms underlying learning and memory deficits associated with adult-onset hypothyroidism.

Topics: Animals; Antithyroid Agents; Body Weight; Electric Stimulation; Electrophysiology; Excitatory Postsynaptic Potentials; Hippocampus; Hypothyroidism; Long-Term Potentiation; Male; Neural Pathways; Prefrontal Cortex; Propylthiouracil; Rats; Rats, Sprague-Dawley; Synapses; Synaptic Transmission; Thyroid Hormones

Oxidative stress has an important role in the development of multiorgan failure after major burn. This study was designed to determine the possible protective effect of experimental hypothyroidism in hepatic and gastrointestinal injury induced by thermal trauma. Sprague Dawley rats were administered saline or PTU (10 mgkg(-1) i.p.) for 15 days, and hypothyroidism was confirmed by depressed serum T(3) and T(4) concentrations. Under brief ether anesthesia, shaved dorsum of rats was exposed to 90 degrees C (burn group) or 25 degrees C (control group) water bath for 10s. PTU or saline treatment was repeated at the 12th hour of the burn. Rats were decapitated 24h after injury and tissue samples from liver, stomach and ileum were taken for the determination of malondialdehyde (MDA) and glutathione (GSH) levels, myeloperoxidase (MPO) activity and collagen contents. Formation of reactive oxygen species in tissue samples was monitored by using chemiluminescence (CL) technique with luminol and lucigenin probes. Tissues were also examined microscopically. Tumor necrosis factor (TNF)-alpha and lactate dehydrogenase (LDH) were assayed in serum samples. Severe skin scald injury (30% of total body surface area) caused a significant decrease in GSH level, which was accompanied with significant increases in MDA level, MPO activity, CL levels and collagen content of the studied tissues (p<0.05-0.001). Similarly, serum TNF-alpha and LDH were elevated in the burn group as compared to control group. On the other hand, PTU treatment reversed all these biochemical indices, as well as histopathological alterations induced by thermal trauma. Our results suggest that PTU-induced hypothyroidism reduces oxidative damage in the hepatic, gastric and ileal tissues probably due to hypometabolism, which is associated with decreased production of reactive oxygen metabolites and enhancement of antioxidant mechanisms.

Topics: Animals; Antithyroid Agents; Burns; Collagen; Enzymes; Female; Glutathione; Hypothyroidism; Male; Malondialdehyde; Multiple Trauma; Propylthiouracil; Rats; Tumor Necrosis Factor-alpha

This work aimed at verifying the influence of propyl-thiouracil (PTU)-induced thyroid hormone deficiency on gingival mucosa of young male rats, measuring total protein concentration, collagen content and DNA concentration as indices of cellular population. Fifty Sprague-Dawley rats were used. The animals were grouped in: PTU-treated (i.p. 10 mg/d) and control rats (C). The experience was maintained for a period of 10 weeks. Total protein content of gingival mucosa tissue was determined by the Lowry method; hydroxyprolin rate, as prototype amino acid of collagen, was determined using the Newman method, and DNA concentration was measured by Burton's methodology. The results showed decreased amounts of PTU-treated rats gingival total protein content (PTU= 41.23 +/- 24.05 vs. C= 63.36 +/- 18.05); no alterations were seen in hydroxyprolin concentration neither in DNA content of PTU treated rats, respectively (PTU= 2.18 +/- 1.48 vs. C= 2.29 +/- 1.51) and (PTU= 0.33 +/- 0.19 vs. C= 0.46 +/- 0.41). Thus, PTU treatment promotes a decrease in total protein content of rat gingival mucosa that may be interpreted as a decrease in protein synthesis induced by the hypothyroid condition, but with no alteration either in collagen or nucleic acid rates.

Topics: Animals; Antithyroid Agents; Collagen; Colorimetry; Disease Models, Animal; DNA; Gingiva; Hydroxyproline; Hypothyroidism; Male; Propylthiouracil; Proteins; Rats; Rats, Sprague-Dawley; Spectrophotometry; Thyroxine; Triiodothyronine

Myosin heavy chain (MHC) isoforms alpha and beta have intrinsically different ATP hydrolysis activities (ATPase) and therefore cross-bridge cycling rates in solution. There is considerable evidence of altered MHC expression in rodent cardiac disease models; however, the effect of incremental beta-MHC expression over a wide range on the rate of high-strain, isometric cross-bridge cycling is yet to be ascertained. We treated male rats with 6-propyl-2-thiouracil (PTU; 0.8 g/l in drinking water) for short intervals (6, 11, 16, and 21 days) to generate cardiac MHC patterns in transition from predominantly alpha-MHC to predominantly beta-MHC. Steady-state calcium-dependent tension development and tension-dependent ATP consumption (tension cost; proportional to cross-bridge cycling) were measured in chemically permeabilized (skinned) right ventricular muscles at 20 degrees C. To assess dynamic cross-bridge cycling kinetics, the rate of force redevelopment (ktr) was determined after rapid release-restretch of fully activated muscles. MHC isoform content in each experimental muscle was measured by SDS-PAGE and densitometry. alpha-MHC content decreased significantly and progressively with length of PTU treatment [68 +/- 5%, 58 +/- 4%, 37 +/- 4%, and 27 +/- 6% for 6, 11, 16, and 21 days, respectively; P < 0.001 (ANOVA)]. Tension cost decreased, linearly, with decreased alpha-MHC content [6.7 +/- 0.4, 5.6 +/- 0.5, 4.0 +/- 0.4, and 3.9 +/- 0.3 ATPase/tension for 6, 11, 16, and 21 days, respectively; P < 0.001 (ANOVA)]. Likewise, ktr was significantly and progressively depressed with length of PTU treatment [11.1 +/- 0.6, 9.1 +/- 0.5, 8.2 +/- 0.7, and 6.2 +/- 0.3 s(-1) for 6, 11, 16, and 21 days, respectively; P < 0.05 (ANOVA)] Thus cross-bridge cycling, under high strain, for alpha-MHC is three times higher than for beta-MHC. Furthermore, under isometric conditions, alpha-MHC and beta-MHC cross bridges hydrolyze ATP independently of one another.

Topics: Adenosine Triphosphate; Animals; Antithyroid Agents; Hypothyroidism; Isomerism; Kinetics; Male; Myocardial Contraction; Myocytes, Cardiac; Myosin Heavy Chains; Propylthiouracil; Rats; Rats, Inbred Lew; Ventricular Myosins

Thyroid hormones are critical for the development and maturation of the central nervous system. Insufficiency of thyroid hormones during development impairs performance on tasks of learning and memory that rely upon the hippocampus and impairs synaptic function in young hypothyroid animals. The present study was designed to determine if perturbations in synaptic function persist in adult euthyroid animals exposed developmentally to insufficient levels of hormone. Pre- and postnatal thyroid hormone insufficiency was induced by administration of 3 or 10 ppm propylthiouracil (PTU) to pregnant and lactating dams via the drinking water from gestation day (GD) 6 until postnatal day (PN) 30. This regimen produced a graded level of hormonal insufficiency in the dam and the offspring. Population spike and population excitatory postsynaptic potentials (EPSP) were recorded at the pyramidal cell layer and the stratum radiatum, respectively, in area CA1 of hippocampal slices from adult male offspring. PTU exposure increased baseline synaptic transmission, reduced paired-pulse facilitation, and increased the magnitude of the population spike long-term potentiation (LTP). Phosphorylation of the extracellular signal-regulated kinases (ERK1 and ERK2) was increased as a function of LTP stimulation in slices from PTU-exposed adult animals. On the other hand, no differences in the basal levels of synaptic proteins implicated in synaptic plasticity (total ERK, synapsin, growth-associated protein-43, and neurogranin) were detected. These results reinforce previous findings of persistent changes in synaptic function and, importantly extend these observations to moderate levels of thyroid hormone insufficiency that do not induce significant toxicity to the dams or the offspring. Such alterations in hippocampal synaptic function may contribute to persistent behavioral deficits associated with developmental hypothyroidism.

Topics: Animals; Antithyroid Agents; Blotting, Western; Disease Models, Animal; Extracellular Signal-Regulated MAP Kinases; Female; Hippocampus; Hypothyroidism; Lactation; Long-Term Potentiation; Nerve Tissue Proteins; Phosphorylation; Pregnancy; Prenatal Exposure Delayed Effects; Propylthiouracil; Rats; Rats, Long-Evans; Synaptic Transmission; Thyroid Hormones

Untreated maternal hypothyroidism (hypoT) has serious consequences in offspring development that may result from the effect on lactation of maternal metabolism dysfunction. We studied the effects of prolonged propylthiouracil (PTU)-induced hypoT (0.1% PTU in drinking water starting 8 days before mating until day 21 of pregnancy or for 30 days in virgin rats) on liver and mammary lipid metabolism and serum lipid concentrations. In virgins, hypoT reduced hepatic mRNAs associated with triglyceride (TG) and cholesterol synthesis (including fatty acid synthase and 3-hydroxy-3-methylglutaryl coenzyme A reductase), and induced lobuloalveolar mammary development. Pregnancy increased hepatic mRNAs associated with TG and cholesterol synthesis and uptake (including LDL receptor) and with lipid oxidation, such as acyl CoA oxidase. HypoT decreased mRNAs and the activity of proteins associated with TG synthesis, and mRNAs associated with cholesterol uptake and lipid oxidation. Pregnancy increased mammary mRNAs related to lipid oxidation and decreased cholesterol synthesis, whereas hypoT decreased mRNAs and activities of proteins associated with TG synthesis and decreased epithelial mammary tissue. Virgin and pregnant hypoT rats had increased circulating VLDL + LDL cholesterol. HypoT decreased circulating TGs in pregnant rats. The observed effects of hypoT may result in decreased mammary lipid availability. This, along with the decreased epithelial mammary tissue during lactogenesis, may contribute to the future lactational deficit of hypoT mothers.

Topics: Animals; Cholesterol; Fatty Acid Synthases; Female; Glucose; Hormones; Hydroxymethylglutaryl-CoA-Reductases, NADP-dependent; Hypothyroidism; Lipid Metabolism; Liver; Mammary Glands, Animal; Pregnancy; Pregnancy Complications; Pregnancy, Animal; Propylthiouracil; Rats; Rats, Wistar; Receptors, LDL; Reverse Transcriptase Polymerase Chain Reaction; RNA; RNA, Messenger; Water

The aim of this work was to analyze beta-adrenergic receptor (betaAR) regulation of T-lymphocyte proliferation in mice according to different thyroid hormone statuses.. T cells from eu-, hypo- (by propylthiouracil treatment) and hyperthyroid (by thyroxine, T4 administration) mice were purified and specific radioligand binding assays were performed. The effects of the beta-agonist isoproterenol (ISO) on intracellular levels of cyclic AMP (cAMP) were determined. Mitogen-induced T-cell proliferation was measured by [(3)H]-thymidine incorporation. Finally, protein kinase C (PKC) activity in cytosol and membrane fractions were determined using radiolabelled enzymatic substrates.. Adecrease or a non-significant increase in betaAR number was found on T lymphocytes from hypo- and hyperthyroid mice compared to euthyroid controls. ISO stimulation of cAMP levels was lower in hypothyroid and higher in hyperthyroid T lymphocytes compared to controls. T-selective mitogen-induced proliferation was increased in T4-treated animals, but decreased in hypothyroid mice. During the peak of proliferation, downregulation of betaAR was observed in all animals. However, a higher or a lower decrease was observed in hyper- and hypothyroid T cells, respectively. In parallel, a higher translocation of PKC activity was observed in hyperthyroid cells, and a lower one was found in hypothyroid lymphocytes with respect to controls.. These results indicate that intracellular signals triggered by mitogen activation, namely PKC, would be related to differential betaAR downregulation in T lymphocytes depending on the thyroid hormone status, contributing to the distinct proliferative responses found in hypo- or hyperthyroidism compared to the euthyroid state.

Topics: Adrenergic beta-Agonists; Animals; Cell Proliferation; Cyclic AMP; Down-Regulation; Female; Hyperthyroidism; Hypothyroidism; Isoproterenol; Mice; Mice, Inbred BALB C; Mitogens; Neuroimmunomodulation; Propylthiouracil; Protein Kinase C; Protein Transport; Receptor Aggregation; Receptors, Adrenergic, beta; T-Lymphocytes; Thymidine; Thyroid Gland; Thyroxine

The efficacy of guggulu, the gum resin of Commiphora mukul in regulating hypothyroidism was evaluated in female mice. In addition to estimating serum levels of thyroxine and triiodothyronine, hepatic 5' monodeiodinase, hepatic glucose-6-phospatase and lipid-peroxidation (LPO), the activities of the anti-oxidative enzymes, superoxide dismutase (SOD) and catalase (CAT), were investigated. While 6-n-propyl-2-thiouracil (PTU, 10.00 mg/kg/d for 30 days) induced hypothyroidism in mice, as evidenced by a decrease in thyroid hormone concentration and in hepatic 5'D-I activity, simultaneous administration of guggulu (200 mg/kg/d for 30 days) reversed this effect, indicating its potential to stimulate thyroid function. Although in PTU treated animals a marginal increase in hepatic LPO was observed, when simultaneously treated with guggulu, it was decreased. A parallel increase in the activity of endogenous antioxidants, SOD and CAT, in the latter group indicated the safe and antiperoxidative nature of the drug. These findings suggest the possible use of guggulu in the amelioration of hypothyroidism.

Topics: Animals; Female; Hypothyroidism; Lipid Peroxidation; Mice; Phytotherapy; Plant Extracts; Propylthiouracil; Sapindaceae; Thyroid Gland; Thyroxine; Triiodothyronine

Thyroid hormone is essential for the proper development of the mammalian central nervous system (CNS). In the present study, we examined behavioural alterations caused by transient perinatal hypothyroidism induced by an anti-thyroid drug, propylthiouracil (PTU). This drug produces perinatal disruption of the thyroid system and subsequent behavioural changes, which we investigated using a series of behavioural tests and focusing particularly on attention-deficit/hyperactivity disorder (ADHD)-like behaviours. In the open field test, both male and female rats that had experienced perinatal hypothyroidism (HT rats) showed an increased percent of locomotion behaviour and reduced grooming behaviour, suggesting that HT rats may be hyperactive and show fewer anxiety characteristics. Neither male nor female HT rats showed retention in the passive avoidance test. Male HT rats showed a significantly lower rate of correct avoidance responses than control rats in earlier sessions in the active avoidance test. In addition, we observed significant increases in the number of times that rats crossed the partition during inter-trial intervals and the percent of failure of avoidance during 5 s electrical stimuli in HT rats, suggesting that HT rats are restless, have a shortened attention span and panic easily. In measuring spontaneous motor activity during a period of darkness, male HT rats appeared to plunge into active phase with short, quick steps, while male control rats showed only long active phases during a stress-free period of darkness. These abnormal behavioural characteristics in HT rats might coincide with those found in some cases of ADHD.

Topics: Animals; Attention; Attention Deficit Disorder with Hyperactivity; Avoidance Learning; Disease Models, Animal; Exploratory Behavior; Female; Hypothyroidism; Male; Motor Activity; Pregnancy; Prenatal Exposure Delayed Effects; Propylthiouracil; Rats

Despite the recognized importance of thyroid hormones for normal brain development, little is known about the critical molecular events underlying this role. We investigated the molecular basis of thyroid hormone action on the developing brain by comparing genome-wide gene expression patterns in the cerebellum between euthyroid and hypothyroid juvenile mice using microarrays. Pregnant dams were treated with 0.1% or 0.04% 6-propyl-2-thiouracil (PTU) in drinking water continuously from day 13 post conception until weaning to produce hypothyroid pups. Cerebella were collected from vehicle and 0.1% PTU treated pups at post-natal day (PND) 15, and mRNA from these was subjected to microarray analysis using Agilent high-density oligonucleotide chips. Statistical analysis (MAANOVA) revealed significant differential expression in 2940 genes including 1357 up- and 1583 down-regulated genes. Further analysis (combined MAANOVA and ANOVA) identified 204 significantly altered genes. Hypothyroidism had a greater effect on gene expression in male than in female pups. Transcriptional changes in several genes [Syt12 (Synaptotagmin 12), Rcor (RE1-silencing transcription factor co-repressor), Bag3 (Bcl-associated athanogene 3), p21, cyclin D, Bax (Bcl2-associated X protein), and Pcp2 (Purkinje cell protein 2)] were confirmed using real-time (RT) PCR analysis. Significantly altered expression of Bag3 in cerebella from PND 15 and PND 60 pups exposed to PTU suggests permanent functional alterations in the hypothyroid brain. The thyroid hormone negative regulation of Rcor expression was confirmed in vitro using HepG2 cells. In addition to Rcor, expression of several other genes that code for critical components of the REST (RE1-silencing transcription factor) pathway was shown to be altered in hypothyroid animals. These results suggest that modification of this pathway may have a significant role in causing impaired development in the hypothyroid brain.

Topics: Animals; Animals, Newborn; Cell Line, Tumor; Cerebellum; Co-Repressor Proteins; Congenital Hypothyroidism; DNA-Binding Proteins; Female; Gene Expression Profiling; Gene Expression Regulation, Developmental; Histone Deacetylases; Hypothyroidism; Male; Mice; Mice, Inbred C57BL; Microarray Analysis; Nerve Tissue Proteins; Pregnancy; Pregnancy Complications; Propylthiouracil; Repressor Proteins; Reverse Transcriptase Polymerase Chain Reaction; Sex Factors; Thyroid Hormones; Tumor Cells, Cultured

To perform a case note review of pregnancies complicated by thyroid dysfunction to determine management and therapeutic intervention in relation to pregnancy outcome.. A retrospective case note analysis of 81 ongoing pregnancies in 70 pregnant women with a history of thyroid dysfunction over a period of 5 years at the Glasgow Royal Maternity Hospital (GRMH), Glasgow, Scotland, United Kingdom. The results of thyroid function tests and whether a change in treatment was instituted were recorded. Thyroid function was assessed by standard laboratory reference ranges for free thyroxine (FT4) and thyroid stimulating hormone (TSH) in all trimesters. Other parameters were also noted.. Medication levels needed to be increased in the hypothyroid group (45%), and decreased (38%) in the hyperthyroid group.. Pregnancy outcome was good in majority of cases given appropriate replacement therapy for stated reference values.

Topics: Antithyroid Agents; Carbimazole; Female; Gestational Age; Humans; Hyperthyroidism; Hypothyroidism; Pregnancy; Pregnancy Complications; Pregnancy Outcome; Propylthiouracil; Retrospective Studies; Risk Factors; Thyroid Function Tests; Thyroxine

It is a common knowledge that metabolic reactions increase in hyperthyroidism and decrease in hypothyroidism. The aim of this work was to investigate how the metabolic reactions could affect the total antioxidant status (TAS), protein concentration (PC) and the activities of acetylcholinesterase (AChE), (Na+,K+)-ATPase and Mg2+ -ATPase in the brain of hyper- and hypothyroid adult male rats. Hyperthyroidism was induced in rats by subcutaneous administration of thyroxine (25 microg/l00 g body weight) once daily for 14 days, while hypothyroidism was induced by oral administration of propylthiouracil (0.05%) for 21 days. TAS, PC, and enzyme activities were evaluated spectrophotometrically in the homogenated brain of each animal. TAS, PC, and Mg2+ -ATPase activity were found unaffected in hyperthyroidism, while AChE and Na+,K+ -ATPase activities were reduced by 25% (p < 0.01). In contrast, TAS, (Na+,K+)-ATPase and Mg2+-ATPase activities were found to be increased (approx. 23-30%, p < 0.001) in the hypothyroid brain, while AChE activity and PC were shown to be inhibited (approx. 23-30%, p < 0.001). These changes on brain enzyme activities may reflect the different metabolic effects of hyper- and hypothyroidism. Such changes of the enzyme activities may differentially modulate the brain intracellular Mg2+, neural excitability, as well as the uptake and release of biogenic amines.

Topics: Acetylcholine; Acetylcholinesterase; Animals; Antioxidants; Brain; Brain Diseases, Metabolic; Ca(2+) Mg(2+)-ATPase; Energy Metabolism; Hyperthyroidism; Hypothyroidism; Male; Nerve Tissue Proteins; Propylthiouracil; Rats; Rats, Wistar; Sodium-Potassium-Exchanging ATPase; Thyroxine; Up-Regulation

Hypothyroidism in the rat induced by perinatal exposure to propylthiouracil (PTU) is a useful animal model to study molecular changes underlying neurobehavioral defects associated with this condition. Understanding the developmental alterations in gene expression related to the neurobehavioral dysfunction should help to identify molecular markers for developmental neurotoxicity at an early stage of development. In the present study, we evaluate the effects of PTU on the expression of a set of genes implicated in neural network formation or synaptic function at a minimal dose of PTU causing behavioral alteration. Various doses of PTU were administered to dams from late pregnancy to the lactation period and the expression of selected genes in the hippocampus and the cerebral cortex of offspring was examined by quantitative RT-PCR. Behavioral performance of PTU-treated rats was also assessed. PTU-treated rats showed increased motor activity and impairment of E-maze learning at weaning and after maturation. At doses causing such behavioral alteration, expression of GAP-43 and M1 mRNAs was changed during neuronal network formation, suggesting that levels of these factors during development are important for accurate postnatal development and function.

Topics: Acoustic Stimulation; Animals; Animals, Newborn; Antithyroid Agents; Behavior, Animal; Cerebral Cortex; Female; GAP-43 Protein; Gene Expression Regulation; Habituation, Psychophysiologic; Hippocampus; Hypothyroidism; Male; Maze Learning; Motor Activity; Pregnancy; Prenatal Exposure Delayed Effects; Propylthiouracil; Rats; Rats, Inbred Strains; Receptor, Muscarinic M1; Swimming; Thyroxine; Triiodothyronine

To investigate the mechanism for the apoptosis of hippocampus neuron induced by hypothyroidism in perinatal rats.. Hypothyroidism was induced by administration of propylthiouracil (PTU, 50 mg/d) solution to the dams from gestational day 15 by gavage. Pups from both hypothyroid and control groups were harvested at 1, 5, 10 and 15d, respectively. Blood samples were collected at the time of death for the determination of thyroid hormone. Serum free triiodothyronine (FT(3)) and free thyroxine (FT(4)) were measured by chemoluminescence. Hippocampus specimens were collected from the control and hypothyroid pups.Mitochondia was examined under transmission electron microscopy. Translocation of apoptogenic molecules (Bax, cytochrome C and AIF) and activation of caspase-3 were analyzed by Western Blotting.. Significantly low circulating FT(3) and FT(4) levels confirmed the hypothyroid status of the experimental pups. Electron microscopy showed that altered morphology of mitochondria significantly increased under hypothyroid conditions. The expression of Bax in the cytosol of hypothyroid pups was higher than that of control pups at all stages of development (P<0.05),and significantly higher in mitochondria (P<0.001). The expression of cytochrome c in the cytosol of hypothyroid pups was significantly higher than that of control pups at all stages of development (1,10 and 15 d:P<0.05, 5d: P<0.001), and lower in mitochondria (P<0.05). The expression of AIF in the cytosol of hypothyroid pups was higher than that of control pups at all stages of development (P<0.001), and significantly lower in mitochondria (1, 5d: P<0.001, 10, 15 d: P<0.01). he expression of caspase-3 P20 in the cytosol of hypothyroid pups was significantly higher as compared with that of the age-matched controls (1, 15d: P<0.01, 5,1 0 d: P<0.001).. The intrinsic death pathway in mitochondria may be one of the mechanisms with which hypothyroid induces apoptosis of hippocampus neuron in developing rats.

Topics: Animals; Animals, Newborn; Apoptosis; Female; Hippocampus; Hypothyroidism; Neurons; Pregnancy; Pregnancy Complications; Propylthiouracil; Rats; Rats, Wistar

Intrapituitary triiodothyronine (T3) production plays a pivotal role in the control of TSH secretion. Its production is increased in the presence of decreased serum thyroxine (T4) concentrations and the enzyme responsible, deiodinase type 2 (D2), is highest in hypothyroidism. In order to document the role of this enzyme in adult rats we developed an experimental model that inhibited this enzyme using the specific inhibitor, reverse T3 (rT3).. Hypothyroidism was induced with propylthiouracil (PTU; 0.025 g/l in drinking water) which in addition blocked deiodinase type 1 (D1) activity, responsible for the rapid clearance of rT3 in vivo. During the last 7 days of the experiment, the hypothyroid rats were injected (s.c.) for 4 days with 0.4 or 0.8 nmol T4 per 100 g body weight (bw) per day. For the last 3 days, the same amount of T4 was infused via s.c. minipumps. In additional groups, 25 nmol rT3/100 g bw per day were added to the 3-day infusion of T4.. Infusion of 0.4 nmol T4/100 g bw per day did not affect the high serum TSH levels, 0.8 nmol T4/100 g bw per day decreased them to 57% of the hypothyroid values. The infusions of rT3 inhibited D2 activity in all organs where it was measured: the pituitary, brain cortex and brown adipose tissue (BAT). In the pituitary, the activity was 27%, to less than 15% of the activity in hypothyroidism. Despite that, serum TSH levels did not increase, serum T4 concentrations did not change and the changes in serum T3 were minimal.. We conclude that in partly hypothyroid rats, a 3-day inhibition of D2 activity, without concomitant change in serum T4 and minimal changes in serum T3 levels, is not able to upregulate TSH secretion and we postulate that this may be a reflection of absent or only minimal changes in circulating T3 concentrations.

Topics: Animals; Enzyme Inhibitors; Hypothyroidism; Iodide Peroxidase; Male; Propylthiouracil; Rats; Rats, Wistar; Thyrotropin; Thyroxine; Triiodothyronine, Reverse

Thyroid dysfunction brings about pathological changes in different organs of the body. The aim of the present study was to examine how experimental hypothyroidism and additional short-term high-dose thyroxine administration (one-week) affected lipid peroxidation in renal and testicular tissues of rats. The study was carried out on 30 male Spraque-Dawley rats. The experimental animals were divided into 3 groups as control, hypothyroidism and hypothyroidism + thyroxine administration. Both malondialdehyde (MDA) and glutathione (GSH) levels were lower in renal and testicular tissues of the hypothyroidism group than the control and hypothyroidism + thyroxine administration groups and the levels in hypothyroidism + thyroxine administration group were higher than those in the control and hypothyroidism groups (p < 0.001). Results of the study demonstrate that hypothyroidism reduced oxidant stress in kidney and testis tissues, but short-term, high-dose thyroxine administration in addition to hypothyroidism increased oxidant stress in the same tissues of rats.

Topics: Animals; Antithyroid Agents; Glutathione; Hypothyroidism; Kidney; Lipid Peroxidation; Male; Malondialdehyde; Oxidative Stress; Propylthiouracil; Rats; Rats, Sprague-Dawley; Testis; Thyroxine

The rat model of N-methyl-N-nitrosourea (MNU)-induced mammary carcinomas is well-established animal model for breast cancer. This study was carried out to investigate whether hypothyroid (thyroidectomy or PTU treatment) or hyperthyroid status of female rats would affect MNU-induced mammary carcinogenesis with specific focus on both retinoid and rexinoid receptor expression in mammary tumours. Application of PTU before and during MNU-induced mammary gland carcinogenesis yielded in a marked decrease of the number and volume of tumours per animal, however, there was no effect of hypothyroid state in thyroidectomized rats as well as hyperthyroid state concerning the number and volume of tumours. Mammary tumours of in euthyroid group of MNU animals showed that there was no tumour, in which all of subtypes of retinoid and rexinoid receptors were expressed. A different pattern of expression of retinoid or rexinoid receptors was found either in MNU-induced mammary carcinomas in both hypothyroid and hyperthyroid rats.

Topics: Animals; Carcinogens; Female; Gene Expression; Hyperthyroidism; Hypothyroidism; Mammary Neoplasms, Experimental; Methylnitrosourea; Propylthiouracil; Rats; Rats, Sprague-Dawley; Receptors, Retinoic Acid; RNA, Messenger; Thyroid Hormones; Thyroidectomy

Both hypothyroid (Hypo) and hypozincemia are commonly observed in patients and animals with chronic renal failure (CRF). In CRF whether the hypothyroid plays a role in the pathogenesis of hypozincemia is unclear. This study is designed to investigate the effects of hypothyroid on intestinal zinc absorption and urinary zinc excretion in 5/6 nephrectomized (Nx) rats, because plasma zinc balance is attained through a controlled rate of intestinal uptake as well as renal reabsorption. Intestinal zinc absorption was carried out in jejunum and ileum segments by an in vivo perfusion technique and the renal zinc disposal was evaluated by a conventional method using a standard formula to calculate the zinc tubular reabsorption and the excretion of urinary zinc in 5/6 Nx rats with hypothyroidism. The Hypo-NxT rats showed a significant decrease in the rate of intestinal zinc absorption and in the response of plasma zinc levels during intestinal zinc perfusion compared with Eu-NxT rats. They also had significantly lower levels of mucosal zinc and MT as well as lower content of liver zinc than Eu-NxT rats after intestinal zinc perfusion for 80 min. Hypo-NxT rats showed low plasma zinc levels, but had a similar output of pancreaticobiliary zinc and excretion of 24-h urine zinc compared with the Eu-NxT rats. When 2% alcohol intestinal perfusion was used to produce water diuresis, the Hypo-NxT rats presented a higher excretion of urinary zinc than the Eu-NxT rats did, especially during 2% alcohol intestinal zinc perfusion. In the Hypo-NxT rats, the lower plasma zinc levels may thus result from the hypothyroid because it reduces intestinal zinc absorption. Increasing the urine flow rate may aggravate the reduction of plasma zinc level in Hypo-NxT rats because of the increased excretion of urinary zinc.

Topics: Animals; Hypothyroidism; Intestinal Absorption; Kidney; Kidney Failure, Chronic; Male; Metallothionein; Nephrectomy; Propylthiouracil; Rats; Rats, Sprague-Dawley; Zinc

It is claimed in a limited number of studies carried out on human beings that plasma homocysteine levels increased in hypothyroid patients and decreased in hyperthyroid patients.. The aim of this study is to determine total plasma homocysteine, thyroid function tests, vitamin B12, folic acid and lipid levels and to explore the relations among them in rat models with induced hypothyroidism and hyperthyroidism with a view to investigating whether hypothyroid and hyperthyroid rat models could represent human hypothyroidism and hyperthyroidism models.. The study included 30 male Wistar Albino species rats with a mean weight of 200 - 250 g. Rats were randomly divided into 3 groups as 1) hypothyroid group, 2) hyperthyroid group and 3) control group. Hypothyroidism was induced by adding 10 mg/kg/day propylthiouracil to rats' drinking water for 30 days. In order to induce hyperthyroidism, rats were administered 10 microg/100 g L-thyroxin ampule via intraperitoneal route for 10 days.. We found that total plasma homocysteine level of the hypothyroid group was significantly lower than those of the control group (p<0.05) and the hyperthyroid group (p<0.001). Total plasma homocysteine level of the hypothyroid group was found insignificantly higher than that of the control group (p>0.05) and significantly higher than that of the hyperthyroid group (p<0.001). We established a significant and positive correlation between total plasma homocysteine level and thyroid hormone levels. We did not identify a significant relation between total plasma homocysteine level and serum folic acid and serum vitamin B12 levels.. Our findings are different from the findings reported in human hypothyroidism and hyperthyroidism studies. We believe that hypothyroid and hyperthyroid rat models cannot represent human hypothyroidism and hyperthyroidism models.

Topics: Animals; Antithyroid Agents; Cholesterol; Folic Acid; Homocysteine; Hyperthyroidism; Hypothyroidism; Lipids; Male; Propylthiouracil; Rats; Rats, Wistar; Thyroid Function Tests; Thyroxine; Vitamin B 12

It is known that there is abnormal osteopontin (OPN) expression at the sites of atherosclerotic lesions. In the Apolipoprotein E gene knockout (ApoE-KO) mouse, a model of the atherosclerotic process, altered cholesterol metabolism with associated increase in OPN expression is evident at 12-22 weeks in the aorta and at 22 weeks in the heart. In this study, we analyzed another animal model of hypothyroid mice created by ingestion of propylthiouracil (PTU). After 2 weeks of PTU ingestion, the animals had significant decreases in thyroid hormones (T3 and T4) and immediate increases in blood lipids/cholesterol. Hypothyroid mice showed 1.3-, 1.5-, 2-fold increases in blood levels of total cholesterol, triglycerides, and low density lipoprotein-cholesterol respectively. Semi-quantitative RT-PCR analysis showed that hypothyroid mice had 1.4- to 2-fold increases of OPN mRNA expression in the aorta and 1.5-fold increases in the heart. Hypothyroid animals treated with T3 (5 microg/day for 6 days) or statin (0.2 mg/30 g for 2 weeks) reduce blood lipids and aortic OPN mRNA expression. Data obtained with ELISA analyses showed 1.5- and 1.7-fold increases in OPN protein in the aorta (10 weeks) and the heart (22 weeks), respectively. This increase is close to the mRNA expression in both tissues of hypothyroid mice. In addition, western blots showed several variants of OPN protein expressed in the aorta and the heart. The decrease in the 70 kDa OPN is accompanied by an increase in 45 kDa OPN in the aorta of hypothyroid mice. In contrast, only 45 kDa OPN is found in the heart of control and hypothyroid mice. These data indicate that the increase of OPN mRNA and protein expression occurs in cardiovascular tissues of hypothyroid mice.

Topics: Animals; Aorta; Apolipoproteins E; Atherosclerosis; Blood Pressure; Blotting, Western; Body Weight; Cardiovascular System; Cholesterol; Cholesterol, LDL; Disease Models, Animal; Electrophoresis, Agar Gel; Enzyme-Linked Immunosorbent Assay; Gene Expression Regulation; Heart; Heart Rate; Hypothyroidism; Lipids; Male; Mice; Mice, Inbred ICR; Mice, Knockout; Mice, Transgenic; Models, Statistical; Myocardium; Osteopontin; Propylthiouracil; Reverse Transcriptase Polymerase Chain Reaction; RNA; RNA, Messenger; Sialoglycoproteins; Thyroxine; Time Factors; Triglycerides; Triiodothyronine

Effects of transient neonatal hypothyroidism (HPOT) on adult testis size and serum hormone profiles were evaluated in the Charles foster strain of rats, maintained under the temperature of 21 degrees C (HPOTL) or of 34 degrees C (HPOTH).. Hypothyroidism was induced in suckling pups in preweanling period (1-21 days), by administering 0.1% 6-propyl-2-thiouracil in drinking water to mothers. Body mass and testis characteristics, the steroidogenic potential [measured by histochemical localization of 3alpha-, 3beta- and 17beta-hydroxysteroid dehydrogenases (HSDHs)] and serum concentrations of thyroid-stimulating hormone (TSH), triiodothyronine (T3), thyroxine (T4), luteinizing hormone (LH), testosterone (T) and corticosterone (Cort) were evaluated on the 35th, 45th, 60th and 90th day of age.. The HPOTH rats showed lower testis masses, while the HPOTL rats showed higher testis masses and lower body masses after 90 days. Histologically, the testes of the HPOTH rats demonstrated increased germ cell degeneration after 35 and 45 days and reduced tubular size, germ cell numbers and sperm density after 90 days. In contrast, the testes of the HPOTL rats showed reduced tubular diameters after 35 and 45 days, and increased tubular diameters, germ cell numbers and sperm density after 90 days. Serum TSH, T3, T4, LH and T concentrations and 3beta- and 17beta-HSDH activities were reduced in both groups of the HPOT rats after 35 and 45 days. Intratubular steroidogenesis and a prominent triangle up5 pathway were also found in the HPOT animals.. The temperature has a definite influence on the thyroid hormone action, postnatal growth and function of rat testes.

Topics: Age Factors; Animals; Animals, Newborn; Body Weight; Corticosterone; Female; Germ Cells; Hydroxysteroid Dehydrogenases; Hypothyroidism; Luteinizing Hormone; Male; Organ Size; Pregnancy; Propylthiouracil; Rats; Temperature; Testis; Thyroid Hormones; Thyrotropin

Transient reductions in thyroid hormone during critical periods of brain development can have devastating and irreversible effects on neurological function. The hippocampus is a brain region sensitive to thyroid hormones and is a necessary substrate for some forms of learning and memory. Subregions within the hippocampus display distinct ontogenetic profiles and have shown differential vulnerability to some indices of thyrotoxic insult. Synaptic function can be readily assessed in the hippocampus, yet little information exists on the consequences of early thyroid hormone insufficiency on the neurophysiological integrity of this structure. Previous work has examined the long-term consequences of perinatal hypothyroidism on neurophysiology of the dentate gyrus of the hippocampal formation. The current study reveals that alterations in synaptic function also exist in area CA1, and some differences in the pattern of effects are evident between the two hippocampal subfields. Developing rats were transiently exposed to the thyrotoxicant, propylthiouracil (PTU; 0 or 15 ppm), through the drinking water of pregnant dams beginning on gestational day 18. This regimen markedly reduced circulating levels of thyroid hormones and stunted pup growth. PTU exposure was terminated on postnatal day (PN) 21 and electrophysiological assessments were conducted by recording field potentials in area CA1 of hippocampal slices derived from adult male offspring. Synaptic transmission, short-term, and long-term synaptic plasticity were assessed. Consistent with observations in the dentate gyrus, somatic population spike amplitudes were reduced in assessments of baseline synaptic transmission of slices from PTU-exposed animals. No differences were identified in excitatory postsynaptic potentials (EPSP). Short-term plasticity of the EPSP as indexed by paired pulse facilitation was markedly impaired by PTU exposure. Long-term potentiation (LTP) of the population spike was enhanced, consistent with findings in dentate gyrus, but no change in EPSP LTP was detected. Perturbations in synaptic function in the hippocampus of adult rats transiently exposed to a period of hormone insufficiency during the perinatal period are likely to contribute to cognitive deficits associated with developmental hypothyroidism.

Topics: Aging; Animals; Animals, Newborn; Body Weight; Electric Stimulation; Electrophysiology; Excitatory Postsynaptic Potentials; Female; Hippocampus; Hypothyroidism; In Vitro Techniques; Long-Term Potentiation; Male; Neuronal Plasticity; Pregnancy; Propylthiouracil; Radioimmunoassay; Rats; Rats, Long-Evans; Synaptic Transmission; Thyroid Hormones; Time Factors

Thyroid hormone is essential for fetal neurological development. Among other etiologies, fetal hypothyroidism may be caused by maternal exposure to antithyroid drugs (ATDs). The most common presentation of fetal hypothyroidism is fetal goiter, which can cause dystocia, in addition to airway obstruction in the neonate. Intra-amniotic treatment with levothyroxine normalizes fetal thyroid status and reduces goiter size. We present a case of fetal hypothyroidism diagnosed in a patient who was treated with propylthiouracil (PTU) for Grave's disease. The fetus had marked hydrops fetalis and a large goiter. In addition, anal stenosis, vesicovaginal fistula, bilateral pyelectasia and polydactyly were diagnosed in the neonate. Intra-amniotic treatment with levothyroxine resulted in a regression of the hydrops and a reduction in the goiter size. A euthyroid, non-edematous, non-goitrous neonate was delivered. At the age of 27 months the child's psychomotor development was normal. The present case indicates that hydrops fetalis may be an unusual manifestation of fetal hypothyroidism, caused by intrauterine exposure to maternal antithyroid drugs (ATDs), and that it may be resolved by treatment with intra-amniotic levothyroxine.

Topics: Adult; Antithyroid Agents; Female; Fetal Diseases; Goiter; Graves Disease; Humans; Hydrops Fetalis; Hypothyroidism; Maternal Exposure; Pregnancy; Pregnancy Complications; Prenatal Care; Propylthiouracil; Ultrasonography, Prenatal

The present study was undertaken to examine the systemic role of thyroid hormones by analyzing changes in reproductive functions in hypothyroid female rats. Serum concentrations of triiodo-thyronine (T3) significantly decreased 1 week after the initiation of propyl-thiouracil treatment or thyroidectomy. The estrous cycle became irregular 3 and 2 weeks after the initiation of propyl-thiouracil treatment and thyroidectomy, respectively. Serum luteinizing hormone (LH) levels significantly reduced in both groups on the day of diestrus-1 about 1 month later. Hypothyroid rat shows the high progesterone and low testosterone levels. No significant changes in inhibin and estradiol levels were detected. The serum levels of FSH decreased in the thyroidectomy group. The irregular estrous cycle and the above changes in hormone levels were recovered by administration of T4. Compensatory secretions of FSH and LH induced by ovariectomy were enhanced by thyroidectomy and suppressed by T4 treatment. These results suggest that thyroid hormones play a role in the regulation of reproductive hormones secretion in the cyclic rat ovary.

Topics: Animals; Antithyroid Agents; Estradiol; Estrous Cycle; Female; Follicle Stimulating Hormone; Hypothyroidism; Inhibins; Luteinizing Hormone; Ovariectomy; Progesterone; Propylthiouracil; Rats; Rats, Wistar; Testosterone; Thyroidectomy; Triiodothyronine

The present study was developed to ascertain whether or not susceptibility to lidocaine-kindling persists into adulthood in perinatal hypothyroid rats. Pregnant Wistar rats were randomly divided into two groups: the first one, a control group, that drank tap water; and a second one, a hypothyroid group, were treated with 0.02% propylthiouracil in their drinking water from the 14th gestational day to the 10th postpartum day. The pups of both groups were maintained with food and tap water ad libitum until the experiment was over. The pups of each group were divided to test the susceptibility to lidocaine-kindling at 30 and 100 days old, for this, lidocaine (50 mg/kg, i.p.) was administered daily. The seizures were usually present in the form of tonic attacks of fore and hind limbs, followed by intermittent clonic movements. An animal was considered kindled when it showed clonic movements for two consecutive days. We observed that the number of stimuli necessary to produce lidocaine-kindling seizures in hypothyroid rats was significantly lower than in the control group for both ages. Also, the percentage of kindled rats aged 30 days (73% and 89%) was greater than aged of 100 days (26% and 59%) in both control and hypothyroid groups, respectively. In conclusion, the perinatal hypothyroidism increases the susceptibility to lidocaine-kindling in adult rats.

Topics: Age Factors; Animals; Animals, Newborn; Disease Susceptibility; Female; Hypothyroidism; Kindling, Neurologic; Lidocaine; Male; Pregnancy; Prenatal Exposure Delayed Effects; Propylthiouracil; Random Allocation; Rats; Rats, Wistar; Seizures

The objective of the current study was to find out whether thyroid hormone influences antioxidant defense parameters of rat brain. Several oxidative stress and antioxidant defense parameters of mitochondrial (MF) and post-mitochondrial (PMF) fractions of cerebral cortex (CC) of adult rats were compared among euthyroid (control), hypothyroid [6-n-propylthiouracil (PTU)-challenged], and hyperthyroid (T3-treatment to PTU-challenged rats) states. Oxidative stress parameters, such as thiobarbituric acid-reactive substances (TBA-RS) and protein carbonyl content (PC), in MF declined following PTU challenge in comparison to euthyroid rats. On the other hand, when PTU-challenged rats were treated with T3, a significant increase in the level of oxidative stress parameters in MF was recorded. Hydrogen peroxide content of MF as well as PMF of CC was elevated by PTU-challenge and brought to normal level by subsequent treatment of T3. Although mitochondrial glutathione (reduced or oxidized) status did not change following PTU challenge, a significant reduction in oxidized glutathione (GSSG) level was noticed in PMF following the treatment. T3 administration to PTU-challenged rats had no effect on mitochondrial glutathione status. Total and CN-resistant superoxide dismutase (SOD) activities in MF of CC augmented following PTU challenge. CN-resistant SOD activity did not change when PTU-challenged rats were treated with T3. Although CN-sensitive SOD activity of PMF remained unaltered in response to PTU challenge, its activity increased when PTU-challenged rats were treated with T3. Catalase activity in PMF of CC of PTU-challenged rats increased, whereas the activity was decreased when hypothyroid rats were treated with T3. Similarly, total and Se-dependent glutathione peroxidase (GPx) activities of MF increased following PTU challenge and reduced following administration of T3. Se-independent GPx activity of MF and PMF and glutathione reductase activity of PMF decreased following PTU challenge and did not change further when rats were treated with T3. On the other hand, glutathione S-transferase activity of MF and PMF of CC did not change following PTU challenge but decreased below detectable level following T3 treatment. Results of the current investigation suggest that antioxidant defense parameters of adult rat brain are considerably influenced by thyroid states of the body.

Topics: Animals; Antioxidants; Brain; Cerebral Cortex; Hypothyroidism; Male; Mitochondria; Propylthiouracil; Rats; Rats, Wistar; Triiodothyronine

To develop a method to reliably induce congenital hypothyroidism in guinea pigs (Cavia porcellus) and assess similarities between the resultant developmental abnormalities and those described in horses with congenital hypothyroidism.. 35 female guinea pigs and their offspring.. Guinea pigs were allocated to control groups or groups treated with a low-iodine diet before and throughout gestation; an s.c. injection of 100 or 200 microCi of radioactive iodine 131 (131I) on day 40 of gestation; or 0.1% propylthiouracil (PTU) continuously in the drinking water, beginning day 3 or 40 of gestation. In all groups, assessments included gestation duration, litter size, proportion of stillborn pups, and laboratory analyses in live pups and dams; postmortem examinations were performed on all pups and dams and selected tissues were examined histologically.. Compared with control animals, pups from dams receiving a low-iodine diet or 131I s.c. had mild changes in their thyroid glands but no grossly or radiographically detectable lesions of hypothyroidism. Pups from dams receiving PTU were often stillborn (24/27 pups) and had enlarged thyroid glands (characterized by large, variably sized follicles of tall columnar epithelium and little or no colloid), an incomplete coat, and radiographically detectable skeletal dysgenesis.. Many of the lesions detected in guinea pig pups from the experimentally treated dams were similar to those described in foals with congenital hypothyroidism. Experimental induction of congenital hypothyroidism in guinea pigs may be useful for the study of naturally occurring congenital hypothyroidism in horses.

Topics: Animals; Body Weight; Bone and Bones; Congenital Hypothyroidism; Female; Guinea Pigs; Histological Techniques; Horse Diseases; Horses; Hypothyroidism; Iodine; Iodine Radioisotopes; Litter Size; Models, Animal; Propylthiouracil; Radiography; Thyroxine; Triiodothyronine

We used our nonsurgical technique for collecting pituitary venous blood to relate the dynamics of thyrotrophin-releasing hormone (TRH) secretion to the secretion patterns of both prolactin and thyrotrophin in periovulatory mares, either euthyroid (n = 5) or made hypothyroid by treatment with propyl-thiouracil (n = 5). Pituitary venous blood was collected continuously and divided into 1-min aliquots for 4 h. To test the effect of dopamine on the relationship between secretion patterns, sulpiride, a selective D2 receptor antagonist, was given i.m. after 2 h of sampling. Thorough testing of the model and blood collection procedure revealed no sites of TRH loss. Hypothyroidism increased the mean secretion rates of TRH (P = 0.04) and thyrotrophin (P < 0.0001) but not prolactin. Sulpiride increased prolactin secretion rates in hypothyroid (P < 0.0001) and control (P = 0.007) mares, but did not alter TRH or thyrotrophin secretion rates. In both groups of mares, all three hormones were secreted episodically but not rhythmically. In both groups, the secretion pattern of TRH was almost always significantly related to that of thyrotrophin, as assessed by cross correlation and cross approximate entropy (ApEn) analysis. However, the degree of linear correlation was weak, with only 14% (hypothyroid) or 8% (controls) of the variation in thyrotrophin secretion rates attributable to TRH. Prolactin and TRH secretion patterns before sulpiride were coupled on cross ApEn analysis in both groups, and the minute-to-minute secretion rates of the two hormones were correlated in four hypothyroid and three euthyroid mares. Overall, the small, but significant, degree of association between TRH and prolactin was similar to that between TRH and thyrotrophin. In hypothyroid mares, sulpiride increased (P = 0.02) the synchrony between TRH and prolactin patterns. We conclude that in horses: (i) little TRH degradation occurs during passage through the pituitary or in blood after 1 h at 37 degrees C; (ii) TRH is not the major factor controlling minute-to-minute fluctuations in either thyrotrophin or prolactin; and (iii) reducing two strongly inhibitory inputs (i.e. dopamine and thyroid hormones) may magnify the stimulatory effect of TRH on prolactin secretion.

Topics: Animals; Biological Assay; Blood Specimen Collection; Estrous Cycle; Female; Horses; Hypothyroidism; Ovulation; Pituitary Gland; Prolactin; Propylthiouracil; Thyrotropin; Thyrotropin-Releasing Hormone

Recent data have shown that fine regulation of retinoid mediated gene expression is fundamentally important for optimal brain functioning in aged mice. Nevertheless, alteration of the thyroid hormone signalling pathway may be a limiting factor, which impedes retinoic acid (RA) from exerting its modulating effect. Mild hypothyroidism is often described in the elderly. Thus, in the present study, it was of interest to determine if RA exerts its neurological modulating effect in mild hypothyroidism. To obtain further insight into this question, mice were submitted to a low propylthiouracyl (PTU) drink (0.05%) in order to slightly reduce the serum level of triiodothyronine (T3). A quantitative evaluation of RA nuclear receptors (RAR, RXR), T3 nuclear receptor (TR) and of neurogranin (RC3, a RA target gene which codes for a protein considered as a good marker of synaptic plasticity) in PTU treated mice injected with vehicle or RA or T3 was carried out. The PTU-related decrease in expression of RAR, RXR and RC3 was restored following RA or T3 administration, as observed in aged mice. The amount of TR mRNA, which was not affected in PTU treated mice, was increased only after T3 treatment as observed in overt hypothyroidism. These results suggest that neurobiological alterations observed in aged mice are probably related to RA and T3 signalling pathway modifications associated, in part, with mild changes in thyroid function.

Topics: Animals; Calmodulin-Binding Proteins; Hypothyroidism; Male; Mice; Mice, Inbred C57BL; Nerve Tissue Proteins; Neurogranin; Propylthiouracil; Receptors, Retinoic Acid; Retinoid X Receptors; RNA, Messenger; Tretinoin; Triiodothyronine

It has been established that thyroid hormone and neurotrophic factors both orchestrate developmental events in the brain. However, it is not clear how these two influences are related. In this study, we investigated the effects of thyroid hormone on cerebellar development and the coincident expression of transforming growth factor-alpha (TGF-alpha), a ligand in the epidermal growth factor (EGF) family, and the epidermal growth factor receptor (EGFR). Profiles of thyroid hormone expression were measured in postnatal animals and were found to peak at postnatal day 15 (P15). These levels dropped below detectable levels when mice were made hypothyroid with propylthiouracil (PTU). TGF-alpha and EGFR expression, as determined by RNAse protection assay, was maximal at P6 in normal animals, but remained low in hypothyroid animals, suggesting that thyroid hormone was responsible for their induction. In situ hybridization and immunohistochemical analysis of EGFR expression revealed that this receptor was present on granule cells within the inner zone of the external granule cell layer (EGL), suggesting that EGFR-ligands were not inducing granule cell proliferation. The persistence of EGFR expression on migrating granule cells and subsequent down-regulation of expression in the internal granule cell layer (IGL) implicates a role for EGFR-ligands in differentiation and/or migration. In hypothyroid animals, we observed a delayed progression of granule cell migration, consistent with the persistence of EGFR labeling in the EGL, and in the 'pile-up' of labeled cells at the interface between the molecular layer and the Purkinje cell layer. Taken together, these results implicate thyroid hormone in the coordinated expression of TGF-alpha and EGFR, which are positioned to play a role in post-mitotic developmental events in the cerebellum.

Topics: Aging; Animals; Cerebellum; ErbB Receptors; Female; Gene Expression Regulation; Glial Fibrillary Acidic Protein; Hypothyroidism; Male; Mice; Mice, Inbred C57BL; Mice, Inbred CBA; Mitosis; Propylthiouracil; Reference Values; Thyroid Gland; Thyroxine; Transcription, Genetic

The objectives of this study were to determine the effects of propylthiouracil (PTU)-induced neonatal hypothyroidism on the gap junctional protein Cx43 in rat testis and epididymis. PTU (0.02%) was administered via lactation from birth to Day 30, and the rats were sampled at 14, 18, 22, 26, 30, and 91 days of age. Testicular Cx43 was localized along the plasma membranes and cytoplasm of Sertoli cells until Day 22. At Day 30, the immunostaining was localized exclusively along the plasma membrane of Sertoli cells. In PTU-treated rats, Cx43 did not localize to the plasma membrane and was still cytoplasmic at 30 days of age. Occludin was present in tubules of treated rats, but was not localized to the blood-testis barrier in 30-day-old rats, as in controls. There were no differences in Cx43 immunostaining in the adult testis. In the proximal epididymis (initial segment, caput, corpus), Cx43 mRNA levels were lower in PTU-treated rats at 14, 18, and 22 days of age, but no differences were observed in the distal (cauda) epididymis at these ages. In 22- and 30-day-old rats, Cx43 was localized along the plasma membrane between principal and basal cells throughout the epididymis. In PTU-treated rats, Cx43 was not detectable in initial segment, caput, or corpus epididymidis. In the cauda epididymidis, however, Cx43 immunostaining in PTU-treated rats was similar to controls. These data suggest that thyroid hormones regulate Cx43-dependent gap junctional communication in the testis and epididymis.

Topics: Animals; Animals, Newborn; Antithyroid Agents; Cadherins; Connexin 43; Epididymis; Female; Hypothyroidism; Male; Propylthiouracil; Rats; Rats, Sprague-Dawley; Receptors, Thyroid Hormone; RNA, Messenger; Testis

Young boars were treated with propiothiouracil to induce hypothyroidism to examine its effects on postnatal testicular development. Treatments with 0.1% 4-propyl-2-thiouracil (PTU) in drinking water started after weaning, at 3 weeks of age and all boars were severely hypothyroid at 6 weeks of age as determined by measuring T3 and T4 in blood plasma. Boars were castrated at different ages up to 20 weeks and their testes used for histological and immunohistochemical analyses. Although small but significant reduction in testis weight was observed from 8 to 12 weeks of age, this was not accompanied by significant difference in testicular volume. By 20 weeks of age, at the beginning of puberty, the differences in testis weights between control and treated groups of boars disappeared suggesting there is no lasting effect of hypothyroidism on postnatal development of boar testis. Immunohistochemical staining was used to determine the presence of molecular markers in both Sertoli and Leydig cells. Again, there were no differences between testes from control and treated boars in the pattern or intensity of immunostaining using antibodies against 3beta-hydroxysteroid dehydrogenase, antimullerian hormone or proliferating cell nuclear antigen (PCNA). Immunostaining with antibodies against PCNA showed interesting results as it was observed that Sertoli cells still express this marker of proliferating cells at 14 weeks of age, later than previously suggested cessation of Sertoli cell proliferation. This study suggests that hypothyroidism in boars does not have similar effects on postnatal testis development as reported in some other species.

Topics: Animals; Animals, Newborn; Hypothyroidism; Immunohistochemistry; Male; Organ Size; Propylthiouracil; Seminiferous Tubules; Swine; Swine Diseases; Testis; Thyrotropin; Thyroxine

There exists a need for better diagnostic tests to characterise thyroid disease in horses. Currently available diagnostic tests fail to differentiate between thyroid gland disorders and thyroid abnormalities resulting from pituitary or hypothalamic problems.. To evaluate the effects of treatment with propylthiouracil (PTU) and bromocryptine (BROM) on serum concentrations of triiodothyronine (T3), thyroxine (T4), reverse T3 (rT3) and equine thyroid-stimulating hormone (e-TSH, thyrotrophin) in mature horses.. Healthy mature horses were treated using either PTU or BROM for 28 days. The effect of treatment on the thyroid axis was assessed by measuring T3, T4, rT3 and e-TSH before and at +14 and +28 days. The effect of PTU and BROM on the response of T3, T4, rT3 and e-TSH to thyrotrophin-release hormone (TRH) administration was also assessed before and at +14 and +28 days of treatment.. Treatment with PTU led to a significant reduction in serum concentrations of T3, T4 and rT3 on Day 28 and increase of e-TSH on Day 28 (P < 0.05). Treatment with BROM did not cause any measurable effect on serum concentrations of T3, T4, rT3 or e-TSH. The percentage increment by which serum concentration of T4, T3 and e-TSH increased following stimulation with TRH was decreased by treatment with PTU for 28 days (P < 0.05) but were not affected by treatment with BROM for 28 days.. These results suggest that 1) treatment with PTU may be used in horses as a model of primary hypothyroidism; 2) the use of BROM as a model of secondary hypothyroidism in horses is not supported; and 3) e-TSH assay deserves further investigation for the clinical diagnosis of thyroid axis dysfunction in horses.. Propylthiouracil effectively causes primary hypothyroidism. There is substantial variability between horses with respect to their sensitivity to this substance when administered orally. Further studies pertaining to the characterisation of equine thyroid disorders are warranted and the use of both PTU for the experimental induction of primary hypothyroidism and e-TSH for the diagnostic characterisation of thyroid disorders in horses should be considered.

Topics: Animals; Antithyroid Agents; Bromocriptine; Disease Models, Animal; Female; Hormone Antagonists; Horse Diseases; Horses; Hypothyroidism; Propylthiouracil; Thyroid Hormones; Thyrotropin; Thyroxine; Triiodothyronine

Hypothyroidism is associated with impaired blood flow to skeletal muscle under whole body exercise conditions. It is unclear whether poor cardiac and/or vascular function account for blunted muscle blood flow. Our experiment isolated a small group of hindlimb muscles and simulated exercise via tetanic contractions. We hypothesized that muscle blood flow would be attenuated in hypothyroid rats (HYPO) compared with euthyroid rats (EUT). Rats were made hypothyroid by mixing propylthiouracil in their drinking water (2.35 x 10-3 mol/l). Treatment efficacy was evidenced by lower serum T3 concentrations and resting heart rates in HYPO (both P<0.05). In the experimental preparation, isometric contractions of the lower right hindlimb muscles at a rate of 30 tetani/min were induced via sciatic nerve stimulation. Regional blood flows were determined by the radiolabelled microsphere method at three time points: rest, 2 min of contractions and 10 min of contractions. Muscle blood flow generally increased from rest ( approximately 5-10 ml/min per 100 g) through contractions for both groups. Further, blood flow during contractions did not differ between groups for any muscle (eg. red section of gastrocnemius muscle; EUT, 59.9 +/- 14.1; HYPO, 61.1 +/- 15.0; NS between groups). These findings indicate that hypothyroidism does not significantly impair skeletal muscle blood flow when only a small muscle mass is contracting. Our findings suggest that impaired blood flow under whole body exercise is accounted for by inadequate cardiac function rather than abnormal vascular function.

Topics: Animals; Disease Models, Animal; Heart Rate; Hindlimb; Hypothyroidism; Male; Microspheres; Muscle Contraction; Muscle, Skeletal; Physical Exertion; Propylthiouracil; Random Allocation; Rats; Rats, Sprague-Dawley; Regional Blood Flow

The purpose of this study was to immunohistochemically evaluate the effects of thyroid hormones on the olfactory epithelium (OE) in adult rats. Study design and setting Hypothyroidism was induced in rats by propylthiouracil (PTU) administration. Animals were grouped into 5 consisting of a control group, and 4 groups that had been treated with PTU for 3, 6, 9, or 12 weeks, respectively. The thickness and cell densities of the OE were examined according to the duration of PTU treatment. Changes to OE cell properties were investigated with immunohistochemical stains.. No statistically significant differences were found in the thickness and cell densities of the OE among the 5 groups. The number of olfactory receptor neurons positive for neuron-specific enolase or protein gene product 9.5, however, decreased with increasing duration of PTU treatment.. Thyroid hormones play an important role in the maturation of olfactory receptor neurons.

Topics: Animals; Hypothyroidism; Models, Animal; Olfactory Mucosa; Olfactory Receptor Neurons; Phosphopyruvate Hydratase; Proliferating Cell Nuclear Antigen; Propylthiouracil; Rats; Rats, Sprague-Dawley; Thiolester Hydrolases; Thyroid Hormones; Time Factors; Ubiquitin Thiolesterase

Thyroid hormones are essential for neonatal brain development. It is well established that insufficiency of thyroid hormone during critical periods of development can impair cognitive functions. The mechanisms that underlie learning deficits in hypothyroid animals, however, are not well understood. As impairments in synaptic function are likely to contribute to cognitive deficits, the current study tested whether thyroid hormone insufficiency during development would alter quantitative characteristics of synaptic function in the hippocampus. Developing rats were exposed in utero and postnatally to 0, 3, or 10 ppm propylthiouracil (PTU), a thyroid hormone synthesis inhibitor, administered in the drinking water of dams from gestation d 6 until postnatal day (PN) 30. Excitatory postsynaptic potentials and population spikes were recorded from the stratum radiatum and the pyramidal cell layer, respectively, in area CA1 of hippocampal slices from offspring between PN21 and PN30. Baseline synaptic transmission was evaluated by comparing input-output relationships between groups. Paired-pulse facilitation, paired-pulse depression, long-term potentiation, and long-term depression were recorded to examine short- and long-term synaptic plasticity. PTU reduced thyroid hormones, reduced body weight gain, and delayed eye-opening in a dose-dependent manner. Excitatory synaptic transmission was increased by developmental exposure to PTU. Thyroid hormone insufficiency was also dose-dependently associated with a reduction paired-pulse facilitation and long-term potentiation of the excitatory postsynaptic potential and elimination of paired-pulse depression of the population spike. The results indicate that thyroid hormone insufficiency compromises the functional integrity of synaptic communication in area CA1 of developing rat hippocampus and suggest that these changes may contribute to learning deficits associated with developmental hypothyroidism.

Topics: Action Potentials; Animals; Animals, Newborn; Antithyroid Agents; Cognition Disorders; Dendrites; Excitatory Postsynaptic Potentials; Female; Hippocampus; Hypothyroidism; Long-Term Potentiation; Long-Term Synaptic Depression; Neuronal Plasticity; Pregnancy; Prenatal Exposure Delayed Effects; Propylthiouracil; Rats; Rats, Long-Evans; Synaptic Transmission

Amiodarone is an iodine-rich drug widely used for the management of various arrhythmias, but its clinical utility is usually limited by the high frequency of numerous side effects, most frequently disturbance of thyroid function.. The present study presents the laboratory tests, color flow Doppler sonography (CFDS) findings, treatment and prognosis of 22 patients with amiodarone-induced thyroid dysfunction.. Eleven patients developed amiodarone- induced thyrotoxicosis (AIT), ten developed amiodarone-induced hypothyroidism (AIH) and one patient first developed AIT, followed by AIH. Age, amiodarone doses, duration of amiodarone treatment and discontinuation of amiodarone were similar in the patients with AIT and AIH. AIT was found more commonly in male patients, AIH in female patients. Color flow Doppler sonographic examination was performed in all patients with AIT to differentiate type 1 and 2 AIT. In ten patients, CFDS demonstrated increased glandular vascularity, diagnostic for type 1 AIT.. This paper presents patients with AIT treated successfully with propylthiouracil or prednisolone after developing thyroid dysfunction as a consequence of amiodarone use. The role of thyroid Doppler in managing these patients is emphasized.

Topics: Adult; Aged; Amiodarone; Antithyroid Agents; Atrial Fibrillation; Diagnosis, Differential; Female; Humans; Hypothyroidism; Male; Middle Aged; Propylthiouracil; Tachycardia, Ventricular; Thyrotoxicosis; Ultrasonography, Doppler, Color

The present study investigated the response of the hypothyroid heart to ischaemia-reperfusion. Hypothyroidism was induced in Wistar rats by oral administration of propylthiouracil (0.05%) for 3 weeks (HYPO rats), while normal animals (NORM) served as controls. Isolated hearts from NORM and HYPO animals were perfused in Langendorff mode and subjected to zero-flow global ischaemia followed by reperfusion (I/R). Post-ischaemic recovery of left ventricular developed pressure was expressed as % of the initial value (LVDP%). Basal expression of protein kinase C epsilon (PKCepsilon) and PKCdelta and phosphorylation of p46 and p54 c-jun NH(2)-terminal kinases (JNKs) in response to I/R were assessed by Western blotting. LVDP% was found to be significantly higher in HYPO hearts than in NORM. At baseline, PKCepsilon expression was 1.4-fold more in HYPO than in NORM hearts, P<0.05, while PKCdelta was not changed. Furthermore, basal phospho-p54 and -p46 JNK levels were 2.2- and 2.6-fold more in HYPO than in NORM hearts, P<0.05. In response to I/R, in NORM hearts, phospho-p54 and -p46 JNK levels were 5.5- and 6.0-fold more as compared with the baseline values, P<0.05, while they were not significantly altered in HYPO hearts. HYPO hearts seem to display a phenotype of cardioprotection against ischaemia-reperfusion and this is associated with basal PKCepsilon overexpression and attenuated JNK activation after I/R.

Topics: Animals; Blotting, Western; Hypothyroidism; JNK Mitogen-Activated Protein Kinases; Male; MAP Kinase Kinase 4; Mitogen-Activated Protein Kinase Kinases; Models, Animal; Myocardial Contraction; Myocardial Reperfusion Injury; Myocardium; Perfusion; Phosphorylation; Propylthiouracil; Protein Kinase C; Protein Kinase C-epsilon; Rats; Rats, Wistar; Ventricular Pressure

Thyroid dysfunctions can produce reproductive problems. Untreated maternal hypothyroidism has serious consequences on development of offspring, resulting in stunted growth and mental retardation. The effects of propylthiouracyl-induced hypothyroidism (0.1 g l(-1) in drinking water starting 8 days before mating, or given to virgin rats for 30 or 50 days) on the serum profiles of hormones related to reproduction and mammary function (prolactin, growth hormone (GH), progesterone, corticosterone, oestradiol, insulin-like growth factor I (IGF-I), thyroid-stimulating hormone (TSH), triiodothyronine and tetraiodothyronine), and on mammary function in virgin, pregnant and lactating rats, were investigated. Propylthiouracyl treatment severely decreased circulating triiodothyronine and tetraiodothyronine concentrations, and increased serum TSH concentrations. Virgin rats showed prolonged periods of vaginal dioestrus, increased circulating progesterone concentrations and afternoon peaks of prolactin concentration, which are indicative of prolactin-induced pseudopregnancy. Propylthiouracyl-treated virgin rats had mammary development comparable to that of midpregnancy, and half of these rats had increased mammary casein and lactose concentrations. Serum prolactin concentrations were decreased on the afternoon of day 5 of pregnancy, increased during late pregnancy (days 15-21) and were normal during lactation. Circulating GH concentrations decreased on days 15-21 of pregnancy, whereas progesterone concentrations increased during late pregnancy and early lactation. Circulating oestradiol (measured in late pregnancy and in virgin rats), IGF-I and corticosterone concentrations were decreased. Although assessment of mammary histology showed no differences in extent of development, casein content was increased in propylthiouracyl-treated rats on day 21 of pregnancy; litter growth was severely reduced and at day 20 of age the pups were hypothyroid, with decreased GH serum concentrations. An acute suckling experiment was performed on days 10-12 of lactation to determine whether some impairment in mammary function or the suckling reflex might account for these differences. After an 8 h separation of mothers from their litters and 30 min of suckling, circulating prolactin values were not affected by propylthiouracyl treatment, but serum oxytocin concentration and milk excretion were reduced. In conclusion, hypothyroidism induces various alterations in the hormone profiles of vi

Topics: Animals; Caseins; Corticosterone; Estradiol; Female; Growth Hormone; Hypothyroidism; Insulin-Like Growth Factor I; Iodide Peroxidase; Lactation; Lactose; Litter Size; Mammary Glands, Animal; Milk Ejection; Pregnancy; Progesterone; Prolactin; Propylthiouracil; Pseudopregnancy; Rats; Rats, Wistar; Thyrotropin; Triiodothyronine

Each year, 75 million pounds of the broadleaf herbicide atrazine (ATR) are applied to crops in the United States. Despite limited solubility, ATR is common in ground and surface water, making it of regulatory concern. ATR suppresses the immunomodulatory hormones prolactin (PRL) and the thyroid hormones (THs), with developmental exposure to ATR permanently disrupting PRL regulation. We hypothesized that ATR may cause developmental immunotoxicity through its disruption of PRL or THs. To test this hypothesis, pregnant Sprague-Dawley (SD) rats were exposed to 35-mg ATR/kg/d from gestational day (GD) 10 through postnatal day (PND) 23. Separate groups were exposed to bromocryptine (BCR) at 0.2 mg/kg/2x/day to induce hypoprolactinemia or to propylthiouracil (PTU) at 2 mg/kg/day to induce hypothyroidism. After the offspring reached immunologic maturity (at least 7 weeks old), the following immune functions were evaluated: natural killer (NK) cell function; delayed-type hypersensitivity (DTH) responses; phagocytic activity of peritoneal macrophages; and antibody response to sheep erythrocytes (SRBC). ATR decreased the primary antibody and DTH responses in male offspring only. Neither PTU nor BCR caused immunosuppression in any measured variable, although PTU increased phagocytosis by peritoneal macrophages. These results demonstrate that developmental exposure to ATR produced gender-specific changes in immune function in adult rats and suggest that immune changes associated with ATR are not mediated through the suppression of PRL or THs.

Topics: Abnormalities, Drug-Induced; Adjuvants, Immunologic; Administration, Oral; Animals; Animals, Suckling; Atrazine; Body Weight; Bromocriptine; Congenital Hypothyroidism; Female; Herbicides; Hypoproteinemia; Hypothyroidism; Immune System; Immunity; Lactation; Longevity; Organ Size; Pregnancy; Propylthiouracil; Rats; Rats, Sprague-Dawley; Sex Factors

The effect of hypothyroidism on some oxidative stress parameters is reported. Moderate hypothyroid state was induced in two groups of female rabbits (3 and 12 months old) by giving 50 mg/kg body weight (BW) of propylthiouracil (PTU) per os for 6 days and 20 mg/kg BW of methimazole (MMI) for further 14 days. Serum T4 and T3 concentrations decreased by about 38-40 and 32-36%, respectively. The induced hypothyroidism resulted in a significant decrease in the serum concentration of the lipid peroxidation end-product malondialdehyde, as measured by the thiobarbituric-acid assay. Erythrocytes of hypothyroid animals exhibited higher resistance to oxidative stress, while submitted to free radicals generator 2,2'-azo-bis(2-amidinopropane) hydrochloride (AAPH) in vitro. Using two detector systems (phospholipid liposomes and deoxyribose), sensitive to either organic or inorganic oxygen radical damage, the ability of euthyroid and hypothyroid rabbit plasma to protect against oxygen radicals was evaluated. The plasma of hypothyroid animals showed about 20% higher ability to protect against iron-binding organic radicals, but about 50% lower chain-breaking antioxidant activity. The antioxidant capacity of plasma against inorganic radicals was not affected by hypothyroidism. In conclusion, the results show that thyroid hormones modulate the free-radical-induced oxidative damage of lipids and that hypothyroidism offers some protection against lipid peroxidation.

Topics: Animals; Antioxidants; Erythrocytes; Female; Hypothyroidism; Lipid Peroxidation; Methimazole; Propylthiouracil; Rabbits; Thiobarbituric Acid Reactive Substances; Thyroxine; Triiodothyronine

Reductions in thyroid hormone during critical periods of brain development can have devastating effects on neurological function that are permanent. Neurochemical, molecular and structural alterations in a variety of brain regions have been well documented, but little information is available on the consequences of developmental hypothyroidism on synaptic function. Developing rats were exposed to the thyrotoxicant, propylthiouracil (PTU: 0 or 15 ppm), through the drinking water of pregnant dams beginning on GD18 and extending throughout the lactational period. Male offspring were allowed to mature after termination of PTU exposure at weaning on PND21 and electrophyiological assessments of field potentials in the dentate gyrus were conducted under urethane anesthesia between 2 and 5 months of age. PTU dramatically reduced thyroid hormones on PND21 and produced deficits in body weight that persisted to adulthood. Synaptic transmission was impaired as evidenced by reductions in excitatory postsynaptic potential (EPSP) slope and population spike (PS) amplitudes at a range of stimulus intensities. Long-term potentiation of the EPSP slope was impaired at both modest and strong intensity trains, whereas a paradoxical increase in PS amplitude was observed in PTU-treated animals in response to high intensity trains. These data are the first to describe functional impairments in synaptic transmission and plasticity in situ as a result of PTU treatment and suggest that perturbations in synaptic function may contribute to learning deficits associated with developmental hypothyroidism.

Topics: Aging; Analysis of Variance; Animals; Animals, Newborn; Antimetabolites; Body Weight; Dentate Gyrus; Disease Models, Animal; Dose-Response Relationship, Drug; Dose-Response Relationship, Radiation; Electric Stimulation; Electrophysiology; Excitatory Postsynaptic Potentials; Female; Hippocampus; Hypothyroidism; Male; Neuronal Plasticity; Pregnancy; Prenatal Exposure Delayed Effects; Propylthiouracil; Radioimmunoassay; Rats; Rats, Long-Evans; Synaptic Transmission; Thyroid Hormones

Evidence of the connections between the immune system and the thyroid axis is increasingly strong; however, much of the data are focused on immune effects of altered thyroid status in adults or rodents with congenital defects of the pituitary/thyroid axis. The object of the present study was to determine the effects of PTU-induced hypothyroidism on the developing immune system of the rat by focussing on both the spleen and thymus gland. Male Sprague-Dawley rat pups were exposed to PTU through maternal milk by giving the mothers 0.02% PTU in their drinking water starting on the pups' day of birth until day 24 (d24), shortly before weaning on d28. Animals were sampled on days 14, 22, 30, and 91. The mean body weight was decreased in the PTU-treated animals on days 14, 22, and 30. The mean spleen and thymic weights and cellularity were all decreased in the PTU-treated animals on d22 and d30. PTU exposure increased the proportion of NK cells in the spleen on days 14, 22, and 30. The proportion of T-cells was increased on days 22 and 30 with a particular increase in the CD4+ T-cells, resulting in an increase in the ratio of helper T-cells to suppressor/cytotoxic T-cells at d22. PTU also decreased the proportion of splenic B-cells at days 14, 22, and 30 which could explain the increased proportion of both NK and T-cells during these sampling periods. PTU treatment decreased the lytic ability of NK cells at d22, but no functional differences were observed at days 14, 30, 91, despite the increased proportion of NK cells in PTU-exposed animals at days 14, 22, and 30. PTU exposure also increased the proportion of CD4+CD8- cells in the thymus on d22 and caused an increase in both the CD4+CD8- and CD4-CD8+ populations on d30. These data suggest that the effects of temporary, PTU-induced hypothyroidism on the cell populations in the spleen partially result from transient changes in thymic T-cell development, including a shift towards increased CD4+CD8- cells. The data also suggest that temporary hypothyroidism early in development decreases B-cell development in a transient fashion. Temporary hypothyroidism induced from birth to the latter stages of the weaning period induced transitory effects on the spleen, thymus, and immune cell sub-populations--all of which recovered to normal values when the animals matured.

Topics: Animals; Animals, Newborn; Antithyroid Agents; B-Lymphocytes; CD4-CD8 Ratio; CD4-Positive T-Lymphocytes; Diet; Female; Flow Cytometry; Hypothyroidism; Killer Cells, Natural; Lymphocyte Subsets; Male; Propylthiouracil; Rats; Spleen; Thymus Gland

Free radicals are now well known to damage cellular components. To investigate whether age and thyroid level affect peroxidation speed, we examined the levels of malondialdehyde and antioxidant enzyme activities in different age groups of hypothyroid rats. Hypothyroidism was induced in 30- and 60-day-old Wistar Albino rats by the i.p. administration of propylthiouracil (10 mg kg(-1) body weight) for 15 days. While malondialdehyde levels of 30- or 60-day-old hypothyroid rats were increased in liver, they were decreased in the tissues of the heart and thyroid. While glucose-6-phosphate dehydrogenase activity levels did not change in heart, brain and liver tissues of 30-day-old rats, they increased in brain and heart tissues of 60-day-old experimental groups, but decreased in the liver. Catalase activities decreased in the liver and heart of rats with hypothyroidism, but increased in erythrocytes. In control groups while malondialdehyde levels increased in brain, heart and thymus with regard to age, they decreased in plasma. Glucose-6-phosphate dehydrogenase and catalase activities were not affected by age in tissues of the thymus, thyroid and brain, but they were decreased in the heart tissue. The changes in the levels of lipid peroxidation and antioxidant enzyme activities which were determined in different tissues of hypothyroid rats indicate a cause for functional disorder of these tissues. Moreover, there may be changes depending on age at lipid peroxidation and antioxidant enzyme activity levels.

Topics: Aging; Animals; Antioxidants; Catalase; Female; Glucosephosphate Dehydrogenase; Hypothyroidism; Malondialdehyde; Oxidative Stress; Propylthiouracil; Rats; Rats, Wistar; Thyrotropin; Thyroxine; Triiodothyronine

We have investigated immunohistochemically the effect of dl-alpha-tocopherol (vitamin E) on thyroid gland with 6-n-propyl-2-thiouracil (PTU)-induced hypothyroidism in rats. The animals were divided into four groups. Rats in group I were designated as control, rats in group II were treated with injections of PTU (10 mg/kg) for 15 days, rats in group III were treated with injections of PTU+vitamin E (10 mg/100 g) for 15 days. Rats in group IV were treated with injections PTU for 15 days and kept for 15 next days after cessation of PTU treatment. At the end of experiment, the animals were killed by decapitation, blood samples were obtained, thyroid tissues were collected and processed for quantitative evaluation of immunohistochemical PCNA (marker of cell proliferation), Bax (pro-apoptotic marker) and Bcl-2 (anti-apoptotic marker) staining. There was an increase in the number of PCNA-immunopositive cells in follicular epithelial cells of group II rats compared with other groups (p<0.05). After vitamin E treatment, the number of PCNA-immunopositive cells decreased (p<0.05) while the number of Bax-immunopositive cells increased (p<0.05). The number of Bcl-2-positive follicular epithelial cells of group IV rats was higher than in those of other groups (p<0.05). The results of this study indicate that hypothyroidism induces cell proliferation in the thyroid gland and vitamin E may promote involution of the gland.

Topics: Animals; Apoptosis; bcl-2-Associated X Protein; Biomarkers; Cell Division; Down-Regulation; Epithelial Cells; Goiter; Hypothyroidism; Immunohistochemistry; Male; Proliferating Cell Nuclear Antigen; Propylthiouracil; Proto-Oncogene Proteins; Proto-Oncogene Proteins c-bcl-2; Rats; Rats, Wistar; Signal Transduction; Thyroid Gland; Up-Regulation; Vitamin E

The aim of the present study was to investigate the effects of hypothyroidism induced during the pre- and postnatal periods of life on ovarian function and structure in offspring (pups) 120 days of age. Three groups were used. In the prenatal group, treatment was given from conception to parturition. In the postnatal group, treatment was given from parturition to 25 days postpartum. Hypothyroidism was induced by administration of 0.1% 6-n-propyl-2-thiouracil (PTU) in the drinking water of mothers. Body weights of the offspring were measured weekly. In each group, ten offspring were sacrificed at 120 days of age. Postnatal PTU treated pups showed delay in eye opening, teething, fur development, and weaning (35-37 days) compared to control animals (28-30 days). Body weight of offspring in the postnatal PTU treatment group was significantly decreased (P < 0.001), while the prenatal PTU treatment group showed a significant increase (P < 0.0001) compared to control animals. There was a significant (P < 0.05) reduction in paired ovarian weight of offspring in the postnatal PTU treatment group compared to control animals. Diameter of the ovaries was not affected by any treatment. Regarding the morphometery, only offspring in the prenatal PTU treatment group showed a significant (P < 0.001) increase in the diameter of graafian follicles. No significant difference was observed in morphometery of the granulosa layer, primary, and developing follicles of control and all treated groups. Number of primary, developing, and graafian follicles of all the treated groups was similar to that of the control group. The corpora lutea of the postnatal PTU treated group contained a population of large numbers of luteal cells compared to the control group. The prenatal PTU treated group did not exhibit a profound effect on ovarian morphology, histology, and morphometery. No difference was found in the serum estradiol concentration of control and PTU treated groups. J. Exp. Zool. 293:407-413, 2002.

Topics: Animals; Gene Expression Regulation, Developmental; Humans; Hypothyroidism; Mothers; Ovarian Follicle; Ovary; Propylthiouracil; Rats

The ascites syndrome in broiler chickens is attributed to the progress in genetic selection for rapid growth, coupled with the metabolic burden imposed by exposure to a relatively low-ambient temperature (T(a)). The syndrome is mainly characterized by hematocrit elevation, decline in blood oxygen saturation, accumulation of fluid in the abdominal cavity, and finally, death. Ascitic chickens have demonstrated hypothyroidism coupled with a marked stress response (high corticosterone concentration) and reduction in the hemoglobin content. The objective of the present study was to examine the role of thyroid and corticosterone hormones in the development of the syndrome. Ascites was induced by exposure to a gradually declining T(a) and supplementation of a pellet-form diet. Exogenous thyroxin (T(4)) and propylthiouracil (PTU) (in Experiments 1 and 2, respectively) were supplemented in drinking water to induce hyper- or hypothyroidism, respectively. Ascites syndrome was developed in 21.5% and 23% of the birds exposed to ascites-induced conditions (Exps. 1 and 2, respectively). Excess T(4) (Exp. 1) significantly reduced the percentage of ascites (down to 7%), whereas PTU (Exp. 2) significantly increased the appearance of the syndrome (35%). In the T(4)-treated chickens, although the T(4) concentration reached pharmacological levels, the triiodothyronine (T(3)) concentration remained within physiological levels, whereas T(3) in the ascitic birds exhibited a reduction pattern similar to that observed in the ascitic non-supplemented ones. In the PTU-treated chickens, however, both ascitic and non-ascitic birds demonstrated significant reductions in both T(4) and T(3) concentrations. In both experiments, ascitic chickens exhibited a considerable stress response, characterized by a significant and persisted elevation in plasma corticosterone concentration, which was in accordance with a similar elevation of hematocrit, and the PTU-treated non-ascitic birds exhibited a similar stress response. At 5 weeks of age, ascitic birds and the PTU-treated non-ascitic ones exhibited significant reductions in the hemoglobin content of their red blood cells. It may be concluded that deficiency in the thyroid hormones and elevated corticosterone may play a key deleterious role in the development of the ascites syndrome.

Topics: Aging; Animals; Ascites; Chickens; Corticosterone; Hematocrit; Hemoglobins; Hyperthyroidism; Hypothyroidism; Male; Poultry Diseases; Propylthiouracil; Syndrome; Thyroxine; Triiodothyronine

We present a 21-yr-old female with a large hepatic vascular tumor and subclinical hypothyroidism. A high level of the thyroid hormone inactivating enzyme type 3 iodothyronine deiodinase (D3) was detected in her tumor, and the TSH of 26.2 mU/liter returned to normal after surgical resection of the mass. This indicates that the vascular tumor caused this adult's hypothyroidism as has now been documented in nine infants with this syndrome. This first example of consumptive hypothyroidism in an adult indicates that the inactivation rate of thyroid hormone by D3 in a vascular tumor can stress the secretory capacity even of the TSH-stimulated normal adult thyroid gland.

Topics: Adult; Female; Humans; Hypothyroidism; Iodide Peroxidase; Kinetics; Liver; Propylthiouracil; Vascular Neoplasms

Topics: Animals; Antithyroid Agents; Body Temperature; Female; Hippocampus; Hypothyroidism; Methimazole; Propylthiouracil; Pyramidal Cells; Rats

Because we previously reported that T3 and 3,5-diiodo-L-thyronine (3,5-T2) both increase resting metabolic rate (RMR), 3,5-T2 could be another thyroidal regulator of energy metabolism. This effect of 3,5-T2 is evident in rats made hypothyroid by propylthiouracil and iopanoic acid, not in normal euthyroid (N) rats. Possibly, under euthyroid conditions, active 3,5-T2 may need to be formed intracellularly from a precursor such as T3. We tested this hypothesis by giving a single injection of T3 to N rats and comparing the time course of the variations in RMR with those of the changes in the serum and hepatic levels of 3,5-T2. Acute injection had an evident effect on RMR, 25 h earlier, in N rats than in rats made hypothyroid by propylthiouracil and iopanoic acid, maximal values (+40%) being reached in the former at 24-26 h. In N rats, the simultaneous injection of actinomycin D with the T3 inhibited the late part of the effect (after 24 h) more strongly than the early part (14-24 h). In serum and liver, 3,5-T2 levels were increased significantly at 12-24 h after T3 injection into N rats, a time at which RMR was rising rapidly to peak. These results seem to indicate that when T3 is injected into N animals, not all the effects on RMR are attributable to T3 itself, the early effect presumably being largely because of its in vivo deiodination to 3,5-T2. Because the effects of T3 and 3,5-T2 are additive, in N rats, the two iodothyronines probably cooperate in vivo to determine the total metabolic rate.

Topics: Animals; Antithyroid Agents; Basal Metabolism; Dactinomycin; Diiodothyronines; Enzyme Inhibitors; Hypothyroidism; Iodide Peroxidase; Iopanoic Acid; Liver; Male; Propylthiouracil; Protein Synthesis Inhibitors; Radioimmunoassay; Rats; Rats, Wistar; Thyroid Gland; Triiodothyronine

Thyroid status is crucial in energy homeostasis, but despite extensive studies the actual mechanism by which it regulates mitochondrial respiration and ATP synthesis is still unclear. We studied oxidative phosphorylation in both intact liver cells and isolated mitochondria from in vivo models of severe not life threatening hyper- and hypothyroidism. Thyroid status correlated with cellular and mitochondrial oxygen consumption rates as well as with maximal mitochondrial ATP production. Addition of a protonophoric uncoupler, 2,4-dinitrophenol, to hepatocytes did not mimic the cellular energetic change linked to hyperthyroidism. Mitochondrial content of cytochrome oxidase, ATP synthase, phosphate and adenine nucleotide carriers were increased in hyperthyroidism and decreased in hypothyroidism as compared to controls. As a result of these complex changes, the maximal rate of ATP synthesis increased in hyperthyroidism despite a decrease in ATP/O ratio, while in hypothyroidism ATP/O ratio increased but did not compensate for the flux limitation of oxidative phosphorylation. We conclude that energy homeostasis depends on a compromise between rate and efficiency, which is mainly regulated by thyroid hormones.

Topics: Adenosine Triphosphate; Animals; Disease Models, Animal; Electron Transport Complex IV; Hepatocytes; Hyperthyroidism; Hypothyroidism; Mitochondria, Liver; Oxidative Phosphorylation; Oxygen Consumption; Propylthiouracil; Proton Pumps; Rats; Rats, Wistar; Thyroid Gland

We examined the issue of whether germ cell factors are required for testicular enlargement that occurs after recovery from neonatal hypothyroidism. Experiments were performed using W/Wv mutant mice (lacking germ cells) and normal mice (ICR). The pups in experimental group (neonatal hypothyroid) received 6 propyl 2-thio-uracil (PTU) treatment, administered by adding 0.1% (w/v) to the water provided to the mother from day 1 of birth through day 25 postpartum, while the pups of control group received drinking water only. Mice were sacrificed at the age of day 25, 50 and 90, in the case of ICR mice, or at day 25 and 90 in the case of W/Wv mutant mice. In both groups, early hypothyroidism caused a partial recoverable decrease in body growth and testicular development. Both ICR and W/Wv mutant mice, those recovered from neonatal hypothyroidism showed an increase in testis weights, the number of Sertoli cells, and the diameter of the semniferous tubules. This study demonstrates that neonatal hypothyroidism led recovery caused testicular enlargement not only in ICR mice but also in germ cell depleted W/Wv mutant mice. Hence these findings deny direct involvement of the germ cell factors in the process of testicular enlargement in recovered mice even in vivo, and reaffirm the notion that thyroid hormone directly regulates the dynamics of Sertoli cell maturation.

Topics: Animals; Animals, Newborn; Antithyroid Agents; Growth; Hypothyroidism; Male; Mice; Mice, Inbred ICR; Mice, Mutant Strains; Organ Size; Propylthiouracil; Seminiferous Tubules; Sertoli Cells; Spermatozoa; Testis

Radioactive iodine ((131)I) has become the most widely used therapy for patients with hyperthyroidism caused by Graves' disease in the United States. There remains, however, significant variability among (131)I dosing regimens, and it is clear that most patients ultimately develop hypothyroidism after therapy. To avoid persistent hyperthyroidism, we adopted a high dose (131)I therapy protocol based on measurement of 24-h thyroid (123)I uptake designed to deliver 8 mCi (296 MBq) to the thyroid gland 24 h after (131)I administration. To evaluate the efficacy of this protocol, we reviewed our clinical experience over a 7-yr period. We treated 261 patients (219 women and 42 men) with hyperthyroidism caused by Graves' disease with (131)I [mean dose, 14.6 mCi (540 MBq)] between 1993 and 1999. Before treatment, 207 (79%) had received an antithyroid drug (109 propylthiouracil and 98 methimazole). We determined their thyroid status 1 yr after treatment in relation to age, pretreatment with an antithyroid drug, pretreatment thyroid size, and dose of (131)I retained in the thyroid 24 h after treatment. Among the 261 patients, 225 (86%) were euthyroid or hypothyroid 1 yr after treatment, and 36 patients (14%) had persistent hyperthyroidism and required a second treatment. The patients who had persistent hyperthyroidism were younger (P < 0.01), had larger thyroid glands (P < 0.01), higher pretreatment thyroid (123)I uptake values (P < 0.01), and higher serum T(4) concentrations (P < 0.01) and were more likely to have taken antithyroid medication before administration of (131)I (P = 0.01). Five of these patients developed transient hypothyroidism, followed by thyrotoxicosis. There was an asymptotic, inverse relationship between the retained dose of (131)I at 24 h and persistent hyperthyroidism, revealing a 5-10% failure rate despite delivery of up to 400 microCi (14.8 MBq)/g. A dose of (131)I that results in accumulation of 8 mCi (296 MBq) in the thyroid gland 24 h after administration is an effective treatment for the majority of patients with Graves' hyperthyroidism. Young patients with larger thyroid glands, higher serum T(4) concentrations, and higher 24-h thyroid (123)I uptake values, and those pretreated with antithyroid medication for greater than 4 months are at higher risk for treatment failure. A higher dose of (131)I may be advisable in such patients.

Topics: Adult; Antithyroid Agents; Dose-Response Relationship, Radiation; Female; Graves Disease; Humans; Hypothyroidism; Iodine Radioisotopes; Male; Methimazole; Middle Aged; Propylthiouracil; Retreatment; Retrospective Studies; Thyrotoxicosis; Treatment Outcome

The effects of thyroid hormone depletion and enhancement on litter size, survival, body mass, ambulation, quadrant crossing, home orientation, day of eye opening, and free serum T3 and T4 levels were examined in Study 1. In Study 2, the effects of the timing of prenatal insult and the level of thyroid hormone depletion on litter size, survival, body mass, and free serum T3 and T4 levels were examined. Upon the completion of Study 1, randomly selected pups were maintained on ad-libitum water and food for 2 years, and performance was evaluated on fixed and variable ratio schedules, fixed and variable interval schedules, and probability and reversal learning tasks (Study 3). In Study 4, human subjects diagnosed with and treated for either congenital hypothyroidism or congenital hyperthyroidism were tested on the operant procedures used in Study 3, as well as on a series of simple reaction time, serial timing, and conjunctive and disjunctive search tasks. Dose-dependent decreases in survival and delays in the presentation of early motor and exploratory skills were observed following thyroid hormone depletion; dose-dependent accelerations in the presentation of early motor and exploratory skills were observed following thyroid hormone enhancement. Pups that had been prenatally exposed to propylthiouracil (PTU) 1-2 years after the return of thyroid hormones to baseline levels were significantly less accurate at timing on fixed and variable interval schedules, demonstrated an inability to allocate responding on probability tasks, and committed more errors during original learning (OL) and on each reversal problem. Similar deficits were observed in follow-up tests with humans diagnosed with congenital hypothyroidism, as were deficits in serial timing and visual searching. Collectively, the present results demonstrate that the pervasive and negative effects of prenatal thyroid deficiency on early behavior are also expressed during adult operant performance.

Topics: Analysis of Variance; Animals; Antithyroid Agents; Body Mass Index; Conditioning, Operant; Dose-Response Relationship, Drug; Exploratory Behavior; Female; Hyperthyroidism; Hypothyroidism; Litter Size; Motor Activity; Pregnancy; Prenatal Exposure Delayed Effects; Propylthiouracil; Random Allocation; Rats; Reaction Time; Reinforcement, Psychology; Survival Rate; Thyroid Function Tests; Thyroid Hormones; Thyroxine

Topics: Abdomen; Antithyroid Agents; Congenital Hypothyroidism; Female; Graves Disease; Humans; Hypothyroidism; Infant, Newborn; Male; Maternal-Fetal Exchange; Pregnancy; Pregnancy Complications; Propylthiouracil

Topics: Antithyroid Agents; Humans; Hypothyroidism; Insulin-Like Growth Factor I; Lung Neoplasms; Propylthiouracil; Survival Rate

Only three of the four thyroid hormone receptor (TR) isoforms, alpha1, beta1, and beta2, bind thyroid hormone (TH) and are considered to be true TRs. TRalpha2 binds to TH response elements on DNA, but its role in vivo is still unknown. We produced mice completely deficient in TRalpha (TRalpha(o/o)) that maintain normal serum thyroid-stimulating hormone (TSH) concentration despite low serum thyroxine (T(4)), suggesting increased sensitivity to TH. We therefore examined the effects of TH (L-3,3',5-triiodothyronine, L-T3) given to TH-deprived and to intact TRalpha(o/o) mice. Controls were wild-type (WT) mice of the same strain and mice resistant to TH due to deficiency in TRbeta (TRbeta(-/-)). In liver, T3 produced significantly greater responses in TRalpha(o/o) and smaller responses in TRbeta(-/-) as compared with WT mice. In contrast, cardiac responses to L-T3 were absent or reduced in TRalpha(o/o), whereas they were similar in WT and TRbeta(-/-) mice, supporting the notion that TRalpha1 is the dominant TH-dependent TR isoform in heart. 5-Triiodothyronine (L-T3) given to intact mice produced a greater suppression of serum T(4) in TRalpha(o/o) than it did in WT mice and reduced by a greater amount the TSH response to TSH-releasing hormone. This is an in vivo demonstration that a TR deficiency can enhance sensitivity to TH. This effect is likely due to the abrogation of the constitutive "silencing" effect of TRalpha2 in tissues expressing the TRbeta isoforms.

Topics: Animals; Antithyroid Agents; Cholesterol; Feedback; Gene Deletion; Gene Expression Regulation; Heart; Heart Rate; Hypothyroidism; Liver; Male; Mice; Mice, Knockout; Myocardium; Pituitary Gland; Propylthiouracil; Receptors, Thyroid Hormone; RNA, Messenger; Thyroid Function Tests; Thyroid Hormones; Thyrotropin; Triiodothyronine

Thyroid hormone is essential for mammalian brain development, but the mechanisms by which thyroid hormone exerts its effects, the developmental processes affected, and the timing of thyroid hormone effects are poorly understood. An important question is whether thyroid hormone of maternal origin is essential in guiding fetal brain development. In both humans and rats, thyroid hormone of maternal origin reaches the fetus before the onset of fetal thyroid function. Moreover, receptors for thyroid hormone (TRs) are present in the fetal brain and are occupied by thyroid hormone. Finally, a recent report strongly indicates that transient undiagnosed maternal hypothyroidism can lead to measurable neurological deficits in the offspring despite the lack of neonatal hypothyroidism. Considering that TRs are ligand-activated transcription factors, we recently initiated a project to identify thyroid hormone-responsive genes in the fetal cortex before the onset of fetal thyroid function. One of the thyroid hormone-responsive genes we identified, neuroendocrine-specific protein (NSP), is expressed as two separate transcripts, NSP-A and NSP-C. Only NSP-A is affected by maternal thyroid hormone. We now demonstrate that the messenger RNA encoding NSP-A is expressed exclusively in the proliferative zone of the fetal cortex, and that its expression is affected by maternal hypothyroidism. Moreover, as development proceeds, NSP-A becomes selectively expressed in Purkinje cells of the cerebellum, a well known thyroid hormone-responsive cell. These findings strongly support the concept that thyroid hormone of maternal origin exerts specific receptor-mediated effects on fetal brain development.

Topics: Animals; Cerebral Cortex; Female; Fetus; Gene Expression Regulation, Developmental; Gestational Age; Hypothyroidism; Mice; Nerve Tissue Proteins; Neurons; Pregnancy; Pregnancy Complications; Propylthiouracil; Protein Isoforms; Rats; Rats, Sprague-Dawley; RNA, Messenger; Thyroxine; Transcription, Genetic

The effect of thyroid status on arterial baroreflex function and autonomic contributions to resting blood pressure and heart rate (HR) were evaluated in conscious rats. Rats were rendered hyperthyroid (Hyper) or hypothyroid (Hypo) with triiodothyronine and propylthiouracil treatments, respectively. Euthyroid (Eut), Hyper, and Hypo rats were chronically instrumented to measure mean arterial pressure (MAP), HR, and lumbar sympathetic nerve activity (LSNA). Baroreflex function was evaluated with the use of a logistic function that relates LSNA or HR to MAP during infusion of phenylephrine and sodium nitroprusside. Contributions of the autonomic nervous system to resting MAP and HR were assessed by blocking autonomic outflow with trimethaphan. In Hypo rats, the arterial baroreflex curve for both LSNA and HR was shifted downward. Hypo animals exhibited blunted sympathoexcitatory and tachycardic responses to decreases in MAP. Furthermore, the data suggest that in Hypo rats, the sympathetic influence on HR was predominant and the autonomic contribution to resting MAP was greater than in Eut rats. In Hyper rats, arterial baroreflex function generally was similar to that in Eut rats. The autonomic contribution to resting MAP was not different between Hyper and Eut rats, but predominant parasympathetic influence on HR was exhibited in Hyper rats. The results demonstrate baroreflex control of LSNA and HR is attenuated in Hypo but not Hyper rats. Thyroid status alters the balance of sympathetic to parasympathetic tone in the heart, and the Hypo state increases the autonomic contributions to resting blood pressure.

Topics: Animals; Antithyroid Agents; Baroreflex; Blood Pressure; Consciousness; Ganglionic Blockers; Heart Rate; Hyperthyroidism; Hypothyroidism; Male; Propylthiouracil; Rats; Rats, Sprague-Dawley; Sympathetic Nervous System; Thyroid Gland; Triiodothyronine; Trimethaphan

Thyroid dysfunction produces multiple alterations in plasma lipoprotein levels, including high-density lipoprotein (HDL). Cholesteryl ester transfer protein (CETP) and hepatic lipase (HL) are important proteins that modulate the metabolism of HDL. Thus, the effect of thyroid hormone on the activities of CETP and of HL was investigated using hypothyroid and hyperthyroid CETP transgenic (Tg) and nontransgenic (nTg) mice. Hyperthyroid Tg mice plasma lipoprotein (LP) profile analysis showed a significant increase in the very-low-density lipoprotein (VLDL) fraction (P <.001) and decrease in the HDL fraction (P <.005), whereas in the hypothyroid Tg mice an increase in low-density lipoprotein (LDL) was observed (P <.02). CETP activity was measured as the transfer of (14)C-cholesteryl ester (CE) from labeled HDL to LDL by an isotopic assay indicative of mass. Hyperthyroid Tg mice had twice as much plasma CETP activity as compared with their controls, while in hypothyroid Tg mice plasma CETP activity did not change. The role of CETP in determining the changes in LP profile of hyperthyroid animals was confirmed by showing that nTg wild-type hyperthyroid and euthyroid mice exhibited the same percent cholesterol distribution in LP. Postheparin HL activity measured in hyperthyroid Tg mice was significantly reduced (P <.05). (3)H-cholesteryl oleoyl ether ((3)H-Cet)-HDL plasma fractional removal rate (FRR) was approximately 2-fold faster in the hyperthyroid Tg mice than in controls, but was not modified in hypothyroid animals. Tissue uptake of (3)H-Cet was examined in 10 tissue samples: levels were significantly increased in skeletal muscle and decreased in small intestine in hyperthyroid Tg mice, and decreased in the small intestine of hypothyroid Tg mice. In conclusion, the excess of thyroid hormone accelerates HDL metabolism in CETP transgenic mice mainly due to an increase in plasma CETP activity and independently from the HL activity. Hypothyroid status did not change CETP activity and HDL metabolism.

Topics: Animals; Carrier Proteins; Cholesterol; Cholesterol Ester Transfer Proteins; Chromatography, High Pressure Liquid; Female; Glycoproteins; Humans; Hyperthyroidism; Hypothyroidism; Kinetics; Lipase; Lipoproteins, HDL; Lipoproteins, LDL; Lipoproteins, VLDL; Liver; Male; Mice; Mice, Inbred C57BL; Mice, Transgenic; Propylthiouracil; Triiodothyronine; Tritium

A 45 year-old man had a typical episode of subacute thyroiditis with tender goiter, depressed radioiodine uptake (RAIU) and elevated erythrocyte sedimentation rate. The titer of TSH binding inhibitor immunoglobulin (TBII), which had been 8.6% at initial presentation, rose to 14.9% in 2 weeks. TBII consisted of high titers (94%) of TSH stimulation-blocking antibodies (TBAb) and negative thyroid stimulating antibodies (TSAb). About 2 months after the first visit, TBII titers had risen to 48.9% and were persistently elevated for 5 months with high TBAb activity. The patient developed hypothyroidism with a maximum serum TSH level of 54.5 microU/ml. TBII and TBAb titers then gradually decreased, and the patient spontaneously recovered from hypothyroidism. Eighteen months after the episode of subacute thyroiditis, he became hyperthyroid with elevated TSAb and negative TBAb values. Doppler ultrasonography showed increased blood flow in the thyroid, and RAIU at 24 h was 53%. He was treated with antithyroid drugs, and soon became euthyroid. This case indicates that subacute thyroiditis can induce thyroid autoimmunity, and that the character of TSH receptor antibodies (TSHRAb) in these patients can change thereby modifying their thyroid function.

Topics: Antithyroid Agents; Autoantibodies; Autoimmune Diseases; Humans; Hyperthyroidism; Hypothyroidism; Immunoglobulins, Thyroid-Stimulating; Iodine Radioisotopes; Male; Middle Aged; Propylthiouracil; Receptors, Thyrotropin; Thyroid Gland; Thyroiditis; Thyrotropin; Thyroxine; Triiodothyronine; Ultrasonography

In the present study the effect of thyroid hormone (T(3)) on oxidative stress parameters of mitochondria of rat liver is reported. Hypothyroidism is induced in male adult rats by giving 0.05% propylthiouracil (PTU) in drinking water for 30 days and in order to know the effect of thyroid hormone, PTU-treated rats were injected with 20 microg T(3)/100 g body weight/day for 3 days. The results of the present study indicate that administration of T(3) to hypothyroid (PTU-treated) rats resulted in significant augmentation of oxidative stress parameters such as thiobarbituric acid reactive substances and protein carbonyl content of mitochondria in comparison to its control and euthyroid rats. The hydrogen peroxide content of the mitochondria of liver increased in hypothyroid rats and was brought to a normal level by T(3) treatment. Induction of hypothyroidism by PTU treatment to rats also resulted in the augmentation of total and CN-sensitive superoxide dismutase (SOD) activities of the mitochondria, which was reduced when hypothyroid rats were challenged with T(3). Although CN-resistant SOD activity of the mitochondria remained unaltered in response to hypothyroidism induced by PTU treatment, its activity decreased when hypothyroid rats were injected with T(3). The catalase activity of the mitochondria decreased significantly by PTU treatment and was restored to normal when PTU-treated rats were given T(3). Total, Se-independent and Se-dependent glutathione peroxidase activities of the mitochondria were increased following PTU treatment and reduced when T(3) was administered to PTU-treated rats. The reduced and oxidised glutathione contents of the mitochondria of liver increased significantly in hypothyroid rats and their level was restored to normal when hypothyroid rats were injected with T(3). The results of the present study suggest that the mitochondrial antioxidant defence system is considerably influenced by the thyroid states of the body.

Topics: Animals; Body Weight; Glutathione; Glutathione Disulfide; Glutathione Peroxidase; Hydrogen Peroxide; Hypothyroidism; Lipid Peroxidation; Male; Mitochondria, Liver; Propylthiouracil; Proteins; Rats; Rats, Wistar; Reactive Oxygen Species; Superoxide Dismutase; Triiodothyronine

The objective of the present study was to examine whether hypothyroidism affects the reproductive system of adult female rats by evaluating ovarian morphology, uterus weight and the changes in serum and pituitary concentrations of prolactin and gonadotropins. Three-month-old female rats were divided into three groups: control (N = 10), hypothyroid (N = 10), treated with 0.05% 6-propyl-2-thiouracil (PTU) in drinking water for 60 days, and T4-treated group (N = 10), receiving daily sc injections of L-thyroxine (0.8 microg/100 g body weight) during the last 10 days of the experiment. At the end of 50 days of hypothyroidism no hypothyroid animal showed a regular cycle, while 71% of controls as well as the T4-treated rats showed regular cycles. Corpora lutea, growing follicles and mature Graafian follicles were found in all ovaries studied. The corpora lutea were smaller in both the hypothyroid and T4-replaced rats. Graafian follicles were found in 72% of controls and only in 34% of hypothyroid and 43% of T4-treated animals. Serum LH, FSH, progesterone and estradiol concentrations did not differ among the three groups. Serum prolactin concentration and the pituitary content of the three hormones studied were higher in the hypothyroid animals compared to control. T4 treatment restored serum prolactin concentration to the level found in controls, but only partially normalized the pituitary content of gonadotropins and prolactin. In conclusion, the morphological changes caused by hypothyroidism can be a consequence of higher prolactin production that can block the secretion and action of gonadotropins, being the main cause of the changes observed.

Topics: Animals; Antithyroid Agents; Body Weight; Estradiol; Female; Gonadotropins; Hypothyroidism; Infertility, Female; Ovary; Pituitary Gland; Progesterone; Prolactin; Propylthiouracil; Rats; Rats, Wistar; Thyrotropin; Thyroxine; Uterus

Membrane and cytosolic fractions prepared from ventricular myocardium of young (21-day-old) hypo- or hyperthyroid rats and adult (84-day-old) previously hypo- or hyperthyroid rats were analyzed by immunoblotting with specific anti-G-protein antibodies for the relative content of Gs alpha, Gi alpha/Go alpha, Gq alpha/G11 alpha, and G beta. All tested G protein subunits were present not only in myocardial membranes but were at least partially distributed in the cytosol, except for Go alpha2, and G11 alpha. Cytosolic forms of the individual G proteins represented about 5-60% of total cellular amounts of these proteins. The long (Gs alpha-L) isoform of Gs alpha prevailed over the short (Gs alpha-S) isoform in both crude myocardial membranes and cytosol. The Gs alpha-L/Gs alpha-S ratio in membranes as well as in cytosol increased during maturation due to a substantial increase in Gs alpha-L. Interestingly, whereas the amount of membrane-bound Gi alpha/Go alpha and Gq alpha/G11 alpha proteins tend to lower during postnatal development, cytosolic forms of these G proteins mostly rise. Neonatal hypothyroidism reduced the amount of myocardial Gs alpha and increased that of Gi alpha/Go alpha proteins. By contrast, neonatal hyperthyroidism increased expression of Gs alpha and decreased that of Gi alpha and G11 alpha in young myocardium. Changes in G protein content induced by neonatal hypo- and hyperthyroidism in young rat myocardium were restored in adulthood. Alterations in the membrane-cytosol balance of G protein subunits associated with maturation or induced by altered thyroid status indicate physiological importance of cytosolic forms of these proteins in the rat myocardium.

Topics: Age Factors; Animals; Animals, Newborn; Cytosol; Heterotrimeric GTP-Binding Proteins; Hyperthyroidism; Hypothyroidism; Isoenzymes; Male; Membrane Proteins; Myocardium; Organ Size; Propylthiouracil; Protein Subunits; Rats; Rats, Wistar; Subcellular Fractions; Triiodothyronine

The developmental profile of the different isoforms of NaKATPase have been investigated during the first three weeks of postnatal development using primary cultures of isolated glial cells derived from neonatal rat cerebra. Northern and Western blot analysis show that the expression of four isoforms (alpha1, alpha2, beta1 and beta2) in these cells increases progressively between 5 to 20 days of culture. Comparison of the mRNA levels of these isoforms in thyroid hormone deficient (TH def) and thyroid hormone supplemented (TH sup) cells cultured for 5-10 days, revealed for the first time that all four isoforms are sensitive to T3 in the glial cells. Furthermore immunocytochemical staining of these cells with isoform specific NaKATPase antibodies also showed that the localization of the different isoforms in the TH def cells were altered in comparison to that in the TH sup cells. These results establish glial cells as the target cells for the regulation of NaKATPase by TH in the developing brain.

Topics: Animals; Animals, Newborn; Blotting, Northern; Blotting, Western; Brain; Cells, Cultured; Female; Hypothyroidism; Immunohistochemistry; Isoenzymes; Neuroglia; Pregnancy; Prenatal Exposure Delayed Effects; Propylthiouracil; Rats; Rats, Sprague-Dawley; RNA, Messenger; Sodium-Potassium-Exchanging ATPase; Triiodothyronine

To investigate and quantify structural parameters in the developing cerebellum during hypothyroidism in pre and postnatal stages in 15 day old rat pups in comparison with 5 and 24 day old.. Propylthiouracil (PTU) was fed to rat dams during mating, pregnancy and nursing and their pups in drinking water. Consequently hypothyroxinemia was induced in the dams and the developing foeti during prenatal period and maintained in the dams and pups. The number of treated and control dams was five in each group. The treated and control pups were eight and eleven respectively. The whole cerebellum was dissected out and routinely processed for histological and morphometric analysis. Structural changes in cerebellum were estimated using "design based" stereological methods. The total volume of cerebellum, intracerebellar nuclei and cerebellar compartments were estimated using Cavalieri Principle. Numerical density of cells was estimated using the disector method and the total cell number was then calculated.. In the 15 day pups there was significant reduction (P<0.05) in the mean volumes of cerebellum, internal granular layer, molecular layer, cerebellar cortex, mean ratio of the total volume of intracerebellar nuclei to the cerebellar volume and increased mean volume of external granular layer in treated pup group compared with control. The mean volumes of intracerebellar nuclei and white matter and the mean numerical densities and total numbers of neurons and Purkinje cells in intracerebellar nuclei and cerebellum respectively were nearly equal in control and treated groups. Significant increase (P<0.05) in the mean numerical density and total number of glial cells in treated pups compared with control was observed. There was significant decrease (P<0.05) in the mean neuron/neuroglia ratio in the intracerebellar nuclei, mean numerical density and mean total number of granule cells and reduction in the mean ratio of total number of granule/Purkinje cells in the treated group compared with control. The linear regression comparison for the total volume of the intracerebellar nuclei to total volume of the cerebellum in 5, 15 and 24 day control and treated pups and for the total number of glial cells on the total volume of intracerebellar nuclei in the same were significantly different (P<0.05). Total numbers of neurons and glial cells in the intracerebellar nuclei showed peak values in 15 day pups.. Thus PTU-induced hypothyroidism causes variation in quantitative structural parameters in developing cerebellum and disrupts progressive cellular developmental processes. Maintenance of normal T4 and T3 levels during growth and maturation of cerebellum is absolutely essential.

Topics: Aging; Animals; Animals, Newborn; Cell Count; Cerebellum; Female; Hypothyroidism; Male; Models, Animal; Neuroglia; Neurons; Pregnancy; Propylthiouracil; Rats; Rats, Wistar; Thyroxine; Triiodothyronine

To investigate the structural parameters of the developing cerebellum in propylthiouracil (PTU)-induced hypothyroidism during pre and postnatal stages in 24 day old rat pups.. Hypothyroidism was induced by feeding the breeding dams with PTU in water before and during copulation, pregnancy and lactation and the pups through the dams and ingestion in water. The number of control and treated dams and pups was five for each dam group and twelve and thirteen for pups respectively. The whole cerebellum was dissected out from the pups and processed routinely for histological examination and morphometric analysis. The total volumes of cerebellum, intracerebellar nuclei and cerebellar compartments were estimated by Cavalieri method. The mean numerical densities of neurones and neuroglia in the intracerebellar nuclei and Purkinje, granule and combined stellate and basket cells in cerebellar cortex were estimated using optical disector and the total numbers calculated as the product of the respective numerical densities and reference volumes.. The treated dams and pups had relatively lower mean body weights and etraiodothyronine (T4) serum concentrations. The serum Triiodothyronine (T3) was normal and lower in the treated dams and pups respectively. The differences in the respective body weights and dam T4 concentration in treated dams and pups were significant (p<0.05) compared to the control. Morphometric results showed that the mean volumes of cerebellum, intracerebellar nuclei, white matter, internal granular layer, molecular layer and the cerebellar cortex were lower and the differences between the values for each parameter were significant (p<0.05) in the treated pups compared to the control. The mean numerical densities of neurones and neuroglia in the intracerebellar nuclei (Nvne; Nvgl) and the combined stellate and basket cells (Nvsb) in the cerebellar cortex were relatively higher and the mean values for the respective numerical densities of Purkinje and granule cells (Nvpu; Nvgr) were relatively lower in the treated pups compared to the control. On the other hand the treated pups had relatively lower values for the respective total numbers of neurons (Nne), neuroglia (Ngl), Purkinje (Npu), granule (Ngr) and the combined stellate and basket (Nsb) cells compared to the control. The differences between the respective values for Nvne, Nvsb, Npu, and Ngr, were significant (p<0.05).. These results show that rat pups with PTU-induced hypothyroidism have relatively lower mean values for the structural parameters in the cerebellum when compared to control pups. This confirms that growth and maturation of the cerebellum is dependent on the maintenance of normal T4 and T3 levels, underscores the magnitude of the deviations from the normal and sheds light on possible structural limitations in the cerebellum in cretins.

Topics: Animals; Animals, Newborn; Antithyroid Agents; Cell Count; Cerebellum; Female; Hypothyroidism; Pregnancy; Pregnancy Complications; Propylthiouracil; Rats; Rats, Wistar

The iron binding protein ferritin is a heterogeneous mix of 24 heavy (H) and light (L) subunits. The H subunit is associated with iron utilization, while the L subunit is responsible for iron storage. Examination of the developmental pattern of mRNA abundance in rat brain revealed that ferritin L mRNA is highest at birth and declines during the first postnatal week. A similar decline was seen in ferritin H mRNA, but was followed by an increase in ferritin H mRNA in the second postnatal week which continued through postnatal day 21. The pattern of H mRNA regulation is similar to that in previous reports of total ferritin protein in the developing rat brain and is consistent with the fact that brain ferritin is predominately ferritin H. The effect of thyroid hormone on the developmental regulation of ferritin mRNAs was examined by the subcutaneous injection of a single dose of exogenous thyroxine (T(4); 2 microg/g) on postnatal day 1. Hypothyroidism was induced in pregnant dams with propylthiouracil (PTU; 0.05% in drinking water) from gestational day 7. Northern analysis from postnatal days 2-21 showed that T(4) increased ferritin H mRNA throughout development, while ferritin L mRNA was decreased compared to age-matched controls. PTU treatment decreased ferritin H and increased L mRNA in the later stages (days 14-21) of development. Given the distinct functions of ferritin H and L this suggests a role for thyroid hormone in the ability of the brain to regulate stored vs. utilizable iron during critical periods of development.

Topics: Animals; Antithyroid Agents; Blotting, Northern; Brain; Female; Ferritins; Gene Expression Regulation, Developmental; Hypothyroidism; Male; Maternal-Fetal Exchange; Pregnancy; Propylthiouracil; Radioimmunoassay; Rats; Rats, Sprague-Dawley; RNA, Messenger; Thyroxine

Thyroid hormones play an important role in cardiac electrophysiology through both genomic and nongenomic mechanisms of action. The effects of triiodothyronine (T(3)) on the electrophysiological properties of ventricular myocytes isolated from euthyroid and hypothyroid rats were studied using whole cell patch clamp techniques. Hypothyroid ventricular myocytes showed significantly prolonged action potential duration (APD(90)) compared with euthyroid myocytes, APD(90) of 151 +/- 5 vs. 51 +/- 8 ms, respectively. Treatment of hypothyroid ventricular myocytes with T(3) (0.1 microM) for 5 min significantly shortened APD by 24% to 115 +/- 10 ms. T(3) similarly shortened APD in euthyroid ventricular myocytes, but only in the presence of 4-aminopyridine (4-AP), an inhibitor of the transient outward current (I(to)), which prolonged the APD by threefold. Transient outward current (I(to)) was not affected by the acute application of T(3) to either euthyroid or hypothyroid myocytes; however, I(to) density was significantly reduced in hypothyroid compared with euthyroid ventricular myocytes.

Topics: 4-Aminopyridine; Action Potentials; Animals; Cadmium Chloride; Electric Conductivity; Heart; Heart Ventricles; Hypothyroidism; Male; Patch-Clamp Techniques; Propylthiouracil; Rats; Rats, Sprague-Dawley; Triiodothyronine; Triiodothyronine, Reverse

Circulating T(4) and T(3) were measured during the first three post-natal weeks in the mouse and found to increase in a triphasic manner. The first increase occurred at post-natal day 6 and was simultaneous with a decrease in bromodeoxyuridine incorporation in areas showing post-natal mitosis. We investigated whether there was a causal relationship between increased thyroid hormone levels and decreased proliferation by inducing hypothyroidism in dams and progeny. Hypothyroidism prolonged mitotic activity in the olfactory bulb, hippocampus, subventricular zone and the cerebellar cortex. This suggests that the increase in T(3) at the end of the first postnatal week is implicated in terminating progenitor proliferation in many parts of the mouse brain.

Topics: Animals; Animals, Newborn; Brain; Bromodeoxyuridine; Cerebellum; Female; Hippocampus; Hypothyroidism; Male; Mice; Mitosis; Olfactory Bulb; Pregnancy; Propylthiouracil; Thyroxine; Time Factors; Triiodothyronine

Several anecdotal reports indicate that cancer may occasionally remain in a dormant state for prolonged periods in patients with hypothyroidism. Once the hypothyroid state is recognized and supplementation therapy with thyroid hormones is initiated, disease progression occurs. In this experiment, 6-n-propyl-2-thiouracil (PTU) was added to the water of athymic nude mice. The animals were subsequently inoculated with cells from a human prostate cancer cell line.. The growth rate of subcutaneously implanted prostate xenografts was significantly slower in mice treated with PTU compared with mice that did not receive PTU. In a separate experiment, tritiated thymidine incorporation assays were performed in DU145 and PC3 human prostate cancer cells with and without PTU. No significant differences were observed, indicating that PTU did not exert any antitumor effect in vitro.. Our study demonstrates that PTU inhibits the growth of human prostate tumors in nude mice via an indirect effect. This antitumor effect may be caused by hypothyroidism. This is the first in vivo study suggesting potential therapeutic applications for thyroid hormone manipulations in human cancer of the prostate. Further studies will determine growth kinetics of xenotransplanted prostate cancer in vitro and in vivo. PTU-induced hypothyroidism may be further explored in conjunction with other antineoplastic therapy.

Topics: Animals; Antimetabolites, Antineoplastic; Contrast Media; Disease Models, Animal; Humans; Hypothyroidism; Male; Mice; Mice, Nude; Propylthiouracil; Prostatic Neoplasms; Thymidine; Thyroid Hormones; Transplantation, Heterologous; Tumor Cells, Cultured

Mitochondrial heat shock protein 70 (mtHsp70), an important mitochondrial chaperone, is increased in cardiac muscle mitochondria of hyperthyroid rats. To determine the mechanism(s) underlying this increase, we used variations in thyroid status. In Series I, rats were made hyperthyroid by injecting them with 3,3', 5-triiodo-l-thyronine (T(3)) for 5 days, or by treating them with vehicle. In Series II, animals were given 6-n-propyl-2-thiouracil in their drinking water (0.05% w/v) for a period of 32-42 days to make them hypothyroid. During the last 5 days of treatment these animals received injections of either T(3) or vehicle. T(3) treatment resulted in parallel increases in mtHsp70 protein and mRNA levels in a variety of tissues, suggesting transcriptional regulation. However, evidence of tissue-specific post-transcriptional regulation was also apparent. In isolated heart mitochondria, T(3) treatment resulted in a 1.8-fold increase in mtHsp70. This was due to the 1. 6-fold greater import of mtHsp70 into mitochondria in T(3), compared with hypothyroid animals, and it could not be attributed to an altered rate of intramitochondrial mtHsp70 degradation. The rate of processing of mtHsp70 to its mature form, reflecting mitochondrial processing peptidase activity, was unaffected by T(3), but was more rapid than mtHsp70 import. These data indicate a novel mechanism by which T(3) modifies the mitochondrial phenotype via the adaptations in the protein import pathway.

Topics: Animals; HSP70 Heat-Shock Proteins; Hyperthyroidism; Hypothyroidism; Male; Mitochondria, Heart; Propylthiouracil; Rats; Rats, Sprague-Dawley; RNA, Messenger; Transcription, Genetic; Triiodothyronine

We have recently demonstrated that the rates of both active and passive proximal straight tubule (PST) NaCl transport in neonatal rabbits were less than in adults. In this segment NaCl entry across the apical membrane is via parallel Na(+)/H(+) and Cl(-)/OH(-) exchangers, which increases in activity with maturation. The present in vitro microperfusion study examined whether thyroid hormone plays a role in the maturational increase in PST NaCl transport. Neonatal and adult PST were perfused with a high-chloride-low bicarbonate solution without organic solutes, simulating late proximal tubule fluid. Thyroid hormone-treated neonates had a higher rate of PST total and passive NaCl transport. In 8-wk-old animals that were hypothyroid since birth, the maturational increase in total and passive NaCl transport was prevented. Thyroid treatment for 4 days in hypothyroid 8-wk-old rabbits increased the rate of both total and passive NaCl transport. The maturational increases in both Na(+)/H(+) and Cl(-)/OH(-) exchange activities were blunted in 8-wk-old hypothyroid animals and increased to control levels with thyroid treatment. This study demonstrates that thyroid hormone is a factor responsible for the maturational increase in both active and passive PST NaCl transport.

Topics: Aging; Animals; Animals, Newborn; Antiporters; Antithyroid Agents; Biological Transport; Cell Membrane; Female; Hypothyroidism; Kidney Tubules, Proximal; Male; Propylthiouracil; Rabbits; Sodium Chloride; Sodium-Hydrogen Exchangers; Triiodothyronine

This study was performed to investigate the effect of propylthiouracil (PTU) on rat testis, and to compare the results of the different treatment regimens of levothyroxine and zinc. Twenty sexually mature Wistar albino rats were subjected to PTU for 14 days intraperitoneally to make them hypothyroidic. The effect of PTU on testicular function was assessed histopathologically after unilateral orchiectomy on day 15, and treatment was evaluated by measuring serum thyroid-stimulating hormone (TSH), T3, T4, and zinc levels on days 0, 7, and 15. The rats were then divided into five groups which were given levothyroxine and/or zinc treatment for 15 days. Orchiectomies were repeated on day 30, and specimens were evaluated histopathologically. Although serum T3, T4 and zinc levels decreased, serum TSH levels increased in PTU-treated rats, and the difference to the control group was statistically significant (P < 0.001). Maturation arrest of spermatogenesis, a reduced number of Sertoli and Leydig cells, a decreased tubular diameter, interstitial oedema, and thickening of basal membrane were observed in hypothyroidic testicles. After treatment, testicular histology and spermatogenesis gradually recovered in all groups with hypothyroidism, but maximum improvement was achieved in the levothyroxine + zinc sulphate replacement group, indicating a possible role of zinc in testicular function.

Topics: Animals; Atrophy; Hypothyroidism; Leydig Cells; Male; Propylthiouracil; Rats; Rats, Wistar; Sertoli Cells; Spermatogenesis; Testis; Thyrotropin; Thyroxine; Triiodothyronine; Zinc

Propylthiouracil (PTU) or low-iodine diet (LID) treatment increases thyroid-follicular-cell proliferation, possibly by disrupting the movement of small molecules (< 1.2 kD) through membrane channels called gap junctions. Numerous tumor promoters and proliferative disease states exhibit inhibited gap-junctional-intercellular communication (GJIC) prior to the induction of cell proliferation, yet the association between GJIC and apoptosis is unclear. In the present study, we used an ex vivo method to examine whether GJIC is inhibited in the thyroid of PTU- or LID-treated rats. In addition, the effect of these models of hypothyroidism on thyroid-follicular-cell proliferation and apoptosis was examined to determine the association between GJIC and cell homeostasis. After 14 days of treatment of either PTU or LID (plus 1% KClO4 in the drinking water), serum tri-iodothyronine (T3) and thyroxine, (T4) was decreased to nearly undetectable levels and serum TSH was increased in PTU- and LID-treated rats. At the same time point, GJIC was decreased 30-35% in PTU- and LID-treated rats while thyroid-follicular-cell proliferation increased nearly threefold in both treatment groups. Interestingly, apoptosis increased twofold in both hypothyroid treatment groups. These data suggest that PTU or LID treatment inhibit thyroid GJIC during a state of increased thyroid-follicular-cell proliferation and apoptosis. While the increase in proliferation was anticipated, the paradoxical increase in apoptosis during decreased GJIC in thyroid-follicular cells warrants further examination.

Topics: Animals; Antithyroid Agents; Apoptosis; Body Weight; Cell Communication; Cell Division; Diet; Gap Junctions; Hypothyroidism; Immunohistochemistry; Iodine; Male; Propylthiouracil; Rats; Rats, Sprague-Dawley; Thyroid Gland; Thyrotropin; Thyroxine; Triiodothyronine

Congenital hypothyroidism results in deafness that is caused by changes in the auditory receptor, including scanty development of the outer hair cells and a lack of synaptogenesis between these cells and the efferent system. although the afferent population is present. The normal efferent innervation of the cochlea originates in the superior olivary complex, arising from efferent neurons belonging to the lateral or to the medial olivocochlear system. In the rat, the former is constituted by neurons located in the lateral superior olivary nucleus, that project to the inner hair cells, while the later originates in the ventral nuclei of the trapezoid body and project to the outer hair cells. The aim of this work is to study the localization, number and morphology of the olivochochlear neurons in congenital hypothyroid animals by means of the injections of the retrograde tracers, either fast blue or cholera toxin, in the cochlea. The mean total number of labeled olivocochlear neurons after injection of fast blue in hypothyroid animals was 1,016, and in control ones was 1,027. Using cholera toxin, the mean total number of labeled olivocochlear neurons was slightly lower: 863 in hypothyroid animals versus 910 in control ones. Although both tracers showed no significant differences between groups, when the somatic area of the labeled olivocochlear neurons is considered, the size of all of the three different population of cells (lateral olivocochlear neurons, medial olivocochlear neurons and shell neurons) was significantly lower in the hypothyroid rats. This is the first study of the olivocochlear neurons in hypothyroid animals. The conclusion from this work is that in hypothyroid rats the labeled olivocochlear neurons are significantly smaller but that there is not any modification in the localization and number of the labeled olivocochlear neurons, suggesting that thyroid hormones are necessary for the neuronal growth. However, most of the medial olivocochlear neurons do not make contact with their target, so their maintenance suggests that the axons are in contact with other structures of the cochlea.

Topics: Abnormalities, Drug-Induced; Afferent Pathways; Amidines; Animals; Cholera Toxin; Cochlea; Cochlear Nucleus; Congenital Hypothyroidism; Disease Models, Animal; Female; Fluorescent Dyes; Hypothyroidism; Olivary Nucleus; Pregnancy; Propylthiouracil; Rats; Rats, Wistar

Thyroid hormone exerts predictable effects on the contractile performance of the heart in part by regulating the transcription of genes encoding specific calcium transporter proteins. In a rat model of hypothyroidism, left ventricular (LV) contractile function as measured by ejection fraction was decreased by 22% (P < 0.05), and this was returned to control values with T3 treatment. In confirmation of prior studies, LV phospholamban (PLB) protein content was significantly decreased by 25% and 40% compared with hypothyroid LV when the animals were treated with T3 at two doses, 2.5 and 7.0 microg/day, respectively. The ratio of sarcoplasmic reticulum calcium adenosine triphosphatase (SERCA2) to PLB protein content was thus increased by 171% and 207%, respectively (P < 0.01). Resolution of the phosphorylated PLB pentamers by SDS-PAGE showed that T3 infusion at 2.5 and 7.0 microg/day decreased (P < 0.001) the amount nonphosphorylated pentamers by 82% and 95%, respectively, in a dose-dependent manner. T3 treatment produced an increase in the proportion of highly phosphorylated PLB pentamers (more than five phosphates) when expressed as a fraction of total pentameric molecules (P < 0.05). Site-specific antibodies showed that the T3-induced increase in phosphorylated PLB pentamers was the result of an increase in both serine 16 and threonine 17 phosphorylation. We conclude that thyroid hormone, in addition to regulating the expression of cardiac PLB, is able to alter the degree of PLB phosphorylation, which correlates with enhancement of LV contractile function. These studies suggest that T3 may augment myocyte calcium cycling via changes in both cAMP- and calcium/calmodulin-dependent protein kinase activities.

Topics: Animals; Calcium-Binding Proteins; Calcium-Transporting ATPases; Hypothyroidism; Male; Myocardial Contraction; Myocardium; Phosphorylation; Propylthiouracil; Rats; Rats, Sprague-Dawley; RNA, Messenger; Sarcoplasmic Reticulum; Triiodothyronine

We have previously reported that changes in thyroid status are associated with significant alterations in skeletal muscle blood flow during exercise and that changes in endothelium-dependent vasodilation may contribute to these blood flow abnormalities. The purpose of this study was to test the hypothesis that altered endothelium-dependent vasoconstriction is also associated with changes in thyroid status. To test this hypothesis, rats were rendered hypothyroid with propylthiouracil (Hypo, n = 14) or hyperthyroid with triiodothyronine (Hyper, n = 14) over approximately 3 mo. Treatment efficacy was confirmed by altered (P < 0.05) citrate synthase activity in several hindlimb skeletal muscles from Hypo and Hyper, compared with that in muscles from euthyroid rats (Eut, n = 12). Vascular rings were prepared from abdominal aortae, and responses to several vasoactive agents were determined in vitro. As found previously, maximal acetylcholine-induced vasorelaxation was modulated by thyroid status (Eut, 47 +/- 9; Hypo, 28 +/- 6; Hyper, 68 +/- 5%; P < 0.05). Contractile responses of vascular rings with intact endothelium to the endothelium-derived constrictor endothelin-1 (ET-1), however, were similar among groups across a range of ET-1 concentrations. In addition, maximal responses [Eut, 3.75 +/- 0.47; Hypo, 2.72 +/- 0.25; Hyper, 3.22 +/- 0.42 g; not significant (NS)] and sensitivities (Eut, 8.12 +/- 0.09; Hypo, 8.10 +/- 0.06; Hyper, 8.28 +/- 0.09 -log M; NS) to ET-1 were similar among groups. If these findings from the conduit-type abdominal aorta extend into resistance vasculature, it appears that changes in endothelium-dependent vasoconstriction do not contribute to skeletal muscle blood flow abnormalities associated with thyroid disease states.

Topics: Acetylcholine; Animals; Aorta, Abdominal; Citrate (si)-Synthase; Dose-Response Relationship, Drug; Endothelin-1; Hyperthyroidism; Hypothyroidism; In Vitro Techniques; Male; Muscle, Skeletal; Muscle, Smooth, Vascular; Nitroprusside; Norepinephrine; Propylthiouracil; Rats; Triiodothyronine; Vasoconstriction; Vasoconstrictor Agents; Vasodilator Agents

The role of glutamate receptors in the inferior colliculus (IC) in audiogenic and audiogenic-like seizures was investigated in adult rats with transient neonatal hypothyroidism by 0.02% propylthiouracil (PTU) treatment through mother's milk (PTU rats) and in naive rats treated intracisternally with N-methyl-d-aspartate (NMDA), alpha-amino-3-hydroxy-5-methyl-4-isoxazole-proprionic acid (AMPA), or cyclothiazide, an inhibitor of rapid AMPA receptor desensitization. All rats showed audiogenic or audiogenic-like seizures characterized by running fit (RF) and generalized tonic-clonic seizures (GTCS). While systemically administered MK-801 inhibited GTCS, intracisternally administered NBQX inhibited RF and GTCS in both audiogenic and audiogenic-like seizures. Auditory stimulation shortened the latency to GTCS induced by AMPA, but not NMDA, at a subclinical dose and further elongated the shortened duration of RF, but not GTCS, induced by MK-801 pretreatment. Furthermore, Northern blot analysis was used to evaluate the expression of the immediate-early gene c-fos in the IC following induction of audiogenic or audiogenic-like seizures. The significant induction of c-fos mRNA by audiogenic seizures in PTU rats or by AMPA- or cyclothiazide-induced seizures in naive rats was prominent in the IC. MK-801 suppressed c-fos mRNA expression in the IC induced by audiogenic seizures in PTU rats or by AMPA-induced seizures in naive rats. NBQX suppressed the expression of c-fos mRNA in the IC induced by AMPA-induced seizures but did not suppress c-fos mRNA in PTU rats or rats with cyclothiazide-induced seizures. Auditory stimuli failed to affect c-fos mRNA induction by AMPA. The present study suggests that audiogenic-like seizures can be reproduced by glutamate receptor agonists in which AMPA receptors are primarily linked to the initiation of audiogenic seizures (RF) while NMDA receptors presumably located within the IC are involved in the propagation of GTCS in audiogenic seizures.

Topics: Acoustic Stimulation; alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid; Animals; Animals, Suckling; Benzothiadiazines; Dizocilpine Maleate; Drug Administration Routes; Excitatory Amino Acid Antagonists; Female; Hypothyroidism; Inferior Colliculi; Injections, Intraventricular; Male; Maternal Exposure; N-Methylaspartate; Propylthiouracil; Proto-Oncogene Proteins c-fos; Quinoxalines; Rats; Rats, Sprague-Dawley; Reaction Time; Receptors, AMPA; Receptors, N-Methyl-D-Aspartate; RNA, Messenger; Seizures

Recent clinical studies have indicated that plasma homocysteine was significantly increased in hypothyroid patients. Since hyperhomocysteinemia is an independent risk factor for cardiovascular disease we investigated homocysteine metabolism in hypothyroid rats. Hypothyroidism was induced in one study by addition of propylthiouracil (PTU) to the drinking water for 2 weeks. In a second study, thyroidectomized and sham-operated rats were used with thyroid hormone replacement via mini-osmotic pumps. Unlike the human hypothyroid patients, both groups of hypothyroid rats exhibited decreased total plasma homocysteine (30% in PTU rats, 50% in thyroidectomized rats) versus their respective controls. Thyroid replacement normalised homocysteine levels in the thyroidectomized rat. Increased activities of the hepatic trans-sulfuration enzymes were found in both models of hypothyroidism. These results provide a possible explanation for the decreased plasma homocysteine concentrations. The hypothyroid rat cannot be used as a model to study homocysteine metabolism in hypothyroid patients.

Topics: Animals; Cystathionine beta-Synthase; Homocysteine; Hypothyroidism; Male; Propylthiouracil; Rats; Rats, Sprague-Dawley; Thyroidectomy

We tested the effects of thyroid hormone on Leydig cell (LC) regeneration in the adult rat testis after ethane dimethyl sulphonate (EDS) treatment. Ninety-day-old, thyroid-intact (n = 96) and thyroidectomized (n = 5) male Sprague-Dawley rats were injected intraperitoneally (single injection) with EDS (75 mg/kg) to destroy LC. Thyroid-intact, EDS-treated rats were equally divided into three groups (n = 32 per group) and treated as follows: control (saline-injected), hypothyroid (provided 0.1% propyl thiouracil in drinking water), and hyperthyroid (received daily subcutaneous injections of tri-iodothyronine, 100 microg/kg). Testing was done at Days 2, 7, 14, and 21 for thyroid-intact rats and at Day 21 for thyroidectomized rats after the EDS treatment. Leydig cells were absent in control and hyperthyroid rats at Days 2, 7, and 14; in hypothyroid rats at all ages; and in thyroidectomized rats at Day 21. The LC number per testis in hyperthyroid rats was twice as those of controls at Day 21. 3beta-Hydroxysteroid dehydrogenase (LC marker) immunocytochemistry results agreed with these findings. Mesenchymal cell number per testis was similar in the three treatment groups of thyroid-intact rats on Days 2 and 7, but it was different on Days 14 and 21. The highest number was in the hypothyroid rats, and the lowest was in the hyperthyroid rats. Serum testosterone levels could be measured in control rats only on Day 21, were undetectable in hypothyroid rats at all stages, and were detected in hyperthyroid rats on Days 14 and 21. These levels in hyperthyroid rats were twofold greater than those of controls on Day 21. Serum androstenedione levels could be measured only in the hyperthyroid rats on Day 21. Testosterone and androstenedione levels in the incubation media showed similar patterns to those in serum, but with larger values. These findings indicate that hypothyroidism inhibits LC regeneration and hyperthyroidism results in accelerated differentiation of more mesenchymal cells into LC following the EDS treatment. The observations of the EDS-treated, thyroidectomized rats confirmed that the findings in hypothyroid rats were, indeed, due to the deficiency of thyroid hormone.

Topics: Androstenedione; Animals; Antithyroid Agents; Body Weight; Cell Differentiation; Hydroxysteroid Dehydrogenases; Hyperthyroidism; Hypothyroidism; Leydig Cells; Luteinizing Hormone; Male; Mesoderm; Mesylates; Organ Size; Propylthiouracil; Rats; Rats, Sprague-Dawley; Regeneration; Testis; Testosterone; Thyroid Hormones; Thyroidectomy

The development of spinal cord or dorsal root ganglia neurons expressing calretinin (CR) was studied in thyroid hormone-deficient rats. Immunocytochemical and morphometric analyses showed that the hypothyroidism induced a significant decrease in the number and size of immunoreactive neurons in the spinal cord, as well as stunted growth and arborization of the axons and dendrites. These alterations were observed at different embryonic ages and persisted during the whole postnatal life. In adult hypothyroid rats, the mean number of CR-positive neurons per spinal cord section (31.2 +/- 2.3 in laminae I and II and 30.5 +/- 5.5 in laminae III-X) was significantly decreased (P < 0.001 and P = 0.024, respectively) compared with adult normal rats (68.7 +/- 8.9 and 50.0 +/- 11.0, respectively). In the peripheral nervous system, hypothyroidism altered the growth of sensory neurons expressing CR protein mainly during embryonic life. In comparison with normal rats, hypothyroid embryonic animals showed not only reduced cell size but also a significantly decreased percentage of CR-positive neurons (6.6 +/- 0. 9% in normal, 2.1 +/- 0.3% in hypothyroid rats, P < 0.001). In contrast, although the size of neurons was reduced in hypothyroid young and adult rats, there was no reduction in the percentage of CR-positive neurons. These results showed that thyroid hormone deficiency altered differentially the development of neurons expressing CR protein in the central and peripheral nervous systems. This suggests that central and peripheral neurons are heterogeneous in their sensitivity to thyroid hormone.

Topics: Animals; Antithyroid Agents; Calbindin 2; Cell Count; Cell Size; Ganglia, Spinal; Hypothyroidism; Neurons; Propylthiouracil; Rats; Rats, Wistar; Reference Values; S100 Calcium Binding Protein G; Spinal Cord; Thyroid Hormones

Adults rats with hypothyroidism were prepared by administration of 6-propyl-2-thiouracil (PTU) or methimazole, and the tissues were examined for their gangliosides through methods including glycolipid-overlay techniques. Normal thyroid tissue contained GM3, GD3, and GD1a as the major gangliosides, with GM1, GD1b, GT1b, and GQ1b in lesser amounts. The goitrous tissue of PTU-induced hypothyroid rats had higher concentrations of GM1 and GD1a with a concomitant decrease of GM3. The amount of GT3 in thyroid tissue was increased in hypothyroid animals. While normal liver tissue had a complex ganglioside pattern with a- and b-series gangliosides, the PTU-induced hypothyroid tissue showed a simpler ganglioside profile that consisted mainly of a-series gangliosides with almost undetectable amounts of b-series gangliosides. The expression of c-series gangliosides was suppressed in the hypothyroid liver tissue. Heart tissue had higher contents of GM3 and GT3 than control. No apparent change was observed in the compositions of major and c-series gangliosides in other extraneural tissues (i.e., kidney, lung, spleen, thymus, pancreas, testis, skeletal muscle, and eye lenses), and neural tissues (i.e., cerebrum and cerebellum) from PTU-induced hypothyroid rats. The ganglioside changes of thyroid, liver, and heart tissues were reproduced in corresponding tissues of methimazole-induced hypothyroid rats. These results suggest that hypothyroid conditions affect the biosynthesis and expression of gangliosides in specific tissue and cell types.

Topics: Animals; Body Weight; Gangliosides; Heart; Hypothyroidism; Liver; Male; Methimazole; Myocardium; Propylthiouracil; Rats; Rats, Sprague-Dawley; Reference Values; Thyroid Gland; Thyroxine

Mitochondria seem to be involved in oxygen radical damage and aging. However, the possible relationships between oxygen consumption and oxygen radical production by functional mitochondria, and oxidative DNA damage, have not been studied previously. In order to analyze these relationships, male Wistar rats of 12 weeks of age were rendered hyper- and hypothyroid by chronic T(3) and 6-n-propyl-2-thiouracil treatments, respectively. Hypothyroidism decreased heart mitochondrial H(2)O(2) production in States 4 (to 51% of controls; P<0.05) and 3 (to 21% of controls; P<0.05). In agreement with this, 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-oxodG) decreased in the heart genomic DNA of hypothyroid animals to 40% of controls (P<0.001). Studies with respiratory inhibitors showed that the decrease in oxygen radical generation observed in hypothyroidism occurred at Complex III (mainly) and at Complex I; that decrease was due to the presence of a lower free radical leak in the respiratory chain (P<0.05). Hyperthyroidism did not significantly change heart mitochondrial H(2)O(2) production since the increase in State 4 oxygen consumption in comparison with control and hypothyroid animals (P<0.05) was compensated by a decrease in the free radical leak in relation to control animals (P<0.05). In agreement with this, heart 8-oxodG was not changed in hyperthyroid animals. The lack of increase in H(2)O(2) production per unit of mitochondrial protein will protect mitochondria themselves against self-inflicted damage during hyperthyroidism.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Animals; Cell Fractionation; Deoxyguanosine; DNA Damage; Free Radicals; Hydrogen Peroxide; Hyperthyroidism; Hypothyroidism; Male; Mitochondria, Heart; Myocardium; Oxidation-Reduction; Oxygen Consumption; Propylthiouracil; Rats; Rats, Wistar; Rotenone; Thyroid Gland; Thyroid Hormones; Triiodothyronine; Uncoupling Agents

How borderline impairment of thyroid function can affect thermoregulation is an important issue because of the antithyroidal properties of a many environmental toxicants. This study compared the efficacy of heat and cold stress to identify thermoregulatory deficits in rats subjected to borderline and overt hypothyroidism via subchronic exposure to propylthiouracil (PTU). After 3 wk of exposure to PTU in the drinking water (0, 2.5, 5, 10, and 25 mg/l), rats were subjected to a heat stress challenge (34 degrees C for 2.5 h). After one more week of PTU treatment, the same rats were subjected to a cold stress challenge (7 degrees C for 2.5 h). Core temperature (T(c)) was monitored by radiotelemetry. Baseline T(c) during the light phase was reduced by treatment with 25 mg/l PTU. The rate of rise and overall increase in T(c) during heat stress was attenuated by PTU doses of 10 and 25 mg/l. Cold stress resulted in a 1.0 degrees C increase in T(c) regardless of PTU treatment. The rate of rise in T(c) during the cold stress challenge was similar in all PTU treatment groups. There was a dose-related decrease in serum thyroxine (T(4)) at PTU doses >/=5 mg/l. Serum triiodothyronine (T(3)) was reduced at PTU doses of 5 and 25 mg/l. Serum thyroid-stimulating hormone (TSH) was marginally elevated by PTU treatment. Overall, heat stress was more effective than cold stress for detecting a thermoregulatory deficit in borderline (i.e., 10 mg/l PTU) and overtly hypothyroid rats (i.e., 25 mg/l PTU). A significant thermoregulatory deficit is manifested with a 78% decrease in serum T(4). A thermoregulatory deficit is more correlated with a reduction in serum T(4) compared with T(3). Serum levels of TSH are unrelated to thermoregulatory response to heat and cold stress.

Topics: Acclimatization; Activity Cycles; Animals; Body Temperature; Body Temperature Regulation; Cold Temperature; Hot Temperature; Hypothyroidism; Motor Activity; Propylthiouracil; Rats; Rats, Long-Evans; Stress, Physiological; Triiodothyronine

Many millions of people throughout the world are at risk of developing iodine deficiency-associated disorders. The underlying effects of iodine deficiency on neuroendocrine function are poorly defined. We have studied stress-induced and diurnal variation in corticosterone secretion in female rats rendered chronically hypothyroid by feeding them an iodine-free diet for 6 months. Corticosterone secretory responses in iodine deficient animals were compared to those seen in animals rendered hypothyroid with propylthiouracil and untreated controls. By using a well-validated, automated blood sampling system to collect small samples of blood over the complete daily cycle in unrestrained animals, we have demonstrated for the first time that the normal diurnal rhythm of corticosterone secretion is lost in chronic iodine deficiency and that the corticosterone secretory response to the psychological stress of 10 min exposure to white noise is attenuated. Despite restoration of circulating triiodothyronine and thyrotropin releasing hormone- and thyroid stimulating hormone beta-transcript prevalence in the hypothalamus and pituitary, respectively, 1 month after restoration of normal iodine-containing diet both the diurnal variation in corticosterone levels and the corticosterone secretory response to the noise stress remained reduced in amplitude compared to control animals. Thus, chronic hypothyroidism induced by iodine deficiency significantly attenuates hypothalamo-pituitary-adrenal axis activity, an effect that persists after functional recovery of the thyroid axis.

Topics: Acoustic Stimulation; Animals; Antithyroid Agents; Body Weight; Circadian Rhythm; Corticosterone; Diet; Feedback; Female; Gene Expression; Hypothalamo-Hypophyseal System; Hypothyroidism; In Situ Hybridization; Iodine; Pituitary-Adrenal System; Propylthiouracil; Rats; Rats, Wistar; Receptors, Thyroid Hormone; RNA, Messenger; Stress, Psychological; Transcription, Genetic; Triiodothyronine

In hypothyroid rats, partial hepatectomy does not induce liver regeneration until 120 h after surgical operation. when, instead, in normal rats a complete recovery of the liver mass, in this interval, is observed. In normal rats, a good efficiency of mitochondrial oxidative phosphorylation is needed as an energy source for liver regeneration (Guerrieri, F. et al., 1995); in hypothyroid rats the efficiency of mitochondrial oxidative phosphorylation is low in the 0-120 h interval after partial hepatectomy. This low efficiency of oxidative phosphorylation appears to be related to a low mitochondrial content of F0F1-ATP synthase, in liver of hypothyroid rats, which does not recover after partial hepatectomy. In the liver of hypothyroid rats, low levels of the nuclear-encoded mitochondrial catalytic betaF1 subunit and of its transcript are observed and they do not increase, as occurs in normal rats, after partial hepatectomy.

Topics: Adenosine Triphosphate; Animals; Antithyroid Agents; Disease Models, Animal; Gene Expression; Hepatectomy; Hypothyroidism; Liver; Liver Regeneration; Male; Mitochondria, Liver; Propylthiouracil; Proton-Translocating ATPases; Rats; Rats, Wistar; Time Factors

Although studies have documented the regulatory effects of thyroid hormones on the Na,K-ATPase in peripheral tissues, there is little information on the regulation of this transporter in the thyroid gland itself. Accordingly, we investigated the effects of thyroid status on Na,K-ATPase specific activity and the abundance of its constituent subunits in rat thyroid. Exogenous tri-iodothyronine (T3) was administered daily to produce hyperthyroidism. 6n-propyl-2-thiouracil (PTU), an inhibitor of thyroid hormone synthesis, was used to induce hypothyroidism. There was a four-fold increase in Na,K-ATPase specific activity in the follicular membranes from PTU-treated animals after 7 days. Enzymatic activities were not changed in the T3-treated glands. Immunoblotting of membranes from T3-treated rats revealed a 75% reduction in alpha1 subunit abundance and a slight, but nonsignificant reduction in beta1 abundance. On the other hand, the membranes from PTU-treated rats displayed 136 and 567% increases in the abundance of the alpha1 and beta1 subunits respectively. These data demonstrate that thyroid hormone status regulates Na,K-ATPase in the gland, but the effects are in direct contrast to those seen in the periphery.

Topics: Analysis of Variance; Animals; Electrophoresis, Polyacrylamide Gel; Hypothyroidism; Immunoblotting; Isoenzymes; Male; Propylthiouracil; Rats; Rats, Sprague-Dawley; Sodium-Potassium-Exchanging ATPase; Thyroid Gland; Triiodothyronine

The abundance of Na,K-ATPase and its alpha and beta subunit mRNAs is upregulated in cardiac and other target tissue by thyroid hormone (T3). Multiple Na,K-ATPase mRNA beta 1 species encoding an identical beta 1 polypeptide are expressed in the heart. The different mRNA beta 1 species result from utilization of two transcription start-sites in the first exon and multiple (five) poly(A) signals in the terminal exon of the beta 1 gene. In the present study we identify the mRNA beta 1 species that are expressed in rat ventricular myocardium under basal conditions, and determine whether they are differentially regulated by T3. mRNA beta 1 species were identified by 3'-RACE followed by DNA sequencing, and by Northern blotting using probes derived from different regions of rat cDNA beta 1. Five mRNA beta 1 species are expressed in rat heart: mRNA beta 1 species that are initiated at the first transcription start-site and end at the first, second and fifth poly(A) sites (resulting in mRNAs of 1630, 1810, and 2780 nucleotides), and mRNA beta 1 species initiated at the second transcription start-site and ending at the second and fifth poly(A) sites (resulting in mRNAs of 1500 and 2490 nucleotides); in order of increasing length, the five mRNAs constitute 0.04, 0.15, 0.38, 0.11 and 0.32 of total mRNA beta 1 content. In hypothyroid rats (induced by addition of propyl-thiouracil to the drinking water for 3 weeks), total mRNA beta 1 content decreased to 0.18 euthyroid levels, which was associated with a disproportionate 7.5-fold decrease in the abundance of the longest transcript (P < 0.05); transcripts initiating at the first transcription start-site and ending at the second poly(A) signal in hypothyroid hearts were 0.26 euthyroid levels (P < 0.05). Hyperthyroidism induced by injection of normal rats with three doses of 100 micrograms T3/100 g body weight every 48 h resulted in an overall approximately 2-fold increase in mRNA beta 1 content with no change in the fractional contribution of any of the mRNA beta 1 species. The results indicate a complex heterogeneity in the expression of mRNA beta 1 in myocardium.

Topics: Animals; Base Sequence; Blotting, Northern; Gene Expression Regulation; Hyperthyroidism; Hypothyroidism; Male; Molecular Sequence Data; Myocardium; Propylthiouracil; Rats; Rats, Sprague-Dawley; RNA, Messenger; Sequence Alignment; Sodium-Potassium-Exchanging ATPase; Thyroid Gland; Transcription, Genetic; Triiodothyronine

Cardiac beta-myosin heavy chain (beta-MHC) gene expression is mainly regulated through transcriptional processes. Although these results are based primarily on in vitro cell culture models, relatively little information is available concerning the interaction of key regulatory factors thought to modulate MHC expression in the intact rodent heart. Using a direct gene transfer approach, we studied the in vivo transcriptional activity of different-length beta-MHC promoter fragments in normal control and in altered thyroid states. The test beta-MHC promoter was fused to a firefly luciferase reporter gene, whereas the control alpha-MHC promoter was fused to the Renilla luciferase reporter gene and was used to account for variations in transfection efficiency. Absolute reporter gene activities showed that beta- and alpha-MHC genes were individually and reciprocally regulated by thyroid hormone. The beta-to-alpha ratios of reporter gene expression demonstrated an almost threefold larger beta-MHC gene expression in the longest than in the shorter promoter fragments in normal control animals, implying the existence of an upstream enhancer. A mutation in the putative thyroid response element of the -408-bp beta-MHC promoter construct caused transcriptional activity to drop to null. When studied in the -3, 500-bp beta-MHC promoter, construct activity was reduced ( approximately 100-fold) while thyroid hormone responsiveness was retained. These findings suggest that, even though the bulk of the thyroid hormone responsiveness of the gene is contained within the first 215 bp of the beta-MHC promoter sequence, the exact mechanism of triiodothyronine (T3) action remains to be elucidated.

Topics: Animals; Coleoptera; Enhancer Elements, Genetic; Female; Gene Expression Regulation; Heart; Hyperthyroidism; Hypothyroidism; Luciferases; Myocardium; Myosin Heavy Chains; Promoter Regions, Genetic; Propylthiouracil; Rats; Rats, Sprague-Dawley; Thyroid Gland; Transcription, Genetic; Triiodothyronine

Previous evidence suggests the existence of a thyroid hormone-IGF axis in the liver and changes in hepatic insulin-like growth factor binding protein (IGFBP) expression in rats with altered thyroid status have been previously reported. The aim of this study was to check if the higher IGFBP-2 mRNA levels observed in liver of hypothyroid rats could be due to a direct effect of thyroid hormone on the IGFBP-2 gene. In our experiments, cultured hepatocytes isolated from normal and hypothyroid adult rats were used. Northern blot analysis revealed barely detectable IGFBP-2 mRNA in normal rat hepatocytes, but easily detectable signal in hypothyroid rat cells. Therefore, the effect of tri-iodothyronine (T3) was investigated using cultured hepatocytes from hypothyroid rats as an in vitro model. The IGFBP-2 message was increased in a dose-dependent manner in hepatocytes cultured for 12-24 h in the presence of T3. A similar increase occurred in accumulation of IGFBP-2 in the culture medium, as measured by RIA. The effect of T3 on IGFBP-2 transcript levels appeared to consist of enhanced gene transcription and was independent of ongoing protein synthesis, but it was completely abolished by the incubation of hepatocytes with insulin. The latter result confirmed the dominant role of insulin in regulating IGFBP-2 expression by cultured hepatocytes. In vivo experiments confirmed an increase in hepatic IGFBP-2 mRNA and serum IGFBP-2 levels in hypothyroid rats and demonstrated, in addition, a significant increase in these measures in T3-treated rats. Taken together, our in vitro and in vivo results support a role for a thyroid hormone-IGF axis in the liver and suggest that other factors, such as insulin, interact in vivo with thryoid hormone in regulating hepatic IGFBP-2 expression.

Topics: Animals; Anisomycin; Blotting, Northern; Cells, Cultured; Cycloheximide; Dactinomycin; Gene Expression; Hypothyroidism; Insulin-Like Growth Factor Binding Protein 2; Liver; Male; Methimazole; Propylthiouracil; Protein Synthesis Inhibitors; Rats; RNA, Messenger; Triiodothyronine

The effect of dietary taurine, 2-aminoethanesulfonic acid, on hypercholesterolemia caused by thiouracil-induced hypothyroidism was investigated in hypothyroid rats. Serum total- and HDL-cholesterol were significantly increased, and the excretion of fecal bile acids was significantly decreased. Taurine did not change the hypercholesterolemia, but significantly recovered the excretion of bile acids.

Topics: Animals; Antithyroid Agents; Bile Acids and Salts; Diet; Eating; Feces; Hypercholesterolemia; Hypothyroidism; Male; Propylthiouracil; Rats; Rats, Wistar; Taurine; Thyroid Hormones; Weight Gain

Concanavalin A (Con A) activates T lymphocytes and causes acute T-cell-mediated hepatic injury in mice. Decreased thyroid hormonal production is associated with a variety of immunological manifestations, including inactivation of macrophages with reduced TNF production and reduced soluble IL-2 receptors in the serum. We have recently shown that hypothyroidism prevents the development of cirrhosis and also minimizes hepatic damage in rats with fulminant hepatic failure. In the present study we examined the effects of hypothyroidism on a mouse model of Con A induced T cell-mediated acute hepatitis.. Hypothyroidism was induced both medically (MMI, PTU) and surgically. Eight groups of 10 mice each were studied: euthyroid controls (2 groups: water, Con A) and hypothyroid (6 groups: MMI, PTU, Surgical, MMI-Con A, PTU-Con A, Surgical-Con A).. Hepatic inflammation was significantly decreased in each of the Con A treated hypothyroid groups of mice. The serum transaminases, TNF-alpha and IL-6 levels were significantly elevated in the Con A treated group while near normal levels were found in the hypothyroid Con A treated groups (mean+/-SE AST: 1499+/-18 vs 78+/-10 IU/l, p<0.001; TNF: 2500+/-250 vs 135+/-15 pg/ml, p<0.001, IL-6: 12,200+/-300 vs 1260+/-140 pg/ml, p<0.001, respectively).. Hypothyroidism, independent of the mode of induction, can effectively inhibit the development of acute T cell-mediated liver damage in mice. These results suggest that some decrease in thyroid function might have a role in the prevention of immune mediated liver diseases.

Topics: Alanine Transaminase; Animals; Aspartate Aminotransferases; Concanavalin A; Cytokines; Hypothyroidism; Immunity, Cellular; Inflammation; L-Lactate Dehydrogenase; Liver; Male; Methimazole; Mice; Mice, Inbred BALB C; Propylthiouracil; T-Lymphocytes; Thyroidectomy; Time Factors

Patient aged 49 who developed hypothyroidism after receiving 1131 for relapsing Graves' disease after treatment with propylthiouracil followed by homeopathy. Substitution with thyroxine (0.05 mg/day) was prescribed. Depressed by the perspective of a life long treatment, the patient swallowed 400 pills (20 mg). The evolution was uncomplicated after betablockers administration at hospital. One year later she became euthyroid without further medication. The occurrence of transient hypothyroidism after curitherapy is discussed. The importance of mutual participation in the patient/physician relationship is underlined in the framework of divergent conceptions of medicine.

Topics: Antithyroid Agents; Brachytherapy; Female; Graves Disease; Humans; Hypothyroidism; Middle Aged; Physician-Patient Relations; Propylthiouracil; Suicide, Attempted; Thyroxine

Primiparous, spring-calving Brahman cows (BW = 425.0 +/- 13.8 kg, body condition score [BCS] = 5.0 +/- .2 units; SEM) were used to study the effects of thyroid manipulation on weight gain, milk production, and reproduction. Nine cows served as controls. Nine cows were induced to become hypothyroid by daily ingestion of 4 mg/kg BW of 6-n-propyl-2-thiouracil (PTU). Cows were stratified to treatment 1 d after calving based on season of birth, BW, BCS, calf sex, and calf sire. The treatment period lasted for 84 d and was followed by a 56-d posttreatment period. Cow BW, BCS, and calf weight were recorded twice weekly. Milk production was estimated at 14, 28, 56, 84, 98, 112, and 140 d after calving. Weekly blood samples were obtained for analysis of triiodothyronine (T3), thyroxine (T4), and progesterone (P4). Estrus was monitored twice daily with the aid of a fertile bull equipped with a chin ball marker. Hypothyroidism was effectively induced in all PTU cows during the treatment period. The PTU cows gained more (P = .002) weight (54.6 +/- 7.6 kg) and tended (P = .06) to increase body condition (.61 +/- .17 units) more than control cows (15.7 +/- 7.6 kg; .11 +/- .17 units) during the treatment period. Control calves gained at a faster rate (.85 +/- .04 kg/d; P < .01) than PTU calves (.70 +/- .04 kg/d) during the treatment period. Milk production was lower (P < .05) in PTU cows on d 56 and 84. During posttreatment all trends were reversed, and BW, BCS, calf weight, and milk production were similar between the two groups by d 140. Reproductive performance was not affected by induction of hypothyroidism. In conclusion, induction of hypothyroidism was successful in increasing cow weight and BCS gains and suppressing milk production during the treatment period, but these changes were not successful in improving reproductive performance of primiparous Brahman cows.

Topics: Animals; Antithyroid Agents; Birth Weight; Body Composition; Cattle; Female; Hypothyroidism; Lactation; Progesterone; Propylthiouracil; Reproduction; Weight Gain

In the rat cerebellum, migration of neurons from the external granular layer to the internal granular layer occurs postnatally and is dependent upon the presence of thyroid hormone. In hypothyroidism, many neurons fail to complete their migration and die. Key guidance signals to these migrating neurons are provided by laminin, an extracellular matrix protein that is fixed to the surface of astrocytes. Expression of laminin in the brain is developmentally timed to coincide with neuronal growth spurts. In this study, we examined the role of thyroid hormone on the expression and distribution of laminin in the rat cerebellum. We show that laminin content steadily increased 2- to 3-fold from birth to maximal levels on postnatal day 8-10 then steadily decreased to a plateau by postnatal day 12 in the euthyroid cerebellum. Immunoreactive laminin appeared in the molecular layer of the euthyroid cerebellum by postnatal day 4, reached maximal intensity by postnatal day 8-10, and was gone by postnatal day 14. In contrast, laminin content in the hypothyroid cerebellum remained unchanged from birth until postnatal day 10 and then increased to maximal levels over the next two days; maximal levels were approximately 35% less than those levels in the euthyroid cerebellum. Laminin staining did not appear in the molecular layer of the hypothyroid rat cerebellum until postnatal day 10, reached maximal intensity by postnatal day 15 and disappeared by postnatal day 18, despite the continued presence granular neurons in the external granular layer. These data indicate that the disruption of the timing of the appearance and regional distribution of laminin in the absence of thyroid hormone may play a major role in the profound derangement of neuronal migration observed in the cretinous brain.

Topics: Aging; Animals; Animals, Newborn; Antithyroid Agents; Cerebellum; Hypothyroidism; Immunoblotting; Immunohistochemistry; Laminin; Propylthiouracil; Rats; Rats, Sprague-Dawley; Thyroid Hormones; Tissue Distribution

To evaluate the effects of hypothyroidism on ovarian function, multiparous, nonlactating Brahman cows (n = 18) were assigned randomly to dietary treatments containing either 0 (C; n = 9) or 4 mg x kg BW(-1) x d(-1) 6-n-propyl-2-thiouracil (PTU; n = 9), to suppress thyroid function, in the feed concentrate. Weekly changes in BW and body condition score (BCS) were recorded. Dietary treatments began on d 10 of the estrous cycle. Ten days after the first treatment estrus, all cows received daily i.m. injections of 25 IU of porcine FSH over a 3-d period. Seven days after AI, embryos were collected nonsurgically, and the ovaries were removed via midflank laparotomy. Based on thyroxine (T4) concentrations after 49 d of treatment, five cows were hypothyroid (H-PTU) and four were partially suppressed (P-PTU). Cows in the PTU group had greater (P<.01) ADG, (P<.05) ovarian weights, and numbers of large (> or =8 mm) (P<.05) follicles. Cows in the PTU group had lower embryo recovery rate (P<.001), fertilization rate (P<.001), and percentage of blastocysts (P<.1) than C cows. The H-PTU cows had greater numbers of luteinized follicles (P<.06), greater concentrations of progesterone (P4) in the follicular fluid at all size categories (P<.1), and greater numbers of corpora lutea (P<.05) than C cows. The ratio of luteal to serum P4 on d 7 was greater (P<.05) in hypothyroid cows. Induced hypothyroidism improved weight gain and BCS, increased ovarian response to FSH, and affected ovulation, fertility, and P4 secretion in superovulated Brahman cows.

Topics: Animals; Body Composition; Body Weight; Cattle; Corpus Luteum; Female; Hypothyroidism; Ovary; Progesterone; Propylthiouracil; Superovulation; Thyroxine; Tissue and Organ Harvesting; Triiodothyronine

Thyroid hormones are endocrine modulators of several vital processes that are crucial to tumor growth and differentiation. Several anecdotal reports in the literature suggest that some histologic types of carcinoma may remain in a dormant state for prolonged periods of time in patients with hypothyroidism, with eventual progression of the disease once the decreased thyroid function is identified and corrected.. Oral propylthiouracil (PTU) was used to induce hypothyroidism in athymic nude mice that were subsequently inoculated with lung adenocarcinoma and prostate adenocarcinoma cells. Mice were also treated with a combination of PTU and thyroxine, which resulted in hyperthyroid levels of T(4).. Subcutaneous lung and prostate xenografts grew significantly more slowly in hypothyroid mice treated with PTU than in euthyroid or hyperthyroid mice, regardless of treatment with PTU. Tumors grew well in groups of mice that were changed from a hypothyroid state to a euthyroid state by withdrawal of oral PTU. Administration of PTU 3 weeks after tumor inoculation also caused the tumor growth to slow significantly compared with tumors in mice that did not receive PTU. Mice that received PTU and thyroxine had tumors that grew as well as the tumors in euthyroid control animals.. Our study indicates that human lung and prostate tumors do not grow well in hypothyroid nude mice, and that rendering these animals euthyroid has a significant impact on the growth rate of these tumors. Furthermore, in vitro and in vivo data indicated that this was not a result of an interaction of the tumor cells with PTU, but rather a result of the hypothyroid state.

Topics: Animals; Antithyroid Agents; Cell Division; Humans; Hypothyroidism; Male; Mice; Mice, Nude; Neoplasm Transplantation; Neoplasms, Experimental; Propylthiouracil; Thyroxine; Time Factors; Transplantation, Heterologous; Tumor Cells, Cultured

Intestinal fructose transport rates or GLUT5 mRNA levels typically show a two- to threefold increase after weaning in rats allowed to wean normally but can be enhanced precociously by high-fructose diets during early weaning. Developmental increases in serum thyroxine levels coincide with the onset of weaning and have been linked to changes in intestinal sucrase and lactase activities.. Rat pups were made hypothyroid by giving the dam 0.01% propylthiouracil as drinking water from day 18 of gestation. The hypothyroid pups and age-matched euthyroid control pups were then fed high-fructose or high-glucose solutions by gavage, twice a day starting at 17 days of age for 3 days, and then killed at 20 days of age.. Serum thyroxine levels were five times lower in the hypothyroid pups. Rates of intestinal fructose uptake in the proximal and middle small intestine were 2.0 to 2.5 times higher in the hypothyroid and euthyroid pups fed high-fructose solution than in littermates fed high-glucose solution or those allowed to wean normally with the dam. Intestinal glucose uptake also increased in hypothyroid but not in euthyroid pups fed high-fructose or high-glucose solutions. GLUT5 mRNA levels increased in euthyroid and hypothyroid pups fed high fructose and paralleled the increase in fructose uptake.. During weaning, dietary fructose can precociously enhance intestinal fructose uptake and GLUT5 mRNA expression, independent of developmental increases in serum thyroxine levels. Modest changes in glucose transport rates indicate that nonspecific mechanisms may provide a minor contribution to diet-induced changes in nutrient absorption in hypothyroid pups.

Topics: Animals; Biological Transport; Blotting, Northern; Body Weight; Diet; Female; Fructose; Glucose; Glucose Transporter Type 5; Hypothyroidism; Intestinal Mucosa; Intestines; Monosaccharide Transport Proteins; Organ Size; Propylthiouracil; Rats; Rats, Sprague-Dawley; RNA, Messenger; Solutions; Thyroxine

Altered thyroid statuses are associated with autonomic disorders. Thyrotropin-releasing hormone (TRH) in medullary nuclei regulates vagal efferent activity. Induction of Fos-like immunoreactivity (IR) in medullary TRH-synthesizing neurons was investigated in 24-h fasted rats with different thyroid statuses. Hypo- and hyperthyroidism were induced by 6-N-propyl-2-thiouracil (PTU) in drinking water and a daily intraperitoneal injection of thyroxine (T(4); 10 microgram. 100 g(-1). day(-1)), respectively, for 1-4 wk. The numbers of Fos-like IR positive neurons in the raphe pallidus, raphe obscurus, and parapyramidal regions, which were low in euthyroid rats (0-2/section), increased remarkably as the hypothyroidism progressed and were negatively correlated with serum T(4) levels. At the 4th wk, Fos-like IR positive neurons were 10- to 70-fold higher compared with euthyroid controls. Simultaneous T(4) replacement (2 microgram. 100 g(-1). day(-1)) prevented the increases of Fos-like IR in PTU-treated rats. Hyperthyroidism did not change the number of Fos-like IR neurons in the raphe nuclei but reduced it in the parapyramidal regions. Double immunostaining revealed that most of the Fos-like IR induced by hypothyroidism was located in the prepro-TRH IR positive neurons. The selective and sustained induction of Fos-like IR in TRH-synthesizing neurons in ventral medullary nuclei by hypothyroidism indicates that these neurons play a role in the autonomic disorders observed in altered thyroid statuses.

Topics: Animals; Antibodies; Antithyroid Agents; Cell Count; Hypothyroidism; Male; Medulla Oblongata; Neurons; Propylthiouracil; Protein Precursors; Proto-Oncogene Proteins c-fos; Raphe Nuclei; Rats; Rats, Sprague-Dawley; Thyrotropin-Releasing Hormone; Thyroxine

The diagnosis of fetal hypothyroidism is based at present on measurements of TSH and free thyroxine (FT4) in fetal blood samples obtained by cordocentesis. The measurement of maternal serum and urinary concentrations of compound W, immunologically similar to but chromatographically distinct from diiodothyronine sulfate (T2S), has been advocated as a new possible marker for fetal hypothyroidism.. In this paper, we measured serum compound W levels in 84 pregnant women, 20 with and 64 without thyroid disorders before and during specific treatment. Compound W was also assessed in fetal blood obtained by cordocentesis from 49 normal fetuses and 4 fetuses with suspected hypothyroidism due to transplacental passage of propylthiouracil (PTU). Compound W levels were measured by T2S RIA in maternal and fetal serum. To assess the possible usefulness of 3, 5,3'-triiodothyroacetic acid (TRIAC) for therapy of fetal hypothyroidism we evaluated the transplacental passage of TRIAC by administering the drug to four pregnant women before therapeutic abortion.. In normal pregnancies, both maternal and fetal compound W levels increased progressively during gestation with a significant direct correlation (P<0.001, in both mothers and fetuses). Moreover, a significant positive correlation was observed between fetal compound W and fetal FT4 values (P<0.005), whereas no correlation was observed between maternal serum compound W and maternal FT4 in either euthyroid or hyperthyroid women, suggesting the fetal origin of compound W. The hypothyroid fetuses of PTU-treated mothers showed low compound W levels, and maternal compound W values were in the low normal range and did not show the typical increase during progression of gestation. A significant increase of maternal compound W was observed when the PTU dose was reduced. TRIAC was documented to cross the placental barrier and the treatment of a hyperthyroid pregnant woman on PTU caused the high fetal TSH levels and goiter to normalize.. Serial measurements of 3,3'-T2S crossreactive materials (compound W and 3, 3'-diiodothyroacetic acid sulfate) in maternal blood and the administration of TRIAC to the mother may represent a useful and safe alternative to invasive techniques for the diagnosis and therapy of fetal hypothyroidism.

Topics: Biomarkers; Cordocentesis; Diiodothyronines; Female; Fetal Blood; Fetal Diseases; Gestational Age; Humans; Hypothyroidism; Maternal-Fetal Exchange; Placenta; Pregnancy; Propylthiouracil; Thyrotropin; Thyroxine; Triiodothyronine

The characteristics, cellular locus and regulation of the enzyme gamma-glutamyltranspeptidase (gammaGT) in brain were examined. In rat brain homogenates, the activity of the enzyme exhibited tissue differences--kidney>>>brain==testis>>liver>>skeletal muscle=ventricular muscle and regional differences--brain stem>hippocampus=cerebellum>cerebral cortex, with no significant species/strain differences in the select group of mammals studied. Methods were developed for the isolation from brain of microvessels (MV) and plasma membranes from neuronal/glial cells (N/G PM) utilizing morphological indicators and marker analyses. GammaGT activity was >12 higher in MV than N/G PM; however the enzyme displayed: stability, heat-activation and inhibition with maleate to the same extent in both fractions. A comparative study indicated that in the N/G PM fraction, gammaGT activity was low in all animals studied; gammaGT activity in MV however, was barely detectable in amphibians and reptiles, very low in birds and very high in mammal -mirroring the phylogenetic development of a functional blood-brain barrier. In the rat, gammaGT in both MV and N/G PM displayed a pronounced postnatal increase in activity but the extent and the patterns were different--in all cases, that of the MV greatly exceeded that of the N/G PM and in the MV, the enzyme activity the exhibited the same pattern as the postnatal development of the blood-brain barrier. The induction of congenital hypothyroidism by propylthiouracil (PTU) had no effect on gammaGT in N/G PM but effected a one third reduction in the activity of gammaGT in MV. The normalization by thyroid hormone replacement indicated that MVgammaGT is under thyroid hormone control. The induction of hypothyroidism by PTU in the adult, however, was without effect on enzyme activity in either fraction. The implications of the thyroid hormone dependency of MVgammaGT in the neonatal period and the relationship of gammaGT to the function of the blood brain-barrier is discussed.

Topics: Aging; Animals; Brain; Cell Membrane; Cerebrovascular Circulation; Female; gamma-Glutamyltransferase; Hypothyroidism; Male; Microcirculation; Neuroblastoma; Neuroglia; Neurons; Organ Specificity; Pregnancy; Prenatal Exposure Delayed Effects; Propylthiouracil; Ranidae; Rats; Rats, Inbred F344; Rats, Wistar; Species Specificity; Thyroid Hormones; Tumor Cells, Cultured; Turtles

We report three patients with Down syndrome that developed a hyperthyroidism. A 25 years old female and a 18 years old male had Basedow Graves disease and were treated with radioiodine. A 19 years old male had a Hashitoxicosis and is presently being treated with propylthiouracyl. Clinical and subclinical thyroid dysfunction is frequent in patients with Down syndrome and the risk increases with age. Therefore a surveillance with yearly TSH measurements should be done in these patients, since signs and symptoms of thyroid disease are barely detected in them. Hypothyroidism is the most frequent dysfunction but hyperthyroidism is also associated to Down syndrome.

Topics: Adolescent; Adult; Age of Onset; Down Syndrome; Female; Humans; Hyperthyroidism; Hypothyroidism; Iodine Radioisotopes; Male; Propylthiouracil

Thyroid hormone (T3) affects muscle development and muscle regeneration. It also interacts with the muscle regulatory gene MyoD in culture and affects myoblast proliferation. We studied the localization of MyoD protein using a well-characterized polyclonal antibody for immunohistochemistry. Relative numbers of myogenic precursor cells per field were identified by their MyoD expression during muscle regeneration in normal and mdx dystrophic mice, with particular reference to the expression in mononuclear cells and myotubes at various T3 levels. In regeneration by normal muscles, relatively few MyoD+ nuclei per field were present in mononuclear cells of euthyroid and hypothyroid mice. MyoD staining of mononuclear cell nuclei was approximately doubled in fields of regenerating muscles of normal hyperthyroid compared to euthyroid mice, and was observed in precursors that appeared to be aligned before fusion into myotubes. In mdx regenerating muscle, twofold more mononuclear cells positive for MyoD were present in all three treatment groups compared to normal muscles regenerating under the same conditions. Localization was similar to the pattern in normal euthyroid mice. However, in muscles regenerating in hyperthyroid mdx mice, both mononuclear cell nuclei and centrally located nuclei in a subpopulation (about 15%) of new myotubes formed after the crush injury were intensely stained for MyoD protein. The changes observed are consistent with reports on T3-induced alteration of muscle repair, and propose a link between MyoD regulation and the accelerated differentiation during regeneration under high T3 conditions. (J Histochem Cytochem 46:59-67, 1998)

Topics: Animals; Hypothyroidism; Immunohistochemistry; Mice; Mice, Inbred C57BL; Mice, Inbred mdx; Microscopy, Fluorescence; Muscle Fibers, Skeletal; Muscle, Skeletal; MyoD Protein; Myofibrils; Propylthiouracil; Species Specificity; Triiodothyronine; Wound Healing; Wounds, Nonpenetrating

Multiparous Brahman cows (n = 21) were randomly assigned during late fall within BW and body condition score (BCS) to receive either 3.0 mL of corn oil (C; n = 7), 3.0 mg/(cow x d) triiodothyronine (T3) s.c. in 3.0 mL of corn oil (HYPER; n = 7), or 4.0 mg/(kg x d) 6-n-propyl-2-thiouracil (PTU; fed with concentrate) plus 3.0 mL/d corn oil (HYPO; n = 7). Water, minerals, and Coastal bermudagrass hay were available free choice, and all cows received 3.2 kg x cow(-1) x d(-1) of 5:1 corn:soybean meal concentrate. The feeding period extended through three normal estrous cycles. Blood samples were collected weekly during the first and second estrous cycle, or until d 42 for anestrous cows, and daily throughout the third cycle. Also, between d 9 and 14 of the third cycle, or after d 35 in anestrous cows, intensive samples were collected at 2-h intervals for 24 h. Serum T3, thyroxine (T4), and progesterone (P4) were measured in weekly and intensive samples, and cortisol, insulin, GH, and thyroid-stimulating hormone (TSH) were measured in intensive samples. The altered thyroid status of HYPER and HYPO cows was evident (P < .001) during the third estrous cycle in mean daily T3, T4, and intensive TSH (P < .001) concentrations. Changes in BW and BCS were influenced by treatment (P < .001). A greater (P < .001) proportion of HYPER cows exhibited abnormal cycle length, and three of seven cows became anestrous. For cows that continued normal cycles, treatment did not affect (P > .05) the number of follicular waves, diameter of the dominant follicle, diameter of the ovulatory follicle, or P4 profiles during the third cycle. Insulin and GH concentrations did not differ (P > .05) among treatments in intensive samples, but, mean cortisol was greatest (P < .02) in HYPER cows. For Brahman cows that maintained normal estrous cycles, induced hyper-or hypothyroid status did not influence ovarian function.

Topics: Animal Feed; Animals; Cattle; Corpus Luteum; Estrus; Female; Hormones; Hyperthyroidism; Hypothyroidism; Ovarian Follicle; Ovary; Progesterone; Propylthiouracil; Thyrotropin; Thyroxine; Time Factors; Triiodothyronine

We have monitored estrous cycle and measured serum estradiol, GH, IGF-1, T4 and T3 levels in adult hypothyroid female rats which were divided into four groups: H group, hypothyroid rats without treatment; H-T4 group, hypothyroid rats injected daily with T4; HT4-PTU group, hypothyroid rats injected daily with T4 plus PTU (propylthiouracil), and H-T4-IOP group, hypothyroid rats injected daily with T4 plus IOP (iopanoic acid); Euthyroid rats (E group) were used as control. Our results indicate that the lack of sexual cycle in H animals was associated with lower values of estradiol, GH and IGF-1 in comparison to E group; the restoration of sexual cycle in H-T4 group was associated with values of estradiol, GH and IGF-1 higher than those of H group, whereas in H-T4-PTU and H-T-IOP groups the restoration was associated with higher values of GH and IGF-1 and values of estradiol similar to those of H group. These data could suggest a potential role of GH/IGF-1 axis, at least in part, in the lack of sexual cycle in H group and in the ovulation induction in H-T4, H-T4-PTU and H-T4-IOP groups.

Topics: Animals; Estradiol; Estrus; Female; Growth Hormone; Hypothyroidism; Insulin-Like Growth Factor I; Iopanoic Acid; Ovary; Propylthiouracil; Rats; Rats, Wistar; Thyroid Gland; Thyroxine; Triiodothyronine

Deficiency of thyroid hormone (TH) during the perinatal period results in severe neurological abnormalities in rodent cerebellar development. However, the molecular mechanisms of TH action in the developing cerebellum are not fully understood. Of note, a mutant mouse, staggerer, in which the orphan nuclear hormone receptor ROR alpha gene is disrupted, exhibits cerebellar abnormalities similar to those seen in the hypothyroid animals, despite normal thyroid function. We, therefore, speculated that TH (tetraiodo-L-thyronine; T4) may regulate ROR alpha gene expression, which then may regulate genes essential for normal brain development. To test this hypothesis, we studied the changes in ROR alpha gene expression in perinatal hypothyroid rat cerebellum and the effect of TH replacement using Northern blot analysis, ribonuclease protection assay and in situ hybridization histochemistry. During cerebellar development, an approximately 3-fold increase in the cerebellar content of ROR alpha messenger RNA (mRNA) was seen in both propylthiouracil-treated, and propylthiouracil-treated and T4-replaced animals. However, the increase was accelerated when T4 was injected, although the ROR alpha mRNA content was identical, with or without T4, by 30 days after birth (P30). In contrast, T4 treatment suppressed the TH receptor alpha1 and c-erbA alpha2 mRNA content by P30; retinoic acid X receptor-beta mRNA content was not influenced by thyroid status. A significant hybridization signal for ROR alpha mRNA was seen only over Purkinje cells in the cerebellar cortex by in situ hybridization histochemistry. These results indicate that TH alters the timing of expression of the ROR alpha gene in the Purkinje cells of the cerebellar cortex, which may, in turn, influence Purkinje cell differentiation.

Topics: Amino Acid Sequence; Animals; Animals, Newborn; Base Sequence; Blotting, Northern; Cerebellum; DNA, Complementary; Female; Gene Expression Regulation; Humans; Hypothyroidism; In Situ Hybridization; Mice; Molecular Sequence Data; Nuclear Receptor Subfamily 1, Group F, Member 1; Polymerase Chain Reaction; Pregnancy; Propylthiouracil; Purkinje Cells; Rats; Rats, Sprague-Dawley; Receptors, Cytoplasmic and Nuclear; Receptors, Retinoic Acid; Receptors, Thyroid Hormone; Retinoid X Receptors; RNA-Directed DNA Polymerase; RNA, Messenger; Thyroxine; Trans-Activators; Transcription Factors

The relation of plasma lipids and pseudocholinesterase (PChE) activity was studied in rats made hypothyroid by treatment with propylthiouracil (0.05% in drinking water for 28 days) and in hypothyroid patients prior and after L-thyroxine-therapy (1. week 25-50 microg, 2.-4. week 100 microg daily). In rats, thyroid hormone deficiency caused a significant increase in plasma and adipose tissue PChE activity as well as total plasma cholesterol (TC) concentration, and a decrease in plasma triglyceride (TG) concentration. In contrast to rats, thyroid-deficient humans demonstrated a decrease in plasma PChE activity and an increase in both TC and TG, in comparison with euthyroid controls. After one month's therapy with L-thyroxine, reversion of PChE activity and lipid concentrations occurred. The opposite changes of PChE elicited by thyroid hormone deficiency in men and rats are similar to the respective changes in lipoprotein lipase (LPL) activity, observed by other authors. The inverse correlation between both PChE and LPL activity and TG concentration suggests that PChE, similarly to LPL, may be involved in TG hydrolysis.

Topics: Adipose Tissue; Animals; Butyrylcholinesterase; Cholesterol; Female; Hypothyroidism; Lipids; Male; Propylthiouracil; Rats; Rats, Wistar; Thyroxine; Triglycerides; Triiodothyronine

The neonatal proximal tubule has a lower rate of bicarbonate absorption than that of adults. This is due, in part, to a lower rate of apical membrane Na+/H+ antiporter activity. The purpose of these studies was to examine if thyroid hormone could be a factor in the maturational increase in Na+/H+ antiporter activity. Hypothyroid (0.01% propylthiouracil in drinking water starting at day 14 gestation and throughout the postnatal period), euthyroid, and hyperthyroid (intraperitoneal triiodothyronine, 10 micrograms/100 g body wt, once daily on days 17 to 20 of postnatal life) rats were all studied at 21 days of life. Renal cortical brush border Na+/H+ antiporter activity was 453 +/- 24, 527 +/- 30 and 608 +/- 25 pmol/mg protein in the hypothyroid, euthyroid and hyperthyroid groups, respectively (P < 0.001). Hyperthyroid neonates had approximately twofold greater renal cortical NHE-3 mRNA abundance than euthyroid and hypothyroid neonates (P < 0.05). Brush border membrane NHE-3 protein abundance in hypothyroid and hyperthyroid neonates was one-third and twofold that of euthyroid 21-day-old rats, respectively (P < 0.001). These data are consistent with a potential role of thyroid hormone in the postnatal increase in Na+/H+ antiporter activity.

Topics: Animals; Animals, Newborn; Antithyroid Agents; Female; Hyperthyroidism; Hypothyroidism; Kidney Cortex; Kidney Tubules, Proximal; Maternal-Fetal Exchange; Pregnancy; Propylthiouracil; Rats; Rats, Sprague-Dawley; RNA, Messenger; Sodium-Hydrogen Exchanger 3; Sodium-Hydrogen Exchangers; Sodium-Potassium-Exchanging ATPase; Triiodothyronine

Topics: Adult; Antithyroid Agents; Female; Fetal Diseases; Goiter; Graves Disease; Humans; Hypothyroidism; Pregnancy; Pregnancy Complications; Prenatal Diagnosis; Propylthiouracil

To characterize developmental changes in the extracellular matrix of the postnatal rat testis in relationship to the timing of germ cell maturation, we immunolocalized fibulin-1, fibulin-2, and other matrix components in the testes of normal and propyl-thiouracil (PTU)-induced hypothyroid animals. Unlike laminin, nidogen, and perlecan, which were present in the seminiferous tubule basement membrane (BM) throughout postnatal development, fibulins were found to disappear from the postnatal tubule BM. Fibulin-1 was no longer detected after Day 5 whereas fibulin-2 became localized in a segmental manner within the BM of each seminiferous tubule on Days 10 and 15 and disappeared by Day 20. Fibronectin showed a segmental pattern in the level of immunostaining of the tubule BM on Days 10 and 15, with a more uniform staining seen at earlier and later ages. Collagen VI was initially confined to the interstitial matrix in the Day 5 testis and became progressively more closely associated with the seminiferous tubule BM at later stages. The disappearance of fibulin-2 and the BM-association of collagen VI were both delayed in the PTU-treated testes. The developmental changes in the staining patterns for fibulin-2 and fibronectin coincide with the adhesion and alignment of peritubular cells on the inner seminiferous tubule BM. The delay in maturation of the seminiferous tubule BM in the testes of PTU-treated rats demonstrates a correlation between changes in the composition of the tubule BM and cellular development of the testis.

Topics: Animals; Animals, Newborn; Antithyroid Agents; Basement Membrane; Body Weight; Calcium-Binding Proteins; Extracellular Matrix Proteins; Fibronectins; Fluorescent Antibody Technique, Direct; Hypothyroidism; Male; Organ Size; Propylthiouracil; Protein Biosynthesis; Rats; Rats, Sprague-Dawley; Testis

The importance of local formation of T3 in the feedback effect of the thyroid gland on hypothalamic TRH-producing cells has been established. Primary failure of the thyroid gland results in a fall in circulating T4 and T3 levels, leading to an elevation in the production and release of TRH in the hypothalamic paraventricular nucleus. In contrast, during short term fasting, declining plasma levels of thyroid hormones coincide with suppressed TRH production and release. In the brain, the prevalent enzyme that converts T4 to T3 is type II iodothyronine deiodinase (DII). The present study was undertaken to determine whether a differential hypothalamic expression of type II deiodinase may exist in fasted rats and in animals that are hypothyroid due to the failure of the thyroid gland. Using in situ hybridization, we assessed type II deiodinase messenger RNA (mRNA) levels in the hypothalamus of rats that were control euthyroid, hyperthyroid (T4), hypothyroid induced by propylthiouracil (PTU), and fasted. A group of fasted rats also received exogenous T4. DII mRNA was detected around the third ventricle, including the ependymal layer and adjacent periventricular regions as well as in the arcuate nucleus and the external layer of the median eminence. Quantitative in situ hybridization analysis demonstrated that PTU treatment and short term fasting resulted in significant elevations in DII messenger levels compared with those in euthyroid controls. Three weeks of PTU administration induced a consistent decline in circulating T3 and undetectable T4 levels, whereas 3 days of fasting resulted in only a 50% fall in the concentration of serum thyroid hormones. Interestingly, however, the expression of the DII mRNA was more than 2-fold higher in fasted animals compared with the values in PTU-treated rats. Furthermore, although T4 administration repressed DII mRNA expression in euthyroid animals, the same treatment had no effect on the fasting-induced elevations of DII message. To assess whether DII enzymatic activity is also affected during food deprivation, hypothalami were dissected out, and DII activity was measured in control euthyroid, fasted, and fasted plus T4-treated rats. To determine whether comparable changes in plasma thyroid hormone levels induced by fasting and PTU treatment could have affected DII enzymatic activity in a similar manner, animals were injected ip with PTU for 5 days to decrease plasma thyroid hormones to levels similar to those caused by fa

Topics: Animals; Antithyroid Agents; Fasting; Histocytochemistry; Hyperthyroidism; Hypothalamus; Hypothyroidism; In Situ Hybridization; Iodide Peroxidase; Isoenzymes; Male; Propylthiouracil; Rats; Rats, Sprague-Dawley; Reference Values; RNA, Messenger; Thyroxine

We evaluated the concentration of epidermal growth factor (EGF) in platelets, serum and plasma obtained from 47 patients with Graves' disease, 7 with hypothyroidism and 20 healthy subjects. The platelets of the subjects were collected from platelet rich plasma and lysed by freezing and thawing. Subsequently the platelet debris was treated with Triton X-100. The EGF concentration was determined by homologous radioimmunoassay. The concentration of EGF in the platelets in 14 patients with untreated Graves' disease was significantly higher than that in the healthy controls. After treating these 14 patients with antithyroid agents, the EGF concentration in the platelets decreased to the level of the healthy controls. The EGF concentration in the platelets in the 7 untreated hypothyroid patients decreased after replacement therapy with thyroxine. The mean volume of the platelets in the 14 patients with untreated Graves' disease was significantly larger than in the control and decreased after treatment with antithyroid agents. The serum and plasma levels of EGF in the 7 untreated hypothyroid increased after replacement therapy. In conclusion, thyroid function affected the concentration of EGF in the platelets of patients with thyroid disorders.

Topics: Adult; Blood Platelets; Epidermal Growth Factor; Female; Graves Disease; Humans; Hypothyroidism; Male; Methimazole; Middle Aged; Platelet Count; Propylthiouracil; Thyroid Diseases; Thyroxine

We have investigated the biological effects of physiological doses of 3,5-diiodo-L-thyronine (3,5-T2) and 3,3'-diiodo-L-thyronine (3,3'-T2) (at doses from 2.5 to 10 microg/100 g BW) on serum TSH and GH levels in rats made hypothyroid by propylthiouracil and iopanoic acid administration. In such animals deiodinase activities were inhibited and thyroid hormones serum levels strongly reduced. The effects of T2s were compared with those elicited by 3,5,3'-triiodo-L-thyronine (T3) (2.5 microg/100 g BW).The serum TSH level was much greater in hypothyroid rats than in euthyroid ones. T3 administration suppressed TSH by 88% compared to control (i.e, the level in hypothyroid rats); it thus reached a value not significantly different from that seen in the euthyroid rats. 3,5-T2 produced a similar effect, suppressing the TSH level by about 75% compared to control; it thus reached values not significantly different from those of the euthyroid and T3-treated rats. By contrast, 3,3'-T2 had no effect on TSH, whatever the dose. The serum GH level was much lower in hypothyroid rats than in euthyroid ones. T3 administration increased the GH level by about 5-fold, restoring it to the value seen in euthyroid rats. 3,5-T2-treated hypothyroid rats, at all the doses used (from 2.5 to 10 microg/100 g BW), showed increased serum GH levels: at a dose of 10 microg/100 g BW the level reached a value about 5-fold higher than that in hypothyroid rats. This value was not significantly different from those of euthyroid and T3-treated rats. 3,3'-T2 did not affect GH levels whatever the dose. Thus, 3,5-T2 (but not 3,3'-T2) seems to mimic the effects of T3 on serum TSH and GH levels in rats.

Topics: Animals; Antithyroid Agents; Basal Metabolism; Diiodothyronines; Growth Hormone; Hypothyroidism; Iodide Peroxidase; Iopanoic Acid; Male; Propylthiouracil; Rats; Rats, Wistar; Thyrotropin

1. Duchenne and Becker muscular dystrophies are X-linked disorders caused by defects in muscle dystrophin. The mdx mouse is an animal model for Duchenne muscular dystrophy which has a point mutation in the dystrophin gene, resulting in little (<3%) or no expression of dystrophin in muscle. Mdx mice show a characteristic pattern of muscle necrosis and regeneration. Muscles are normal until the third postnatal week when widespread necrosis commences. This is followed by muscle regeneration, with the persistence of centrally nucleated fibres. 2. This work has examined the hypothesis that the onset of this muscle necrosis is associated with postnatal maturation of the thyroid endocrine system and that pharmacological inhibition of thyroid hormone synthesis delays the onset of muscle necrosis. 3. Serum T4 and T3 concentrations of mice were found to rise immediately before the onset of muscle necrosis in the mdx mouse, and induction of hypothyroidism by treatment of animals with propylthiouracil was found to delay the onset of muscle necrosis. 4. The results provide the first demonstration of experimental delay of muscle necrosis by manipulation of the endocrine system in muscle lacking dystrophin, and provide a novel insight into the way in which a lack of dystrophin interacts with postnatal development to precipitate muscle necrosis in the mdx mouse.

Topics: Animals; Animals, Newborn; Antithyroid Agents; Body Weight; Disease Models, Animal; Dystrophin; Hypothyroidism; Mice; Mice, Inbred mdx; Muscle, Skeletal; Muscular Dystrophy, Animal; Propylthiouracil; Thyroxine; Triiodothyronine

The effects of propyl thiouracil (PTU)-induced hypothyroidism on testicular interstitial cells and androgen secretion in vitro in the neonatal rat were investigated using Sprague Dawley rats of 1, 7, 14, and 21 days. The results revealed that the fetal Leydig cell (FLC) number per testis was unchanged between and within treatment groups at all ages tested. FLC size was 50% smaller in 21-day controls than in all other groups. Adult Leydig cells (ALCs) were present at Days 14 and 21 in controls but were absent in PTU rats. ALCs approximated FLCs of 21-day controls in size. ALC number per testis showed a sharp increase at Day 21. 11ss-HSD1-positive cells were absent in 21-day PTU testes, but a few were present in 21-day control testes. Testosterone secretion per testis was unchanged in 1- to 21-day controls and 7- to 21-day PTU rats. However, at Day 21, a significantly lower value was seen in controls compared to PTU rats. Testicular androstenedione secretion was not significantly different between control and PTU rats up to 14 days, but a sharp rise was observed in controls at Day 21. At this age, androstenedione levels in PTU rats were similar to those at younger ages. In summary, histological studies showed that hypothyroidism prevented the hypotrophy of FLC and the emergence of ALC in the neonatal rat testis, and agreed favorably with results concerning testicular androgen secretion in vitro. These findings suggest that thyroid hormones have a regulatory role in precursor cell differentiation into Leydig cells in the neonatal rat testis to establish the ALC population.

Topics: 11-beta-Hydroxysteroid Dehydrogenases; Aging; Androstenedione; Animals; Animals, Newborn; Body Weight; Cell Differentiation; Female; Hydroxysteroid Dehydrogenases; Hypothyroidism; Immunohistochemistry; Leydig Cells; Male; Organ Size; Pregnancy; Propylthiouracil; Rats; Rats, Sprague-Dawley; Testis

Thyroid hormone (TH) levels increase in the postnatal life and are essential for maturation of myocardial Ca2+ handling. During this time, the sarcolemmal (SL) Na+/Ca2+ exchanger (NCX) function decreases and the sarcoendoplasmic reticulum (SR) Ca2+-ATPase (SERCA2) function increases. We examined the effects of postnatal hypo- or hyperthyroidism on NCX and SERCA2 in rat hearts. Animals were rendered hypothyroid by 0.05% 6-n-propyl-2-thiouracil in drinking water given to nursing mothers from days 2 to 21 postpartum. Hyperthyroidism was induced by daily injections of 10 microg/100 g body weight of 3,3',5-triiodo-L-thyronine during this period. Ventricular steady-state mRNA and protein levels of NCX and SERCA2 were analyzed by Northern and Western blotting. These were compared with SL Na+ gradient-induced and SR oxalate-supported Ca2+ transports in isolated membranes. In hypothyroidism, NCX mRNA and protein were elevated by 66 and 80%, respectively, and SERCA2 mRNA and protein were reduced to 55 and 70%, respectively (P < 0.05 vs. euthyroid). Corresponding differences were observed in the respective Ca2+ transports. Conversely, reduced NCX (by 50%) and elevated SERCA2 (by 150%) activities were found in hyperthyroidism (P < 0.05). The levels of NCX and SERCA2 mRNA and protein were, however, unchanged in hyperthyroidism, indicating that functional changes are not due to altered NCX and SERCA2 expression. In this case, a decline in noninhibitory phosphorylated phospholamban is a likely explanation for the elevated SR Ca2+ transport. In conclusion, physiological TH levels appear to be essential for normal reciprocal changes in the expression and function of myocardial NCX and SERCA2 during postnatal development.

Topics: Animals; Animals, Newborn; Calcium-Binding Proteins; Calcium-Transporting ATPases; Gene Expression Regulation, Developmental; Heart; Hyperthyroidism; Hypothyroidism; Membrane Proteins; Myocardium; Propylthiouracil; Rats; Rats, Wistar; Regression Analysis; RNA, Messenger; Sarcolemma; Sarcoplasmic Reticulum; Sodium-Calcium Exchanger; Thyroid Gland; Transcription, Genetic; Triiodothyronine

Leptin, the product of the adipose specific ob gene, regulates food intake and energy expenditure. However, little is known about the effects of thyroid status on plasma leptin levels in women. We determined fasting plasma leptin levels before and 1 month after restoration of euthyroidism in 20 female patients with hypothyroidism, 20 female patients with hyperthyroidism and 20 age and BMI-matched female controls. To restore the normal thyroid function patients with hypothyroidism were treated with levothyroxine, whereas patients with hyperthyroidism were treated with propylthiouracil. Plasma leptin levels were measured by a RIA method with a sensitivity of 0.5 microgram/l. Leptin levels were significantly lower in patients with hypothyroidism before treatment (4.17 +/- 2.58 micrograms/l) than in patients with hyperthyroidism (6.80 +/- 4.3 micrograms/l; z = -2.06, p = 0.037). Leptin levels were significantly higher in hyperthyroid patients than in the control group (3.71 +/- 1.69 micrograms/l, z = -2.44, p = 0.014) whereas leptin levels in the hypothyroid patients were not significantly different from those in control subjects (z = -0.16, p = 0.87). Restoration of euthyroid state was not associated with a significant change in leptin levels either in the hypothyroid (from 4.17 +/- 2.58 to 5.22 +/- 3.4 micrograms/l; z = -1.74, p = 0.08) or in the hyperthyroid group (from 6.80 +/- 4.37 micrograms/l to 7.93 +/- 6.25 micrograms/l z = -0.89, p = 0.37), although a tendency for leptin to increase was observed in both groups. There was no correlation between plasma leptin and FT3, FT4, TSH, or BMI either before or after therapy in both groups. Leptin levels were significantly correlated with BMI in the control group (r = -0.53, p = 0.018). We conclude that plasma leptin levels are increased in hyperthyroidism and unchanged in hypothyroidism. Furthermore, our study demonstrates that mean plasma leptin levels are not influenced by short term restoration of euthyroidism in both hypothyroidism and hyperthyroidism, although an effect of long-term treatment may not be excluded.

Topics: Adult; Body Mass Index; Fasting; Female; Humans; Hyperthyroidism; Hypothyroidism; Leptin; Propylthiouracil; Proteins; Thyroid Hormones; Thyroxine

Hypothyroidism was induced in a group of male Fischer 344 rats by administration of 0.05% propylthiouracil (PTU) in the drinking water for 12 weeks. Control rats were not treated. Plasma levels of thyroid hormones indicated that PTU treatment had produced severe thyroid hormone deficiency. In PTU-treated rats compared to control rats, levels of total T3 and total T4 were reduced 54.5% and 53.7%; while levels of free T3 and free T4 were reduced 87.1% and 96.5%. Functional hypothyroidism was demonstrated by: (i) a 49.1% decrease in hepatic plasma membrane alpha1-adrenergic receptor binding, and (ii) a 11.2-fold increase in hepatic gamma-glutamyltranspeptidase activity; relative to the expression of these parameters in control rats. Membranes were isolated from hippocampi of control, PTU-induced hypothyroid and thyroxine-replaced rats and specific adrenergic receptor binding determined by radioligand binding techniques. Hypothyroidism resulted in a shift in the balance of alpha1 and beta2 adrenergic receptor binding by evoking: an increase in alpha1-adrenergic receptor binding to 1.57-fold of control levels; and, a decrease in beta2-adrenergic receptor binding to 64% of control levels. Thyroid hormone replacement carried out in PTU-treated hypothyroid rats at 30 microg/kg s.c. per day for the last 3 days of the 12 week PTU-treatment protocol, which reversed physical and functional hypothyroidism, reversed the observed changes in hippocampal adrenergic receptor binding, indicating them to be thyroid hormone, and not PTU, -dependent. This receptor shift evoked by hypothyroidism may, in part, explain the protective effect of hypothyroidism on ischemia-induced hippocampal damage by favoring inhibitory input and limiting excitotoxic input by catecholamines.

Topics: Animals; Hippocampus; Hypothyroidism; Ischemia; Liver; Male; Propylthiouracil; Rats; Rats, Inbred F344; Receptors, Adrenergic; Reperfusion Injury; Thyroid Hormones

Hypothyroidism in the human female is often associated with ovarian follicular cysts and hyperandrogenism, two cardinal signs of polycystic ovary syndrome. To explore the intraovarian changes that lead to follicular cyst formation in hypothyroidism, we have created a prepubertal hypothyroid rat model. These hypothyroid rats are hyperandrogenic and develop transient ovarian follicular cysts. Hypothyroidism in newborn rats was induced by providing the lactating dams with 0.04% propylthiouracil (PTU)-containing water. Subsequently, female rats were weaned and kept on PTU-containing water. On Day 25 of age, the rats were primed with 15 international units of pregnant mare's serum gonadotropin (PMSG) in 100 microl of phosphate buffered saline. Two days later, to initiate pseudopregnancy, they were injected with five international units of human chorionic gonadotropin (hCG). The animals were sacrificed at appropriate times, and blood and ovaries were collected for analyses. Control experiments were done with euthyroid rats. Two days after PMSG injection, well-developed antral follicles were observed in both the hypothyroid and euthyroid rats. Two days after hCG injection, while the euthyroid rat ovaries, as expected, contained numerous corpora lutea (CL), the hypothyroid rat ovaries still retained antral follicles. Some of these follicles with degenerating oocytes showed signs of luteinization. By 3-4 days post-hCG injection, the hypothyroid rat ovaries developed cystic follicles. By Day 6, however, the hypothyroid rat ovaries were indistinguishable from those of the euthyroid rats. Although serum testosterone concentrations were significantly elevated in the hypothyroid rats on Days 1-3, progesterone concentrations were not significantly different from the euthyroid animals. However, by Days 8-14, the hypothyroid rats had significantly higher serum progesterone concentrations. This model will be useful for investigating the intraovarian biochemical changes that lead to follicular cyst development in response to acute gonadotropin treatment.

Topics: Animals; Animals, Newborn; Antithyroid Agents; Body Weight; Disease Models, Animal; Female; Follicular Cyst; Hypothyroidism; Lactation; Male; Organ Size; Ovary; Polycystic Ovary Syndrome; Progesterone; Propylthiouracil; Pseudopregnancy; Rats; Testosterone

We measured the soluble cytokine CD27 in a variety of thyroid disorders. Soluble CD27 was increased in untreated Graves' hyperthyroidism and in euthyroid ophthalmopathy. Levels of sCD27 were normal after the establishment of euthyroidism with propylthiouracil (PTU) or radio iodine in primary hypothyroidism, chronic thyroiditis, and the hyperthyroid and euthyroid phases of subacute thyroiditis. Soluble CD27 is a marker for cellular activation as in Graves' hyperthyroidism, but it is not predictive of the outcome of PTU therapy.

Topics: Acute Disease; Adult; Aged; Antithyroid Agents; Biomarkers; Chronic Disease; Female; Graves Disease; Humans; Hypothyroidism; Iodide Peroxidase; Male; Middle Aged; Propylthiouracil; Receptors, Thyrotropin; Thyroid Diseases; Thyroiditis; Thyrotropin; Thyroxine; Tumor Necrosis Factor Receptor Superfamily, Member 7

Thyroid hormones and leptin are both involved in the regulation of energy metabolism. Serum leptin concentrations were measured in women with thyrotoxicosis (n = 21, mean age 45 years) or hypothyroidism (n = 14, mean age 44 years) before and 3 months after restoration of the euthyroid state. Serum leptin concentration tended to increase in both hypothyroid (14.7+/-3.5 vs 17.8+/-3.9 ng/ml, p = 0.06) and thyrotoxic (11.9+/-1.7 vs 14.4+/-2.0, p = 0.08) women after treatment (values given as mean +/- SE in the untreated and the euthyroid state respectively). Body mass index (BMI) was lower in thyrotoxic women than in hypothyroid women in the untreated state (22.1+/-0.7 vs. 26.2+/-1.9, p < 0.05). BMI was not different between both groups after treatment (24.5+/-0.7 vs. 26.3+/-2.1, p = 0.37), due to an increase of BMI in the thyrotoxic women; BMI did not change in the hypothyroid group. After controlling for BMI in a multivariate regression analysis, serum leptin concentrations were lower in hypothyroid women than in thyrotoxic women (p < 0.05), whereas posttreatment values of leptin did not differ (p = 0.44). When leptin concentrations were expressed as standard deviation scores (Z-scores) from the mean value of female controls matched for BMI and age as reported earlier, Z-scores were lower in the hypothyroid than in the thyrotoxic women (-0.63+/-0.21 vs. 0.53+/-0.18, p = 0.001). After treatment, Z-scores did not deviate from the expected values (0.05+/-0.28 vs. 0.08+/-0.16, p = 0.98). Z-scores differed before and after treatment in both hypothyroid (p = 0.01) and thyrotoxic (p = 0.02) patients. In conclusion, these data obtained in thyrotoxic and hypothyroid women indicate that thyroid states modulates serum leptin concentrations independent of BMI, with a small decrease in hypothyroidism and a small increase in thyrotoxicosis.

Topics: Adult; Aged; Body Mass Index; Female; Humans; Hypothyroidism; Leptin; Methimazole; Middle Aged; Multivariate Analysis; Propylthiouracil; Proteins; Regression Analysis; Thyroid Hormones; Thyrotoxicosis; Thyrotropin; Thyroxine; Triiodothyronine

The effect of pre and postnatal hypothyroid environment on the development of cerebellum in the rat pups was determined. Four groups of rat dams, namely control, Group I, II and III were treated with propylthiouracil (PTU) in water for different length of time during pregnancy and nursing periods. The pups born from these dam groups were subsequently named after the corresponding dam group, namely control, Group I, II and III. General quantitative results showed that pups from the treated dams had significantly lower (p < 0.05) body weights compared to control pups. Cerebella from five day old pups were taken and structural changes estimated using unbiased "design based" stereological methods, which have made it possible to investigate specific qualities in the organ. The total volumes of cerebellum and intracerebellar nuclei were estimated using Cavalieri Principle. The mean total volume of cerebellum and the mean total volume of intracerebellar nuclei were significantly lower (p < 0.05) in all the pup groups (I, II, III) from the treated dams compared to control pups from the control dams. The cerebellar volume decreased in relation to the duration of treatment. The mean ratio of the total volume of intracerebellar nuclei to volume of cerebellum was significantly increased (p < 0.05) in Group III pups compared to control and Group I pups. The mean numerical density of neurones in the intracerebellar nuclei was nearly equal in all the pup groups except in Group III pups whereby it was increased. The mean total number of neurones in Groups I and II pups was reduced, but did not reach statistical significance. The mean numerical density of neuroglia in the intracerebellar nuclei was nearly the same in all the pup groups, the mean total number of glial cells was significantly reduced (p < 0.05) in Groups I and II pups compared to control and the mean neuron/glial ratio was increased in Group III pups compared to control and other treated groups. Thus, the neuroglia appear to be more sensitive to hypothyroidism than neurons. The above results show that PTU-induced hypothyroidism causes reduction in structural parameters in developing cerebellum and confirm that growth and maturation of the foetal cerebellum is dependent on the maintenance of normal T4 and T3 levels in the pregnant dam and developing pups during pre and postnatal stages of development.

Topics: Animals; Animals, Newborn; Antithyroid Agents; Cerebellum; Disease Models, Animal; Embryonic and Fetal Development; Female; Hypothyroidism; Male; Neurons; Organ Size; Pregnancy; Pregnancy Complications; Propylthiouracil; Rats; Rats, Wistar; Thyroxine; Triiodothyronine

The effect of thyroid hormones on glucose-induced secretion of gastric inhibitory polypeptide (GIP) and insulin was studied. Male rats were thyroidectomized (Tx) or sham Tx. Sham Tx rats were injected with either propylthiouracil ([PTU] 20 mg/kg intraperitoneally) or saline for 2 weeks. In addition, thyroid-intact rats were injected intravenously with triiodothyronine ([T3]5 microg/kg) or saline 10 minutes before an oral glucose load (3.2 g/kg). Blood samples were collected from each animal via a jugular catheter at 0, 10, 20, 30,45, 60, and 90 minutes following glucose ingestion. Plasma levels of GIP and insulin were measured by specific radioimmunoassays (RIAs). Thyroidectomy-induced hypothyroidism increased the basal level of plasma GIP, but decreased that of insulin. Insulin levels at 10, 20, and 30 minutes following oral glucose were lower in hypothyroid rats than in euthyroid rats. Conversely, GIP levels at 60 and 90 minutes following glucose ingestion in PTU-induced hypothyroid rats were higher than those in euthyroid rats. Furthermore, glucose-stimulated insulin secretion was unaltered by pretreatment with T3, whereas the glucose-induced increase in plasma GIP was completely abolished by preinjection of T3 in thyroid-intact rats. These results suggest that thyroid functions are involved in the regulation of insulin and GIP secretion in rats.

Topics: Animals; Blood Glucose; Calcium; Gastric Inhibitory Polypeptide; Hyperthyroidism; Hypothyroidism; Injections, Intravenous; Insulin; Insulin Secretion; Male; Propylthiouracil; Rats; Thyroid Hormones; Thyroidectomy; Thyrotropin; Triiodothyronine

Administration of streptococcal cell wall (SCW) preparation induces an inflammatory response in susceptible animals that is a model frequently used for rheumatoid arthritis. The degree of inflammation produced by SCW is greatly enhanced by low endogenous levels of glucocorticoids due to diminished hypothalamic-pituitary-adrenal activity. Because decreased glucocorticoid production is known to occur in the hypothyroid state, we tested whether hypothyroidism would increase, and conversely, whether hyperthyroidism would decrease, the inflammatory responses to SCW. Adult female Sprague Dawley rats were fed a regular diet (control), L-T4 (T4; hyperthyroid), or 6-propyl-thiouracil (hypothyroid) in drinking water for 7 weeks. Hypothyroidism resulted in elevated plasma levels of TSH and hypothalamic preproTRH messenger RNA (mRNA) while reducing anterior pituitary POMC mRNA and plasma ACTH and corticosterone levels. In contrast, hyperthyroid rats produced opposite results: decreased measures of central thyroid function but increased pituitary-adrenal function. Three days after administration of SCW, macrophage inflammatory protein-1alpha and interleukin-1beta mRNA expression increased dramatically in controls and even further in hypothyroid animals, as measured by Northern blot analysis. In contrast, T4-treated rats showed significant inhibition of these inflammatory markers. Thus, the hyperthyroid state combined with increased endogenous glucocorticoid levels is protective against inflammatory challenges. The inverse relationship between preproTRH expression and pituitary-adrenal function suggests the possibility of a direct inhibitory link connecting the hypothalamic-pituitary-adrenal and thyroid axes, and suggests alternative sites of therapeutic intervention for rheumatoid arthritis and other inflammatory associated disorders.

Topics: Animals; Arthritis, Infectious; Blotting, Northern; Cell Wall; Chemokine CCL4; Female; Hyperthyroidism; Hypothyroidism; Interleukin-1; Macrophage Inflammatory Proteins; Macrophages; Propylthiouracil; Rats; RNA, Messenger; Streptococcal Infections; Thyroxine

During a period of 7 years at our institution, four girls and one boy with Down's syndrome, ages 9 to 16 years, were examined and treated for hyperthyroidism. Two patients had Graves' disease and they responded to propylthiouracil (PTU) with a predictable clinical course resulting in remission within 4 years. The remaining three patients included in this report had hyperthyroid profiles similar to those of the two with Graves' disease except for their antibody panels. These patients, in addition to the elevated thyroid-stimulating immunoglobulin (TSI) level observed in Graves' disease, also had significantly elevated antimicrosomal antibody (AMA) and antithyroglobulin antibody (ATGA) at the time of diagnosis. Elevated TSI level was again present in two patients who had a recurrence of hyperthyroidism after PTU therapy was discontinued. Treatment of these three patients was best done with the continuation of PTU therapy at a lower dose and the addition of thyroxine as soon as mild hypothyroidism developed. Treatment with PTU and thyroxine was continued until the TSI level was no longer elevated. Levels of AMA and ATGA remained elevated long after the TSI level became normal. All three patients eventually had hypothyroidism and continue to require thyroxine replacement.

Topics: Adolescent; Antithyroid Agents; Autoantibodies; Child; Down Syndrome; Female; Graves Disease; Humans; Hyperthyroidism; Hypothyroidism; Immunoglobulins, Thyroid-Stimulating; Male; Microsomes; Propylthiouracil; Recurrence; Remission Induction; Thyroglobulin; Thyroxine

Cardiolipin plays an important role in mitochondrial membrane structure and function. We have recently reported a decrease in the cytochrome c oxidase activity in heart mitochondria from hypothyroid rats (G. Paradies et al. (1993) Arch. Biochem Biophys. 307, 91-95). A possible involvement of cardiolipin in such a decrease has been proposed. The aim of this work was to test our earlier proposal. We have investigated whether addition of exogenous cardiolipin to hypothyroid mitochondria is able to reverse, in situ, their decreased cytochrome oxidase activity. The method of fusion of liposomes with mitochondria developed by Hackenbrock (Hackenbrock and Chazotte (1986) Methods Enzymol. 125, 35-45) was employed in order to enrich the mitochondrial cardiolipin content. We demonstrate that the decreased activity of this enzyme complex in heart mitochondria from hypothyroid rats can be completely restored to the level of control rats by exogenously added cardiolipin but not by other phospholipids. These data provide strong evidence for the involvement of cardiolipin in the thyroid hormone induced changes of mitochondrial cytochrome oxidase activity.

Topics: Animals; Cardiolipins; Electron Transport Complex IV; Hypothyroidism; Mitochondria, Heart; Propylthiouracil; Rats; Rats, Wistar; Thyroid Hormones

The purpose of this study was to examine whether changes in growth, ductal histology, and expression of plasminogen activator (PA) and matrix metalloproteases are associated with the increased prostatic weight and DNA content seen in adult rats that were treated neonatally with the goitrogen 6-propyl-2-thiouracil (PTU). Ventral prostatic weights were initially reduced in PTU-treated rats but were increased 40% over those of controls by Day 180; this increase in prostatic weight was also accompanied by increases in the number of prostatic ductal tips. In controls, prostatic PA and gelatinase A activities decreased after completion of morphogenesis at 21-28 days of age. In contrast to controls, PA and gelatinase A activities were maintained through puberty (42 days) in PTU-treated rats but declined by 90 days. The elevated PA activity in both prostatic lobes at 42 days of age in PTU-treated rats was inhibited by amiloride, indicating that it is the urokinase form of PA. These data show that the increased prostatic weight and DNA content in adult rats following neonatal PTU treatment results from a delayed but extended period of growth and the formation of new ductal elements. There is a temporal overexpression of urokinase and gelatinase A associated with the increased ductal branching, indicating as well an extended period of morphogenesis that results in their eventual increased adult size. The prostatic enlargement in PTU-treated rats may serve as a useful model to study regulation of both normal and abnormal prostatic growth and morphogenesis.

Topics: Amiloride; Animals; Animals, Newborn; Cell Differentiation; Enzyme Inhibitors; Female; Gelatinases; Hypothyroidism; Male; Matrix Metalloproteinase 2; Metalloendopeptidases; Organ Size; Pregnancy; Propylthiouracil; Prostate; Rats; Rats, Sprague-Dawley; Urokinase-Type Plasminogen Activator

To examine the effect of thyroid status on the homeostatic control of intracellular Na+, we studied the effect of treatment of hypothyroid rabbits with 3,5,3'-triiodothyronine (T3). Intracellular Na+ and pH (pHi) in papillary muscles and Na+-K+ pump current (Ip) in ventricular myocytes were measured with ion-sensitive microelectrode and whole cell patch-clamp techniques. Na+ influx, estimated from the rate of increase in intracellular Na+ on sudden Na+-K+ pump blockade with dihydroouabain, and Na+ efflux, calculated from Ip, were similar. Treatment with T3 induced an increase in both Na+ influx and Ip. The treatment-induced increase in Na+ influx was eliminated by 5-(N,N-dimethyl)amiloride (DMA) but not by tetrodotoxin. Treatment with T3 increased the rate of fall in pHi on exposure of the papillary muscles to DMA; when the buffer capacity was taken into account, the T3 treatment-induced increase in this rate corresponded well with the treatment-induced, DMA-inhibitable estimate of Na+ uptake. We conclude that thyroid hormone enhances both Na+-H+ exchange-mediated Na+ uptake and Na+-K+ pump-mediated Na+ efflux.

Topics: Amiloride; Animals; Cells, Cultured; Heart; Heart Ventricles; Homeostasis; Hydrogen-Ion Concentration; Hypothyroidism; In Vitro Techniques; Kinetics; Male; Membrane Potentials; Myocardium; Ouabain; Papillary Muscles; Propylthiouracil; Rabbits; Sodium; Sodium-Potassium-Exchanging ATPase; Tetrodotoxin; Thyroid Gland; Triiodothyronine

During development, gene expression of medium-chain acyl-CoA dehydrogenase (MCAD), a nuclear-encoded mitochondrial enzyme that catalyses the first step of medium-chain fatty acid beta-oxidation, is highly regulated in tissues in accordance with fatty acid utilization, but the factors involved in this regulation are largely unknown. To investigate a possible role of thyroid hormones, rat pups were made hypothyroid by the administration of propylthiouracyl to the mother from day 12 of gestation, and their kidneys, heart and liver were removed on postnatal day 16 to determine MCAD mRNA abundance, protein level and enzyme activity. Similar experiments were run in 3,3',5-tri-iodothyronine (T3)-replaced hypothyroid (1 microg of T3/100 g body weight from postnatal day 5 to 15) and euthyroid pups. Hypothyroidism led to an increase in MCAD mRNA abundance in kidney and a decrease in abundance in heart, but had no effect in liver. The protein levels and enzyme activity were lowered in hypothyroid heart and kidney, suggesting that hypothyroidism affects post-transcriptional steps of gene expression in the kidney. All the effects of hypothyroidism were completely reversed in both heart and kidney by T3 replacement. Injection of a single T3 dose into 16-day-old euthyroid rats also led to tissue-specific changes in mRNA abundance. Nuclear run-on assays performed from hypothyroid and hypothyroid plus T3 rats showed that T3 stimulates MCAD gene transcription in heart and represses it in the kidney. These results indicate that the postnatal rise in circulating T3 is essential to the developmental regulation of the MCAD gene in vivo.

Topics: Acyl-CoA Dehydrogenase; Acyl-CoA Dehydrogenases; Animals; Cell Nucleus; Female; Gene Expression Regulation, Developmental; Gene Expression Regulation, Enzymologic; Heart; Hypothyroidism; Kidney Cortex; Liver; Myocardium; Pregnancy; Prenatal Exposure Delayed Effects; Propylthiouracil; Rats; Rats, Wistar; Reference Values; Triiodothyronine

Propylthiouracil (PTU), an antithyroidal drug that reduces serum L-thyroxine (T4) and 3,5,3'-triiodothyronine (T3), is presumed to lower core temperature (T0) by impairing metabolic thermogenesis. However, it is not understood why PTU-treated animals cannot use behavioral and other thermoeffectors to maintain normal Tc. Male rats were administered PTU in drinking water (0.05 mg/ml) while the following parameters were measured: 1) Tc and motor activity (MA) recorded by radiotelemetry for 24 h at ambient temperatures (Ta) of 10-30 degrees C; 2) selected Ta, MA, and Tc in a temperature gradient; and 3) Tc, MA, and grooming behavior during exposure to heat stress (TH = 34.5 degrees C) for 2 h. PTU reduced serum levels of T4, and T3 by 95 and 60%, respectively. Tc decreased after 3 days of PTU treatment; a 0.5 degree C decrease in Tc persisted throughout the PTU treatment. PTU rats exposed to Ta of 10-30 degrees C maintained a consistent hypothermic Tc during the light phase; however, a deficit in the stability of Tc at night was noted during exposure to 10 degrees C. In the temperature gradient, PTU rats selected warmer Ta, but their Tc was maintained at the same hypothermic levels as observed at fixed Ta values of 15-30 degrees C. Heat stress caused Tc of control rats to increase to 39 degrees C, whereas Tc of the PTU rats was maintained below 38 degrees C. The regulation of Tc at hypothermic levels over a wide range of Ta values and when rats were housed in a temperature gradient indicates that chronic PTU induces a state of regulated hypothermia.

Topics: Animals; Behavior, Animal; Body Temperature; Body Temperature Regulation; Heat Stress Disorders; Hypothermia; Hypothyroidism; Male; Motor Activity; Propylthiouracil; Rats; Thyroxine; Triiodothyronine

Transient neonatal hypothyroidism, induced with the goitrogen 6-n-propyl-2-thiouracil (PTU), results in dramatic increases in both testis size and sperm production in the adult rat. The observed increases in testis size and function occur in the presence of normal circulating testosterone levels. However, circulating gonadotropin levels are chronically reduced by 30-50% at all times in treated males. To better understand the permanent reduction in serum gonadotropin levels following transient neonatal hypothyroidism, we conducted a series of experiments to evaluate pituitary and hypothalamic function in the adult male PTU-treated rat. PTU treatment led to a significant reduction in GnRH-stimulated LH production. Castration resulted in 3.9- to 8.5-fold increases in circulating gonadotropin levels in both treated and control males; however, the absolute increases were significantly reduced in treated males. In contrast to circulating levels, pituitary gonadotropin contents did not increase in treated males after castration. PTU treatment did not lead to a reduction in the density of either luteotropes or folliculotropes, and both cell types increased in size and density after castration. The relative concentrations of both gonadotropin beta-subunit messenger RNAs increased more slowly in treated males than in controls after castration. Thus, although treated rats have the intrinsic ability to produce normal circulating levels of LH and FSH, gonadal feedback and an overall reduction in gonadotrope synthetic ability combine to produce the chronically reduced circulating levels of these hormones.

Topics: Animals; Animals, Newborn; Castration; Female; Follicle Stimulating Hormone; Gonadotropin-Releasing Hormone; Hypothyroidism; Luteinizing Hormone; Male; Organ Size; Pituitary Gland, Anterior; Pregnancy; Propylthiouracil; Rats; Rats, Sprague-Dawley; RNA, Messenger; Testis; Thyroid Gland

Reports of the coexistence of hyperparathyroidism and thyroid disease have raised the issue of a possible etiologic relationship. The present study tests the hypothesis that chronic elevation of thyroid-stimulating hormone (TSH) is related to the development of hyperparathyroidism. Four groups of 60 female rats were treated as follows: group 1, control; group 2, propylthiouracil (PTU) 0.0025%; group 3, PTU 0.0025% plus thyroxine, 5 microg two times per week; and group 4, only thyroxine. The animals' serum calcium, phosphorus, TSH, thyroxine, and parathyroid hormone (PTH) levels were evaluated at 0, 6, 12, and 18 months. Significant elevation of TSH was sustained throughout the 18 months in groups 2 and 3. The PTH levels were also significantly elevated in both group 2 and group 3 animals (P = 0.02). The histopathologic features of the parathyroids were evaluated at 18 months. In the group 2 (PTU only) animals, which had profound hypothyroid, 44% developed parathyroid adenomas. In the group 3 (PTU plus thyroxine) animals, who had mildly elevated TSH levels, 53% developed parathyroid adenomas. These findings are consistent with the hypothesis that prolonged TSH stimulation may lead to hyperparathyroidism in the rat model.

Topics: Adenoma; Animals; Antithyroid Agents; Calcium; Chronic Disease; Disease Models, Animal; Female; Hyperparathyroidism; Hyperplasia; Hypothyroidism; Parathyroid Glands; Parathyroid Hormone; Parathyroid Neoplasms; Phosphorus; Propylthiouracil; Rats; Rats, Sprague-Dawley; Survival Rate; Thyroid Gland; Thyrotropin; Thyroxine

In the present study, we describe the modifications in the expression of type II 5'deiodinase activity (5'D) in Xenopus laevis oocytes by injection of polyadenylated (poly A) mRNA from hypothyroid rat Harderian gland. The time-course study showed that the expression of the enzyme was dependent on time. Thus, enzyme activity was observed in oocytes 6 and 12 hours after the injection with poly A mRNA, reaching a maximal value at 24 hours. The activity was partially inhibited by 6-n-propyl-thiouracil, completely inhibited by iopanoic acid and exhibited a higher affinity for the T4 (Km=1.5 nM) than rT3 (Km=20 nM). The expression of the enzyme was modified in different experimental conditions: (a) exhibited diurnal variations with maximal peak values at night, (b) was inhibited by light at night and, (c) was activated by isoproterenol. On the other hand, we have also identified, for the first time, the size of mRNA capable of inducing 5'D in rats.

Topics: Adrenergic beta-Agonists; Animals; Circadian Rhythm; Darkness; Female; Gene Expression Regulation, Enzymologic; Harderian Gland; Hypothyroidism; Iodide Peroxidase; Iodothyronine Deiodinase Type II; Iopanoic Acid; Isoproterenol; Kinetics; Light; Male; Microinjections; Oocytes; Propylthiouracil; Rats; Rats, Wistar; RNA, Messenger; Thyroxine; Triiodothyronine, Reverse; Xenopus laevis

To investigate the effects of growth hormone (GH) on 11beta-HSD1, we determined changes in hepatic 11beta-HSD1 activity in hypothyroid rats following treatment with subcutaneous (s.c) injection of GH for periods ranging from 24 h to 7 days. In male rats, hypothyroidism markedly reduced the hepatic 11beta-HSD1 activity and serum testosterone levels (p < 0.01). Subcutaneous injection of GH once daily to male hypothyroid rats for 48 h inhibited hepatic 11beta-HSD1 activity. However, the same daily dose of GH administered to male hypothyroid rats for 7 days, resulted in a marked increase in hepatic 11beta-HSD1 activity and gene expression (p < 0.01). Furthermore, daily s.c injections of GH to castrated male hypothyroid rats for 7 days reduced hepatic 11beta-HSD1 activity rather than inducing it, the same response seen in hypothyroid female rats. In addition, the treatment of castrated male hypothyroid rats with testosterone for 7 days significantly increased this enzyme activity (p < 0.01). The changes in hepatic 11beta-HSD1 were demonstrated to be associated with the testes in hypothyroid male rats following treatment with GH for 7 days. Moreover, the prolonged exposure to GH required to induce hepatic 11beta-HSD1 in intact hypothyroid male rats and the lack of a similar effect in castrated male hypothyroid rats suggests that this action is indirect and that it may be mediated by androgen production from Leydig cells of the testes and induced by the daily injections of GH. Treatment of hypothyroid male rats with GH at 6-h intervals, however, feminized the hepatic 11beta-HSD1 gene expression.

Topics: 11-beta-Hydroxysteroid Dehydrogenases; Aging; Animals; Female; Gene Expression; Growth Hormone; Hydroxysteroid Dehydrogenases; Hypothyroidism; Liver; Male; Orchiectomy; Propylthiouracil; Rats; Rats, Sprague-Dawley; RNA, Messenger; Sex Characteristics; Testis; Testosterone

A reduced body temperature is a common symptom of hypothyroidism and may result from a deficiency in metabolic heat production. However, a reduced metabolism does not necessarily imply a failure in thermoregulatory control if other thermoeffectors, in particular behavioral thermoregulation, are operative. To address this issue, selected ambient temperature (Ta) in a temperature gradient, core temperature (Tc), heart rate (HR), and motor activity (MA) were monitored via radiotelemetry in euthyroid rats and rats made hypothyroid by the administration of 0.05 mg/ml propylthiouracil (PTU) in drinking water for approximately 15 days. Core temperature of PTU-treated rats was reduced by 0.3 degree, whereas selected Ta was increased by 2.3 degrees. PTU treatment led to significant reductions in HR, whereas MA was unaffected. Thermoregulatory behavior did not reverse the PTU-induced hypothermia, suggesting that PTU-induced hypothyroidism leads to a regulated reduction in body temperature (i.e., decrease in the set point). A reduced set point seems to be an adaptive response that lowers the metabolic requirements for thermoregulation in the hypothyroid rat.

Topics: Animals; Antithyroid Agents; Autonomic Nervous System; Behavior, Animal; Body Temperature Regulation; Heart Rate; Hypothyroidism; Male; Motor Activity; Propylthiouracil; Rats; Rats, Inbred F344; Telemetry; Thyroxine; Triiodothyronine

The function and the growth of adult thyroid gland is controlled by the opposite actions of thyrotropin (TSH) and iodide, the main substrate of the gland. Iodide deprivation leads to stimulation of the thyroid, improving the efficiency of iodide transport for hormone biosynthesis. We have investigated cell proliferation and thyroid specific gene expression 24 and 48 h after administering KI to dogs previously treated with goitrogens and perchlorate. In the hypothyroid dogs T3 and T4 serum levels decreased from 53 +/- 4 to < 30 ng/dl and from 1.6 +/- 0.6 to < 1 microg/dl respectively; TSH concentration increased from 0.16 +/- 0.02 to 2.7 +/- 0.4 ng/ml. After a 24 h moderate KI treatment (300 microg KI/dog of +/- 10 kg) serum T3 concentrations rose higher than the initial normal values, while T4 concentrations increased to reach values equivalent to the normal level. The high TSH concentration did not change significantly. The hyperplasia of the chronically stimulated thyroid resulting from goitrogens/NaClO4 treatment was not modified by this short term treatment with KI. In contrast, KI decreased the weight of the total gland and the level of cell proliferation, as determined by the fraction of cells incorporating BrdU. The effect of acute administration of KI on the expression of four major thyroid genes, the TSH receptor (TSHr), thyroglobulin (Tg), thyroperoxidase (TPO), and Na+/I- symporter (NIS) was analyzed by Northern blot. Tg, TPO and NIS mRNA expressions were up-regulated by chronic stimulation. The expression of the mRNAs of TSHr and Tg did not significantly differ between hyperstimulated and KI-treated dogs while TPO and NIS mRNA expression decreased after a 48 h KI treatment. TPO and NIS are therefore the only of these four genes whose expression is acutely modulated by iodide in vivo. Under TSH stimulation low doses of iodide resulted in: (1) decreased cell proliferation, (2) reestablished synthesis and secretion of thyroid hormones, (3) diminished TPO and NIS mRNA expression. Notably low doses of iodide under the same conditions had no effect on Tg and TSHr mRNA expression.

Topics: Animals; Blotting, Northern; Carrier Proteins; Cell Division; Dogs; Gene Expression; Hypothyroidism; Iodide Peroxidase; Membrane Proteins; Perchlorates; Potassium Iodide; Propylthiouracil; Receptors, Thyrotropin; RNA, Messenger; Sodium Compounds; Symporters; Thyroglobulin; Thyroid Gland; Thyrotropin; Thyroxine; Triiodothyronine

Thionamide therapy is a mainstay of the treatment of hyperthyroidism complicated by pregnancy, but it can expose the fetus to hypothyroidism. In terms of fetal thyroid status, propylthiouracil (PTU) has been preferred over methimazole (MMI) based on experimental data on limited transplacental passage, and lower doses have been recommended. However, neither of these practices is supported by convincing clinical evidence. We compared the effect of maternal ingestion of PTU with that of MMI on fetal thyroid status using cord sera at delivery in 77 mothers with Graves' hyperthyroidism who were receiving thionamides and whose free T4 (FT4) levels were within the normal range. We also examined the dose effects on fetal thyroid status in these women. Thirty-four women were taking PTU (group P), and 43 were taking MMI (group M). Neither the mean fetal FT4 nor the mean fetal TSH level was significantly different between the two groups. No significant difference in the occurrence of low FT4 levels or high fetal TSH levels was found between group P and group M (low FT4, 6% vs. 7%; high TSH, 21% vs. 14%). Little relationship was observed between maternal doses and fetal thyroid status; in fact, when low doses of both PTU (100 mg daily or less) and MMI (10 mg daily or less) were administered, high TSH levels in the fetus were observed in 7 of the 34 fetuses (21%) and in 6 of the 43 fetuses (14%), respectively. Higher doses were associated with normal or low fetal TSH levels. These findings demonstrate that in terms of fetal hypothyroidism-inducing potential, there is little reason to choose PTU over MMI. Individualized, not uniformly low, doses of these drugs may prevent fetal hypothyroidism.

Topics: Female; Fetal Blood; Fetal Diseases; Graves Disease; Humans; Hypothyroidism; Maternal-Fetal Exchange; Methimazole; Pregnancy; Pregnancy Complications; Propylthiouracil; Thyrotropin; Thyroxine

Recently, we have shown an extended distribution pattern of the TR-beta2 isoform in specific sites of rat brain which may be indicative that the localization of this receptor also confers functional specificity. The beta2 thyroid hormone receptor (TR-beta2) is by far the most abundant isoform in the pituitary, although transcripts of TR-alpha and TR-beta1 genes have been reported in developmental and adult rat pituitary gland. Using both in situ hybridization histochemistry (ISH) and immunocytochemistry, we mapped the expression of beta2 thyroid hormone receptor mRNA and protein in euthyroid and hypothyroid adult rat pituitary, particularly in relation to the thyrotrope population. TR-beta2 mRNA localization by ISH showed an anteromedial spatial distribution pattern in euthyroid rat anterior pituitary gland. This localization coincided with the immunostaining pattern for thyrotropes. TR-beta2-immunoreactive cells showed strongly positive signals in the nuclei. Hypothyroidism, induced by propylthiouracil (PTU), abolished the specific localization of TR-beta2 mRNA and upregulated the transcription of TR-beta2 mRNA in vivo and in vitro. Image analysis revealed that the optical density signals within hypothyroid rat pituitary were significantly stronger (2.6-fold) compared with euthyroid counterparts. This correlated strongly with an increased number and staining of TR-beta2 protein positive cells, demonstrating both nuclear and cytoplasmic staining. In response to thyroid hormone deficiency, there was also a marked percentage increase in the thyrotrope population from 10 to 20% of anterior pituitary cells to approximately 80%. In conclusion, these results demonstrate the specific localization of TR-beta2 to the anterior pituitary, especially to the thyrotrope population, and its regulation by thyroid hormone. Hypothyroidism leads to an upregulation of TR-beta2 mRNA and protein in the anterior pituitary, explained not only by an absolute increase in the percentage of thyrotropes but increased expression of TR-beta2 mRNA and protein per cell. These data allude to the TR-beta2 isoform playing a critical role in thyroid hormone-dependent TSH gene expression, although contributions from the other TR isoforms may still remain important.

Topics: Animals; Base Sequence; Female; Hypothyroidism; Immunohistochemistry; In Situ Hybridization; Molecular Sequence Data; Oligodeoxyribonucleotides; Organ Specificity; Pituitary Gland; Propylthiouracil; Rats; Rats, Wistar; Receptors, Thyroid Hormone; Thyroid Gland; Thyrotropin; Transcription, Genetic

Thyroid hormone is required for basal and estrogen-induced expression of anterior pituitary galanin. Steady-state anterior pituitary galanin mRNA levels decreased 6-fold in hypothyroid rats after 3 weeks of treatment. Similarly, hypothyroidism resulted in a 2.6-fold decrease in estrogen induction of galanin gene expression. The effect of thyroid hormone on anterior pituitary galanin gene expression appears to be exerted, at least in part, at the pituitary itself. Transient expression assays in GH3 cells suggest the involvement of transcriptional mechanisms in the regulation of galanin gene expression by thyroid hormone. A region between -41 and -132 bp upstream of the transcriptional start site confers thyroid hormone responsiveness to the galanin gene. Gel-mobility shift assays show specific binding of 'SPI-like' proteins in GH3 nuclear extracts to this region of the galanin gene. This binding was greatly enhanced by thyroid hormone.

Topics: Animals; Base Sequence; Cell Line; Cells, Cultured; Estradiol; Galanin; Gene Expression Regulation; Genes, Reporter; Hypothyroidism; Male; Molecular Sequence Data; Pituitary Gland, Anterior; Propylthiouracil; Rats; Rats, Sprague-Dawley; Recombinant Fusion Proteins; Regulatory Sequences, Nucleic Acid; RNA, Messenger; Thyroxine; Transcription, Genetic; Transfection; Triiodothyronine

A study was conducted to determine the effects of transient hypothyroidism induced by propylthiouracil (PTU) on termination of photorefractoriness and reinitiation of lay in turkey breeder hens. The PTU was given for 6- or 8-wk periods via the feed and at various doses to yearling hens that had been continuously exposed to long photoperiods [16 h light (L):8 h dark (D)] for at least 25 wk. There was a dose-dependent cessation of lay as well as deletion of thyroxine (T4) and triiodothyronine (T3) during the treatment period. Hens receiving 0.1% PTU or more had little or no circulating thyroid hormones after 2 wk of treatment. Furthermore, resumption of a normal rate and duration of egg laying occurred following withdrawal of the PTU, without any changes in photoperiod. However, this effect only occurred in those hens that had received PTU doses of 0.1% or more and only when the treatment had been given for greater than 6 wk. The resumption of normal levels of egg laying occurred in the absence of a typical preceding molt. Body weights, livability, and fertility and hatchability of eggs from these hens were similar to those of controls. Clearly, turkey hens can be effectively recycled by pharmacological manipulation of the thyroid gland and the results are supportive of thyroid hormone(s) involvement in maintaining photorefractoriness in turkey hens.

Topics: Animals; Antithyroid Agents; Body Weight; Dose-Response Relationship, Drug; Eating; Female; Fertility; Hypothyroidism; Oviposition; Photoperiod; Poultry Diseases; Propylthiouracil; Thyroid Gland; Thyroxine; Time Factors; Triiodothyronine; Turkeys

In developing chicken brain Ca2+/calmodulin-stimulated protein kinase II (CaMPK-II) changes from being primarily cytosolic to being primarily particulate during the protracted maturation period. To investigate whether thyroid hormone levels may be involved in regulating this subcellular redistribution, we raised chickens from 1 day posthatching on food soaked in 0.15% (wt/vol) propylthiouracil (PTU) plus 0.05% (wt/vol) methimazole (MMI). This produced a mild hypothyroidism specifically during the maturation period and resulted in a 67% reduction in the levels of free triiodothyronine (T3) at 42 days. The concentrations of alpha- and beta-CaMPK-II in cytosol (S3) and crude synaptic membrane (P2M) fractions from forebrain were measured by three methods: Ca2+/calmodulin- or ZN2+-stimulated autophosphorylation or binding of biotinylated calmodulin. By all three methods hypothyroid animals showed a marked retardation of the redistribution of both subunits of CaMPK-II: an increase in the concentration of the enzyme in S3 and a corresponding decrease in P2M with no overall change in the total amount of enzyme and little apparent change in the concentration of other proteins. In both fractions, there was a parallel change in the Ca2+/calmodulin-stimulated phosphorylation of endogenous protein substrates but no change in the basal or cyclic AMP-stimulated protein phosphorylation. Supplementing the PTU/MMI-treated diet with thyroxine (0.5 ppm) prevented all of the observed changes.

Topics: Age Factors; Animals; Autoradiography; Blotting, Western; Calcium-Calmodulin-Dependent Protein Kinase Type 2; Calcium-Calmodulin-Dependent Protein Kinases; Cell Fractionation; Cell Membrane; Chickens; Cytosol; Hypothyroidism; Methimazole; Phosphorylation; Propylthiouracil; Prosencephalon; Proteins; Synapses; Triiodothyronine; Zinc

The aim of this study was to examine the effects of prepubertal hypothyroidism on ovarian development in rats. Therefore, from birth up to day 40 postpartum, rats were given 6-propyl-2-thiouracil (PTU) via the drinking water of mothers and pups. At ages ranging from 12 to 40 days, ovarian weights were measured and serum was collected to estimate thyrotrophin (TSH), follicle-stimulating hormone (FSH) and inhibin levels. Two hours before sacrifice the animals received an injection of bromodeoxyuridine (BrdU) to estimate the proliferative activity of the follicular granulosa cells. Ovaries were fixed in Carnoy's fluid and follicle counts were performed on sections stained with anti-BrdU and with haematoxylin and eosin. The PTU treatment resulted in increased serum TSH levels, indicative of hypothyroidism, and markedly lower body and ovarian weights, whereas serum FSH and inhibin levels were hardly affected. At day 40, ovaries of PTU-treated animals contained relatively more secondary and less antral follicles, smaller non-atretic antral follicles and more atretic follicles when compared with untreated rats, while corpora lutea were absent. It is concluded that this disturbed folliculogenesis is due to inadequate thyroid hormone supply, which hampers the differentiation and not the proliferation of granulosa cells because diameters of antral follicles were significantly smaller whereas the BrdU-labelling index had not changed.

Topics: Animals; Body Weight; Cell Division; Female; Follicle Stimulating Hormone; Follicular Atresia; Granulosa Cells; Hypothyroidism; Inhibins; Organ Size; Ovarian Follicle; Ovary; Pregnancy; Propylthiouracil; Rats; Rats, Wistar; Thyrotropin

It has previously been demonstrated that thyrotropin-releasing hormone (TRH) mRNA expression is dramatically increased in limbic structures including dentate gyrus granular layer, and pyriform, entorhinal and perirhinal cortices following amygdala kindling. Since thyroid hormone regulates TRH mRNA in the paraventricular nucleus of the hypothalamus (PVN), we investigated whether basal or kindling-induced TRH mRNA expression in limbic regions is also regulated by thyroid hormone. Hypo- and hyperthyroidism was induced by treating rats with 0.05% 6-n-propyl-2-thiouracil (PTU) (equivalent to approximately 30 mg/kg/day) or 0.9 microM 3,5,3'-triiodo-L-thyronine (T3) (equivalent to approximately 50 micrograms/kg/day), respectively, in their drinking water for 10 days before kindling and throughout the kindling procedure. Rats were sacrificed 4 h after their first stage 5 seizure. None of the thyroid hormone manipulations altered kindling development, or behavioral and electrographic after-discharge seizure durations. Pituitary TSH beta mRNA levels were significantly increased by PTU and suppressed by T3, but unaffected by kindling. In addition, in situ hybridization showed that PTU administration increased and T3 administration decreased TRH mRNA levels in the PVN, consistent with thyroid hormone's negative feedback effects. At the same time, kindling had no effect on TRH mRNA in the PVN. In contrast, kindling dramatically increased TRH mRNA in the dentate gyrus granular layer, and pyriform, entorhinal and perirhinal cortices, but thyroid hormone manipulations did not affect either basal or kindling-induced TRH mRNA expression in limbic structures. These findings demonstrate that TRH mRNA expression is differentially regulated in the hypothalamic PVN and limbic structures.

Topics: Amygdala; Animals; Base Sequence; Gene Expression; Hyperthyroidism; Hypothalamus; Hypothyroidism; Kindling, Neurologic; Limbic System; Male; Molecular Sequence Data; Propylthiouracil; Rats; Rats, Sprague-Dawley; RNA, Messenger; Thyrotropin; Thyrotropin-Releasing Hormone; Triiodothyronine

The objective of the present study was to test in vivo the metabolic effects of 3,5-di-iodothyronine (3,5-T2) in unanesthetized and unrestrained male Sprague-Dawley rats. Amino acid and lipid metabolisms were investigated by breath tests using as tracers the 13C-carboxyl-labeled molecules of leucine, alpha-ketoisocaproic acid (KIC) and octanoic acid, in four different groups of rats: hypothyroid animals (receiving propylthiouracil (PTU) and iopanoic acid), hypothyroid animals treated with either a daily i.p. injection of 3,5-T2 (25 micrograms/100 g body weight), or tri-iodothyronine (T3) (1 microgram/100 g body weight), and control euthyroid animals receiving equivalent volumes of the vehicle solutions. Energy expenditure was measured by continuous monitoring of O2 consumption and CO2 production in these different groups. Daily energy expenditure was decreased by 30% in PTU-treated rats. The chronic treatments with 3,5-T2 and T3 restored daily energy expenditure to the control level. 13CO2 recovered in breath following the i.v. injection of octanoic acid-[1-13C] was decreased in hypothyroid animals compared with control animals (P < 0.05) and restored to control values by T3 and 3,5-T2 treatments. The 13CO2 recovered in breath after i.v. injection of leucine-[1-13C] was increased in PTU-treated compared with control animals (P < 0.05). Chronic treatment with either 3,5-T2 or T3 restored 13CO2 to control values. Excretion of 13CO2 recovered in breath following the i.v. injection of KIC-[1-13C] was increased in PTU-treated compared with control animals. Chronic treatments with either 3,5-T2 or T3 did not restore KIC decarboxylation. These results suggest that 3,5-T2 exerts metabolic effects on energy expenditure, on both lipid beta-oxidation and leucine metabolism in hypothyroid rats. We conclude that 3,5-T2 is a metabolically active iodothyronine.

Topics: Amino Acids; Animals; Breath Tests; Caproates; Caprylates; Diiodothyronines; Energy Metabolism; Hypothyroidism; Keto Acids; Leucine; Lipid Metabolism; Male; Propylthiouracil; Rats; Rats, Sprague-Dawley; Thyroxine; Triiodothyronine

In the developing brain the active neurite outgrowth during the early phase of synaptogenesis is associated with a thyroid hormone dependent expression of tubulin and actin. In this study, the molecular mechanism of thyroid hormone (TH) action on actin and tubulin gene expression in the developing rat brain has been investigated by comparing the steady state levels of both mRNAs with their respective rates of transcription in cerebra from normal and hypothyroid animals. The developmental profile of actin as well as tubulin mRNAs in both normal and hypothyroid brains display a biphasic pattern, increasing progressively during the first week after birth and declining thereafter. However, hypothyroidism resulted in a significant reduction in the steady state levels of both mRNAs during the first postnatal week. During the second and third weeks, in contrast to their rapid decline in the normal controls, the corresponding decrease in the hypothyroid cerebra was retarded and prolonged resulting in their higher levels under TH-deficient condition. Kinetics of stimulation of actin and tubulin mRNAs in the 5-day hypothyroid cerebra following injection of the optimal dose of TH (200 micrograms T3/100 g body wt.) demonstrated elevation of both mRNAs within 1 h indicating a possible role of TH at the transcriptional level. In vitro transcription experiments by nuclear run off assay unambiguously confirmed that actin gene transcription is depressed in the hypothyroid cerebra compared to normal control. This reduced rate of transcription could be significantly induced in the hypothyroid cerebra by incubation of hypothyroid nuclei with T3 prior to transcription. In contrast, except for a reduced transcription in 5-day hypothyroid nuclei, no effect on tubulin gene transcription was evident at any other age. Moreover preincubation of hypothyroid nuclei from all three ages with T3 had no stimulatory effect on tubulin gene transcription. Analysis of age related changes in the rates of transcription of actin and tubulin genes with their corresponding steady state mRNA levels in normal and hypothyroid developing brain provides strong evidence that although additional modes of regulation may be operative, transcription represents an important level of control for thyroidal regulation of actin gene expression while tubulin gene expression is primarily regulated at post-transcriptional level.

Topics: Actins; Aging; Animals; Brain; Cell Nucleus; Female; Gene Expression Regulation, Developmental; Hypothyroidism; Pregnancy; Propylthiouracil; Rats; Rats, Sprague-Dawley; Reference Values; RNA, Messenger; Transcription, Genetic; Tubulin

Topics: Animals; Animals, Newborn; Antithyroid Agents; Glucocorticoids; Hypothyroidism; Methylprednisolone; Methylprednisolone Acetate; Mice; Mice, Inbred C57BL; Polycystic Kidney Diseases; Propylthiouracil; Thyrotropin; Triiodothyronine

In situ hybridization histochemistry was used to evaluate the expression of the immediate-early gene c-fos following the induction of audiogenic seizures in adult rats with transient neonatal hypothyroidism. The rats treated with 0.02% propylthiouracil (PTU) through mother's milk during days 0-19 after delivery showed a high incidence of seizures to auditory stimulation at the age of 4 months. The significant induction of c-fos mRNA by audiogenic seizures is prominent in several brain areas including central gray, peripeduncular nucleus, inferior colliculus, septal nucleus, bed nucleus of stria terminalis, and dorsomedial hypothalamus. However, the expression of c-fos mRNA was comparable in neocortex, dorsal hippocampus and medial geniculate body between control rats and PTU-treated, seizure-induced rats. These results confirm the previous report on the c-fos expression following audiogenic seizure sensitized during development by a loud noise [20]. The present results indicate that the neonatal PTU treatment may provide a useful tool for studying the mechanism underlying the seizure susceptibility and development after maturation.

Topics: Acoustic Stimulation; Animals; Animals, Newborn; Hypothyroidism; Male; Nerve Tissue Proteins; Propylthiouracil; Proto-Oncogene Proteins c-fos; Rats; Rats, Sprague-Dawley; RNA, Messenger; Seizures

Rat pups were made hypothyroid by exposure to propylthiouracil in drinking water beginning at 1 week of age, and the degree of long-term potentiation (LTP) in hippocampal area CA1 determined from brain slices of animals ranging in age from 2 to 6 weeks. Serum T3 levels were less than 20% of that of age matched controls after 3 weeks of treatment, and remained at that level. Relative to the age-matched controls, LTP was reduced significantly after 2 weeks of treatment. These observations are consistent with the conclusion that LTP magnitude is a reflection of cognitive function, which is known to be depressed in hypothyroid conditions in both animals and man.

Topics: Administration, Oral; Animals; Animals, Newborn; Antithyroid Agents; Electrophysiology; Hippocampus; Hypothyroidism; Long-Term Potentiation; Membrane Potentials; Neurons; Propylthiouracil; Rats

We investigated the effect of hyper- and hypothyroidism on tyrosine hydroxylase protein concentration in the locus coeruleus (divided into anterior and posterior parts), the substantia nigra and the adrenals of adult rats. Rats were made hypothyroid with propylthiouracile (PTU, 0.02% in drinking water for 21 days) or hyperthyroid by thyroxine injection (100 or 250 micrograms/kg/day), for 3 or 17 days. PTU treatment resulted in statistically significant decrease of tyrosine hydroxylase in the anterior locus coeruleus (-13%) and the adrenals (-14%). After thyroxine treatment, in the anterior locus coeruleus, tyrosine hydroxylase was significantly higher (2 way ANOVA) after the 3 day treatment than after the 17 day treatment: tyrosine hydroxylase showed a trend to increase the 3 day treatment (+20% with the 250 micrograms/kg dose) and to decrease after the 17 day treatment (-15% with the 250 micrograms/kg dose). In the adrenals, tyrosine hydroxylase was increased by the 3 day treatment (+42% after the 250 micrograms/kg dose), but this increase was not observed after 17 days of treatment. Tyrosine hydroxylase was not altered in the posterior locus coeruleus and the substantia nigra, whatever the treatment. Together, our results support the hypothesis that in the anterior locus coeruleus and in the adrenals tyrosine hydroxylase level is positively modulated by thyroid hormones. After long-term treatment (17 days) this effect is not observed.

Topics: Adrenal Glands; Animals; Antithyroid Agents; Brain; Catecholamines; Hyperthyroidism; Hypothyroidism; Immunoblotting; Locus Coeruleus; Male; Nerve Tissue Proteins; Propylthiouracil; Rats; Rats, Sprague-Dawley; Substantia Nigra; Thyroid Hormones; Thyroxine; Tyrosine 3-Monooxygenase

Following the diagnosis of fetal goitre at 22 and 24 weeks' gestation in two hyperthyroid pregnant women who underwent treatment with 400-500 mg of propylthiouracil in the first weeks of pregnancy, a total of seven fetal blood samplings were performed to evaluate thyroid function before and after the initiation of two different treatment regimens. L-Thyroxine (600 micrograms) was injected five times intra-amniotically in one woman and continuous maternal administration of the thyroid analogue 3, 5, 3'-triiodothyroacetic acid (Triac) was attempted in the other. Normalization of fetal thyroid function and reduction of fetal goitre were achieved in both fetuses and transplacental passage of Triac was indirectly demonstrated by high levels of free triiodothyronine in fetal blood. In cases of fetal hypothyroidism, direct or indirect prenatal therapy can be adopted successfully and safely.

Topics: Adult; Amniotic Fluid; Female; Fetal Blood; Gestational Age; Humans; Hyperthyroidism; Hypothyroidism; Maternal-Fetal Exchange; Pregnancy; Pregnancy Complications, Cardiovascular; Prenatal Exposure Delayed Effects; Propylthiouracil; Thyrotropin; Thyroxine; Triiodothyronine

The influence of hypothyroidism on the odor detection ability of male Long-Evans rats was determined using high-precision olfactometry and a go/no-go operant task. Nonparametric signal detection measures of sensitivity and responsitivity, as well as measures of S+ response latency, the number of aborted trials, and session time were obtained in daily 200-trial test sessions prior to, during, and after 50 days of maintenance on 0.1% propylthiouracil (PTU). Similar determinations were made in control animals. Neither odor detection nor associated nonsensory performance measures were influenced by hypothyroidism. These results suggest that PTU-induced hypothyroidism does not affect the odor detection performance of rats.

Topics: Animals; Antithyroid Agents; Conditioning, Operant; Hypothyroidism; Propylthiouracil; Psychomotor Performance; Rats; Signal Transduction; Smell; Thyroid Gland

Mental retardation associated with hypothyroidism may be caused by impairment of brain ketone body-metabolizing enzymes during the suckling period. However, much evidence suggests that, immediately after delivery, lactate, instead of ketone bodies or glucose, may be the best substrate for the brain. In this work, we have studied the effect of experimentally induced congenital hypothyroidism on the rate of lactate, glucose, and 3-hydroxybutyrate utilization in early neonatal brain slices. Methimazole (MMI) administration to the mothers caused a 5.4- and 1.7-fold decrease in neonatal plasma concentrations of L-thyroxine (T4) and 3,5,3'-triiodo-L-thyronine (T3), respectively. Propylthiouracil (PTU) administration to the mothers caused a 7.3- and > 2-fold decrease in plasma T4 and T3 concentrations, respectively. MMI-induced hypothyroidism did not significantly modify the rate of lactate, glucose, or 3-hydroxybutyrate oxidation to CO2 and their incorporation into lipids by the neonatal brain. However, PTU-induced hypothyroidism decreased the rate of lactate and glucose oxidation to CO2 and their incorporation into lipids by 17% (p < 0.05). 3-Hydroxybutyrate utilization was not modified by this treatment. Separation by HPLC of the lipids revealed that PTU-mediated inhibition of lipid synthesis from lactate and glucose may be accounted for by specific inhibition of the rate of sterol synthesis (15%, p < 0.05), whereas the rate of phospholipid synthesis was unaffected. These results suggest that the early newborn may develop mechanisms aimed at avoiding the possible brain damage caused by the inhibition of lipid synthesis brought about by mild neonatal hypothyroidism.

Topics: 3-Hydroxybutyric Acid; Animals; Animals, Newborn; Antithyroid Agents; Brain; Congenital Hypothyroidism; Energy Metabolism; Female; Glucose; Hydroxybutyrates; Hypothyroidism; In Vitro Techniques; Lactic Acid; Methimazole; Phospholipids; Pregnancy; Prenatal Exposure Delayed Effects; Propylthiouracil; Rats; Rats, Wistar; Thyroid Hormones

Polyamines such as putrescine, spermidine and spermine have been thought to play an important role in thyroid growth induced by goitrogens. Reduced biosynthesis of these polyamines might play a role in the antigoitrogenic effects of excess iodide. This study was designed to examine the effect of potassium iodide (KI) on ornithine decarboxylase (ODC), a rate-limiting enzyme in the biosynthesis of polyamines. Thyroidal ODC activity, protein content and mRNA were increased in rats made hypothyroid by 10 days of propylthiouracil treatment. The increase in ODC activity was suppressed after subcutaneous injection of KI (13mg/kg body weight); the apparent half-life of ODC activity after the treatment was estimated to be 19 min and the maximum suppression (90%) was seen 60 min after the treatment. On the other hand, administration of iodine-containing compounds including L-thyroxine, L-di-iodotyrosine,amiodarone, iopanoic acid and erythrosine showed no significant effect on ODC activity. The inhibitory effect of excess iodide was not reversed by pretreatment with dibutyryl cAMP and theophylline. The amount of immunoreactive ODC protein was reduced by iodide treatment (40%). However, the decrease was not as great as the decrease in ODC activity (90%). No significant change in thyroidal ODC mRNA content was seen 1 and 3 h following KI treatment. These results suggest that excess iodide reduces ODC activity in the rat thyroid gland by a post-transcriptional mechanism.

Topics: Animals; Blotting, Northern; Bucladesine; Depression, Chemical; Hypothyroidism; Male; Ornithine Decarboxylase; Ornithine Decarboxylase Inhibitors; Potassium Iodide; Propylthiouracil; Rats; Rats, Wistar; RNA, Messenger; Theophylline; Thyroid Gland

The hypothyroid state accompanying diabetes mellitus has been suggested to be partly responsible for the diabetes-induced metabolic, hemodynamic, and pharmacological cardiovascular changes. We assessed the effectivity of streptozotocin (STZ) to induce diabetes mellitus and a hypothyroid state. Furthermore, we investigated the influence of diabetes and hypothyrodism on cardiac function and the inotropic responsiveness to the alpha 1-adrenoceptor agonist cirazoline in isolated perfused hearts. Fasted or nonfasted Wistar rats were made diabetic with STZ 20, 40 or 60 mg/kg intravenously (i.v.). Another group was made hypothyroid by addition of 6-n-propyl-2-thiouracil (PTU) to their drinking water. Rats receiving PTU became hypothyroid, whereas rats receiving STZ became simultaneously diabetic and hypothyroid. Basal functional parameters obtained in isolated perfused hearts were not influenced by diabetes, whereas maximal contractility was reduced in hearts obtained from hypothyroid animals. Cardiac inotropic responses to cirazoline were increased in diabetic rats, whereas responses in hypothyroid rats were not different from those in hearts obtained from control animals. Although diabetes mellitus and hypothyroidism are associated with various similar metabolic and haemodynamic parameters, the increased inotropic response to alpha 1-adrenoceptor stimulation as observed in isolated perfused hearts of diabetic rats cannot be explained by the decrease in serum thyroxine levels.

Topics: Adrenergic alpha-Agonists; Animals; Blood Pressure; Coronary Circulation; Diabetes Mellitus, Experimental; Fasting; Heart; Heart Rate; Hypothyroidism; Imidazoles; Male; Propylthiouracil; Rats; Rats, Wistar; Streptozocin; Thyroxine; Ventricular Pressure

The abundances of G protein alpha-subunits (Gi1 alpha, Gi2 alpha, G0 alpha and Gq/ll alpha) were measured in synaptosomal membranes isolated from forebrain and hindbrain regions of euthyroid and hypothyroid neonatal rats at 10, 15, 20 and 25 days post-partum. The findings show that hypothyroidism causes a distinct perturbation of the normal developmental profile of these signalling components. It is suggested that these changes may contribute to some of the neurological deficits arising from hypothyroidism in early development.

Topics: Animals; Animals, Newborn; Brain; Congenital Hypothyroidism; Female; GTP-Binding Proteins; Hypothyroidism; Iodine; Nerve Tissue Proteins; Organ Size; Pregnancy; Pregnancy Complications; Propylthiouracil; Rats; Rats, Sprague-Dawley; Signal Transduction; Synaptosomes

In the developing rat cerebrum, the level of different isoforms of Na-K-ATPase mRNA increases significantly during the first three postnatal weeks, which represent the critical period of synaptogenesis and myelination-the two thyroid hormone-sensitive maturational events. To determine the possible functional relationship of these isoforms with maturational events in the developing brain and their mode of regulation by T3, we have examined the effect of hypothyroidism on the expression of the different alpha-isoforms (alpha 1, alpha 2, and alpha 3) of Na-K-ATPase mRNA covering the first 3 wk of postnatal development. Quantitation of these mRNAs from cerebra of 1-, 5-, 10-, 15-, and 20-d-old normal and hypothyroid rats by Northern blot analysis indicate that alpha 3 mRNA is not only predominantly expressed throughout this entire period of study but also represents the species which is most severely affected in the hypothyroid brain. The relative sensitivity for the expression of these mRNAs to T3 were alpha 3 > alpha 1 > alpha 2. These results, together with the report of predominant expression of the alpha 3 isoform in neuronal cells, suggest specific functional involvement of this isoform with the decisive maturational events in the rat brain. Kinetic studies on in vivo induction of Na-K-ATPase alpha-mRNAs by T3 in the 15-d-old hypothyroid rat shows clear stimulation of all the isoforms within 1 h of the administration of the optimal dose (200 micrograms T3/100 g body wt) suggesting a direct, possibly transcriptional effect of the hormone on the expression of these genes.

Topics: Aging; Animals; Animals, Newborn; Brain; Enzyme Induction; Female; Gene Expression Regulation, Developmental; Gene Expression Regulation, Enzymologic; Hypothyroidism; Isoenzymes; Pregnancy; Prenatal Exposure Delayed Effects; Propylthiouracil; Rats; Rats, Sprague-Dawley; Reference Values; RNA, Messenger; Sodium-Potassium-Exchanging ATPase; Transcription, Genetic; Triiodothyronine

Morphological changes and the molecular mechanisms associated with the maturation of astrocytes were studied under normal and thyroid hormone-deficient conditions using long-term (30 days) primary cultures derived from the neonatal rat brain. Immunocytochemical staining of cells with a monoclonal antibody specific to glial fibrillary acidic protein demonstrated for the first time that, similar to their maturation in vivo, astrocytes maintained in normal serum-containing medium can undergo complete maturation involving two distinct stages of morphological differentiation (from radial glia to flat polygonal cells with epithelioid morphology and then to mature process-bearing cells with stellate morphology). Deficiency of thyroid hormone delays the first step and totally blocks the second stage of differentiation in the maturation process. Comparative staining of normal and thyroid hormone-deficient astrocytes with filamentous actin-specific fluorescein isothiocyanate-phalloidin and quantitation of the various forms of intracellular actin using an improved DNase I assay demonstrated that maturation of astroglial cells is associated with characteristic alterations in the level of cytoskeletal and noncytoskeletal filamentous (F) actin. In particular, the maintenance of the epithelioid form of the hypothyroid astrocytes is associated with a progressive increase in the level of cytoskeletal F-actin and a concomitant decline in the level of non-cytoskeletal F-actin. Quantitation of actin mRNA by Northern blot analysis and studies on the rate of actin synthesis at various stages of differentiation showed that the initial transformation into the epithelioid form is associated with an increase in the rate of synthesis of actin and the expression of its mRNA, while the final transformation into the nature process-bearing form is correlated with a decline in these parameters. The results indicates that thyroid hormone plays an obligatory role in promoting the differentiation and maturation of astrocytes, and that during this process the hormone regulates the expression of actin and its intracellular organization in a way conducive to morphological differentiation.

Topics: Actins; Aging; Animals; Animals, Newborn; Astrocytes; Brain; Cells, Cultured; Cytoskeleton; Gene Expression Regulation, Developmental; Hypothyroidism; Immunohistochemistry; Propylthiouracil; Rats; Rats, Sprague-Dawley; Reference Values; Time Factors

Neurogenesis and proliferation of olfactory receptor neurons (ORNs) in the olfactory epithelium (OE) are reduced in postnatal hypothyroid rats and upregulated following restoration of thyroid function, leading to compensatory growth and restitution of these deficits [Paternostro M.A. and Meisami E. (1993). Dev. Brain Res. 76, 151-161; Paternostro M.A. and Meisami E. (1994). Dev. Brain Res. 83, 151-162]. To investigate thyroid hormonal role on maturation of ORNs, serial sections of the septal OE from normal newborn, 25- and 90-day-old rats were immunostained for olfactory marker protein (OMP), a marker for mature ORNs, and compared with the same from age-matched hypothyroid rats and those allowed to recover from thyroid deficiency at the time of weaning (day 25). The parameters studied were the localization and distribution of the OMP(+) cells within the OE and their density and total number. Hypothyroidism was induced by adding the reversible goitrogen propylthiouracil (PTU) to the rats' drinking water (1 g/l) from birth to days 25 or 90. Recovery from hypothyroidism was induced by withdrawal of PTU at day 25. The OMP(+) cells occupied a distinct, broad band in the normal rat OE, while in hypothyroid animal, this band was narrow and restricted to OE's apical zones. Recovery resulted in broadening of the OMP(+) cell band and normalized distribution of OMP(+) cells as evident in the 90-day-old recovery animals. In normal control rats, density of OMP(+) cells increased by 2.5- and 1.3-fold during the suckling and post-weaning period (days 25-90), while total numbers of these cells increased by 12- and 3-fold, respectively, during the same age periods. Hypothyroidism decreased the growth in density by 25 and 30%, while total number of OMP(+) neurons were reduced by 40 and 70% in the 25- and 90-day-old animals, respectively. Withdrawal of PTU resulted in marked restoration of these deficits so that, at 90 days, the total number of OMP(+) cells were only 20% less than 90-day-old controls. These results indicate that thyroid hormones are essential for maturation of single ORNs and accretion of new mature ORNs in the OE of suckling and post-weaning rat. Also, the process of maturation and the final number of mature ORNs show remarkable recovery from hypothyroid-induced growth retardation.

Topics: Animals; Animals, Newborn; Animals, Suckling; Biomarkers; Cell Count; Cell Differentiation; Convalescence; Female; Fetal Diseases; Hypothyroidism; Nerve Tissue Proteins; Olfactory Marker Protein; Olfactory Mucosa; Olfactory Receptor Neurons; Pregnancy; Pregnancy Complications; Propylthiouracil; Rats; Thyroid Hormones

The effect of congenital hypothyroidism on the visual system of Wistar rats was studied by determining neuron density in the retinal ganglion cell layer. Retinae of adult rats from mothers treated with propylthiouracil, 50 mg/day, starting on the 15th day of pregnancy (PTU group), and of adult rats from untreated mothers (control group) were examined. Retinae were prepared, and the neurons in the nasotemporal region located above the optic disc were counted. Hypothyroid rats showed a significant reduction in the retinal area (about 6.8%), when compared to controls. The cell density in the retinal ganglion cell layer was significantly decreased in 6 PTU-treated compared to 5 control retinae in total (2,793 +/- 330 vs 3,704 +/- 662 neurons/mm2), nasal (3,031 +/- 580 vs 3,853 +/- 699 neurons/mm2) and temporal (2,555 +/- 155 vs 3,555 +/- 827 neurons/mm2) regions. These alterations in a region considered to be one of the most specialized in the visual process suggest a structural deficiency induced by congenital hypothyroidism, with a possible decrease in the visual acuity of the rat.

Topics: Animals; Cell Count; Congenital Hypothyroidism; Female; Hypothyroidism; Male; Pregnancy; Propylthiouracil; Rats; Rats, Wistar; Retina; Retinal Ganglion Cells; Thyroid Hormones; Visual Acuity

Width of the external plexiform layer in olfactory bulbs and mean area of mitral and granule cell dendritic and glial processes were measured of normal, hypo- and hyperthyroid rat pups at the age of 24 days. Hypothyroidism was induced by treating the rats with a reversible goitrogen 6-n-propyl-2-thiouracil dissolved in their drinking water, while the hyperthyroid group was given water containing thyroxine. The 6-n-propyl-2-thiouracil treatment was begun on gestational day 18 and on the day of birth. Thyroxine treatment started on the day of birth. Both treatments were continued till the day of sacrifice. A significant decrease in the width of the external plexiform layer of the olfactory bulb in the prenatally 6-n-propyl-2-thiouracil treated group and a significant increase in the width of the external plexiform layer of the hyperthyroid group was shown by the Student's paired t-test. The areas of neuronal and glial processes were measured at electron microscopic level by using an IBAS image analysing system. A significant decrease was found by the Kruskal-Wallis test and Dunn's range test in the mean area of (1) mitral cell dendrites in the prenatal 6-n-propyl-2-thiouracil treated group, (2) granule cell dendrites in both the postnatally 6-n-propyl-2-thiouracil treated and in the hyperthyroid groups and (3) glial processes in the thyroxine treated group comparing to controls.

Topics: Animals; Dendrites; Female; Hyperthyroidism; Hypothyroidism; Neuroglia; Olfactory Bulb; Pregnancy; Prenatal Exposure Delayed Effects; Propylthiouracil; Rats; Rats, Inbred Strains; Reference Values; Thyroxine

Deafness is a common result of severe hypothyroidism during development in humans and laboratory animals; however, little is known regarding the sensitivity of the auditory system to more moderate changes in thyroid hormone homeostasis. The current investigation compared the relative sensitivity of auditory function, motor function, and growth to the effects of moderate to severe perinatal hypothyroidism in the rat. Rats received propylthiouracil (PTU) in drinking water at concentrations of 0, 1, 5, and 25 ppm from Gestation Day 18 until postnatal day (PND) 21, and the effects on their offspring were evaluated. At 1 ppm, PTU did not affect any of the measured endpoints. Serum thyroxin concentrations were sharply reduced in the 5 and 25 ppm PTU groups at all ages sampled (PND 1, 7, 14, and 21). Marked reductions in serum triiodothyronine (T3) concentrations were also detected for all ages > or = 7 at 25 ppm PTU, whereas no effects of 5 ppm PTU on serum T3 were apparent until PND 21. Compared to the controls, pups exposed to the highest dose of PTU demonstrated a delay in eye opening, reduced body weights, decreased and/or delayed preweaning motor activity, and persistent, postweaning hyperactivity. Only slight and transient effects on eye opening and ontogeny of motor activity were seen at the intermediate dose of PTU (5 ppm). Reflex modification audiometry revealed that, compared to controls, adult offspring from the 5 and 25 ppm treatment groups showed dose-dependent auditory threshold deficits (35 to > 50 dB) at all frequencies tested (1, 4, 16, 32, and 40 kHz). Such dose-dependent effects indicate that the developing auditory system may be sensitive to mild hypothyroidism, suggesting the possible need for routine audiometric screening for infants and children at risk for iodine deficiency, myxedema, and/or exposure to thyrotoxic environmental agents.

Topics: Acoustic Stimulation; Animals; Animals, Newborn; Audiometry; Behavior, Animal; Body Weight; Drinking; Female; Habituation, Psychophysiologic; Hypothyroidism; Male; Motor Activity; Pregnancy; Propylthiouracil; Rats; Rats, Inbred Strains; Reflex, Startle; Thyroxine; Triiodothyronine

The effect of hypothyroidism induced by 6-propyl-2-thiouracil (PTU) or thiourea (TU) on the development of the reproductive system in male and female neonatal ICR mice was investigated. PTU or TU was injected subcutaneously into experimental animals from postnatal day 1 (PD1) onward. The histological changes of the reproductive organs, formation of ovarian follicles, and spermatogenesis were examined on PD 14, 21, and 28, and the fertility of the hypothyroid mice in adulthood was followed. It was found that PTU or TU treatment did not produce an effect on the histology of the neonatal uterus and oviduct. In contrast, the drugs induced a decrease in the number of primordial follicles, multilaminar follicles, and Graafian follicles in the ovary. The number of follicles with degenerated follicular cells was increased. In the testis both PTU and TU treatments brought about a decrease in the number of seminiferous tubules with developing spermatids although the mean diameter of seminiferous tubules and the histology of the testis, epididymis, seminal vesicle, and coagulating gland was unaffected. The mating between hypothyroid females and euthyroid males and that between hypothyroid males and euthyroid females were normal with regard to the pregnancy rate, litter size, and sex ratio of offspring. The somatic growth of the resulting offspring was normal. It is concluded that the retarding effect on ovarian and testicular development in mice during neonatal period was not serious enough to adversely affect reproduction in the hypothyroid animals.

Topics: Animals; Female; Fertility; Hypothyroidism; Male; Mice; Mice, Inbred ICR; Ovarian Follicle; Ovary; Pregnancy; Propylthiouracil; Spermatogenesis; Testis; Thiourea

The effect of propylthiouracyl (PTU)-induced low thyroid function on insulin responsiveness to glucose and glucose responsiveness to insulin in sheep was studied by performing hyperglycemic and euglycemic clamp experiments. All sheep were maintained at a level of 125% daily metabolizable energy intake and were housed in an environmental room that was maintained at 20 degrees C with a 16-hr lighting period. In the first study, eight female Suffolk sheep were divided equally into two groups and were subjected to oral PTU treatments of 4 mg/kg body weight (BW) per day for 7 d (low PTU) and 8 mg/kg BW per day for 14 d (high PTU). A hyperglycemic clamp experiment was conducted in each group on both control and PTU treatment periods. Plasma concentrations of triiodothyronine and thyroxine decreased (P < 0.05) in high PTU-treated sheep compared with those of low PTU-treated and control sheep. Both PTU treatments did not significantly influence basal insulin and glucose levels. Results of the hyperglycemic clamp experiment indicated that the mean plasma insulin increment and the ratio of mean plasma insulin increment to glucose infusion rate were significantly higher (P < 0.01) in high PTU-treated sheep than in low PTU-treated and control sheep. In the second study, the PTU treatment (8 mg/kg BW per day) was applied for 17 d in four male Suffolk sheep. A euglycemic clamp experiment with two insulin infusion rates (1.0 and 10.0 mU/kg per minutes) for two sequential periods of 2 hr each and thyroid hormone responses to intrajugular injection of thyrotropin-releasing hormone (1 microgram/kg BW) were performed in each sheep on both control and PTU treatment periods. In the euglycemic clamp experiment, the glucose infusion rate and the ratio of glucose infusion rate to mean plasma insulin increment were significantly reduced (P < 0.05) during the PTU treatment period for 10.0 mU/kg BW per minute of insulin infusion rate. The response areas of plasma thyroxine and triiodothyronine to thyrotropin-releasing hormone injection were blunted (P < 0.01) in PTU-treated sheep compared with those of control sheep. The high PTU treatment induced low thyroid function, enhanced insulin secretion response, and impaired insulin action in sheep.

Topics: Animals; Blood Glucose; Female; Glucose; Glucose Clamp Technique; Hyperglycemia; Hypothyroidism; Insulin; Male; Propylthiouracil; Sheep; Sheep Diseases; Thyroid Gland; Thyroid Hormones; Thyronines; Thyrotropin-Releasing Hormone; Triiodothyronine

The testes of rats treated neonatally with propylthiouracil (PTU) grow to almost twice their normal size. The cause of testicular enlargement has been suggested to be the result of delayed maturation of Sertoli cells, allowing Sertoli cell division to occur beyond the 15th postnatal day, the commonly recognized cutoff date for Sertoli cell divisions. It has been shown that an increased population of Sertoli cells in postnatal development supports increased numbers of germ cells in adult animals. After examining developing rats treated neonatally with PTU, we hypothesized that an approximate 10-day delay in maturation was occurring and proceeded to test this hypothesis experimentally. Thus the purpose of this report was to determine if a 10-day delay in maturation could explain the increased numbers of Sertoli cells and increased testis size in PTU-treated animals.. Both control animals and animals treated neonatally with PTU N = 5/group were sacrificed at 15 and 25 days of age and prepared for electron microscopy.. Micrographs show and morphometric ultrastructural analysis of numerous parameters demonstrated at the 95% probability level that Sertoli cells from 25-day-old PTU animals are not different in size and most constituents (volume and surface area) from 15-day-old control animals and are less mature than 25-day-old control animals. Mitosis of Sertoli cells was observed in PTU-treated animals in 25-day-old animals but not in age-matched controls. The number of Sertoli cells in 25-day-old PTU-treated animals is significantly increased over age-matched controls. Micrographs show the presence of immature Sertoli cell nuclei in 25-day-old animals receiving PTU as well as increased germ cell degeneration in this group. Sertoli cell tight junction formation is also delayed in PTU-treated animals as compared with controls.. Together, the data show that delayed maturation of Sertoli cells occurs in treated animals that corresponds to a minimum of 10 developmental days. In the immature state, Sertoli cells continue to divide. Data presented herein and published data related to PTU treatment indicate that delayed maturation of the Sertoli cell results in delayed maturation and proliferation of other testicular cell types. From this and from published data, the hypothesis is presented that the Sertoli cell is responsible for the overall control of testis development.

Topics: Animals; Animals, Newborn; Cell Count; Cell Division; Cell Size; Female; Hypothyroidism; Male; Organ Size; Propylthiouracil; Rats; Rats, Sprague-Dawley; Seminiferous Tubules; Sertoli Cells; Testis; Time Factors

In systemic nonthyroidal illness (NTI), peripheral production of T3 from T4 is decreased, resulting in a decreased serum T3 concentration. We investigated whether factors in serum of NTI patients may play a role in this energy-saving adaptation mechanism. Metabolism of T4 and T3 by rat hepatocytes in primary culture was measured in the presence of 10% serum of normal subjects or of patients with NTI and related to the severity of disease. Patients with NTI were grouped according to serum thyroid hormone abnormalities: group I, serum rT3, T3, and T4 normal; group III, rT3 elevated, T3 decreased, T4 normal; group IV, rT3 elevated, T3 and T4 decreased. Compared with metabolism in the presence of normal serum, metabolism of T4 and to a lesser extent of T3 was progressively decreased in the presence of serum of patients of groups I-IV. A decreased net deiodination of T4 and T3 (corrected for differences in free hormone concentration) without an increase in conjugated T4 and T3 (corrected for differences in free hormone concentration) was observed, similar to results in experiments with compounds inhibiting transport into the cells and not the metabolic processes (5' deiodination) per se. Deiodination of T4 in vitro was correlated with serum T3 concentration of the patient (r = 0.69). Serum of patients with NTI influences thyroid hormone handling by hepatocytes comparable to the effect of transport inhibitors and not to that of the 5'-deiodinase inhibitor propylthiouracil, suggesting that decreased thyroid hormone transport over the cell membrane may play a role in lowered T3 production in NTI.

Topics: Animals; Cells, Cultured; Culture Media; Disease; Humans; Hyperthyroidism; Hypothyroidism; Liver; Male; Monensin; Ouabain; Propylthiouracil; Rats; Rats, Wistar; Reference Values; Regression Analysis; Thyrotropin; Thyroxine; Triiodothyronine; Triiodothyronine, Reverse

Clinical studies in thyrotoxicosis reveal a state of high bone turnover leading, eventually, to osteoporosis. Recently there has been concern that thyroxine (T4) treatment may have a similar effect on bone. Rat models have been used to study the effects of T4 on bone, but the majority of studies have looked at the effects of T4 after only 3 weeks of treatment. The aim of this study was to evaluate histomorphometric changes in rats after 12 weeks of thyroxine overtreatment or 12 weeks of hypothyroidism compared with untreated control animals. Animals received either T4 200 micrograms/kg per day, 0.1% propylthiouracil, or vehicle for 12 weeks. Tetracycline was administered 1 week and 3 weeks prior to killing. Iliac crest bone was used for histomorphometry. Serum T4 measurements (taken at killing) confirmed hyper- and hypothyroidism in the appropriate animal groups (between group difference p < 0.001 by ANOVA). In hyperthyroid animals there was an increase in mineral apposition rate (MAR; 0.94 vs. 0.59 microns/day, p < 0.001) and mineral formation rate (MFR/BS; 0.24 vs. 0.12 x 10(-2) micron3/micron2 per day, p < 0.001) and a slight increase in eroded surfaces (ES/BS%; 1.54 vs. 1.36, p < 0.05) compared with controls, consistent with previous in vitro and in vivo observations. In hypothyroid rats there was a marked reduction in osteoid surfaces (OS/BS%; 1.7 vs. 24.8, p < 0.001) and MAR (0.3 vs. 0.59 micrograms/day, p < 0.001), a reduction in ES/BS% (0.51 vs. 1.36, p < 0.05), and an increase in cancellous bone volume (BV/TV%; 30.29 vs. 19.6, p < 0.05), suggesting that thyroid hormones are a requirement for normal bone turnover.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Analysis of Variance; Animals; Body Weight; Calcinosis; Disease Models, Animal; Drug Overdose; Hyperthyroidism; Hypothyroidism; Ilium; Male; Propylthiouracil; Radioimmunoassay; Rats; Rats, Wistar; Tetracycline; Thyroid Function Tests; Thyroxine

The purposes of this study were to determine whether expression of the gene encoding ornithine aminotransferase (OAT) in the rat liver and kidney is regulated by retinoic acid (RA) and to characterize further the role of thyroid hormone in regulating the expression of this gene. The level of OAT messenger RNA (mRNA) was reduced 70% in the liver of animals fed a vitamin A-deficient diet relative to that in animals fed a vitamin A-sufficient diet. RA, administered at a dose of 20 micrograms/rat to A-deficient rats for 1 or 3 days, restored OAT mRNA to near the level observed in animals fed the A-sufficient diet. Retinol was also effective in this regard. T3, when injected alone at a dose of 10 micrograms/100 g BW, had no effect on the level of OAT mRNA in the liver. However, when injected concurrently with RA, T3 blocked the ability of RA to induce OAT mRNA in the liver of rats fed the vitamin A-deficient diet. Animals made both vitamin A deficient and hypothyroid responded to RA in a manner similar to vitamin A-deficient animals. The vitamin A-deficient, hypothyroid rats responded somewhat differently to T3, however. T3 was unable to block the induction of OAT mRNA in the liver of vitamin A-deficient, hypothyroid rats when injected concurrently with RA for 1 day, but did block the induction of OAT mRNA by RA when these two hormones were injected concurrently for 3 days. These data indicate that RA and T3 exert opposing effects on the level of OAT mRNA in the liver. The effects of RA and T3 on OAT mRNA were markedly different in the kidney. Neither vitamin A deficiency nor RA had any apparent affect on the level of OAT mRNA in the kidney. T3, however, increased the level of OAT mRNA in the kidney of vitamin A-deficient rats. In the kidney of vitamin A-deficient, hypothyroid rats, T3 was unable to increase OAT mRNA when injected for 1 day, but did increase this mRNA when injected for 3 days. Together, these data indicate cell-type specific effects of both RA and T3 on the OAT gene.

Topics: Animals; Animals, Newborn; Female; Gene Expression Regulation, Enzymologic; Hypothyroidism; Kidney; Lactation; Liver; Male; Organ Specificity; Ornithine-Oxo-Acid Transaminase; Propylthiouracil; Rats; Rats, Inbred Lew; RNA, Messenger; Thyroxine; Tretinoin; Triiodothyronine; Vitamin A; Vitamin A Deficiency

Ketone bodies represent preferred energy substrates in the adult rat proximal tubule. They are abundant in the plasma of suckling rats and might represent an important oxidative substrate for the immature proximal tubule. The postnatal development of two enzymes involved in ketone body oxidation pathway, 3-ketoacid-CoA transferase and acetoacetyl-CoA thiolase, and of citrate synthase and carnitine acetyltransferase was studied in microdissected rat proximal convoluted tubule (PCT) at 1, 8, 16, and 21 days after birth. The enzyme levels in PCT of juxtamedullary and subcapsular nephrons were compared at 8, 16, and 21 days. A role of thyroid hormones in regulating the development of these enzymes was investigated by studying 8- and 21-day-old pups made hypothyroid by propylthiouracyl (PTU) treatment, as well as 21-day hyperthyroid rats. PTU treatment had no effect on enzyme activities on day 8. In contrast, the activity of all mitochondrial enzymes, except acetoacetyl-CoA thiolase, was significantly decreased in 21-day-old hypothyroid pups. In hypothyroid animals, the normal development of 3-ketoacid-CoA transferase, citrate synthase, and carnitine acetyltransferase could be restored after treatment by triiodothyronine (T3). In addition, one single injection of T3 to 8-day-old control pups induced a precocious rise in the activity of 3-ketoacid-CoA transferase, citrate synthase, and carnitine acetyltransferase in juxtamedullary PCT and in the activity of citrate synthase and carnitine acetyltransferase in subcapsular PCT. Altogether, these results point out the importance of the postnatal physiological rise in T3 in triggering the development of some mitochondrial oxidative enzymes in the PCT.

Topics: Aging; Animals; Animals, Newborn; Body Weight; Coenzyme A-Transferases; Energy Metabolism; Hypothyroidism; Kidney Tubules, Proximal; Mitochondria; Nephrons; Organ Size; Oxidation-Reduction; Propylthiouracil; Rats; Rats, Wistar; Reference Values; Thyroid Hormones; Triiodothyronine

During hepatic development, beta-adrenergic receptors are replaced by alpha 1-receptors, an important event in the switchover from neonatal to adult glucose metabolism. In mature tissues, expression of adrenergic receptor subtypes is regulated, in part, by thyroid hormones; the current study examines whether they also participate in the transition of hepatic receptors. When triiodothyronine (T3) was given to rat pups on postnatal days 11-15, just before the receptor transition period, the developmental increase of alpha 1-receptors was accelerated but there was no change in the ontogenetic decline of beta-receptors. When propylthiouracil (PTU) was given over the same period to induce hypothyroidism, neither alpha 1- nor beta-receptor development were affected, thus, despite the selective promotion of alpha 1-receptor sites by exogenous thyroid hormone, endogenous hormone is not obligatory for receptor switching to take place. Finally, to distinguish whether the receptor transition is a function of general growth and cell differentiation, which are also impacted by thyroid status, animals were given PTU from gestational day 17 through postnatal day 5, a treatment that reproduces the growth defects of congenital cretinism, but that allows hormone levels to return to normal during the receptor transition period; the appropriate switchover still occurred. These studies indicate that thyroid hormone selectively promotes hepatic alpha 1-receptor expression during development, but is not itself responsible for the ontogenetic switchover in adrenergic receptor subtypes. Because other factors, such as glucocorticoids, have similar modulatory effects, the timing of hepatic adrenergic receptor development may be governed by multiple factors, no one of which is absolutely sufficient or essential.

Topics: Animals; Animals, Newborn; Female; Hyperthyroidism; Hypothyroidism; Liver; Membranes; Pregnancy; Propylthiouracil; Rats; Rats, Sprague-Dawley; Receptors, Adrenergic; Receptors, Adrenergic, alpha-1; Receptors, Adrenergic, beta; Thyroid Hormones; Triiodothyronine

TSH initiates its action by binding to specific membrane receptors' thyroid cells and induces activation of the adenylate cyclase-cAMP cascade. The factors involved in the regulation of TSH receptors are poorly known, except for the TSH dose-dependent regulatory effect. The fact that the thyroid gland of Graves' patients has a normal density of TSH receptors with suppressed TSH and high T4 and T3 levels suggests a modulatory role of thyroid hormones on TSH receptors. To evaluate this hypothesis, the density of TSH receptors and the activity of adenylate cyclase were determined in the thyroid membranes from hyperthyroid and hypothyroid adult male rats; they were rendered hyperthyroid either with bovine TSH, TRH, or T3 for 7 days and hypothyroid by propylthiouracil treatment or by hypophysectomy. NaCl was given to the control group. Plasma T4, T3, and TSH were also quantified. Bovine TSH and TRH treatments induced mild hyperthyroidism with a small goiter and a 50% reduction in the density of TSH receptors due to hyperstimulation of the gland by either exogenous or endogenous high TSH levels. Severe hyperthyroidism caused by T3 treatment resulted in low T4, high T3, and suppressed TSH thyrocyte stimulation; it was associated with a significant increase in the number of TSH receptors (29.6 +/- 2.3 vs. control 17.9 +/- 1.7 mU TSH/mg protein). These last results suggest a putative positive effect of T3 on TSH receptors. To confirm this effect, hypothyroid rats were investigated. Severe primary hypothyroidism due to propylthiouracil treatment was associated with a large goiter, high plasma TSH levels (11.8 +/- 1.2 vs. control 1.5 +/- 0.1 mU TSH/ml), low plasma T4 and T3, and a 70% reduction in TSH receptors, confirming the down-regulatory effect of high TSH on the thyroid cell. However, in hypophysectomized rats, a 45% reduction in the density of TSH receptors was also observed in the absence of TSH. Injections of either TSH or T3 to these hypophysectomized rats restored a normal number of TSH-binding sites, and simultaneous TSH and T3 treatments resulted in a mildly additive effect in the number of TSH receptors, which was slightly greater than that of the controls. No important changes were found in the adenylate cyclase activity in the thyroid membrane preparations from hyperthyroid and hypothyroid rats despite variations in the density of TSH receptors.(ABSTRACT TRUNCATED AT 400 WORDS)

Topics: Adenylyl Cyclases; Animals; Cattle; Graves Disease; Hyperthyroidism; Hypophysectomy; Hypothyroidism; Male; Propylthiouracil; Rats; Rats, Wistar; Receptors, Thyrotropin; Thyroid Gland; Thyrotropin; Thyrotropin-Releasing Hormone; Thyroxine; Triiodothyronine

A fetal goitre is a potentially dangerous phenomenon because of mechanical obstruction and possible fetal thyroid function disorders. In this report we describe a patient with Graves' disease diagnosed in early pregnancy and treated with propylthiouracil, which resulted in a large fetal goitre and fetal hypothyroidism. The diagnostic problems are discussed and we focus on the need for fetal thyroid hormone serum evaluation. The only reliable way to obtain information about the fetal thyroid status is percutaneous fetal umbilical cord blood sampling, since amniotic fluid levels do not properly represent the fetal thyroid function. Fetal hypothyroidism can thus be diagnosed in utero and treated with intra-amniotic injections of thyroxine. The recommended dose and frequency of injections are only based on a few case reports and for that reason we performed a second fetal blood sampling 1 week later to evaluate our therapy. Weekly intra-amniotic injections of 250 micrograms of thyroxine seem to be sufficient to reduce a fetal goitre and give a normal thyroid hormone level.

Topics: Adult; Dose-Response Relationship, Drug; Female; Fetal Diseases; Goiter; Graves Disease; Humans; Hypothyroidism; Injections; Maternal-Fetal Exchange; Pregnancy; Prenatal Diagnosis; Propylthiouracil; Thyrotropin; Thyroxine; Triiodothyronine

The effects of altered thyroid states on the heart rate and ventricular electrophysiological properties of the frog were examined. Hypothyroidism was induced by a 10-day treatment with propylthiouracil and produced decreased serum-free and total triiodothyronine levels below detectable concentrations. Hyperthyroidism, elicited by a 5-day treatment with triiodothyronine, was associated with increased serum thyroid hormone levels. The hypothyroid state was associated with a significantly decreased heart rate measured in vivo and an increased duration of the action potential recorded in vitro from ventricular fibers. Hyperthyroidism was associated with an increased heart rate and a decreased ventricular action potential duration (APD). The dependence of APD on temperature was affected by thyroid status. An increase from 25 to 30 degrees barely shortened the repolarization phase in hyperthyroids, minimally (13.3%) shortened that in euthyroids, and greatly (43.7%) shortened that in hypothyroids; the APD was similar in euthyroid and hypothyroid frogs. The shortening of the repolarization phase, by increased stimulation frequency, was also greater for hypothyroid frogs. In this case, however, the differences in APD among groups remained significant at all the frequencies tested.

Topics: Action Potentials; Animals; Antithyroid Agents; Electric Stimulation; Electrophysiology; Heart; Heart Rate; Hyperthyroidism; Hypothyroidism; Male; Propylthiouracil; Rana esculenta; Thyroid Gland; Triiodothyronine; Ventricular Function

It is well established that the progressive disappearance of a transient occipito-spinal projection in neonatal rats involves the selective elimination of axonal collaterals. We studied whether the development of the occipito-spinal pathway was affected by hypothyroidism induced by treatment with the goitrogen 6n-propyl-2-thiouracil (PTU) beginning prenatally. Using both anterograde (biocytin and Dil) and retrograde (horseradish peroxidase and Fast Blue) tracing techniques in adult hypothyroid rats, we found that many cells with projections into the pyramidal tract are present in regions of visual cortex that are devoid of such cells in normal adult rats. Our results suggest that hypothyroidism induced by PTU treatment leads to the maintenance of occipito-spinal projections that are normally transient.

Topics: Animals; Hypothyroidism; Neural Pathways; Occipital Lobe; Propylthiouracil; Pyramidal Tracts; Rats; Visual Cortex

Changes in thyroid status have a major effect on the GH/IGF-I axis. In the rat, there is a single gene for the growth hormone receptor (GHR), that is transcribed into two different sized mRNA transcripts following alternative splicing, one transcript codes for the GHR (4.0-4.5 kb) and the other growth hormone binding protein (GHBP) (1.2-1.3 kb). We have studied the regulation of hepatic GHR gene expression by thyroid hormones in male Wistar rats rendered hypothyroid (n = 6) and hyperthyroid (n = 6) compared to controls (n = 6). By northern blot analysis, two transcripts with an estimated size of 4.2 and 1.2 kb, respectively, were detected in all groups. Hyperthyroidism was associated with a significant increase in the 4.2 kb transcript compared to hypothyroidism (P < 0.05), but no changes were observed in the 1.2 kb transcript. Thus, our results suggest that in the rat hyperthyroidism is associated with either increased hepatic gene transcription or decreased clearance of the 4.2 kb transcript for the GHR compared with hypothyroidism.

Topics: Alternative Splicing; Analysis of Variance; Animals; Gene Expression Regulation; Hyperthyroidism; Hypothyroidism; Liver; Male; Propylthiouracil; Rats; Rats, Wistar; Receptors, Somatotropin; Reference Values; RNA, Messenger; Thyroid Gland; Thyroxine; Transcription, Genetic

Programmed cell death is a basic cellular process that has aroused much interest in recent years. Like immune cells, cultures of cerebellar granule neurons are very homogeneous and provide a unique opportunity for quantifying by flow cytometry one form of programmed cell death in the CNS, the apoptosis, and for studying its regulation by neurotrophic factors. We found that thyroid hormone promoted postmitotic survival by preventing the apoptosis of newly formed and early differentiated granule neurons in a dose-dependent manner. This regulation could be through the protein bcl-2, which is known to prevent cell death. This protein was present at all stages of granule neuron differentiation and appeared to be developmentally regulated. It was underexpressed in apoptotic granule neurons. The protein content of the cerebellum in hypothyroid rats was drastically reduced. In contrast, thyroid hormone caused a marked dose-dependent increase in the amounts of this protein in granule neuron cultures. The possibility that thyroid hormone may be directly or indirectly required to promote cell survival is discussed, in terms of the hormone control of the local delivery of neurotrophins, such as NGF and NT-3, as well as the expression of their low affinity receptors, gp75. We suggest that thyroid hormone has a permissive action on the developing CNS.

Topics: Animals; Apoptosis; Blotting, Western; Cell Differentiation; Cell Survival; Cells, Cultured; Cerebellum; DNA; Flow Cytometry; Fluorescent Antibody Technique, Direct; Hypothyroidism; Immunohistochemistry; Neurons; Propylthiouracil; Protein-Tyrosine Kinases; Proto-Oncogene Proteins; Proto-Oncogene Proteins c-bcl-2; Rats; Rats, Wistar; Thyroid Hormones

Ventricular myosin heavy chain (HC) expression undergoes a rapid change from the beta to the alpha isoform shortly after birth. Thyroid hormone is required for this transition to occur, but the time course of developmental changes in circulating thyroid hormone levels suggests that it cannot be the trigger for this event. In this study, the possibility was examined that cyclic AMP (cAMP), either acting separately or as a mediator of the permissive actions of thyroid hormone, triggers the developmental transition in ventricular myosin HC expression. One-day-old euthyroid or propylthiouracil-hypothyroid rat pups were treated with a membrane-permeable cAMP analogue, 8-bromo-cAMP (8-Br-cAMP) or triiodothyronine (T3). Two and four hours after acute treatment, the relative synthetic rates of alpha and beta myosin HC were measured using an in vivo pulse labelling technique. Myosin HC isoforms were separated electrophoretically and then quantitated by densitometry. Acute treatment in vivo with 8-Br-cAMP did not alter the relative rate of alpha myosin HC synthesis in euthyroid animals at either 2 or 4 h. Hypothyroidism significantly reduced the relative rate of alpha HC synthesis and obturated the transition from beta to alpha HC. The effect on synthesis was rapidly reversed by acute treatment with T3, but not with 8-Br-cAMP. Thus, an increase in cAMP does not appear to trigger the developmental change in myosin isoform expression, nor does it appear to mediate the stimulatory effect of thyroid hormone on alpha myosin HC synthesis. Instead, thyroid hormone is likely to be acting directly on the alpha HC gene by binding to the thyroid response element. The identity of stimuli that mediate the increased responsiveness to thyroid hormone during development remains to be determined, but it is not due to an increase in the levels of cAMP in perinatal cardiocytes in vivo.

Topics: 8-Bromo Cyclic Adenosine Monophosphate; Animals; Animals, Newborn; Cyclic AMP; Heart; Heart Ventricles; Hypothyroidism; Kinetics; Myosin Heavy Chains; Propylthiouracil; Rats; Rats, Sprague-Dawley; Thyroid Hormones; Triiodothyronine

Coronary capillary geometry was studied in male rats treated with 3,3',5-triiodo-L-thyronine (T3; Hyper), 6-N-propyl-2-thiouracil (PTU; Hypo), or a sequence of PTU and T3 (Hypo/Hyper). Ventricular mass and heart-to-body mass ratios revealed myocardial hypertrophy in Hyper, atrophy in Hypo, and a return of ventricular mass to control (Con) values in Hypo/Hyper rats. From cross-sectional analysis, capillary densities for Hyper and Hypo/Hyper were comparable with Con, despite increased left ventricular mass. Hypo rats demonstrated increased capillary density. In Hyper and Hypo rats, tissue area surrounding individual capillaries (capillary domain) decreased, compared with Con, for capillaries close to the feeding arteriole. In Hyper and Hypo/Hyper, capillaries distal to the feeding arteriole had similar domain areas as Con; in Hypo, this area was smaller. From longitudinal analysis, capillary segment lengths were significantly shorter in all groups compared with Con. Our data suggest that while hypothyroidism induced myocardial atrophy and hyperthyroidism induced myocardial hypertrophy, both thyroid states stimulated capillary proliferation.

Topics: Alkaline Phosphatase; Animals; Capillaries; Cardiomegaly; Coronary Circulation; Dipeptidyl Peptidase 4; Dipeptidyl-Peptidases and Tripeptidyl-Peptidases; Histocytochemistry; Hyperthyroidism; Hypothyroidism; Male; Mathematics; Myocardium; Propylthiouracil; Rats; Rats, Sprague-Dawley; Silver; Staining and Labeling; Triiodothyronine

The early period of motor innervation development is characterized by multiple innervation of muscle cells. This transitory state in rat extensor digitorum longus (edl) muscle is normally concluded at weaning when a 1:1 ratio between nerve endings and muscle cells is reached. Motor innervation of edl muscle in rats made hypothyroid after weaning was studied in three ways: electrophysiology (intracellular recordings of muscle postsynaptic potentials) was carried out to study neuromuscular transmission; silver impregnation of terminal axons to observe sprouting; force production in twitch and tetanus following direct muscle stimulation and nerve stimulation. A number of multiply innervated muscle cells was found in hypothyroid rats following two months of treatment. This finding seems to be related to the appearance of nodal sprouting in motor axons. No sign of denervated end-plates was found. Twitch and tetanus tension were smaller than in controls, but they were bigger when referred to unitary muscle mass. Time course of twitch, particularly half relaxation, was slowed in muscles of hypothyroid rats. These findings suggest that plastic processes occur in muscle innervation of rats made hypothyroid after weaning. Therefore, thyroid hormones play a role in stabilizing motor innervation not only during development, but also in adults.

Topics: Animals; Hypothyroidism; Male; Muscle Contraction; Muscle Development; Muscles; Neuromuscular Junction; Neuronal Plasticity; Propylthiouracil; Rats; Rats, Sprague-Dawley

Topics: Adult; Age Factors; Aged; Aged, 80 and over; Drug Monitoring; Humans; Hydrocortisone; Hyperthyroidism; Hypothyroidism; Iodine; Iodine Radioisotopes; Methimazole; Middle Aged; Propylthiouracil; Thyrotropin; Thyroxine

Male golden Syrian hamsters made hypothyroid by 5 wk of propylthiouracil (PTU) treatment and control hamsters given tap water were studied. Both groups of nine animals demonstrated increased oxygen consumption after SC naloxone administration relative to saline treatment. Naloxone stimulated ventilation and ventilation in response to hypoxic (10% O2) and hyperoxic, hypercapnic (7% CO2 in oxygen) challenges in control hamsters. Relative to their responses to saline, PTU-treated hamsters exhibited no stimulation of ventilation nor of ventilation in response to the gas challenges after naloxone treatment. These results suggest that (a) the stimulation of oxygen consumption by naloxone does not directly increase ventilation; and (b) thyroid hormone status in the hamster affects opioid modulation of ventilation.

Topics: Animals; Carbon Dioxide; Cricetinae; Hypothyroidism; Injections, Subcutaneous; Male; Mesocricetus; Naloxone; Oxygen; Propylthiouracil; Receptors, Opioid; Respiration; Thyroid Hormones

Propylthiouracil- (PTU) induced transient neonatal hypothyroidism increases adult rat testis weight 80-100%; this effect involves prolongation of Sertoli cell proliferation. To gain insight into developmental effects of PTU on the testis, we used Northern analysis to examine chronological expression of Sertoli cell mRNA in postnatal rat testes from rats that were untreated (controls) or were given PTU from birth to Day 25. Treated rats showed prolonged early expression of genes associated with dividing Sertoli cells such as MIS (Müllerian inhibiting substance) and c-erbA alpha (thyroid hormone receptor). Expression of several other Sertoli cell mRNAs (androgen-binding protein [ABP], clusterin, and inhibin-beta B) was delayed, as was that of hemiferrin, a spermatid-specific mRNA. Temporal expression patterns for other mRNAs (sulfated glycoprotein [SGP]-1, transferrin, and inhibin-alpha) were similar in control and treated animals. Additionally, thyroid hormone replacement in PTU-treated animals decreased MIS and c-erbA alpha mRNA expression to control levels. The altered developmental pattern of expression of a number of major Sertoli cell genes reflects a prolonged mitogenesis and delayed maturation of Sertoli cells in neonatally hypothyroid animals. Furthermore, our results suggest that thyroid hormone may directly potentiate molecular events associated with cessation of Sertoli cell proliferation and maturation during early testis development.

Topics: Animals; Animals, Newborn; Anti-Mullerian Hormone; Blotting, Northern; Cell Differentiation; Cell Division; Gene Expression; Glycoproteins; Growth Inhibitors; Hypothyroidism; Male; Propylthiouracil; Rats; Receptors, Thyroid Hormone; RNA, Messenger; Sertoli Cells; Testicular Hormones; Testis; Thyroxine; Triiodothyronine

The effect of hypothyroidism on the lipid composition of synaptosomes, density and affinity of muscarinic receptor sites, and acetylcholinesterase activity in the cerebral cortex of young and aged rats was investigated. The animals were made hypothyroid by adding 0.05% propyl-2-thiouracil to their drinking water for four weeks. This pathological state induced an increase in the relative percentage of sphingomyelin in young rats. In aged rats hypothyroidism induced a decrease of sphingomyelin and glycerophosphocholine and an increase of cholesterol. The effect of hypothyroid state on cerebral cortex resulted in an increase of acethylcholinesterase activity both in young and aged rats and was also reflected in an increase of density of M1-AChRs but only in the former.

Topics: Acetylcholinesterase; Aging; Animals; Cerebral Cortex; Hypothyroidism; Lipid Metabolism; Male; Propylthiouracil; Rats; Rats, Inbred Lew; Receptors, Muscarinic; Synaptosomes

Hypothyroidism protects the brain from the effects of transient forebrain ischemia in gerbils. The mechanism for this protection is not fully understood. In this study we looked at the release of glutamate during ischemia in gerbils exposed to surgical hypothyroidism (n = 7), chemical hypothyroidism (n = 8), and surgical hypothyroidism thyroxine-treated (n = 3) and compared them to control euthyroid animals (n = 8). The duration of ischemia was 10 min. Glutamate release was measured with in vivo microdialysis. Microdialysis analysis began 2 h after the placement of the probes (to stabilize the baseline) and collections were obtained in 10-min samples. During ischemia, there was an increase in the release of glutamate that returned to the baseline within 20 min following the insult. In animals made hypothyroid surgically and chemically, the extent of glutamate release was significantly lower than that in the controls. The release of glutamate in the surgically hypothyroid thyroxine-treated animals was similar to that in controls. The attenuated glutamate release could be a mechanism of protection during ischemia in hypothyroid gerbils.

Topics: Animals; Brain Ischemia; Gerbillinae; Glutamates; Glutamic Acid; Hypothyroidism; Male; Microdialysis; Propylthiouracil; Thyroidectomy; Thyroxine; Triiodothyronine

The effects of neonatal hypothyroidism on the gene expression of progesterone receptors (PRs) in the 8-day-old female rat brain were examined. The levels of PR ('A'+'B')-, PR ('B')-, estrogen receptor (ER)- and beta-actin mRNAs in the cerebral cortex and hypothalamus-preoptic area of propylthiouracil-treated rats (PTU group) or untreated rats (control group) were analyzed using a quantitative reverse transcription-polymerase chain reaction-Southern blotting assay. When the levels of PR mRNAs were calibrated by respective levels of beta-actin mRNA, the levels of PR ('A'+'B')- and PR ('B') mRNAs in the cerebral cortex of the PTU group were markedly less than those in the control group with no significant changes in the levels of PR messages in the hypothalamus-preoptic area of both groups. No significant difference in the calibrated levels of ER mRNA between both groups was found in these tissues. These results on the PR-, and ER mRNAs were essentially similar to those on the levels of PR- and ER proteins previously reported suggesting that thyroid hormones affect the transcriptional machinery of PR in the developing brain, in a region-specific manner.

Topics: Animals; Animals, Newborn; Base Sequence; Brain; DNA Primers; Female; Gene Expression; Hypothyroidism; Molecular Sequence Data; Propylthiouracil; Rats; Rats, Wistar; Receptors, Progesterone; RNA, Messenger

Eu-, hypo- and hyper-thyroid rats were studied 12 days postpartum. Hypothyroidism was induced by administering propylthiouracil (PTU) via the mother's drinking water between late gestation and throughout lactation. This procedure effectively blocked the normal early postnatal surge of T3 and T4. In contrast, hyperthyroidism was induced in the young pups by daily injections of T4 from day 3 postpartum. The effects of these experimental manipulations of thyroid status on the rates of protein turnover and growth of the liver, kidney, and diaphragm were studied and compared with measurements made on appropriate euthyroid control tissues. Tissue rates of protein synthesis were decreased in response to hypothyroidism with consequent growth retardation of all three tissues and the whole animal. In contrast, the three body tissues responded very differently to the induction of hyperthyroidism. Hepatic rates of protein synthesis and growth were completely unaffected by thyroid excess. The response of the diaphragm was essentially the reverse of that seen with hypothyroidism, i.e., the enhanced rates of protein synthesis and protein degradation leading to muscle hypertrophy. The rates of protein turnover in the kidney were also increased, but unlike the diaphragm the net result was renal atrophy. Clearly, thyroid hormones influence the normal rapid growth of the neonate and its individual tissues. However, beyond a certain concentration the threshold of responsiveness to these hormones seems to vary between individual tissues.

Topics: Animals; Animals, Newborn; Diaphragm; Female; Hypothyroidism; Kidney; Liver; Muscle Development; Propylthiouracil; Rats; Rats, Wistar; Thyroid Gland

The effect of thyroid hormones (TH) on the metabolism of thyrotropin-releasing hormone (TRH) in the olfactory bulb (OB) was compared with the hypothalamic response to TRH. Two methods were used to induce hypothyroidism: propylthiouracyl-methimazole (PTU-M) or 131I treatment. Hyperthyroidism was produced by 3,3',5-triiodo-L-thyronine (T3) injections to the hypothyroid animals. With PTU-M treatment, paraventricular TRH mRNA levels increased 57% and returned to the euthyroid level with T3 treatment. In OB, TRH mRNA was not altered. The TRH content was unaffected in the mediobasal hypothalamus of PTU-M-treated animals whereas it was reduced in OB (31%) with no further response upon T3 treatment. 131I-induced hypothyroidism did not modify the OB TRH content but it was decreased (31%) in hyperthyroids. In the median eminence, TRH increased 26% in hypothyroids, and the response was reversed with T3. Our results demonstrate that treatments that change thyroid status can alter TRH levels in the OB, probably at a translational or postranslational level, though the effects may be pharmacological.

Topics: Animals; Hypothalamo-Hypophyseal System; Hypothyroidism; Male; Methimazole; Olfactory Bulb; Paraventricular Hypothalamic Nucleus; Pituitary Gland, Anterior; Propylthiouracil; Protein Biosynthesis; Protein Processing, Post-Translational; Rats; Rats, Wistar; Thyroid Hormones; Thyrotropin-Releasing Hormone

Hypothyroid animals secrete not only more TSH, but also qualitatively different TSH, with altered oligosaccharides. To explore the cellular mechanism of oligosaccharide modulation by thyroid status, 40 mice were treated without or with propylthiouracil (PTU), and pituitaries were removed after 1, 2, 3, 4, and 6 weeks. Serum T4 levels confirmed that mice receiving PTU were hypothyroid even after only 1 week. Thyrotrophs and corticotrophs were identified in 5-microns thick pituitary slices using immunocytochemistry; in situ hybridization was performed using 35S-labeled 48-mer DNA probes to beta-1,4-galactosyltransferase and alpha-mannosidase-II messenger RNAs (mRNAs). A control probe also was used. Autoradiography was performed for 4 weeks. The cells and silver grains were scored, and the differences reported below were significant by analysis of variance. Compared to euthyroid thyrotrophs, the beta-1,4-galactosyltransferase mRNA level in thyrotrophs increased 440% after mice received PTU for 1 week; the mean increase within thyrotrophs over the 6-week period was 173%, whereas there was little change in corticotrophs. Compared to euthyroid thyrotrophs, the alpha-mannosidase-II mRNA level in thyrotrophs remained unchanged while mice received PTU for 4 weeks, but then increased 150% after week 6 of PTU treatment. Thus, thyroid status modulates mRNA levels of two glycosyltransferases in thyrotrophs, perhaps by affecting gene transcription or mRNA stability. Moreover, the kinetics of the modulation of the two glycosyltransferase mRNAs differ. This is the first report of the modulation of these glycosyltransferase mRNA levels in thyrotrophs and may explain in part the mechanism by which different isoforms of TSH are secreted in different physiological states.

Topics: Animals; Galactosyltransferases; Gene Expression Regulation, Enzymologic; Hypothyroidism; Immunohistochemistry; In Situ Hybridization; Male; Mannosidases; Mice; Propylthiouracil; RNA, Messenger; Thyroid Gland; Thyroxine

To study the regulation of carnitine palmitoyltransferase-I by thyroid hormone, a cDNA was obtained by PCR amplification of DNA obtained by reverse transcription of rat liver RNA. CPT-I mRNA abundance was measured in livers of hyperthyroid, euthyroid and hypothyroid rats. In hypothyroid rats, the CPT-I mRNA levels decreased 40-fold relative to that of the hyperthyroid animals. These changes paralleled alterations in enzyme activity. These data suggest that CPT-I is regulated at the transcriptional level by thyroid hormone.

Topics: Animals; Blotting, Northern; Carnitine O-Palmitoyltransferase; Gene Expression; Gene Expression Regulation, Enzymologic; Hyperthyroidism; Hypothyroidism; Kinetics; Liver; Male; Mitochondria, Liver; Polymerase Chain Reaction; Propylthiouracil; Rats; Rats, Sprague-Dawley; RNA, Messenger; Substrate Specificity; Thyroid Hormones; Transcription, Genetic

Specific binding sites for 3,3'-T2 can be detected in swollen and osmotically treated mitochondria (OTM) from normal and hypothyroid rat liver. In hypothyroid animals, maximal values of binding were obtained at 0 degrees C while values were lower at 37 degrees C and no specific binding could be observed at 60 degrees C. Binding was maximal at pH 6.4 and the mean values for the apparent association constant (Ka) and the binding capacity were on average 0.5 x 10(8) M-1 and 2.4 pmol/mg mitochondrial protein, respectively. No differences were observed between normal and hypothyroid rats with the exception of the capacity that was higher in normal animals (5.5 pmol/mg mitochondrial protein). The specificity of 3,3'-T2 binding, examined in competition studies, followed this order: 3,3'-T2 > 3,5-T2 > rT3. The other iodothyronines (3',5'-T2, T3, T4, 3-T1, 3'-T1, 3,5-Diac and 3,3'-Diac) showed only a small competition or none at all.

Topics: Animals; Binding Sites; Binding, Competitive; Diiodothyronines; Electron Transport Complex IV; Hypothyroidism; Kinetics; Male; Mitochondria, Liver; Osmotic Pressure; Permeability; Propylthiouracil; Rats; Rats, Wistar

Testicular weight and DNA content were markedly reduced (63 and 69%) in weanling Long-Evans rat pups rendered hypothyroid from birth by administration of propylthiouracil (PTU), a reversible goitrogen. These growth deficits worsened to > 80% by continuing hypothyroidism beyond weaning, to days 50 and 90. Recovery of thyroid function, brought about by discontinuing PTU at weaning, resulted in a paradoxical stimulation of testis growth, amounting to increased weight (40%), DNA content (60%) and size by 90 days, compared to age-matched controls. In the 25-day or older hypothyroid rats, testicular structure was immature and spermatogenesis markedly delayed, as evident by closed lumen and significantly reduced diameter of seminiferous tubules (38%), thickness of germinal layer (70%), and number of primary spermatocytes (86%), compared to control. Hypothyroidism did not alter the number of tubules per testis cross section. In the 90-day recovery rats, numbers of seminiferous tubules were unchanged but tubular diameter was significantly (20%) larger than in controls and spermatogenesis appeared very active as indicated by significantly increased germinal layer thickness (22%) and total number and density of primary spermatocytes (55% and 40%). The results show that although postnatal hypothyroidism is deleterious for testicular growth and spermatogenesis, recovery from this condition leads to enhanced seminiferous tubular growth and spermatogenesis.

Topics: Animals; Animals, Newborn; DNA; Hypothyroidism; Male; Organ Size; Propylthiouracil; Rats; Seminiferous Tubules; Spermatocytes; Spermatogenesis; Testis

Hypothyroid patients and mice have been shown to have circulating TSH that is more highly sialylated than their euthyroid counterparts. To learn about the underlying cellular mechanisms responsible for this increased sialylation of TSH, we used in situ hybridization to examine the beta-galactoside alpha-2,6-sialyltransferase (STase) mRNA content in thyrotrophs and corticotrophs of euthyroid and hypothyroid mice. Mice were treated with or without 0.05% propylthiouracil for 1, 2, 3, 4, or 6 weeks, then pituitaries were removed, and 5-microns slices were immunocytochemically stained for TSH and ACTH. Adjacent sections were used for in situ hybridization. A 48-mer deoxynucleotide probe to rat STase and two control probes were labeled with 35S, and autoradiography was performed. There was an approximately 140% increase in STase mRNA in hypothyroid thyrotrophs compared to euthyroid thyrotrophs by the first week, with a mean increase of 170% in weeks 1-6, whereas corticotrophs exhibited no change in STase mRNA. The increase in hybridization of the STase probe in hypothyroid thyrotrophs may be due to an increased transcription of the STase gene, stabilization of the STase mRNA, or both. Thus, modulation of the STase mRNA levels occurs in thyrotrophs and represents one important mechanism by which the oligosaccharides of TSH are altered under different physiological conditions.

Topics: Adrenocorticotropic Hormone; Animals; beta-D-Galactoside alpha 2-6-Sialyltransferase; Hypothyroidism; In Situ Hybridization; Kinetics; Male; Mice; N-Acetylneuraminic Acid; Propylthiouracil; RNA, Messenger; Sialic Acids; Sialyltransferases; Thyroid Gland; Thyrotropin; Thyroxine

The 9-cis-retinoic acid receptors (RXRs), belonging to the members of the steroid/thyroid hormone receptor superfamily, act as auxiliary proteins, heterodimerizing with other nuclear receptors such as retinoic acid receptors (RARs), vitamin D receptor, thyroid hormone receptors, and peroxisome-proliferator activated receptor, thereby transactivating target genes in a ligand-dependent manner. We have previously reported that in the rat, thyroid hormone (TH) positively and negatively regulates the hepatic mRNA levels of RXR beta and RXR gamma, respectively. In the present study, we have tried to elucidate the level at which TH regulates the gene expression of RXR beta and RXR gamma in the rat. A RNA synthesis inhibitor (actinomycin D), but not a protein synthesis inhibitor (cycloheximide), blocked the induction of RXR beta mRNA by TH. On the other hand, none of these drugs inhibited the decrease of RXR gamma mRNA levels caused by TH. Nuclear run-on assays showed that the transcription rate of the RXR beta gene was positively regulated by TH, whereas the transcription of RXR gamma gene was not controlled by TH. Taken together, these results indicate that the gene expression of RXR beta is positively regulated by TH at transcriptional level, while the negative regulation of the RXR gamma gene expression by TH may occur at a post-transcriptional level in intact rat. Thus, the RXR-mediated signal transductions may be modulated in part through TH control of the levels of RXR beta and RXR gamma.

Topics: Animals; Brain; Cell Nucleus; Gene Expression Regulation; Heart; Hypothyroidism; Liver; Myocardium; Propylthiouracil; Rats; Rats, Wistar; Receptors, Cytoplasmic and Nuclear; Receptors, Retinoic Acid; Retinoid X Receptors; Retinoids; RNA Processing, Post-Transcriptional; RNA, Messenger; Transcription Factors; Transcription, Genetic; Triiodothyronine

Endothelin-1 (ET-1) is a 21-residue peptide isolated from the conditioned medium of cultured porcine endothelial cells and is widely distributed throughout the body, with relatively high levels in the kidney and lung. In this study we examined the influence of thyroid hormone status on immunoreactive endothelin (ir-ET) levels in the plasma, lung, and kidney tissues of rats. Three weeks after surgical removal of the thyroid gland from male rats, the ir-ET levels in the lung and kidney were reduced by 39% and 42%, respectively. Similarly, ir-ET levels were decreased by 46% in the lung and 45% in the kidney of rats rendered hypothyroid by treatment with 0.1% (wt/wt) n-propylthiouracil (PTU) in the drinking water for 30 days. Replacement with daily L-thyroxine (T4) injections (5 micrograms/100 g) prevented this decrease. However, thyrotoxicosis induced by daily L-T4 injections (10 micrograms/100 g) also caused a decrease of the lung ir-ET levels by 49%, but had no significant effect on the renal ir-ET levels. However, the plasma ir-ET levels were similar in each group. Fast protein liquid chromatography study verified the presence of ir-ET-1 in the plasma and tissue extracts. This study demonstrates that thyroid hormone status affects tissue levels of ir-ET differently and that a euthyroid status is required for the maintenance of physiologic concentrations of ir-ET in the lung of male rats.

Topics: Animals; Endothelins; Hypothyroidism; Kidney; Lung; Male; Propylthiouracil; Radioimmunoassay; Rats; Thyroid Hormones; Thyroidectomy; Thyrotoxicosis; Thyroxine

In propylthiouracil (PTU)-fed (g/kg feed) hypothyroid cockerels, serum levels of growth hormone (GH), but not insulin-like growth factor (IGF)-1, tended to rise and those of IGF-binding activity to fall. Thyroxine (T4) supplement (200 micrograms/kg/day) to PTU-fed cockerels for 8 days produced a hyperthyroid state and reversed these serum parameters. A chromatographic analysis of serum proteins revealed that T4 supplement markedly enhanced the IGF-binding activity of a 30 kDa protein and slightly lowered that of a 150 kDa protein, suggesting that T4 increases unsaturated IGF-binding proteins by reducing circulating IGF-1 concentrations.

Topics: Animals; Animals, Newborn; Blood Proteins; Body Weight; Carrier Proteins; Chickens; Hyperthyroidism; Hypothyroidism; Insulin-Like Growth Factor Binding Proteins; Iodine Radioisotopes; Male; Organ Size; Propylthiouracil; Protein Binding; Somatomedins; Thyroid Gland; Thyroxine; Triiodothyronine

1. PTU treatment-induced hypothyroidism is associated with a significant decrease in the chick heart rate. 2. Hypothyroidism produces a slow onset of bradycardia, indicating a late effect of thyroid hormone decrease. 3. After 15 days treatment, an increase of action potential duration, similar to that reported for several mammal species, has been found. 4. Action potential duration is frequency and temperature dependent, but it has been found to be significantly different in the euthyroid and hypothyroid chicks.

Topics: Action Potentials; Animals; Chickens; Hypothyroidism; Male; Papillary Muscles; Propylthiouracil; Thyroid Gland

The effect of hypothyroidism on the lipid composition of myelin and synaptosomes isolated from adult rat brain was investigated. The animals were made hypothyroid by adding 0.05% propyl-2-thiouracil to their drinking water for four weeks. This pathological state resulted in a significant increase in the relative percentage of choline glycerophospholipids in synaptosomes with a concomitant decrease in ethanolamine glycerophospholipids as compared to controls. In myelin, hypothyroidism significantly influenced only the relative percentage of sulfatides. The effect of the hypothyroid state on mature brain was also reflected in changes in the membrane fatty acid composition. Myelin and synaptosomes showed an increase in arachidonic (20:4) and eicosatrienoic (20:3) acids and an increase in the fatty acid unsaturation index. Furthermore, the 20:4/20:3 and 20:3/18:2 ratios were lower and higher, respectively, in treated animals. The data indicate that hypothyroidism affects the lipid composition of synaptosomes and myelin even though the effects were less pronounced in myelin. The lipid changes observed in hypothyroidism may be of physiological significance, as it is well known that lipid composition modulates various membrane-bound enzymes, transporters and receptors.

Topics: Animals; Brain; Hypothyroidism; Male; Membrane Lipids; Myelin Sheath; Propylthiouracil; Rats; Rats, Sprague-Dawley; Synaptosomes

Autoimmune thyroid disease has multiple manifestations and its presentation may change with time. We report two patients with primary hypothyroidism due to Hashimoto's disease that unexpectedly, developed a hyperthyroidism due to Basedow-Graves disease. This phenomenon may be explained by variations in the types and proportions of anti TSH receptor antibodies, that can stimulate or block thyroid gland function and growth. It is deducted that the hypothyroidism of these patients was not due to a definitive gland destruction, but to the action of function blocking antibodies.

Topics: Adult; Autoimmune Diseases; Female; Graves Disease; Humans; Hyperthyroidism; Hypothyroidism; Male; Middle Aged; Propylthiouracil; Thyroid Gland; Thyrotropin; Thyroxine

1. The transfer of lipids that constitute the surface of lipoprotein particles, phospholipids and unesterified cholesterol, from chylomicrons and VLDL to other lipoproteins, mainly HDL, was examined. 2. Emulsions known to mimic the metabolism of chylomicrons labeled with [3H]-phosphatidylcholine, [14C]-cholesterol or [3H]-triolein were injected through a cannula implanted into the carotid artery of male Wistar rats weighing 280-350 g. Plasma clearance of the radioactively labeled emulsion lipid constituents and transfer of surface lipids from the emulsions to native HDL and LDL were measured in plasma samples collected at 2-min intervals during 10 min. 3. The transfer was measured in rats with alloxan-induced diabetes (single intraperitoneal dose, 140 mg/kg body weight) or with propylthiouracil-induced hypothyroidism (0.1% v/v in drinking water for 30 days), or given ethanol (20% in drinking water) for a period of 30 days, and in control rats. 4. The entry of emulsion phospholipids into the HDL fraction was not affected by the different treatments (controls: 9.3 +/- 0.6% of injected radioactivity, N = 8; diabetes: 12.5 +/- 2.4%, N = 9; hypothyroidism: 10.9 +/- 0.9%, N = 13; ethanol: 7.8 +/- 0.9%, N = 5). However, phospholipid transfer to the LDL fraction was increased in diabetes (10.0 +/- 2.3%) and hypothyroidism (12.1 +/- 1.3%) compared to controls (6.7 +/- 0.9%). Transfer of unesterified cholesterol from the emulsions to LDL and HDL was increased in both diabetic and hypothyroid rats (controls, LDL: 1.6 +/- 0.6%, HDL: 2.5 +/- 0.6, N = 5; diabetes, LDL: 5.3 +/- 1.2, HDL: 8.4 +/- 2.1 N = 5; hypothyroidism, LDL: 4.0 +/- 0.6, HDL: 3.6 +/- 0.4, N = 8). In ethanol-treated rats, transfer of surface lipids was similar to controls.

Topics: Alloxan; Animals; Cholesterol; Chylomicrons; Diabetes Mellitus, Experimental; Ethanol; Hypothyroidism; Lipolysis; Lipoproteins, HDL; Lipoproteins, LDL; Male; Phospholipids; Propylthiouracil; Rats; Rats, Wistar; Triglycerides

The effect of hypothyroidism on kinetic characteristics of cytochrome oxidase in rat heart mitochondria was studied. Mitochondrial preparations from control and hypothyroid rats had equivalent Km values for cytochrome c, while the maximal activity of the oxidase was significantly decreased (more than 30%) in mitochondrial preparations from hypothyroid rats. This decrease is associated to a parallel decrease in state 3 respiration. The cytochrome aa3 content was slightly decreased (by around 15%) in mitochondria from hypothyroid rats. The Arrhenius plot characteristics differ for cytochrome oxidase activity in mitochondria from hypothyroid rats as compared with control rats in that the breakpoint of the biphasic plot is shifted to a higher temperature. Cardiolipin content was markedly decreased in the mitochondrial membrane from hypothyroid rats. No alterations were found in the pattern of cardiolipin fatty acid distribution of mitochondrial membrane from control and hypothyroid rats. The effects of the hypothyroid state on the activity of cytochrome oxidase, on cytochrome aa3 levels, and on cardiolipin contents were completely reversed by following the treatment of hypothyroid rats with thyroid hormone. The results support the conclusion that the depressed mitochondrial cytochrome oxidase activity in the hypothyroid state is due, at least in part, to a decrease in the cardiolipin content of the mitochondrial inner membrane.

Topics: Animals; Electron Transport Complex IV; Hypothyroidism; Intracellular Membranes; Kinetics; Male; Membrane Lipids; Mitochondria, Heart; Oxygen Consumption; Phospholipids; Propylthiouracil; Rats; Rats, Wistar; Reference Values; Thermodynamics; Triiodothyronine

The effect of thyroid hormones on concentrations of lipoprotein(a) [Lp(a)] was analyzed in 60 patients with active thyroid dysfunction (hyperthyroidism 30 cases, hypothyroidism 32 cases, and 2 cases with opposite changes) and after normalization of the thyroid state. Treatment of hyperthyroidism increased the mean Lp(a) concentrations by 60% (from 73 to 102 mg/L, P < 0.002); at the same time, low-density lipoprotein cholesterol (LDL-C) increased by 53% (from 2.6 to 3.7 mmol/L, P < 0.0001) and apolipoprotein B (apo B) by 35% (from 0.91 to 1.17 g/L, P < 0.0005). In hypothyroidism, the opposite changes were observed: mean Lp(a) decreased from 136 to 114 mg/L (10%, P < 0.02), LDL-C from 4.6 to 3.9 mmol/L (13%, P < 0.01), and apo B from 1.51 to 1.20 g/L (14%, P < 0.01). Although the changes in Lp(a) concentrations did correlate with changes of LDL-C during treatment of hyperthyroidism (r = 0.43, P < 0.05), and with changes in apo B during thyroxine-substitution therapy for hypothyroidism (r = 0.46, P < 0.05), we observed no associations between Lp(a) and LDL-C or apo B in the euthyroid state. These data cannot rule out the possibility that the thyroid hormone-induced increase in LDL-C receptor activity was responsible for the decreased concentrations of Lp(a) in hyperthyroidism. Given that LDL-C is approximately 30% of the Lp(a) molecule but the changes in Lp(a) concentrations are comparable with those in LDL-C (60% vs 53%), and given that Lp(a) is metabolized by an LDL-C-receptor-independent pathway, the present data suggest a direct effect of thyroid hormones on Lp(a) synthesis.

Topics: Adult; Aged; Apolipoproteins B; Cholesterol, LDL; Female; Humans; Hyperthyroidism; Hypothyroidism; Lipoprotein(a); Male; Methimazole; Pregnancy; Propylthiouracil; Thyroxine

Rat lingual lipase undergoes maturational increases during postnatal development. The role of thyroxine (T4) in the control of lingual lipase during development was evaluated. T4 given at an early suckling stage (starting day 4 or 5) moderately increased lingual lipase (20-30%) compared to age-matched controls. A similar dose of T4 given later (age > 2 weeks) was ineffective. The T4-sensitive period coincides with a time of low circulating T4, suggesting a role of T4 in modulating the development of lingual lipase in rat pups. Since simultaneous treatment with U486, a type II glucocorticoid receptor antagonist only partially blocked the T4 induction of lingual lipase, T4 appeared to have a direct action on the lingual gland. Pups of propylthiouracil (PTU)-treated dams (previously found to be hypothyroid) showed a delay in the maturation of lingual lipase compared to age-matched pups whose dam was not given PTU. Pups were most sensitive to PTU in the early suckling stage. PTU-induced delayed maturation of lingual lipase was a result of hypothyroidism, since T4 replacement when given early (at the age of 5 days) abolished most of the effect of PTU. When T4 was given later (at the age of 10 days), recovery was much less. This suggests the presence of an early period that is critically dependent on T4 for the full expression of lingual lipase in the rat tongue serous glands.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Animals, Suckling; Body Weight; Dose-Response Relationship, Drug; Hypothyroidism; Lipase; Mifepristone; Pancreas; Propylthiouracil; Rats; Rats, Sprague-Dawley; Receptors, Glucocorticoid; Thyroid Gland; Thyroxine; Tongue

Subcellular changes of the atrial cardiomyocytes of rats submitted to hypothyroidism caused by administration of 1 mg/100 g of body weight of propylthiouracil showed a) swollen mitochondria and lysis of their cristae; b) myofibrils with marked heterogeneity of patterns, some exhibiting rupture and loss of continuity of their myofilaments; c) lesser concentration of atrial granules in the perinuclear area; d) abundant granular interstitial tissue and collagen separating the myofibrils.

Topics: Animals; Collagen; Connective Tissue; Disease Models, Animal; Heart; Hypothyroidism; Mitochondria, Heart; Myofibrils; Propylthiouracil; Rats; Rats, Inbred Strains

Three studies assessed the effect of thyroid status on regulation of plasma IGF-I in cattle. First, four Angus-Hereford steers (av wt 345 kg) were fed 4 mg/d propylthiouracil daily for 35 d. With continued feeding of PTU steers were sequentially injected with thyroxine (T4, 5 mg/d, IM for 5 d) followed by triiodothyronine (T3, 2 mg/d, IM for 5 d). An injection of bovine pituitary growth hormone (GH, 0.1 mg/kg, IM) was given to each steer on day 35 of PTU, day 5 of T4 and again on day 5 of T3. PTU alone increased plasma thyroid stimulating hormone (TSH), decreased plasma T4 and T3 but had no influence on IGF-I. T3, but not T4, lowered plasma TSH, IGF-I and the IGF-I response to GH (P < .05). Next, twelve bull calves (av wht 167 kg) were divided equally into two groups. A control group was injected daily for five d with buffered saline; the experimental group was concurrently treated with T3 (5 mg/d, sc) for five d. Beginning the sixth day, all calves were injected with GH (0.1 mg/kg, IM daily) for three d with the respective buffer or T3 treatments continuing. Plasma IGF-I was depressed 29% by T3. The incremental area under the three-d response curve was less (P < .03) in T3 cattle. A growth trial was conducted in which twenty-four Angus x Hereford steers were injected daily with T3 (2 mg/kg, bi-daily x 56 d) or implanted with Synovex-S (S) in a 2 x 2 factorial arrangement. Synovex increased empty body protein gain (EBPG) and plasma IGF-I 15.5 and 27.9% (P < .01), respectively; T3 decreased EBPG and plasma IGF-I 13.9 and 15.1% (P < .07), respectively, in steers which maintained suppression in plasma TSH. The data support the conclusion that elevated T3 decreases plasma IGF-I, in part, through a diminished GH-responsiveness and anabolic treatments such as S can reverse the effects of excess T3.

Topics: Animals; Cattle; Cattle Diseases; Drug Combinations; Drug Interactions; Estradiol; Gene Expression Regulation; Growth Hormone; Hypothyroidism; Insulin-Like Growth Factor I; Least-Squares Analysis; Male; Multivariate Analysis; Pituitary Gland; Progesterone; Propylthiouracil; Protein Biosynthesis; Random Allocation; Thyroid Gland; Thyrotropin; Thyroxine; Time Factors; Triiodothyronine

The rat pituitary pars tuberalis (pt) is a functional and morphological unique component of the adenohypophysis. It mainly consists of specific secretory cells whose morphological and functional characterization is far from being complete. In this study the ultrastructure of fetal secretory pt cells developing under hypo- and hyperthyroid conditions was examined. Besides controls, young mature pregnant Wistar rats were treated with propylthiouracil (PTU) or thyroxine (T4). Areas of pt cells and of their nuclei were measured. Different cell organelles per cell were counted, and area densities of these organelles were determined. While the number of dictyosomes per cell area did not change, the area densities of long ribbons increased significantly in the experimental groups. Lysosomes and secretory granules, however, were found to be significantly diminished in pt cells of T4- and PTU-treated animals. The latter finding corresponds to earlier investigations when changes of the thyroid-stimulating-hormone-like immunoreactivity of fetal pt-specific cells were observed under the same experimental conditions. Results indicate that fetal pt-specific cells respond to changes of thyroid status in a manner different from pars distalis thyrotrophs. An interaction of pt-specific cells in thyroid regulation mechanisms is assumed.

Topics: Animals; Cytoplasmic Granules; Female; Hyperthyroidism; Hypothyroidism; Lysosomes; Microscopy, Electron; Pituitary Gland; Propylthiouracil; Rats; Rats, Wistar; Thyroxine

This study was designed to examine the involvement of thyroid hormone in the release of brain natriuretic peptide (BNP) from the heart. We measured plasma immunoreactive BNP (ir-BNP) concentrations in patients with untreated hyperthyroidism. We also measured BNP values in experimental rats with hyperthyroidism induced by thyroxine (T4) and in rats with hypothyroidism induced by propylthiouracil (PTU). The in vitro effects of triiodothyronine (T3) and T4 on the release of BNP were examined in newborn rat atrial and ventricular myocytes in primary culture. Plasma BNP levels were increased in hyperthyroid patients compared with normal control subjects. Plasma BNP levels were increased in hyperthyroid rats and decreased in hypothyroid rats compared with euthyroid rats. Plasma BNP level was correlated with serum T4 level in hyperthyroid patients and hyperthyroid rats. A major component of ir-BNP in plasma from hyperthyroid patients was human BNP-32 and that in plasma from hyperthyroid rats was rat BNP-45. T4 and T3 stimulated release of ir-BNP from both cultured atrial and ventricular myocytes in a dose-dependent manner. Plasma BNP concentration is frequently increased in hyperthyroidism, and thyroid hormone may regulate BNP release from both atrial and ventricular myocytes.

Topics: Adult; Animals; Atrial Natriuretic Factor; Brain Chemistry; Cells, Cultured; Chromatography, High Pressure Liquid; Dose-Response Relationship, Drug; Female; Humans; Hyperthyroidism; Hypothyroidism; Male; Middle Aged; Myocardium; Propylthiouracil; Radioimmunoassay; Rats; Rats, Wistar; Thyroxine; Triiodothyronine

We have used in situ hybridization histochemistry to determine the effect of hippocampal-hypothalamic disconnection on hypothalamic thyrotrophin-releasing hormone (TRH) and anterior pituitary thyrotrophin beta subunit (TSH beta) transcripts in adult male CFY rats. Electrothermal lesions of the fornix pathway significantly increased TRH and TSH transcripts and increased circulating levels of triiodothyronine (T3). Fornix transection did not, however, prevent feedback regulation of TRH and TSH transcripts during exogenous T3-induced hyperthyroidism or propylthiouracil-induced hypothyroidism. Hippocampal inputs to the hypothalamus contribute to setting the basal activity of the thyroid axis, but do not mediate the feedback effects of T3.

Topics: Animals; Base Sequence; Gene Expression; Hippocampus; Hyperthyroidism; Hypothalamus; Hypothyroidism; In Situ Hybridization; Male; Molecular Sequence Data; Paraventricular Hypothalamic Nucleus; Pituitary Gland, Anterior; Propylthiouracil; Rats; RNA, Messenger; Thyrotropin; Thyrotropin-Releasing Hormone; Triiodothyronine

In view of the lack of knowledge on the thyroid hormone (T3) action in adult mammalian brain the present investigation was undertaken to assess the role of this hormone on synaptosomal function of adult rat cerebral cortex. Single injection of various doses of T3 showed dose-dependent inhibition of the synaptosomal Na(+)-K(+)-ATPase activity with its maximum effect at 24 hr in comparison to the untreated control values. The magnitude of the inhibitory response of T3 gradually diminished with the advancement of time (48 and 72 hr). Propylthiouracil (PTU) treatment caused stimulation of the synaptosomal Na(+)-K(+)-ATPase activity in comparison to the untreated control animals. T3 treatment to the PTU-treated animals showed inhibition of the Na(+)-K(+)-ATPase activity at a level very similar to that found in only T3-treated animals. The study indicates involvement of T3 in synaptosomal function of adult rat.

Topics: Animals; Cerebral Cortex; Hypothyroidism; Male; Propylthiouracil; Rats; Sodium-Potassium-Exchanging ATPase; Synaptosomes; Triiodothyronine

Epidermal growth factor (EGF) in mouse submandibular gland (SMG) is synthesized in the granular convoluted tubular (GCT) cells. The synthesis of EGF in SMG has been shown to be increased by thyroid hormone. This increase was attributed to the increase in EGF mRNA. Not known is how thyroid hormone increases the mRNA level. In the present study the effect of thyroid hormone administration on EGF gene expression in SMG was studied in hypothyroid mice. Hypothyroidism was induced by treating the mice with propylthiouracil. The amount of SMG EGF mRNA was markedly decreased in hypothyroid mice. Administration of T3 increased the mRNA in a dose-dependent manner. The increase in EGF mRNA by T3 was evident as early as 6 h after T3 administration. A nuclear run-off assay indicated that the induction of EGF gene expression by T3 is at a transcriptional level. Bromodeoxyuridine incorporation into GCT cells was not affected by T3 administration, suggesting that T3 does not cause the proliferation of these cells. In situ hybridization revealed that T3 increases EGF mRNA in GCT cells at a single cell level. These results suggest that thyroid hormone increases EGF gene transcription without affecting cellular proliferation.

Topics: Animals; Body Weight; Bromodeoxyuridine; Epidermal Growth Factor; Gene Expression; Hypothyroidism; In Situ Hybridization; Male; Mice; Organ Size; Propylthiouracil; RNA, Messenger; Submandibular Gland; Thyroxine; Transcription, Genetic; Triiodothyronine

The genes coding for apolipoproteins A-I, C-III, and A-IV are closely linked to one another in the rat genome. Thyroid hormone stimulates apoA-I expression in rat liver by an unusual mechanism that enhances the maturation of mRNA. This hormone also increases apoA-IV mRNA abundance by a mechanism not yet studied, and its role in the expression of apoC-III has not been defined but may be of relevance to the metabolism of triglyceride-rich lipoproteins. We therefore measured the transcriptional activity of the apoA-IV and apoC-III genes and the abundance of their nuclear RNA and total cellular mRNA in livers of control rats and rats made hyper- and hypothyroid. After a single receptor-saturating dose of triiodothyronine (3 mg/100 g body weight), apoA-IV gene transcription increased at 20 min and reached a maximum of 260% of control at 6 h. Increases of transcription were reflected in increases of nuclear and total apoA-IV mRNA levels. ApoC-III gene transcription was temporarily increased to 160% at 2 h without changes in the abundance of its nuclear or total mRNA over 24 h. Lower hormone doses (20-500 micrograms/100 g body weight) stimulated apoA-IV mRNA transcription as well, but tended to reduce transcription from the apoC-III gene. Upon chronic administration of thyroid hormone, apoA-IV transcription decreased to 55% and nuclear apoA-IV RNA levels to 87% of control. However, total cellular apoA-IV mRNA levels increased to 279% of control, implying stabilization of mRNA in the cytoplasm. ApoC-III transcription decreased to 28% of control, but abundance of nuclear and total cellular apoC-III mRNA was reduced to a lesser extent. In hypothyroid rats, apoA-IV gene expression was decreased fourfold at the transcriptional level. In contrast, apoC-III gene transcription increased to 178% of control, but the abundance of nuclear and total cellular apoC-III mRNA did not differ from control rats. Thus, thyroid hormone affects the abundance of apoA-IV mRNA by changing its synthesis and its rate of degradation and enhances the efficiency of apoC-III mRNA maturation, thereby blunting the net effect of altered mRNA synthesis on mRNA abundance.

Topics: Animals; Apolipoprotein C-III; Apolipoproteins A; Apolipoproteins C; Base Sequence; Blotting, Northern; Gene Expression; Hyperthyroidism; Hypothyroidism; Kinetics; Liver; Male; Molecular Sequence Data; Propylthiouracil; Rats; Rats, Sprague-Dawley; RNA, Messenger; Transcription, Genetic; Triiodothyronine

The coexistence of hyperparathyroidism and thyroid tumors and/or chronic thyroiditis has raised the possibility of an etiologic relationship. The present study was designed to test the hypothesis that the chronic elevation of thyroid-stimulating hormone (TSH) is related to the development of hyperparathyroidism. Three groups of 24 rats each were treated for 12 weeks as follows: group 1 received propylthiouracil (PTU) in their deionized water; group 2 received PTU and thyroid hormone to suppress TSH and to serve as a control group for possible direct effects of PTU; and group 3 was not treated at all and served as another control group. At 12 weeks, 95% of group 1 rats (PTU only) showed hyperplasia of the parathyroids with a 30% mean increase in circulating parathormone.

Topics: Administration, Oral; Animals; Calcium; Delayed-Action Preparations; Drug Implants; Female; Hyperparathyroidism; Hyperplasia; Hypothyroidism; Parathyroid Glands; Parathyroid Hormone; Phosphorus; Propylthiouracil; Rats; Rats, Sprague-Dawley; Thyroid Gland; Thyrotropin; Thyroxine

In the central nervous system, type II 5' deiodinase (5'D-II) is highly regulated, as judged by the dramatic changes in enzyme levels observed after abrupt alterations in thyroid status. In this work, the 5'-DII activity has been studied in different situations of experimental hypothyroidism (propylthiouracil, methimazole, thyroidectomy, and low iodine diet), in various brain regions (pituitary, cerebellum, brain stem, hypothalamus, cortex, and whole brain) in adult rats. Propylthiouracil and methimazole significantly increase the activity in all brain regions. These increases are higher in rats treated with methimazole. Thyroidectomy significantly increases the activity in cortex and pituitary. A low iodine diet significantly increases in all brain regions except in the hypothalamus. The concentration of triiodothyronine (T3) studied in the major brain regions remained unchanged. The results obtained show a compensatory mechanism in pituitary and other brain regions in order to maintain the T3 levels in brain tissue.

Topics: Animals; Body Weight; Brain; Cytosol; Diet; Dithiothreitol; Glycerolphosphate Dehydrogenase; Hypothyroidism; Iodide Peroxidase; Liver; Malate Dehydrogenase; Male; Methimazole; Mitochondria, Liver; Propylthiouracil; Rats; Rats, Wistar; Thyroxine; Triiodothyronine

1. Regulatory interactions between the hypothalamoneurohypophyseal vasopressin (VP) axis and the endocrine systems of the anterior pituitary have been investigated in the rat by observing changes in VP mRNA expression following endocrine manipulations. 2. An increase in the level, but not size, of VP mRNA was found in the supraoptic (SON) and paraventricular nuclei (PVN) of the hypothalamus and in the neurointermediate lobe (NIL) of the pituitary following hypothyroidism (induced by drinking 6-n-propyl-2-thiouracil; PTU) and adrenalectomy. Hypothyroidism induced by alternative procedures (surgical thyroidectomy or PTU injections) did not exert similar effects. 3. Treatment with the dopamine agonist bromocriptine to reduce prolactin secretion raised levels of VP mRNA in the NIL only. Castration did not up-regulate VP mRNA levels. 4. Since the observed effects on VP mRNA levels occur in the absence of changes in plasma osmolality, these results provide evidence of nonosmotic regulation of VP gene expression, an effect which is observed most clearly in the NIL pool of VP mRNA. Furthermore, the effects are distinct from changes in VP mRNA levels associated with raised plasma osmolality since the VP mRNA size was not increased.

Topics: Adrenalectomy; Animals; Bromocriptine; Gene Expression Regulation; Hypothalamo-Hypophyseal System; Hypothyroidism; Male; Orchiectomy; Osmolar Concentration; Propylthiouracil; Rats; Rats, Sprague-Dawley; RNA, Messenger; Thyroidectomy; Vasopressins

Thyroid hormone status has profound effects on signal transduction in various tissues throughout the body. Therefore, we quantified the signal transducing G-proteins in the rat heart, cerebral cortex, vas deferens and liver by immunoblotting and pertussis toxin labeling in response to chemically induced hypothyroidism (treatment with propylthiouracil) and hyperthyroidism (treatment with triiodothyronine). Levels of the pertussis toxin (PTX) substrates Gi alpha and Go alpha in the heart and vas deferens were inversely correlated with thyroid hormone levels, i.e. Gi alpha and Go alpha were decreased or unchanged in hyperthyroid rats and increased in hypothyroid rats compared to control animals. The cerebral cortex and liver expression of PTX substrates Gi alpha and Go alpha was not affected by changes in thyroid hormone. Regulation of Gs alpha protein was more complex in that Gs alpha was unaffected in the other tissues tested. Expression of G-protein beta-subunits was not affected by thyroid status in the heart, liver, or cerebral cortex. Our results suggest that tissue- and G-protein-specific factors are involved in the regulation of G-protein subunits by thyroid hormone. Moreover, cardiac expression of Gs alpha is upregulated by increases or decreases in the normal level of thyroid hormone.

Topics: Animals; Cerebral Cortex; Gene Expression Regulation; GTP-Binding Proteins; Hyperthyroidism; Hypothyroidism; Liver; Male; Muscle, Smooth; Myocardium; Propylthiouracil; Rats; Rats, Wistar; Thyroid Hormones; Triiodothyronine

The effect of a wide range of doses of propylthiouracil (PTU, 0.01-5%) on the immune responses of young male chickens was examined. One-day-old chickens were rendered hypothyroid by PTU supplemented in the feed for 4 weeks. At all doses PTU treatment caused a significant dose-related reduction in body weight (except at 0.01%) and in relative lymphoid organ weights. Skin response to phytohemagglutinin (PHA) was significantly greater in the chickens treated with low doses of PTU (0.01-0.1%) and significantly less in the chickens treated with high doses of PTU (1.5-5%) than that in control chickens. Number of splenic plaque forming cells (PFC) to sheep red blood cells (SRBC) was significantly increased in the chickens treated with low doses of PTU. Concentrations of serum 3,3',5-triiodothyronine (T3) and thyroxin (T4) were significantly lower in the chickens treated with all doses of PTU. Addition of T3 to the feed supplemented with 0.01% PTU replaced the serum T3 concentration and reduced the skin response to PHA and the number of the splenic PFC. These data confirm our previous observations that a low dose of PTU enhances and a high dose suppresses the immune responses of young male chickens.

Topics: Adrenal Glands; Animals; Antibody Formation; Bird Diseases; Body Weight; Chickens; Dose-Response Relationship, Drug; Hemolytic Plaque Technique; Hypothyroidism; Immunity, Cellular; Liver; Lymphoid Tissue; Male; Organ Size; Propylthiouracil; Skin Tests; Thyroid Gland; Thyroxine; Triiodothyronine

Our previous studies have shown that transient neonatal hypothyroidism, induced by treatment with the reversible goitrogen 6-propyl-2-thiouracil (PTU), increases testicular size and daily sperm production in the adult rat by up to 82% and 136%, respectively. The objective of the present study was to examine morphological and functional changes in adult seminiferous tubules associated with PTU-induced increases in testicular size and sperm production. Sprague-Dawley rats were treated with PTU from birth to day 25 or left untreated; for morphometry, all testes were fixed by vascular perfusion at 90 days of age. Although testicular weight was increased 62% in treated rats, gross pathological changes were not evident in these organs, and spermatogenesis appeared morphologically normal. The percent area of testis occupied by seminiferous tubules was equal in control and treated testes, but mean seminiferous tubule diameter and length were increased in the PTU-treated testis. The adult number of Sertoli cells in treated testes was increased by 157%, and the numbers of leptotene spermatocytes and round spermatids were increased 84% and 93%, respectively. These results demonstrate that increases in Sertoli cell numbers result in increased sperm production and support the idea that Sertoli cells are the major regulators of the magnitude of sperm production. Although the round spermatid to Sertoli cell ratio was reduced by nearly 30%, the number of round spermatids per g testis was increased by 14%. This increased efficiency of sperm production was accomplished by an increased density of Sertoli cells along the basement membrane and an increased height of the seminiferous epithelium. Despite the large increase in Sertoli cell numbers in treated rats, Northern blot analysis using Sertoli cell-specific cDNA probes for transferrin and androgen-binding protein indicated that relative steady state levels of mRNAs per Sertoli cell for these two secretory proteins were similar in control and treated rats at 90 days of age.

Topics: Animals; Animals, Newborn; Blotting, Southern; Cell Count; Germ Cells; Hypertrophy; Hypothyroidism; Male; Propylthiouracil; Rats; Sertoli Cells; Testis

The function and structure of the peripheral nervous system of Sprague-Dawley rats, 3 months after the induction of hypothyroidism by administration of N-propylthiouracil in drinking water, has been studied. The motor action potential amplitude of the caudal nerve showed a significant reduction (p < 0.001) when compared with an age-matched control group of animals. Computer-assisted morphometric analysis of sciatic nerves of hypothyroid rats showed normal distribution and density of myelinated fibers, and a normal axon/myelin ratio. Electron microscopy revealed only minor alterations in axons of myelinated fibers characterized by a dissolution of neurotubules. After two months of substitution therapy these effects were reversed. The present data suggest that early impairment of nerves induced by hypothyroidism is rare and could be related to metabolic alterations rather than to structural changes and is reversible with hormone treatment.

Topics: Action Potentials; Animals; Electromyography; Hypothyroidism; Intermediate Filaments; Male; Microtubules; Motor Neurons; Neural Conduction; Peripheral Nerves; Propylthiouracil; Rats; Rats, Sprague-Dawley; Sciatic Nerve; Triiodothyronine

Rats were made hypo and 'hyperthyroid' with propylthiouracil (PTU) and L-Thyroxine (L-T) respectively. The hypo and hyperthyroid status in these rats were confirmed by serum level of T4 and T3. Liver iron was significantly increased in both the hypo and hyperthyroid animals. However, liver ferritin synthesis rate was reduced by 36% in hypothyroid rats, and elevated by 38% in hyperthyroid ones. A similar trend was seen in liver ferritin concentration. Further, serum transaminases were elevated only in animals of the hyperthyroid group. It appears from the present data that ferritin metabolism is influenced by thyroid hormone as well as by iron. Thus, the raised serum ferritin in hyperthyroid patients may be partially attributed to increased ferritin synthesis in the liver and its possible leakage into circulation.

Topics: Albumins; Animals; Ferritins; Hyperthyroidism; Hypothyroidism; Iron; Kinetics; Liver; Male; Propylthiouracil; Rats; Rats, Wistar; Thyroid Gland; Thyroid Hormones; Thyroxine; Triiodothyronine

The effect of propylthiouracil (PTU) on the growth activity of intact liver and liver regenerating after partial (65-70%) hepatectomy (PH) was studied in rats. PTU (Propycil, Kali-Chemie, FRG) was dissolved in drinking water (1 g PTU per litre) and this was given to the rats, as their sole source of fluids, three days before PH and then up to the end of the experiment. In rats given PTU, marked inhibition of liver DNA synthesis and the mitotic activity of hepatocytes was found after PH. This effect was potentiated to some extent by partial inanition of the experimental animals given PTU, as demonstrated in a paired feeding test in control rats. PTU inhibition of DNA synthesis in intact and regenerating liver also took effect in thyroidectomized rats, even with substitution (thyroid hormone) therapy. The experiments demonstrated that the effect of propylthiouracil on DNA synthesis in the liver is mediated primarily by way of its direct effect on the liver.

Topics: Animals; Cell Division; DNA; Female; Hepatectomy; Hypothyroidism; Liver; Liver Regeneration; Male; Mitotic Index; Propylthiouracil; Rats; Thymidine; Thyroidectomy

5'-Nucleotidase was measured in isolated fat cells from normal, hypothyroid and hyperthyroid rats. This was done to find out whether thyroid hormones had an effect on the production of adenosine by the fat cell. The results showed that 5'-nucleotidase is modified when the rats received injections of 3,3',5-triiodo-L-thyronine (T3). There was no change in the enzyme in hypothyroidism or when T3 was added to incubation of cells.

Topics: 5'-Nucleotidase; Adipose Tissue; Animals; Cells, Cultured; Hyperthyroidism; Hypothyroidism; Inosine Monophosphate; Kinetics; Male; Propylthiouracil; Rats; Rats, Wistar; Thyroid Gland; Triiodothyronine

To evaluate the role of perinatal thyroid status in the development of pituitary-thyroid axis regulation, we administered triiodothyronine to newborn rats for the first five days postpartum to achieve hyperthyroidism, or propylthiouracil perinatally to rat dams and pups from gestational day 17 through postnatal day 5 to achieve hypothyroidism. Plasma T4, T3, and TSH levels were determined from birth through 50 days postpartum. Administration of exogenous T3 produced the expected immediate suppression of plasma T4 and TSH, with recovery toward normal values beginning within days of discontinuing the T3 regimen. Plasma T3 values were markedly elevated during the period in which T3 was being given, but subsequently became subnormal, with deficits persisting into young adulthood. With the PTU regimen, plasma T4 and T3 levels were markedly suppressed through postnatal day 10, rose over the ensuing two weeks, but nevertheless showed significant deficits into adulthood. TSH levels in the immediate neonatal period were subnormal in the PTU group, despite the marked lowering of circulating thyroid hormones; TSH then rose dramatically to levels four times normal, subsiding to control values by the end of the first month. These results suggest that a critical period exists in which regulation of pituitary-thyroid axis function is programmed. During this phase, TSH secretion can be suppressed by excess thyroid hormones, but cannot be increased by hormone deficiencies. Perhaps more importantly, perinatal thyroid status "programs" its own future reactivity, so that early hypothyroidism results in reduced T4 and T3 levels in adulthood, despite normal levels of TSH.

Topics: Aging; Animals; Animals, Newborn; Fetus; Hyperthyroidism; Hypothyroidism; Pituitary Gland; Propylthiouracil; Rats; Rats, Sprague-Dawley; Reference Values; Thyroid Gland; Thyrotropin; Thyroxine; Time Factors; Triiodothyronine

In mature animals, thyroid hormone is permissive for beta adrenergic receptor expression and adrenergic control of adenylate cyclase. To determine if endogenous thyroid hormones play a similar role in the development of receptors and transduction mechanisms, we administered propylthiouracil perinatally to rat dams and pups from gestational day 17 through postnatal day 5. Circulating thyroid hormones were completely suppressed through postnatal day 10 and then rose to only slightly subnormal values by the 3rd to 4th postnatal week. In the heart, hypothyroidism completely suppressed the initial development of beta adrenergic receptor binding sites, with recovery paralleling the return of thyroid hormone levels. In contrast, development of basal and isoproterenol-stimulated adenylate cyclase activity showed more lasting deficiencies with a delayed onset corresponding to general growth impairment; however, forskolin-stimulated adenylate cyclase developed in a nearly normal pattern. Effects on development of renal beta receptors and adenylate cyclase were of smaller magnitude and comprised only the delayed onset phase; receptor deficiencies appeared after 10 days and adverse effects on adenylate cyclase were limited to the isoproterenol-sensitive component, consisting of a shift of the ontogenetic peak to later ages. Endogenous thyroid hormones thus contribute two distinct factors to beta receptor/adenylate cyclase development: they are obligatory for cardiac beta receptor development, but also, in parallel with general effects on growth and development, serve to program the ontogeny of transduction factors linking the receptors to adenylate cyclase. The predominance of propylthiouracil effects on isoproterenol-stimulated adenylate cyclase but not on enzymatic responses to forskolin suggests that thyroid hormones may be controlling the development of regulatory G-proteins.

Topics: Adenylyl Cyclases; Animals; Animals, Newborn; Female; Heart; Hypothyroidism; Isoproterenol; Kidney; Maternal-Fetal Exchange; Myocardium; Pregnancy; Propylthiouracil; Rats; Rats, Inbred Strains; Receptors, Adrenergic, beta; Thyroid Hormones

A highly sensitive, specific, and reproducible RIA has been developed to measure rat type I iodothyronine 5'-monodeiodinase (5'-MD). A 16-amino acid peptide (LAP-744) corresponding to a portion of the carboxy-terminal region of the rat liver 5'-MD, as predicted from its cDNA, was synthesized, and rabbits were immunized with the peptide-BSA conjugate. In a final dilution of 1:15,000, our anti-5'-MD antibody bound about 30-35% of a tracer amount of [125I]LAP-744. The detection threshold of the RIA approximated 0.08 pmol LAP-744 or an equivalent amount of 0.08 pmol 5'-MD. Rat liver and kidney microsomes produced dose-response curves that were essentially parallel to that of LAP-744. No inhibition of binding of [125I]LAP-744 to antibody was produced by 0.3 mg or less rat microsomal proteins from testes, heart, brain, muscle, spleen, intestine, lung, placenta, or fetal liver. Recovery of nonradioactive LAP-744 added to spleen microsomes averaged 103%. The coefficient of variation averaged 4% within an assay and 11% between assays. In 16 normal rats studied, the mean (+/- SD) 5'-MD content was 2.4 +/- 0.22 pmol/mg protein in liver microsomes and 2.5 +/- 0.27 pmol/mg protein in kidney microsomes. Fasting of the rat for 2-4 days was associated with a significant reduction in both the activity and the content of the 5'-MD in liver and kidney. Hypothyroidism was also associated with a significant decrease in the activity and content of 5'-MD in both tissues. Significant opposite changes were observed in these parameters in hyperthyroidism. Treatment of the rat with sodium ipodate for 3 days was associated with a significant decrease in both the activity and the content of 5'-MD in liver and kidney. A similar treatment of the rat with propylthiouracil induced a clear reduction in the activity of 5'-MD in liver and kidney, but the content of the enzyme was significantly increased in both tissues. Rats treated with aurothioglucose for 3 days exhibited a significant decrease in 5'-MD activity in liver and kidney microsomes, whereas the tissue content of 5'-MD was not affected. A similar treatment of the rat with methimazole had no significant effect on either the activity or the content of 5'-MD.(ABSTRACT TRUNCATED AT 400 WORDS)

Topics: Amino Acid Sequence; Animals; Fasting; Female; Hyperthyroidism; Hypothyroidism; Iodide Peroxidase; Ipodate; Kidney; Liver; Male; Methimazole; Microsomes; Microsomes, Liver; Molecular Sequence Data; Organ Specificity; Peptide Fragments; Propylthiouracil; Radioimmunoassay; Rats; Rats, Sprague-Dawley

The effects of testosterone (TP) and thyroxine (T4) on the level of epidermal growth factor (mEGF) in the thyroid were compared in a hypothyroid mouse model. Groups of five adult female BALB/c mice were given a "severe" hypothyroid regimen consisting of an iodine deficient diet together with oral and s.c propylthiouracil (PTU). Sialoadenectomy or sham operation was performed after 18 days on the hypothyroid regimen. The mice convalesced on normal diet for 5 days and beginning from day 23 received either T4, 1 ug/g or 2 ug/g, s.c daily or TP, 0.3 mg or 0.75 mg, i.m. every third day until day 33, while continuing the hypothyroid regimen. Control mice received normal diet and vehicles for the various injections. The mice were killed on day 33 and thyroidal EGF levels determined by radioimmunoassay. The mean+S.E. levels of mEGF in the thyroid were 10.12 +/- 1.75 ng/mg protein (control), 3.82 +/- 0.67 ng/mg (hypothyroid; p < 0.01), 3.07 +/- 1.52 (T4, 1 ug/g; p < 0.02), 2.59 +/- 0.46 ng/mg (T4, 2 ug/g; p < 0.01), 8.58 +/- 2.48 (TP, 0.3 mg), and 9.65 +/- 1.86 (TP, 0.75 mg). Thus thyroidal mEGF levels decreased significantly in all groups except those subsequently treated with testosterone; T4 was ineffective in reversing the tissue depletion of mEGF in this model. These results show that mEGF levels in the thyroid could be depleted by hypothyroidism and may also be androgen responsive.

Topics: Animals; Body Weight; Disease Models, Animal; Dose-Response Relationship, Drug; Epidermal Growth Factor; Female; Hypothyroidism; Mice; Mice, Inbred BALB C; Organ Size; Propylthiouracil; Proteins; Radioimmunoassay; Salivary Glands; Testosterone; Thyroid Gland; Thyroxine

The effects of propylthiouracil (PTU)-induced thyroid hormone imbalance on GH, TSH and IGF-I status in cattle were examined. In the first study, four crossbred steers (avg wt 350 kg) were fed a diet dressed with PTU (0, 1, 2 or 4 mg/kg/d BW) in a Latin square design with four 35-d periods. On day 29 in each period, steers were challenged with an intrajugular bolus of thyrotropin releasing hormone (TRH, 1.0 microgram/kg). Blood samples were obtained to assess the change in plasma GH and TSH as affected by PTU. Plasma IGF-I was measured from blood samples obtained before and after (every 6 hr for 24 hr) intramuscular injection of bovine GH (0.1 mg/kg, day 31). Doses of 1 and 2 mg/kg PTU increased plasma T4 (P < .01). At 4 mg/kg, PTU depressed T4 concentrations to 30% of control (P < .01). Plasma T3 linearly decreased with increasing doses of PTU (P < .01). Plasma TSH increased when PTU was fed at 4 mg/kg (P < .05) while the TSH response to TRH declined with increasing PTU (P < .02). Neither basal nor TRH-stimulated plasma concentration of GH was affected by PTU; the IGF-I response to GH tended to increase at the 1 and 2 mg/kg PTU (P < .01). In a second study 24 crossbred steers were fed PTU (1.5 mg/kg) for 119 d in a 2 x 2 factorial design with implantation of the steroid growth effector, Synovex-S (200 mg progesterone + 20 mg estradiol), as the other main effect. Basal plasma GH and IGF-I were not affected by PTU treatment. Synovex increased plasma concentration (P < .01) of IGF-I without an effect on plasma GH. The data suggest that mild changes in thyroid status associated with PTU affects regulation of T3, T4 and TSH more than GH or IGF-I in steers.

Topics: Animals; Cattle; Cattle Diseases; Drug Combinations; Estradiol; Growth Hormone; Hypothyroidism; Insulin-Like Growth Factor I; Male; Progesterone; Propylthiouracil; Thyroid Hormones; Thyrotropin; Thyrotropin-Releasing Hormone

The microheterogeneity of pituitary thyroid-stimulating hormone (TSH) is dependent on variations in the hormone's carbohydrate moieties. In this study, changes in the pattern of heterogeneity have been assessed by chromatofocusing, which separates the isospecies on the basis of their isoelectric points (pI). Rats (n = 6 per group) were either untreated or rendered hypo- or hyperthyroid by including in the drinking water either propylthiouracil (0.05% for 8 weeks) or thyroxine (T4; 4 mg/l for 6 weeks) before they were killed at 16 weeks. On autopsy, serum TSH and total T4 were (means +/- S.E.M.): 2 +/- 0.3 micrograms TSH/l and 64 +/- 5 nmol T4/l (control); < 1 microgram TSH/l and 133 +/- 6 nmol T4/l (hyperthyroid); 58 +/- 6 micrograms TSH/l and 32 +/- 6 nmol T4/l (hypothyroid). The pituitaries were individually homogenized and the TSH isoforms separated by chromatofocusing over a pH range of 7-4. Fractions were assayed for TSH by radioimmunoassay. TSH from the control group was distributed into seven major peaks with pI values of (means +/- S.E.M., n = 6) 6.9 +/- 0.1, 6.6 +/- 0.1, 6.2 +/- 0.1, 5.8 +/- 0.1, 5.5 +/- 0.1, 5.2 +/- 0.1 and 4.8 +/- 0.1; 7 +/- 3% of the TSH had a pI of < 4.0. Six peaks of TSH were conserved in the hypothyroid group (with pI values of 6.8 +/- 0.1, 6.5 +/- 0.1, 6.2 +/- 0.1, 5.8 +/- 0.1, 5.4 +/- 0.1 and 5.2 +/- 0.1), and 11 +/- 4% of the hormone had a pI of < 4.0.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Hyperthyroidism; Hypothyroidism; Isoelectric Point; Male; Pituitary Gland; Propylthiouracil; Rats; Rats, Sprague-Dawley; Thyrotropin; Thyroxine

Male rats made hypothyroid by administration of propylthiouracil plus sodium ipodate in drinking water were compared to controls in terms of period of circadian activity and temperature rhythms, amount of gross motor activity, and mean temperature. Animals were studied under entrainment, constant darkness (DD), and constant dim light (LL). There was no difference in the period of the circadian activity rhythm between groups in DD. However, hypothyroid rats showed significant blunting of the period-lengthening response to increasing ambient illumination. As expected, the period of the circadian temperature rhythm increased in controls with increasing ambient illumination. In contrast, the period of the circadian temperature rhythm in hypothyroid animals actually shortened under LL compared to DD. This blunting of the period-lengthening response to increasing ambient illumination of both activity and temperature rhythms in hypothyroid animals could not be explained by differences in activity level or mean temperature between the groups.

Topics: Animals; Body Temperature; Circadian Rhythm; Hypothyroidism; Ipodate; Lighting; Male; Motor Activity; Propylthiouracil; Rats; Rats, Inbred Strains; Rats, Sprague-Dawley; Thyroid Hormones

The effects of various durations of postnatal hypothyroidism followed by recovery were studied on testicular growth in Long-Evans and Sprague-Dawley rats from birth to 7 months. Hypothyroidism was induced by adding propylthiouracil (PTU) in drinking water (0.1%, w/v). Recovery was induced by withdrawal of PTU. Testicular growth was reduced in rat pups by 20, 65 and 90% at days 10, 25 and 50. Upon withdrawal of PTU at weaning (25 days), testicular growth resumed and became compensatory; catch-up growth occurred by day 65. Paradoxically, testicular growth progressively increased, surpassing the control weights by 40, 50 and 100% at days 75, 90 and 210. Maximal testicular growth rate in the recovery group was 35% higher, occurred 2 weeks later and lasted 2 weeks longer than controls. Testes of rats subjected to prolonged postnatal hypothyroidism (60 or 120 days) also showed recovery and hypertrophy, amounting to nearly twice the normal maximal growth levels, after at least 6 months of recovery. Body weights of recovering rats remained always significantly below those of controls. When the suckling pups were exposed to short, week-long regimes of PTU treatment, only rats treated during the early postnatal weeks (days 1-8 or 9-16) had enlarged testes; PTU treatment during the late suckling period (days 17-24) or later had no effects. Total duration of hypothyroidism in the suckling period was positively correlated with testicular enlargement. The results indicate that hypothyroidism early in life is stimulatory to testicular growth, resulting in a paradoxical twofold increase in final testicular size which occurs even if hypothyroidism is prolonged. These effects occur similarly in different strains of rat with differing sized testes. It is suggested that there is a sensitive period for this effect, i.e. during the first 2 weeks after birth. The marked plasticity of testicular growth as shown by its recovery and hypertrophy, even after long periods of hypothyroid retardation, is unique in the body and may be a useful model for studying hormonal factors regulating testicular growth and for animal breeding and research into infertility.

Topics: Animals; Animals, Suckling; Hypertrophy; Hypothyroidism; Male; Organ Size; Propylthiouracil; Rats; Rats, Sprague-Dawley; Testis; Time Factors

Injection of L-3,5-diiodothyronine (T2) into rats made hypothyroid by 6-n-propyl-2-thiouracil (PTU) increased the respiration rates of subsequently isolated liver mitochondria; this stimulation of respiration by T2 occurred in the presence of cycloheximide and is therefore independent of protein synthesis on cytoplasmic ribosomes. Injection of T3 into PTU-treated rats had a lesser effect than T2 on the respiration rates of subsequently isolated mitochondria; as PTU is an inhibitor of 5'-iodothyronine deiodinases, which convert T3 into T2 in vivo, the rapid stimulation of mitochondrial respiration by T3, which has been shown in a range of systems, may not be due directly to T3 itself, but may be mediated by its deiodination product T2. Injection of T2, or T3, into hypothyroid or euthyroid rats had no effect on the percentage activity of mitochondrial pyruvate hydrogenase assayed 30 min later. The amount of active pyruvate dehydrogenase is regulated by changes in mitochondrial calcium concentration and matrix ATP/ADP ratio; therefore these parameters are not persistently affected by treatment with T3 or T2. In addition, the total amount of pyruvate dehydrogenase present was the same in euthyroid and hypothyroid rats, indicating that the expression of this enzyme is not stringently controlled by thyroid hormone status.

Topics: Adenosine Diphosphate; Adenosine Triphosphate; Animals; Calcium; Cycloheximide; Diiodothyronines; Hypothyroidism; Male; Mitochondria, Liver; Oxygen Consumption; Propylthiouracil; Pyruvate Dehydrogenase Complex; Rats; Rats, Wistar; Triiodothyronine

In this study we show that 6-propyl-2-thiouracil (PTU) treatment of Wistar rats from birth up to day 26 p.p. retards the morphological differentiation of Sertoli cells, and prolongs the proliferation of these cells up to day 30. Sertoli cell numbers per testis, determined at day 36, were increased by 84% compared to controls. PTU treatment increased serum thyroid-stimulating hormone (TSH) levels and reduced serum levels of thyroxine (T4) from 5 days onwards, indicative of severe hypothyroidism. Follicle-stimulating hormone (FSH) levels were reduced from day 5 to 9, normal at day 12 and 16, and reduced again from day 20 to 36. Inhibin levels were decreased from day 9 to 20 and increased at 36 days of age. The increase in the number of Sertoli cells per testis in PTU treated rats, as has been reported in the present study, is likely to be responsible for the increased testis size observed by other groups (1) in these animals, when adult.

Topics: Aging; Animals; Cell Differentiation; Cell Division; Follicle Stimulating Hormone; Hypothyroidism; Male; Propylthiouracil; Rats; Rats, Inbred Strains; Sertoli Cells; Testis; Thyrotropin; Thyroxine

Under defined conditions liver mitochondria from hypothyroid rats show an apparent lowering of the ADP/O ratio, which can be corrected by addition in vitro of 0.1 nM-tri-iodothyronine (T3). Nicotinamide prevents this restoration by hormone, lowers the ADP/O ratio of euthyroid-rat mitochondria to hypothyroid-rat values and induces T3-sensitivity in euthyroid-rat mitoplasts indistinguishable from that found with hypothyroid-rat preparations. Incorporation into the trichloroacetic-acid insoluble fraction of mitoplasts and hypothyroid-rat mitochondria of radiolabel from [adenine-14C]-NAD+ was stimulated by T3: this stimulation was abolished by nicotinamide. The findings strongly suggest that this incorporation occurs external to the matrix. Confirming the work of others, PAGE of radiolabelled mitoplasts shows alkali-labile modification of a major species of approx. 30 kDa: both nicotinamide and T3 abolish this modification. By contrast, T3 promotes incorporation of label into a single major 11 kDa species: this incorporated label is somewhat acid-labile, and the incorporation is abolished by nicotinamide. Comparative electrophoresis of purified sub-mitoplast fractions show that the 11 kDa species is in the inner membrane and absent from the matrix. The findings are consistent with a receptor-mediated ADP-ribosylation mechanism for the rapid action of T3 on mitochondria.

Topics: Adenosine Diphosphate; Adenosine Diphosphate Ribose; Animals; Chemical Precipitation; Electrophoresis, Polyacrylamide Gel; Hydrogen-Ion Concentration; Hypothyroidism; Kinetics; Male; Membrane Proteins; Mitochondria, Liver; NAD; Niacinamide; Oxygen Consumption; Propylthiouracil; Rats; Rats, Inbred Strains; Triiodothyronine

Cerebral cortex, heart, skeletal muscle, and liver mitochondrial glutathione (GSH) levels in severely burned rats are decreased to between approximately 50% to 70% of sham-operated, normally fed controls. In semistarved rats, weight-matched with burned rats, mitochondrial GSH levels in these tissues are decreased to between approximately 70% to 91% of those in sham-operated rats. Total GSH levels in peripheral tissues and brain are decreased to approximately 60% to 65% of control levels in rats with burn injury and food restriction, suggesting a higher mitochondrial GSH turnover in burned rats than in semistarved rats, probably because of higher "stress hormone" levels in burned rats than in semistarved rats. Cerebral cortex mitochondrial GSH levels are unaffected by variations in thyroid hormone status, but liver mitochondrial GSH levels are decreased by triiodothyronine and increased by propylthiouracil. The present results suggest that mitochondrial GSH is not only regulated by the rate of GSH synthesis in the cytosol, but seems to be under hormonal influence as well; stress hormones and triiodothyronine may decrease mitochondrial GSH by increasing mitochondrial oxygen consumption with increased reactive oxygen species formation or by increasing GSH exchange between mitochondria and the cytosol. These findings may be of importance therapeutically in increasing antioxidative defenses to limit oxidative stress injury in hypermetabolic patients.

Topics: Animals; Burns; Cerebral Cortex; Glutathione; Hypothyroidism; Male; Mitochondria; Mitochondria, Heart; Mitochondria, Liver; Mitochondria, Muscle; Propylthiouracil; Rats; Rats, Inbred Strains; Reference Values; Triiodothyronine

We have previously shown that treating rats with the reversible goitrogen 6-propyl-2-thiouracil (PTU) from birth to Day 25 increases testis size and sperm production in adulthood by up to 80% and 140%, respectively. The purpose of this study was to determine the critical period(s) during development when PTU treatment can increase adult testis size and sperm production. Rats were treated with PTU beginning on Days 0, 8, 16, or 24 for periods of 9, 17, or 25 days. To further define the critical period, additional rats were treated with PTU prenatally or on Days 4-24. PTU treatments of 9, 17, or 25 days beginning at birth increased testis weight 18%, 38%, and 69%, respectively, by 135 days of age, while daily sperm production (DSP) increased 35%, 65%, and 94%, respectively. Efficiency of sperm production (DSP/g testis) also increased by approximately 25% in these rats. There was an inverse relationship between testis and body weights: increasing lengths of PTU treatment increased testis weight but decreased body weight. PTU treatment starting on Day 8 or later did not increase testis weight or DSP regardless of duration. Treatment on Days 4-24 increased adult testis weight and DSP similarly to treatment from birth to Day 24, but prenatal PTU treatment was ineffective. Testosterone concentrations were not altered in treated rats, even those with increased testis weight. These results indicate that the later part of the first postnatal week (Days 4-8) is the crucial period during which PTU treatment must begin in order to increase adult testis size and sperm production.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Animals, Newborn; Body Weight; DNA; Hypothyroidism; Male; Organ Size; Propylthiouracil; Rats; Rats, Inbred Strains; Spermatogenesis; Testis; Testosterone

Quantitative and qualitative features of capillary maturation were examined in the ventral horn of the lumbar spinal cord of control and neonatally induced hypothyroid rats from birth to 6 weeks, using light (LM) and electron microscopy (EM). Quantification of the capillary densities by LM in the control animals and their hypothyroid litter mates have shown three- and twofold increases, respectively, from birth to Postnatal (Pn) Day 21. The following features were observed in the control animals at the EM level: (a) The newborn animals showed varying degrees of capillary maturation; (b) The majority of capillaries possessed mature characteristics by Pn Day 21; (c) By Pn Day 42, mature characteristics were found in nearly all capillary profiles. The hypothyroid animals demonstrated: (1) reactive perivascular cells and astrocytes; (2) delayed appearance of glycogen in the early Pn period and its persistence in extensive amounts during the latter part (3-6 weeks) of development; (3) cytoplasmic extensions of endothelial cells and perivascular cells, and (4) the presence of mitotic endothelial cells and perivascular cells even during the latter period of development. The observations suggest that the peak period of vasculogenesis in the lumbar spinal cord of the normal rat occurs during the second and third Pn weeks. The results from the hypothyroid rats point toward a delay in development and maturation of capillaries resulting in a hypoplastic vascular bed of the ventral horn. The reactive cells and the accumulation of glycogen particles could be morphological expressions of biochemical changes in hypothyroidism during the critical period of CNS development.

Topics: Aging; Animals; Capillaries; Endothelium, Vascular; Hypothyroidism; Microscopy, Electron; Propylthiouracil; Rats; Rats, Inbred Strains; Reference Values; Spinal Cord

This investigation was designed to morphologically evaluate the effects of hypothyroidism on the development of myelin and axons in the rat optic nerve. Four pups from each group of normal and propylthiouracil-induced hypothyroid rats were sacrificed at 14, 21, 28, and 35 postnatal days. Optic nerves were studied by both light and electron microscopes. The hypothyroid animals had significantly reduced body and brain weights compared to those of their age-matched controls. In the hypothyroid animals, the cross-sectional area of the optic nerve, the fiber density, and fiber occupancy were significantly diminished compared to those of the controls. The mean individual fiber size was unaffected. However, the relationship between the total axonal area to myelin thickness was similar in the control and experimental groups, implying that the feedback mechanism between myelinating cells and axons was not affected by hypothyroidism. Thus, this study indicates that the principal insult of neonatal hypothyroidism results in a delay in myelin acquisition of myelinated fibers, resulting in diminished cross-sectional area of the optic nerve, fiber density, and fiber occupancy.

Topics: Aging; Animals; Axons; Body Weight; Hypothyroidism; Myelin Sheath; Optic Nerve; Propylthiouracil; Rats; Rats, Inbred Strains; Reference Values; Regression Analysis

Topics: Animals; Cycloheximide; Diiodothyronines; Hypothyroidism; Kinetics; Male; Mitochondria, Liver; Oxidative Phosphorylation; Oxygen Consumption; Propylthiouracil; Rats; Rats, Inbred Strains

We report a patient who underwent, over a mere 3-year period, three successive cycles of oscillation from hypo to hyper-thyroidism and back to hypothyroidism. This unusual sequence of events originated in a rare passage of primary hypothyroidism to hyper-thyroidism. The hyperthyroidism seemed typical of the autoimmune subgroup of toxic multinodular goitre. Stimulating and blocking TSH receptor antibody activities were measured (by cAMP functional bioassays using cultured human thyrocytes) during the course of the fluctuating phases of hypo and hyper-thyroidism. Measurement of such antibody activities revealed the coexistence of both stimulatory and blocking types of antibody in several serum samples from the patient. Throughout the whole course of alterations in thyroid function, thyroid stimulating antibodies were present. This was not the case with thyrotrophin receptor antibodies exhibiting TSH antagonist activity which seemed to appear and disappear. Monitoring such activity indicated that the emergence of blocking antibody seems to herald the onset of hypothyroidism.

Topics: Autoantibodies; Autoimmune Diseases; Biological Assay; Female; Humans; Hyperthyroidism; Hypothyroidism; Iodine Radioisotopes; Middle Aged; Propylthiouracil; Receptors, Thyrotropin; Recurrence; Thyroid Function Tests; Thyroxine

Neonatal treatment with the reversible goitrogen 6-N-propyl-2-thiouracil (PTU) results in a near doubling of testicular size and a 25% increase in the efficiency of spermatogenesis, without affecting circulating testosterone (T) levels in adult rats. The objectives of the present study were to examine the effects of neonatal PTU treatment on the pattern of testicular growth and circulating levels of anterior pituitary (FSH, LH, PRL, GH, and TSH), gonadal [immunoreactive inhibin-alpha (irI alpha) and T], and thyroid (T3 and T4) hormones over the first 100 days of life. Treatment of rats with PTU from birth to 24 days of age significantly reduced testicular weights between 10 and 60 days of age. However, the duration of testicular growth was extended in treated males, resulting in a 68% increase at 100 days of age. Serum gonadotropin levels in treated males were reduced throughout the experimental period, typically remaining between 50-70% of control levels. The characteristic robust prepubertal FSH peak was absent in PTU-treated males. Initially high until 20 days of age, irI alpha levels characteristically declined to adult levels (200-300 pg/ml) in control males. In treated males, irI alpha levels were reduced during the period of hypothyroidism, increased between 30 and 60 days, and then declined, but remained significantly higher (1.7- to 2-fold greater) than those observed in control males. Serum T levels were similar in treated and control males. Control males demonstrated increased T levels beginning at 45 days of age, earlier than observed in treated males; however, similar peak T levels were observed in all males. PTU treatment significantly suppressed serum GH and PRL and led to a 14-fold increase in circulating TSH during the period of treatment. However, unlike the gonadotropins, these hormones returned to control levels after PTU treatment, suggesting that the reduced levels of FSH and LH observed are not due to a generalized reduction in pituitary function. Serum T4 and T3 levels returned to control levels within 15 days after the removal of PTU. These results demonstrate that the neonatal PTU treatment-induced increases in adult testicular size and sperm production were not due to increased levels of FSH at any point in development. On the contrary, the observed increases occur in spite of chronically reduced FSH levels.

Topics: Aging; Animals; Animals, Newborn; Follicle Stimulating Hormone; Growth Hormone; Hypothyroidism; Luteinizing Hormone; Male; Organ Size; Prolactin; Propylthiouracil; Rats; Rats, Inbred Strains; Spermatogenesis; Testis; Thyrotropin; Thyroxine; Triiodothyronine

Twenty-nine patients (22 female) aged 2 to 17 years were followed with serial measurements of serum triiodothyronine, thyroxine, and thyrotropin during medical therapy for Graves disease. Fourteen patients had 17 instances of hypothalamic-pituitary-thyroid suppression with inappropriately low thyrotropin levels. Five patients had six episodes of low thyroxine and triiodothyronine levels with normal levels of thyrotropin, and 10 patients had 11 episodes of normal thyroxine and triiodothyronine levels with subnormal levels of thyrotropin. We conclude that thyrotropin values may not be reliable for diagnosing either mild hypothyroidism or persistent hyperthyroidism during the medical treatment of Graves disease.

Topics: Adolescent; Child; Child, Preschool; Female; Graves Disease; Humans; Hyperthyroidism; Hypothalamo-Hypophyseal System; Hypothyroidism; Male; Methimazole; Propylthiouracil; Retrospective Studies; Thyroid Gland; Thyrotropin; Thyroxine; Triiodothyronine

The aim of this study was to investigate whether the severity and duration of primary hypothyroidism influence hypothalamic TRH release. Hypothyroidism was induced in male Wistar rats by treatment with different thyrostatic drugs or by thyroidectomy. Serum TSH in rats treated for up to 3 weeks with methimazole (MMI; 0.05% in drinking water) increased 20-fold, but TRH release into hypophyseal portal blood (HPB) did not change. Treatment with propylthiouracil (PTU; 0.1% in drinking water), which inhibits thyroidal T4 production and peripheral conversion of T4 to T3, resulted in a more rapid reduction in serum T3 levels and increase in serum TSH than those in rats treated with 0.1% MMI. Although these differences were no longer observed after 3 weeks of treatment, TRH release into HPB of rats treated with PTU was 34-49% higher than that in MMI-treated rats. Combined treatment with MMI (0.05-0.1% in drinking water) and iopanoic acid (IOP; 4 mg/100 g BW.day, ip), an inhibitor of both peripheral and central T4 to T3 conversion, also tended to produce a more rapid decrease in serum T3 and increase in serum TSH. After 3 weeks of treatment, serum T4, T3, and TSH were not different in the two groups, but TRH release into HPB was 48-65% increased by MMI plus IOP vs. MMI alone. Three to 10 weeks after thyroidectomy, TRH release into HPB was 58-72% higher than that in untreated controls. In vitro incubation of hypothalami isolated from rats treated for 3 weeks with MMI, MMI plus IOP, or PTU, as described above, showed that basal and 56 mM K(+)-induced TRH release were not influenced by the different drugs. Also, the total hypothalamic TRH content was not changed by any of these treatments. However, in rats treated for 1 or 2 weeks with MMI or PTU, the TRH content of the median eminence was decreased by 17-25%. These findings indicate that, depending on severity and duration, experimental hypothyroidism may cause a significant increase in hypothalamic TRH release in rats. The magnitude of these changes compared with the much larger increases in serum TSH suggests that the feedback of thyroid hormone on TSH secretion is mainly exerted at the pituitary level.

Topics: Animals; Hypothalamus; Hypothyroidism; In Vitro Techniques; Iopanoic Acid; Male; Median Eminence; Methimazole; Propylthiouracil; Rats; Rats, Inbred Strains; Reference Values; Thyroidectomy; Thyrotropin; Thyrotropin-Releasing Hormone; Triiodothyronine

Quantitative and morphological data were obtained on developing olfactory axons in normal and hypothyroid larvae of the African clawed frog Xenopus laevis. Hypothyroid larvae were produced by rearing the animals, beginning at stage 48, in a 0.01% solution of propylthiouracil (PTU), a treatment that blocks synthesis of thyroid hormone. These PTU-treated larvae were compared to their age-matched siblings when these siblings reached stage 52 (premetamorphic larvae; prior to synthesis of thyroid hormone), stage 57 (late premetamorphic larvae; after the onset of thyroid hormone synthesis), or stage 58 (larvae at the onset of metamorphic climax; thyroid hormone levels continue to rise). The number of olfactory axons did not differ between stage 52 control animals and the age-matched, PTU-treated animals, but there were only about half the number of axons in the PTU-treated animals that were age-matched to the stage 57 or 58 controls. Thus, PTU had no effect on olfactory axon number prior to the normal rise in thyroid hormone levels. But PTU significantly reduced the normal increase in olfactory axon number compared to stage 58 control larvae, whose thyroid hormone levels are high. While PTU also produced some changes in several other body measurements, the effect on the olfactory axons was the most consistent and prominent. The results presented here support our previous findings that thyroid hormone plays a significant role in the development of the olfactory system in Xenopus.

Topics: Animals; Axons; Body Constitution; Embryonic and Fetal Development; Hypothyroidism; Larva; Olfactory Nerve; Propylthiouracil; Thyroid Hormones; Xenopus laevis

The effect of thyroid hormone deficiency and growth hormone (GH) treatment on hypothalamic GH-releasing hormone (GHRH)/somatostatin (SS) concentrations, GHRH/SS mRNA levels, and plasma GH and somatomedin-C (IGF-I) concentrations were studied in 28- and 35-day-old rats made hypothyroid by giving dams propylthiouracil in the drinking water since the day of parturition. Hypothyroid rats, at both 28 and 35 days of life, had decreased hypothalamic GHRH content and increased GHRH mRNA levels, unaltered SS content and SS mRNA levels, and reduced plasma GH and IGF-I concentrations. Treatment of hypothyroid rats with GH for 14 days completely restored hypothalamic GHRH content and reversed the increase in GHRH mRNA, but did not alter plasma IGF-I concentrations. These data indicate that, in hypothyroid rats, the changes in hypothalamic GHRH content and gene expression are due to the GH deficiency ensuing from the hypothyroid state. Failure of the GH treatment to increase plasma IGF-I indicates that the feedback regulation on GHRH neurons is operated by circulating GH and/or perhaps tissue but not plasma IGF-I concentrations. Presence of low plasma IGF-I concentrations would be directly related to thyroid hormone deficiency.

Topics: Analysis of Variance; Animals; Feedback; Gene Expression Regulation; Growth Hormone; Growth Hormone-Releasing Hormone; Hypothalamus; Hypothyroidism; Insulin-Like Growth Factor I; Male; Pituitary Gland; Propylthiouracil; Radioimmunoassay; Rats; Rats, Inbred Strains; RNA, Messenger; Somatostatin

A 56-year-old man presented with clinical and biochemical hyperthyroidism with high thyroid 99mTc uptake, positive result for antimicrosomal antibody (MCHA; 1:8,100) and markedly high activities of thyrotropin-binding inhibitory immunoglobulin (TBII; 90.0%) and thyroid-stimulating antibody (TSAb; 2,400%). Fifty days after the initiation of antithyroid drug therapy, he developed a painful tender enlarged thyroid and an accelerated erythrocyte sedimentation rate (ESR), which were followed immediately by hypothyroidism with a transient increase in MCHA titer (peak; 1:218,700) despite of maintenance of high TBII and TSAb activities. Two and a half months after the recovery from hypothyroidism, recurrent hyperfunction was observed with further elevation of TSAb activity (4,643%). After about 2 weeks, recurrences of a painful tender enlarged thyroid and an accelerated ESR, which were followed by abrupt progression to hypothyroidism, were found. Specimens obtained when he had still slightly tender goiter after the first and second episodes of neck pain showed microscopically extremely extended interstitial fibrosis with collapsed follicles and moderate lymphocytic infiltration. Thyroid-stimulation-blocking antibody was not detected at either onset of hypothyroidism. Thus, it is possible that Graves' disease, subacute aggravation of chronic thyroiditis and hypothyroidism coexist in the same individual. In such patients, thyroid status may be determined by the degree of each of the stimulating factors (TSH, TSAb and/or unknown factors) and suppressive or destructive factors (humoral and/or cellular) and may be changed in a very short interval.

Topics: Autoantibodies; Biopsy, Needle; Blood Sedimentation; C-Reactive Protein; Female; Graves Disease; Humans; Hypothyroidism; Immunoglobulins, Thyroid-Stimulating; Methimazole; Middle Aged; Propylthiouracil; Thyroid Gland; Thyroiditis, Autoimmune; Thyroxine; Triiodothyronine

The object of this experiment was to examine whether the administration of clenbuterol exerts clenbuterol's repartitioning effects in rats with hypothyroidism induced by the oral administration of propylthiouracil (PTU). Male Wistar rats aged 5 weeks were divided into 4 groups: control, PTU administrated (PTU), clenbuterol administrated (CL), and PTU plus clenbuterol administrated (PTU/CL) groups. Rats were raised for 7 weeks at 26 degrees C and given 13 g of diet every day. The PTU and PTU/CL groups were fed a basal diet containing PTU at the level of 30 mg/kg diet throughout the experimental period. Clenbuterol was added to the diet of the CL and PTU/CL groups at the dose of 0.1 ppm from the 3rd week. Serum thyroxine concentrations of rats were significantly lower in rats in the PTU and PTU/CL groups than those in the control and CL groups. Thus, the administration of PTU succeeded to induce hypothyroidism. The clenbuterol administration seemed to exert its repartitioning effects in euthyroid rats, while the administration neither increased body protein nor decreased body fat in hypothyroid rats. This result therefore suggests that the effects of clenbuterol on the alteration of body composition may vary with the level of thyroid activity in rats.

Topics: Adipose Tissue; Animals; Body Composition; Body Weight; Cholesterol; Clenbuterol; Hypothyroidism; Liver; Male; Organ Size; Propylthiouracil; Proteins; Rats; Rats, Inbred Strains; Thyroxine; Triglycerides

The norepinephrine and dopamine content of interscapular brown adipose tissue of developing rats was studied at intervals from birth to 50 days. Throughout this period, neonatal hypothyroidism is associated with a decreased norepinephrine content and with an increased dopamine content.

Topics: Adipose Tissue, Brown; Aging; Animals; Dopamine; Female; Hypothyroidism; Male; Norepinephrine; Propylthiouracil; Rats

To study quantitatively actions of thyroid hormones on maturation of olfactory receptor neurons (ORN), surface density and total number of receptor knobs (1 knob/ORN) were measured in 1 mu sections from septal olfactory epithelium of newborn, 12- and 25 day normal, hypo- and hyperthyroid rats. Hypothyroidism was induced by adding to drinking water n-propylthiouracil (0.1% w/v) from birth. Hyperthyroidism was induced by daily injection of pups with T4 (1-thyroxine, 0.3 microgram/g b.w., s.c.). Experimental pups showed all the signs of hypo- and hyperthyroidism. Between days 1-25, normal pups showed marked increase in surface area of septal olfactory epithelium (6x), total number (12x) and surface density (#/mm2, 2x) of mature ORNs. Thyroid deficient rats showed, by day 12, marked reductions in epithelial surface area and total number of mature ORNs; these and the surface density deficits became very pronounced by 25 day (30% area, 27% density, 47% # mature ORNs). Hyperthyroid rats, however, did not show an increase in any of these parameters over controls. Although total number of ORNs (mature and immature), as measured by number of nuclei, was also reduced in hypothyroid pups, surface density was not altered, indicating that maturation of ORNs, but not their local accretion is altered in thyroid deficiency. The results indicate that thyroid hormones are essential for normal proliferative expansion of olfactory epithelium and for maturation of ORNs postnatally. These actions of thyroid hormones are not increased or accelerated by excess T4 suggesting saturation of the hormone receptor system at the normal plasma level.

Topics: Animals; Animals, Newborn; Cell Division; Cell Nucleus; Dendrites; Female; Hyperthyroidism; Hypothyroidism; Nasal Mucosa; Neurons, Afferent; Pregnancy; Propylthiouracil; Rats; Rats, Inbred Strains; Smell; Thyroid Hormones; Thyroxine

Previous studies have demonstrated that in different cardiac preparations action potential duration (APD) increases with age. As in various species, thyroid hormone levels increase developmentally, and since hyperthyroidism shortens APD while hypothyroidism prolongs it, we hypothesized that developmental changes in APD result from age-related variations in the thyroid state. The hypothesis was tested by analysing ventricular action potentials and total T4 (TT4) levels in guinea-pigs in the age range of 0 days to 3 months (adult), and in hyperthyroid and hypothyroid newborns (0-5 days old). We found that APD50 increased exponentially with age with a time constant of 6.7 days, from 100.6 +/- 3.4 ms in newborns (0-5 days old) to 147.4 +/- 5.2 ms in adults (P less than 0.001). TT4 decreased exponentially with age with a time constant of 4.8 days, from 3.9 +/- 0.4 micrograms/dl in newborns to less than 1.0 microgram/dl in adults. In the age range studied, APD50 and TT4 were linearly correlated: Y = -12.13X + 142, r - 0.865. In contrast to the marked changes in APD, resting potential and action potential amplitude were age-independent, and Vmax only slightly increased with age. Alterations in the thyroid state in newborns affected ventricular action potentials as predicted by the hypothesis. In euthyroid (TT4 = 3.9 +/- 0.4 micrograms/dl), hypothyroid (TT4 = 1.6 +/- 0.4 micrograms/dl) and hyperthyroid (TT4 = 39.8 +/- 10.8 micrograms/dl) newborns, APD50 was: 100.6 +/- 3.4 ms, 117.7 +/- 4.2 ms and 63.7 +/- 7.4 ms, respectively (P less than 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Action Potentials; Aging; Animals; Animals, Newborn; Guinea Pigs; Hyperthyroidism; Hypothyroidism; Papillary Muscles; Propylthiouracil; Thyroxine; Triiodothyronine; Ventricular Function

Several recent reports have indicated that catecholamines may act directly on the crossbridge cycle, independent of intracellular calcium concentration changes. The present study investigated the effect of isoproterenol on peak force during twitches at constant sarcomere length and unloaded velocity of sarcomere shortening in isolated right ventricular trabeculae of hearts with V1 or V3 isomyosin obtained from euthyroid and hypothyroid rats, respectively. Hypothyroidism was induced by treatment of the rats with propylthiouracil for 6 weeks. Electrophoretic analysis showed that the hearts of hypothyroid animals were composed only of V3 isomyosin, whereas the hearts of euthyroid animals were composed predominantly of V1 isomyosin. Force development was measured with a silicon strain gauge and sarcomere length with laser diffraction techniques; the shortening velocity was determined from contractions in which sarcomere length was initially held constant followed by a quick release to zero load and a controlled release at zero load. Both isometric twitch force and unloaded sarcomere shortening velocity were sigmoidal functions of [Ca2+]o and of the concentration of isoproterenol. At optimal [Ca2+]o, unloaded shortening velocity was 40% lower in myocardium of hypothyroid animals than in myocardium of euthyroid animals. Isoproterenol increased the sensitivity of isometric twitch force and unloaded shortening velocity to [Ca2+]o in trabeculae from both euthyroid and hypothyroid animals. Isoproterenol did not increase unloaded shortening velocity at optimal [Ca2+]o, regardless of the thyroid state. From these results we conclude that beta-adrenergic stimulation per se does not accelerate the rate limiting step in the crossbridge cycle that determines unloaded sarcomere shortening velocity in the intact cardiac cell.

Topics: Animals; Calcium; Female; Heart; Hypothyroidism; Isoproterenol; Male; Myocardial Contraction; Myocardium; Myosins; Osmolar Concentration; Propylthiouracil; Rats; Rats, Inbred Strains; Sarcomeres; Time Factors

The effects of a chronic treatment with L-triiodothyronine (T3; 100 mg/rat/day s.c. for 7 days) or with propylthiouracil (PTU; 50 mg/rat/day for 35 days by stomach tube) on the characteristics of alpha 1, alpha 2, beta, imipramine and GABA binding sites in different brain areas of the adult rat have been studied. T3-treatment caused an increase in the number of [3H]dihydroalprenolol and a decrease in the number of [3H]muscimol binding sites in the cerebral cortex. PTU-treatment caused a decrease in the number of [3H]prazosin, [3H]yohimbine and [3H]dihydroalprenolol binding sites in the cerebral cortex, while the number of [3H]imipramine binding sites was reduced in the cerebral cortex and hypothalamus, and increased in the hippocampus. Affinity constants were never modified. Concurrent experiments showed that the "in vitro" addition of T3 and PTU did not influence the binding of any of the ligands employed to control rat brain membranes. The present data further support the view that neurotransmission in the CNS is influenced by the thyroid status.

Topics: Animals; Brain; Dihydroalprenolol; Hyperthyroidism; Hypothyroidism; Imipramine; Kinetics; Male; Muscimol; Organ Specificity; Prazosin; Propylthiouracil; Rats; Rats, Inbred Strains; Receptors, Adrenergic, alpha; Receptors, Adrenergic, beta; Receptors, GABA-A; Reference Values; Thyroid Gland; Triiodothyronine; Yohimbine

The role of thyroid status in the ontogeny of beta adrenergic receptor control of ornithine decarboxylase (ODC) activity was assessed in hearts and kidneys of neonatal rats. Hyperthyroidism induced by administration of tri-iodothyronine on postnatal days 1 to 5 caused a reduction in the ability of isoproterenol to stimulate cardiac ODC but subsequently accelerated the onset of the postweaning peak of the response; the latter effect was even more prominent when tri-iodothyronine administration was given on postnatal days 14 to 18. Hypothyroidism induced by propylthiouracil administration led to persistent subsensitivity of the cardiac ODC response to beta receptor stimulation. Kidney ODC, which does not become subject to beta receptor regulation until after weaning, was resistant to hyperthyroid-induced changes in reactivity, but hypothyroidism still resulted in long-term response deficits. These results suggest that thyroid hormone is permissive for normal development of the beta receptor-ODC link, and that the euthyroid state provides the optimal conditions for maturation of this signal transduction mechanism. The relative resistance of kidney ODC responses to alterations by hyperthyroidism further indicates that the effects of excess hormone can only be expressed when the receptor-enzyme link is already competent. Finally, thyroid status had equivalent effects on the abilities of vasopressin or angiotensin to stimulate ODC, suggesting that the site of thyroid hormone action is at a transduction locus common to several different receptor types.

Topics: Age Factors; Animals; Animals, Newborn; Female; Heart; Hypothyroidism; Kidney; Myocardium; Ornithine Decarboxylase; Pregnancy; Propylthiouracil; Rats; Receptors, Adrenergic, beta; Thyroid Hormones

The photoreactive compound p-nitrophenyl-2-diazo-3,3,3-trifluoropropionate (PAL) was coupled to [125I]rT3, T4, or T3 and incubated with liver and kidney microsomes of hypo-, hyper-, or euthyroid rats to identify the type I iodothyronine deiodinase. Various substrates or inhibitors of the enzyme, including rT3, T4, T3, 6-n-propylthiouracil (PTU), and iopanoic acid, were used as competitors to establish the specificity of protein labeling. The PAL derivatization enhanced the behavior of T4 and T3 as substrates for the type I enzyme. No specific labeling of microsomal proteins was observed with either rT3 or T4-PAL, presumably due to deiodination of the labeled compound. In contrast, T3-PAL labeled a 27-kDa band, the presence of which paralleled thyroid status. The labeling of only this protein was blocked by either substrates or enzyme inhibitors in a dose-dependent fashion, with a rank order of potency predicted by the activity of such compounds in type I enzyme assays. The specific nature of these competitions provides further evidence that this 27-kDa protein, identified in previous studies using N-bromoacetyl [125I]T3 or -T4, contains the active site of the rat type I deiodinase. This is in agreement with the mol wt of the rat type I deiodinase deduced from the recently identified cDNA coding for this protein.

Topics: Affinity Labels; Animals; Binding, Competitive; Diazonium Compounds; Hyperthyroidism; Hypothyroidism; Iodide Peroxidase; Iopanoic Acid; Male; Molecular Weight; Photochemistry; Propionates; Propylthiouracil; Rats; Rats, Inbred Strains; Thyroxine; Triiodothyronine; Triiodothyronine, Reverse

The effects of calmodulin antagonists on the capacity of hydrogen-translocating shuttles were studied in the perfused rat liver. The capacity was estimated by measuring the changes in the rate of production of glucose from sorbitol during the oxidation of ethanol [T. Sugano, T. Ohta, A. Tarui, and Y. Miyamae. Am. J. Physiol. 251 (Endocrinol. Metab. 14): E385-E392, 1986]. Thyroxine given to intact rats increased the activity of alpha-glycerophosphate dehydrogenase (alpha-GPD). Glucocorticoid replacement in adrenalectomized rats decreased the activity of the alpha-GPD to values obtained after treatment with PTU. In either thyroxine-treated or steroid-replaced rats, the capacity of hydrogen-translocating shuttles increased markedly. However, N-(6-aminohexyl)-5-chloro-1-naphthalenesulfonamide (W-7), trifluoperazine, and chlorpromazine inhibited the increased capacity in steroid-replaced rats and had no effect on the increased capacity in thyroxine-treated rats. W-7 inhibited the stimulatory effects of norepinephrine on the capacity of the malate-aspartate shuttle without inhibition of efflux of intracellular Ca2+. The stimulatory effects of vasopressin on the malate-aspartate shuttle were also inhibited by W-7, trifluoperazine, and chlorpromazine. The results suggest that the malate-aspartate shuttle may be regulated by Ca(2+)-calmodulin.

Topics: Adrenalectomy; Alanine; Aminooxyacetic Acid; Animals; Asparagine; Calcium; Calmodulin; Chlorpromazine; Glycerolphosphate Dehydrogenase; Hyperthyroidism; Hypothyroidism; Liver; Male; Mitochondria, Liver; NAD; Oxidation-Reduction; Perfusion; Propylthiouracil; Rats; Rats, Inbred Strains; Reference Values; Sorbitol; Sulfonamides; Thyroxine; Trifluoperazine; Triiodothyronine; Vasopressins

1. Four experiments were conducted to determine if dietary ascorbic acid (AA) affects body weight gain, food intake, organ weights, plasma cholesterol concentration, and ascorbic acid concentration in the plasma and liver of growing male broilers treated with an antithyroidal agent, propylthiouracil (PTU). 2. In the first experiment, 15 mg AA was administered daily into the crop of chicks fed on a diet supplemented with or without PTU (500 mg/kg). Administration of AA reduced plasma cholesterol concentrations in the PTU-treated chicks. 3. In the other three experiments, chicks were given the basal diet or an AA-containing (3 g/kg) diet supplemented with or without PTU (250 mg or 500 mg/kg). Feeding AA partly prevented the decreases in body weight gain, gain:food ratio and weights of the bursa of Fabricius and thymus in chicks fed on the 250 mg/kg PTU diet, and also prevented the increase in plasma cholesterol concentrations in chicks fed on the PTU diet. 4. These results suggest that AA improves the performance of chicks with experimentally induced hypothyroidism.

Topics: Adrenal Glands; Animals; Ascorbic Acid; Bursa of Fabricius; Chickens; Cholesterol; Eating; Hypothyroidism; Liver; Male; Organ Size; Poultry Diseases; Propylthiouracil; Spleen; Thyroid Gland; Weight Gain

1. Rats (4 weeks old) were made hypothyroid by treatment with propylthiouracil together with a low-iodine diet for a further period of 4 weeks. Synaptosomal membranes were obtained from six anatomical regions of the brain. 2. The abundances in these membranes of the G-protein alpha-subunits Gi1 alpha, Gi2 alpha and Go alpha were measured by quantitative immunoblotting. 3. Hypothyroidism significantly increased the abundances of all three G-protein subunits in membranes from the cerebral cortex and the striatum. In the medulla oblongata and the hippocampus the abundances of Gi2 alpha and Go alpha were increased significantly. By contrast, in the cerebellum only Go alpha was increased, and in the hypothalamus only Gi2 alpha was increased. 4. It is suggested that this up-regulation of G-protein abundances may modify signalling pathways and may contribute to the functional changes that are observed in the central nervous system in hypothyroidism.

Topics: Animals; Brain; Cerebellum; Cerebral Cortex; Corpus Striatum; GTP-Binding Proteins; Hippocampus; Hypothalamus; Hypothyroidism; Male; Medulla Oblongata; Propylthiouracil; Rats; Rats, Inbred Strains; Synaptic Membranes

mRNA for a thyroid hormone receptor isoform that is unique to the pituitary gland (TR beta-2) is down-regulated by T3. Increases in the expression of this mRNA are seen in rats rendered hypothyroid by treatment with propylthiouracil (PTU). This study used dual labeling to determine which pituitary cells expressed TR beta-2 mRNA in normal and PTU-treated rats. In situ hybridization protocols localized the mRNA (with biotinylated complementary oligonucleotide probes detected by avidin-biotin-peroxidase), and immunoperoxidase protocols identified the pituitary hormone proteins. In dispersed pituitary cells, 20 +/- 2% (average +/- SD) of cells from normal rats and 30 +/- 3% of cells from PTU-treated rats were labeled for TR beta-2 mRNA. PTU caused increases in the area of the labeled cells (from 114 +/- 11 to 225 +/- 7 microns 2), the area of the label per cell (from 27 +/- 3 to 71 +/- 11 microns 2), and label density. PTU produced increases in the percentage of TSH cells from 8 +/- 1% to 19 +/- 2%, decreases in the percentage of GH cells from 27 +/- 3% to 11 +/- 2%, and no change in other cell types. After dual labeling, 73% of cells that expressed TR beta-2 mRNA stored either TSH (35 +/- 8) or GH (38 +/- 6). Less than 10% stored other hormones. When each cell type was analyzed, 56 +/- 3% of TSH cells and 43 +/- 4% of GH cells expressed TR beta-2 mRNA. When these percentages were multiplied by the percentages of each cell type in the overall population, TSH and GH cells with TR beta-2 mRNA represented 6.8 +/- 1% and 11.6 +/- 1% of the pituitary cells, respectively. Less than 1% of all pituitary cells expressed TR beta-2 and ACTH (0.9 +/- 0.06), LH (0.8 +/- 0.1), FSH (0.8 +/- 0.1), and PRL (0.9 +/- 0.04). PTU treatment increased the percentage of TSH cells with TR beta-2 mRNA to 72 +/- 4% and decreased the percentage of GH cells with TR beta-2 mRNA to 30 +/- 3%. However, some enlarged putative TSH cells could not be identified by immunolabel because the storage levels were low. Thus, changes in TR beta-2 mRNA in hypothyroid rats may be the net result of the increase in the percentage of TSH cells, the amount of mRNA per cell (measured by area and density of label), and the decrease in the percentage of GH cells.(ABSTRACT TRUNCATED AT 400 WORDS)

Topics: Animals; Growth Hormone; Hypothyroidism; Immunohistochemistry; Male; Nucleic Acid Hybridization; Pituitary Gland; Propylthiouracil; Rats; Rats, Inbred Strains; Receptors, Thyroid Hormone; RNA, Messenger; Thyrotropin

Topics: Acoustic Stimulation; Animals; Choline O-Acetyltransferase; Congenital Hypothyroidism; Evoked Potentials, Auditory, Brain Stem; Female; Glutamate Decarboxylase; Hypothyroidism; Nystagmus, Pathologic; Pregnancy; Propylthiouracil; Rats; Reflex, Vestibulo-Ocular; Thyroxine; Vestibule, Labyrinth

The low affinity glucocorticoid binding sites (LAGS) have been described and partially characterized in both the nuclei and microsomes of rat liver. The LAGS concentration is under endocrine regulation, as proved by their decrease after adrenalectomy and their almost complete disappearance after hypophysectomy. This article describes new data that also implicate the thyroid hormones in the endocrine regulation of LAGS. The LAGS were measured by [3H]dexamethasone exchange assay in crude microsome suspensions of rat liver. Propylthiouracil-induced hypothyroidism (TX) provoked a 90% reduction in the LAGS levels with respect to the control value. The administration of T3 to TX rats was able to completely restore the LAGS level. On the other hand, adrenalectomy (ADX) provoked a 50% decrease in LAGS levels, and this effect could be reverted by treatment with corticosterone acetate. TX rats that were also adrenalectomized (TX-ADX) showed a LAGS level similar to that of the TX rats. However, treatment of these rats with T3 was much less effective than in TX rats. A complete restoration of the LAGS level in TX-ADX rats could be achieved only with a combined treatment of corticosterone acetate plus T3. Similar results to those obtained in TX-ADX rats were also obtained in immature or hypophysectomized rats, two experimental models known to possess very low or undetectable levels of LAGS. From these findings we conclude that: 1) thyroid hormones, as well as glucocorticoids, play an important role in the regulation of the LAGS level; 2) glucocorticoids and thyroid hormones act synergistically in the endocrine regulation of LAGS; and 3) the results obtained in the hypophysectomized rats point to a direct action of glucocorticoids and T3 on the LAGS level of the rat liver.

Topics: Adrenalectomy; Animals; Binding Sites; Corticosterone; Dexamethasone; Drug Synergism; Glucocorticoids; Hypophysectomy; Hypothyroidism; Male; Microsomes, Liver; Propylthiouracil; Rats; Rats, Inbred Strains; Receptors, Glucocorticoid; Thyroid Hormones; Triiodothyronine

Functional and metabolic responses of hypothyroid skeletal muscle were evaluated during steady-state isometric contraction conditions, using an isolated perfused rat hindlimb preparation. Treating rats with propylthiouracil (PTU) for 4-5 mo resulted in a 55% decrease (P less than 0.001) in citrate synthase activity in plantaris muscle and phenotypic remodeling of the plantaris, evident by a threefold increase in type I fiber area and a 13% decrease in type II fiber area. Perfusion of PTU (n = 9) and control (n = 9) rat hindlimbs of similar size, with similar inflow (approximately 10 ml/min) and oxygen content (approximately 20 g/100 ml), resulted in similar oxygen deliveries to the contracting muscles (PTU 11.4 +/- 0.58, control 9.54 +/- 0.75 mumol.min-1.g-1; P greater than 0.05). Ten-minute tetanic contraction (100 ms at 100 Hz) periods at 4, 8, 15, 30, and 45 tetani/min were elicited in consecutive ascending order. Oxygen consumption (VO2) was lower in the PTU group at all contraction frequencies (P less than 0.005), with a decrease in peak VO2 of 44% (PTU 3.01 +/- 0.29, control 5.35 +/- 0.42 mumol.min-1.g-1; P less than 0.001). Oxygen extraction by the PTU muscle was only approximately 25% of that delivered. Developed tension was initially less (15%; P less than 0.05) in the PTU group but declined in a similar manner, as a percent of initial, to that of the control group. The slightly lower absolute tension development of the PTU muscle could not account for the large reduction in VO2.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Hypothyroidism; Kinetics; Male; Muscle Contraction; Muscles; Oxygen; Oxygen Consumption; Propylthiouracil; Rats; Rats, Inbred Strains; Reference Values; Regional Blood Flow

The binding properties--binding capacity (MBC) and affinity (Ka)--of T3 nuclear receptors were analyzed in cortex, cerebellum and liver of rats aged 3, 6, 12 and 24 months. A slight but not significant decrease of Ka was observed in different tissues of normal rats. In hypothyroid animals the Ka in cortex at 24 months was significantly lower than at 3 months. During ageing the MBC of brain receptors decreased whereas hepatic receptors were not altered. Hypothyroidism did not further affect the MBC of the receptors. The data indicate that during ageing the T3 nuclear receptors behave differently in brain and liver. The difference in MBC suggests selectivity in organ sensitivity to thyroid hormones.

Topics: Aging; Animals; Brain; Cell Nucleus; Cerebellum; Cerebral Cortex; Hypothyroidism; Liver; Propylthiouracil; Rats; Receptors, Thyroid Hormone

This study was designed to establish whether fluidity and lipid composition of brain membranes were affected by hypothyroidism, in the hope of clarifying the mechanism through which thyroid hormone deficiency might influence nerve cell functions. Rats were made hypothyroid by injections of PTU (dissolved in 0.005 M NaOH, 50 mg/kg, ip, daily for 28 days). Membrane fluidity, cholesterol (chol) and phospholipids (PL) content, and PL and their fatty acid composition were measured in plasma, erythrocyte plasma membranes, liver microsomes and brain subcellular fractions. P2 pellets from brains of hypothyroid animals were less fluid than those of euthyroid ones; subcellular fractionation showed that mitochondrial membranes were responsible for the rigidity observed. Similar changes were found in erythrocyte "ghosts". The reduced fluidity seemed to be related more to alterations in the ratios between phosphatidylcholine, sphingomyelin and phosphatidylethanolamine, than to those of chol/PL, protein/PL or fatty acid unsaturation index. The well known alteration in hypothyroidism-induced desaturase activity, which in peripheral tissue leads to a reduction of 20:4n-6 and to an increase in its precursors (18:2n-6 and 20:3n-6), is barely detectable in brain membranes. Only in phosphatidylcholine of synaptosomes and myelin did slight changes in percentages of the n-6 family fatty acids result in a significant alteration of 20:4n-6/20:3n-6 ratios.

Topics: Animals; Brain; Cholesterol; Fatty Acids; Hypothyroidism; Lipid Metabolism; Male; Membrane Fluidity; Mitochondria; Phospholipids; Propylthiouracil; Rats; Subcellular Fractions; Tissue Distribution

The vertebrate heart contains two myosin heavy chain isoforms, alpha and beta, which are differentially expressed. To establish a murine model for gene-targeting experiments, we defined the precise temporal expression of the myosin isoforms during cardiogenesis and obtained quantitative measurements of cardiac performance. The relative levels of the alpha- and beta-cardiac transcripts were determined by isolating the RNA from the hearts of CD-1 mice during development and hybridizing the preparations to probes that detect specifically the alpha- or beta-cardiac myosin heavy chain mRNAs. The data indicate that, although both isoforms are present from the onset of cardiogenesis, the beta-isoform predominates during embryogenesis and fetal development. This relation is reversed after the first day of life with a significant drop in the absolute transcript levels during the switch; and alpha/beta ratio of 16:1 is maintained in the neonate, and the relatively high levels of the alpha-transcript remain throughout the adult stages. To be able to make functional comparisons between normal and transgenic mice, we obtained indexes of myocardial function in isolated retrogradely perfused and in work-performing heart preparations in normal and hypodynamic mouse hearts. We found that the physiology of the mouse heart is similar to the rat heart in that we observed a positive staircase in the force-frequency relation of the mouse Langendorff preparation. We also saw contractile responses of more than twice control induced by paired stimulation and persistent postextrasystolic potentiation. As is the case for the rat, in the work-performing mouse heart, afterload (Starling resistance, pressure) changes produced a steeper Starling function curve than did changes in preload (volume, venous return).

Topics: Animals; Heart; Hypothyroidism; In Vitro Techniques; Isoenzymes; Mice; Mice, Inbred Strains; Myocardium; Myosins; Propylthiouracil; RNA, Messenger

The role of thyroid hormones in the testis is unclear, although recent evidence indicates they may be important for testicular development. Here we describe a novel method for increasing adult testicular size in the rat by induction of transient hypothyroidism during neonatal life. Rats were treated with a reversible goitrogen, 6-propyl-2-thiouracil from birth to day 25 when treatment was stopped, allowing return to a euthyroid state. At days 90, 135, 160, and 180, wt and DNA content of the testis, epididymis, ventral prostate, seminal vesicle, and those of some nonreproductive organs were determined, as well as serum levels of testosterone (T) and thyroid hormones. Despite decreased body wts in 90-day and older 6-propyl-2-thiouracil-treated rats, testis wt was increased by 40% and 60% at 90 and 135 days, respectively; maximal increase (80%) occurred at 160 days. These wt increases were accompanied by proportional changes in DNA content. Significant enlargements were also seen in other reproductive organs, but they occurred after a time lag and were smaller in magnitude. Interestingly, serum T levels showed no increase at any age. Weight and DNA content of nonreproductive organs, like body wts, were less than controls at all ages but thyroid hormone levels were normal. Thus, transient hypothyroidism in neonatal rats is associated with lasting enlargements in the ultimate size of testis and other reproductive organs in the adult. These changes are not related to excess T levels. The results indicate early critical influences of thyroid hormones on growth and development of the reproductive system and suggest an experimental model for inducing lasting enlargements in testis and reproductive organs. The model may also be useful for studying regulation of reproductive growth and final size.

Topics: Animals; Animals, Newborn; DNA; Epididymis; Genitalia, Male; Hypothyroidism; Male; Organ Size; Propylthiouracil; Prostate; Rats; Rats, Inbred Strains; Seminal Vesicles; Testis; Testosterone; Thyroid Hormones

In the preceding paper it was shown that transient neonatal hypothyroidism induced by treatment of rats from birth to day 25 with the goitrogen 6-propyl-2-thiouracil (PTU) is associated with increases in testis wt and DNA content of up to 80% during adulthood. The testis changes were accompanied by similar, though less marked, increases in the wt and DNA content of epididymis and accessory organs. The purpose of this study was to assess sperm production in these enlarged testes and measure changes in sperm reserves in the epididymis. Testes and epididymides were obtained from control rats or rats given PTU from birth to day 25 (designated "treated") at 90, 135, 160, and 180 days of age. Daily sperm production (DSP), efficiency of sperm production (DSP/g testis), and epididymal sperm reserves were measured in all animals. Compared to controls, DSP of the treated rats was increased by 83%, 86%, 136%, and 132% at 90, 135, 160, and 180 days, respectively. Thus, in the treated rats, DSP, like testis wt, plateaued at day 160. In addition, efficiency of sperm production was increased by 15%-30% at all ages in treated animals. Epididymal sperm reserves were also increased in treated rats at all ages, but the correlation between DSP and epididymal sperm reserves was weak. Sperm motility and concentration in caudal epididymal fluid of adult males treated from birth to day 25 with PTU were normal. These males were fertile and sired litters in which pup wt and pup number were normal. These results indicate that neonatal hypothyroidism in rats is associated not only with increased testis size but also with increased efficiency of sperm production, resulting in increases in DSP of up to 140% in these animals during adulthood. Maximal sperm production is reached at 160 days of age in treated rats (compared to 100 days in controls), coinciding with the attainment of final testicular size. This system represents the first experimental model in which such large increases in sperm production can be produced. The neonatal PTU treatment does not appear to impair fertility or alter sperm characteristics when these animals become adults and may be a useful system with which to study factors which normally regulate sperm production.

Topics: Aging; Animals; Animals, Newborn; Epididymis; Fertility; Hypothyroidism; Male; Organ Size; Propylthiouracil; Rats; Sperm Count; Sperm Motility; Spermatogenesis; Testis

1. Induction of hypothyroidism in rats by feeding propylthiouracil (PTU) significantly increased serum cholesterol concentrations, and the effect was more pronounced for cholesterol in low-density lipoproteins (LDL) rather than high-density lipoproteins (HDL). The concentrations of serum triacylglycerol were decreased in hypothyroidism. These effects on serum lipids were also seen when the normal rats were pair-fed with the PTU-treated group. 2. Feeding a diet rich in saturated fat and cholesterol further increased cholesterol concentrations in LDL and also elevated that in very-low-density lipoprotein (VLDL) of hypothyroid rats. In euthyroid rats such a diet resulted in a relatively small increase in VLDL cholesterol, whereas LDL cholesterol was decreased. 3. Steady-state concentrations of mRNA for the hepatic LDL receptor were significantly decreased in the livers of hypothyroid rats, but were not significantly changed by high-fat feeding in euthyroid or hypothyroid rats. 4. The expression of the LDL receptor in hepatocytes cultured from hypothyroid rats was decreased relative to the euthyroid controls. 5. Whereas the esterification of cholesterol with oleate in hepatocytes cultured from hypothyroid rats was decreased, the activity of acyl-CoA:cholesterol acyltransferase (ACAT) in the livers of these animals was not changed. 6. High-fat feeding increased the hepatic ACAT activity in normal and hypothyroid rats. 7. Incubation of rat hepatocytes with 10 nM-tri-iodothyronine for 4 h increased the relative concentration of the mRNA for the LDL receptor by 25%. 8. It is therefore concluded that thyroid hormones stimulate the synthesis and expression of the hepatic LDL receptor. Elevated cholesterol concentrations in LDL in hypothyroidism probably result from a primary defect in the expression of the hepatic receptor, rather than indirectly via changes in ACAT activity.

Topics: Animals; Body Weight; Cells, Cultured; Cholesterol, VLDL; Diet, Atherogenic; Esterification; Hypothyroidism; Lipoproteins, LDL; Liver; Male; Propylthiouracil; Rats; Rats, Inbred Strains; Receptors, LDL; RNA, Messenger; Sterol O-Acyltransferase; Triiodothyronine

Three patients with Graves' disease who spontaneously developed hypothyroidism after treatment with antithyroid drugs are described herein. Patient 1 developed a painful tender thyroid enlargement with a fever and accelerated erythrocyte sedimentation rate when she was receiving maintenance therapy with methimazole, and she progressed to persistent hypothyroidism with increased titers of antithyroglobulin and antimicrosomal antibodies and marked reduction of goiter size within the subsequent 2 months. Thyroid-stimulating hormone-binding inhibitory immunoglobulins (TBIIs) and thyroid stimulation-blocking antibody (TSBAb) were absent when she was hypothyroid. Hypothyroidism probably resulted from autoimmune thyroid destruction due to subacute aggravation of Hashimoto's thyroiditis. During the clinical course of patient 2, accelerated erythrocyte sedimentation rate and later transient increases of antimicrosomal and antithyroglobulin antibody titers were observed repeatedly (four times), and she finally fell into overt hypothyroidism. She also had negative results of tests for TBII and TSBAb. Her hypothyroidism appeared to result from repeated thyroid destruction due to aggravation of Hashimoto's thyroiditis. Patient 3 fell into hypothyroidism when receiving a small dosage of methimazole. The TBII and TSBAb were strongly active when she developed hypothyroidism, which thus seemed to be due to blocking antibody. Patients with Graves' hyperthyroidism may eventually progress to hypothyroidism later by several different mechanisms. Severe and sudden or slowly repeated thyroid destruction due to aggravation of Hashimoto's thyroiditis is one mechanism. Another may be the appearance of a blocking antibody to the TSH receptor.

Topics: Adult; Antithyroid Agents; Female; Graves Disease; Humans; Hypothyroidism; Methimazole; Middle Aged; Propylthiouracil; Thyroid Function Tests; Thyroiditis, Autoimmune

Thyroid and steroid hormones act by similar mechanisms to influence gene expression in the anterior pituitary gland. The genes encoding the common alpha and TSH-beta glycoprotein subunits are known to be regulated by thyroid hormones; we report here the effects of androgen administration on levels of alpha and TSH-beta mRNA in pituitary cytoplasm in the euthyroid and hypothyroid female rat. Dihydrotestosterone (DHT) suppressed both alpha and TSH-beta mRNAs to levels lower than those found in untreated animals; a similar reduction was seen in hypothyroid animals treated with DHT. A biphasic response of TSH-beta mRNA was seen following administration of tri-iodothyronine (T3) to hypothyroid rats, with early stimulation followed by later inhibition; these changes were also evident after administration of T3 to androgen-treated animals, although mRNA levels were again suppressed. The effects of testosterone were similar to those of DHT. In contrast to the changes in mRNA levels, androgen administration did not lead to significant alterations in serum TSH concentrations or pituitary TSH content. These results indicate that, like thyroid hormones, androgens suppress both alpha and TSH-beta subunit mRNA levels in the female rat. Androgens, however, exert differential effects on TSH synthesis and release which contrast with those of thyroid hormones.

Topics: Analysis of Variance; Androgens; Animals; Dihydrotestosterone; Female; Glycoprotein Hormones, alpha Subunit; Hypothyroidism; Pituitary Gland; Propylthiouracil; Rats; Rats, Inbred Strains; RNA, Messenger; Testosterone; Thyroidectomy; Thyrotropin; Triiodothyronine

We confirm our finding of a major development-regulated thyroxine-binding globulin (TBG) in the serum of the euthyroid mouse and investigate a number of its binding, structural and regulatory properties. Between 16 days foetal and 60 days postnatal life, the thyroxine (T4)- and tri-iodothyronine (T3)-binding activities of the sera show a striking ontogenic pattern: the binding is 2-3 times higher in foetuses than in mothers, then further increases after birth, reaching between 3 and 5 days maximum values which are 7-8 times higher than the adult ones. This pattern is not correlated with the ontogenesis of the acknowledged specific (transthyretin, TTR) and non-specific (albumin, alpha 1-foetoprotein) thyroid-hormone carriers of the mouse sera. PAGE studies demonstrate that the protein responsible for the elevated binding of the perinatal period is an alpha 1-globulin, with a migration similar to that of human and rat TBGs. Scatchard analysis is consistent with the notions that the T4-binding sites of TBG have high association constants, about two orders of magnitude above the T4 sites of TTR (10(9) M-1 as against 10(7) M-1) and low capacities (37 and 4 nmol/g of serum proteins in pups and adults respectively). Isoelectric focusing (i.e.f.) demonstrates that mouse TBG is a microheterogeneous protein separable, as a function of the pH gradient, in up to 10-12 isoforms, Marked shifts of the relative abundance of isoforms in the course of development are evidenced. The modulation of the TBG binding activity by non-esterified fatty acids (NEFA) and the control of its synthesis by the thyroid status are also reported. Mono- and poly-unsaturated NEFAs are strong inhibitors of the TBG, although they affect TTR less readily. On the other hand, the biosynthesis and/or secretion of TBG, but not of TTR, is under thyroid-hormone control, experimental hypothyroidism inducing a marked increase of the serum TBG. The TBG of mouse behaves as a highly significant parameter of development, pointing to a likely important function of the protein in the process of maturation. Our finding of major TBGs in both euthyroid rats and mice suggests that TBG is more widely spread than was thought until now, but difficult to detect in certain species outside definite maturation stages.

Topics: Aging; alpha-Fetoproteins; Animals; Binding Sites; Electrophoresis, Polyacrylamide Gel; Fatty Acids, Nonesterified; Fetal Blood; Hypothyroidism; Isoelectric Focusing; Mice; Prealbumin; Propylthiouracil; Serum Albumin; Thyroxine; Thyroxine-Binding Proteins; Triiodothyronine

Peptidylglycine alpha-amidating monooxygenase (PAM; EC 1.14.17.3) is a copper-, molecular oxygen-, and ascorbate-dependent enzyme which catalyzes the COOH-terminal amidation of bioactive peptides. Expression of PAM in the adult male rat anterior pituitary was evaluated after experimental manipulation of thyroid status. Levels of PAM mRNA increased 4- to 7-fold in animals made hypothyroid by treatment with 6-n-propyl-2-thiouracil or thyroidectomy and were not diminished below control levels in animals made hyperthyroid by treatment with T4. Treatment of thyroidectomized animals with T4 prevented the increase in PAM mRNA levels; similar doses of T4 returned serum TSH and anterior pituitary PAM mRNA to euthyroid values. Based on Northern blot analysis and amplification of fragments derived from rat PAM-1 by reverse transcription and the polymerase chain reaction, thyroid status did not affect the distribution of PAM mRNA among its various alternatively spliced forms. The specific activity of PAM in the anterior pituitary was increased slightly in both the soluble and particulate fractions from chemically hypothyroid rats; the majority of the PAM activity in the rat anterior pituitary was soluble, and increased secretion of enzyme may account for the lesser effect of chemical thyroidectomy on specific activity compared to mRNA levels. Western blot analysis demonstrated a 104-kDa PAM protein in particulate fractions prepared from control, PTU-treated, and T4-treated animals. The soluble fraction contained major PAM proteins of 95 and 75 kDa, and PTU treatment brought about an increase in the prevalence of the 75-kDa form of PAM protein.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Blotting, Western; Gene Expression Regulation; Hypothyroidism; Male; Mixed Function Oxygenases; Multienzyme Complexes; Nucleic Acid Hybridization; Pituitary Gland, Anterior; Polymerase Chain Reaction; Propylthiouracil; Rats; Rats, Inbred Strains; RNA Splicing; RNA-Directed DNA Polymerase; RNA, Messenger; Thyroid Hormones; Thyroidectomy; Thyrotropin; Thyroxine

The effects of the perturbation of the pituitary-thyroid axis induced during development on the functional activity of the growth hormone (GH) regulatory neuronal systems, GH-releasing hormone (GHRH), and somatostatin (SS) were studied in 14- and 21-day-old rats made hypothyroid by giving dams propylthiouracil in the drinking water since the day of parturition. Infant hypothyroid rats, both at 14 and 21 days of life, had elevated plasma thyroid-stimulating hormone levels and decreased pituitary and plasma GH levels. Simultaneous determination of hypothalamic GHRH/SS-like immunoreactivity (LI) and GHRH/SS mRNA levels did not reveal any difference in 14-day-old hypothyroid rats when compared with age-matched controls. In contrast, 21-day-old hypothyroid rats had decreased GHRH-LI content and a striking rise in GHRH mRNA levels, whereas SS-LI content and SS gene expression remained unaltered. These data indicate that in infant hypothyroid rats, changes in the functional activity of the GHRH neuronal system occur later than changes in GH secretion and are probably dependent on the GH deficiency. The functional activity of SS neurons was apparently unaltered in these hypothyroid rats, pointing to a lesser sensitivity of this system to the perturbation of the pituitary-thyroid axis.

Topics: Animals; Animals, Newborn; Female; Gonadotropin-Releasing Hormone; Growth Hormone; Hypothalamus; Hypothyroidism; Male; Pituitary Gland; Propylthiouracil; Rats; Rats, Inbred Strains; RNA, Messenger; Somatostatin; Thyrotropin

1. Adrenal TH activation was elicited in young rats (aged 4, 6 and 14 days) by insulin hypoglycaemia. In the control rats, TH activation varied between 125 and 147% above basal values. 2. Neonatal hypothyroidism induced by PTU treatment impaired TH activation. Compensatory treatment with T3 to the PTU-treated young rats led to a return to control activation.

Topics: Adrenal Glands; Animals; Enzyme Activation; Female; Hypoglycemia; Hypothyroidism; Insulin; Male; Propylthiouracil; Rats; Sodium Chloride; Thyroid Gland; Triiodothyronine; Tyrosine 3-Monooxygenase

Rat liver contains two topologically different TRH-degrading pyroglutamate aminopeptidases. The particulate pyroglutamate aminopeptidase, unlike the soluble one, was highly specific for TRH and shared many physico-chemical properties with serum thyroliberinase, which is controlled by thyroid hormones. Both enzymes convert pGlu His Pro NH2 into His Pro NH2; the latter may be cyclized to cyclo His Pro known to possess several biological activities and specific binding sites in liver. The aim of the present study was to determine the effects of thyroid status on the particulate and soluble enzymes activity and gain more insight into their biological role. The regulatory pathway for the particulate pyroglutamate aminopeptidase was found similar to that of serum thyroliberinase: their specific activities decrease in hypothyroid rats and increase in hyperthyroid rats, whereas that of soluble enzyme remains unchanged. We postulate that the particulate pyroglutamate aminopeptidase may be a determining factor in the concentrations of TRH and/or cyclo His Pro reaching liver cells and a possible source for serum thyroliberinase. Taken together, these data suggest that this "converting enzyme" acts as a physiological regulator.

Topics: Aminopeptidases; Animals; Dipeptides; Hyperthyroidism; Hypothyroidism; Isoflurophate; Kinetics; Liver; Male; Propylthiouracil; Pyroglutamyl-Peptidase I; Pyrrolidonecarboxylic Acid; Rats; Rats, Inbred Strains; Serine Endopeptidases; Thyrotropin-Releasing Hormone; Triiodothyronine

1. In adult male and female rats, liver plasma membrane gamma-glutamyltranspeptidase activities were 16-fold higher in the propylthiouracil (PTU)-induced hypothyroid state than in the control euthyroid state; thyroxine (T4)-replacement resulted in an 80% restoration to control levels. 2. Liver plasma membrane gamma-glutamyltranspeptidase activities were 6.7-fold higher in PTU-induced congenitally hypothyroid rats than in control euthyroid rats; T4-replacement reduced enzyme activities to 37% of control levels. 3. In adult rats, in response to the development and recovery from tri-iodothyronine (T3) excess, liver plasma membrane gamma-glutamyltranspeptidase activities were inversely related to, and out of phase by 12 hr, to the earlier changes in T3. 4. Liver gamma-glutamyltranspeptidase is a thyroid hormone-dependent enzyme.

Topics: Animals; Cell Membrane; Female; gamma-Glutamyltransferase; Hypothyroidism; Liver; Male; Pregnancy; Propylthiouracil; Rats; Rats, Inbred F344; Thyroxine; Triiodothyronine

Control and hypothyroid rats were challenged with a range of doses (0.5-4 mumol/kg) of either the nonselective dopamine agonist, apomorphine, or the selective D2 receptor agonist. LY 171555, and their stereotyped head-down sniffing (SHDS) responses measured. The dose-response curves for both agonists were shifted to the left in the hypothyroid rats compared to water-treated controls. Increasing doses of the selective D2 antagonist, raclopride, caused a parallel shift to the right in the LY 171555-induced SHDS dose-response curve. Schild analysis revealed a decreased sensitivity to raclopride in the hypothyroid animals. The selective D1 antagonist SCH 23390 was observed to decrease the maximal response elicited by LY 171555 in a dose-dependent manner and the hypothyroid rats were more sensitive to this effect. It was concluded that hypothyroid rats showed an apparent increased sensitivity to D2 receptor agonists and a decreased sensitivity to D2 antagonists. In addition, the facilitation effect of the D1 receptor on the D2 receptor appeared less tightly coupled in the hypothyroid rats.

Topics: Animals; Benzazepines; Dopamine Agents; Dopamine Antagonists; Dose-Response Relationship, Drug; Ergolines; Hypothyroidism; Male; Models, Biological; Propylthiouracil; Quinpirole; Raclopride; Rats; Rats, Inbred Strains; Receptors, Dopamine; Salicylamides; Stereotyped Behavior; Thyroxine; Triiodothyronine

Adrenal tyrosine hydroxylase activation was elicited in developing control, hypo- and hyperthyroid rats by insulin-hypoglycaemia. Rats were deeply anaesthetized with chloroform at a low concentration, since intrinsic tyrosine hydroxylase activation was very low with this technique, as compared to Ketamine injection or chloroform at a high concentration. The study of time-course of tyrosine hydroxylase activation showed that the maximum value was observed 2 h after insulin administration. In control animals, tyrosine hydroxylase activation increased between 4 and 20 days, and then decreased. Hypothyroidism is associated with a decreased tyrosine hydroxylase activation between 4 and 50 days, as compared to controls and hyperthyroidism with an increased activation between 6 and 30 days. While tyrosine hydroxylase from saline-treated rats exhibits two different forms (with two apparent Km values for the cofactor), enzyme from insulin-treated animals was present in a single form with a Km corresponding to the low Km value of the saline-injected rats. At 6 and 14 days, hypothyroidism increases tyrosine hydroxylase Km values as compared to euthyroid animals.

Topics: Adrenal Glands; Age Factors; Animals; Animals, Newborn; Embryonic and Fetal Development; Enzyme Activation; Female; Hyperthyroidism; Hypothyroidism; Insulin; Pregnancy; Propylthiouracil; Rats; Rats, Inbred Strains; Thyroxine; Tyrosine; Tyrosine 3-Monooxygenase

Topics: Acetylgalactosamine; Acetylglucosamine; Animals; Hypothyroidism; Propylthiouracil; Rats; Tectorial Membrane

Hypothyroid-induced atrophy of cardiac myocytes was examined in adult female rats in an effort to correlate hemodynamic and cellular changes associated with this disorder. Additional rats were studied 6 weeks after discontinuing antithyroid treatment to determine if structural and functional changes were completely reversible. To induce hypothyroidism, rats were injected daily with propylthiouracil (PTU) for 4 weeks. Control animals were injected similarly with Tris buffer. At the end of the treatment period, hemodynamic measurements were made prior to obtaining isolated myocytes. Cell volume, length, and cross-sectional area were obtained from the septum, and left and right ventricles of treated and untreated rats. After four weeks treatment with PTU, body weight was unchanged but heart weight was significantly reduced by 24%. Characteristic hemodynamic changes associated with hypothyroidism in the rat were noted (eg. reduced heart rate, cardiac output, dP/dtmax, and ventricular pressure). Cell volume was significantly smaller in hypothyroid rats primarily due to a reduction in myocyte cross-sectional area. The hemodynamic and cellular response to hypothyroidism was similar in the right and left ventricle. Six weeks after discontinuing PTU treatment, cellular and hemodynamics changes had returned to normal. It was concluded that hypothyroidism caused a true cardiac atrophy which was reversible. Reduced myocyte cross-sectional area was responsible for most of the myocyte atrophy.

Topics: Animals; Female; Hemodynamics; Hypertrophy; Hypothyroidism; Myocardium; Propylthiouracil; Rats; Rats, Inbred Strains

The reproductive system of immature rats is held to be more influenced by thyroid dysfunction than that of adult animals. The effect of hypothyroidism on the spermatogenic process of the rat has not been reported previously. The objective of the present study was to investigate the spermatogenic and steroidogenic functions of pubertal hypothyroid rats. Hypothyroidism was induced by ad libitum ingestion of a 0.05% solution of propylthiouracil for 60 days, and confirmed by reduced plasma thyroxine levels in treated rats. Plasma testosterone level, the histological features of the testis and cauda epididymis and the concentration of spermatozoa stored in the cauda epididymis were unchanged by hypothyroidism.

Topics: Animals; Gonadal Steroid Hormones; Hypothyroidism; Male; Propylthiouracil; Rats; Rats, Inbred Strains; Spermatogenesis; Testis; Thyroxine

Prenatal plus neonatal administration of methimazole (MMI), a procedure provoking marked hypothyroidism in rats, increased by about 100% the thymic content of oxytocin and severely (by approximately 80%) decreased the thymus weight, compared to euthyroid counterparts. Adult-onset, propylthiouracyl (PTU)-induced hypothyroidism, while provoking thymic involution, or thyroxine (T4) hyperthyroidism, did not affect oxytocin concentrations. Thymic involution and increases in thymus oxytoxin could also be obtained with repeated administration of the potent glucocorticoid dexamethasone. However, since corticosterone, unless subchronically injected at largely supraphysiological doses, was previously shown to have no influence on thymic parameters of young adult rats, a major involvement of the neonatal adrenal axis in oxytocin alterations could be excluded. It is suggested that the ontogenesis of thymic oxytocin production is under thyroid control.

Topics: Aging; Animals; Animals, Newborn; Dexamethasone; Female; Hyperthyroidism; Hypothyroidism; Male; Methimazole; Organ Size; Oxytocin; Propylthiouracil; Rats; Rats, Inbred Strains; Thymus Gland; Thyroxine

The synaptogenesis in the molecular layer of the dentate gyrus was studied during the development of normal and thyroid-deficient rats using a monoclonal antibody directed against synaptophysin, a marker of the synaptic vesicles. Immunostaining appeared after birth in the lateral edge of the molecular layer and spread over the entire length of the layer during the following days. Such a lateral-medial gradient has previously been reported for cell acquisition in the granule cell layer. Thyroid deficiency caused a delay of about 2 days in the progression of labeling along the layer. Synaptogenesis in the molecular layer is thus altered when thyroid hormone is lacking during the critical period of dentate gyrus development, probably affecting the nature and function of the synaptic networks that are formed in this area. This may partly account for the neurological defects observed after perinatal hypothyroidism.

Topics: Aging; Animals; Animals, Newborn; Hippocampus; Hypothyroidism; Immunoenzyme Techniques; Membrane Proteins; Nerve Tissue Proteins; Propylthiouracil; Rats; Rats, Inbred Strains; Reference Values; Synapses; Synaptophysin; Thyroxine

The effect of altered thyroidal status on levels of immunoreactive (ir)- atrial natriuretic peptide (ANP) in serum and the four cardiac chambers, and of tissue ANP mRNA, was determined in groups of rats given vehicle, thyroxine (T4), propylthiouracil (PTU) or T4 plus PTU for 3 weeks. Serum levels of ir-ANP were approximately 3-fold higher in T4-treated animals compared with control; levels in PTU or PTU/T4 groups were not different from control. Right ventricular ANP mRNA was below detection; in other chamber, levels rose with T4, alone or plus PTU, and fell after PTU compared with control. Atrial ir-ANP levels were unchanged by T4, but increased (left atrium, LA) or decreased (right atrium, RA) after PTU alone. After PTU/T4, some indices (e.g. tissue weight) remained at control levels, others (e.g. ANP mRNA levels) were equivalent to levels in the T4-alone group, and others (e.g. LA ir-ANP) were equivalent to those seen with PTU alone. We conclude that the role of thyroid hormones on ANP synthesis may be similar between chambers but their effects on release appear to differ widely. The extent to which this represents secondary rather than direct effects, or possible T3-versus T4-specific events, awaits elucidation.

Topics: Animals; Atrial Natriuretic Factor; Heart Ventricles; Hyperthyroidism; Hypothyroidism; Male; Myocardium; Nucleic Acid Hybridization; Propylthiouracil; Rats; Rats, Inbred Strains; RNA, Messenger; Thyroid Hormones; Thyroxine; Triiodothyronine

There is evidence for the existence of developmental changes in expression of troponin I (TNI) in cardiac thin filaments; however, regulation of TNI expression has not been described. We tested whether thyroid state affects expression of TNI using neonatal and adult rats made hypothyroid by treatment with 6-n-propyl-2-thiouracil. Polyacrylamide gels of myofibrils from hearts of 7-, 14-, 21-, and 28-day-old animals indicated that both euthyroid and hypothyroid rats display a developmental shift toward the adult form of TNI. However, hypothyroid rats displayed a lower percentage of adult TNI at each age studied. When adult rats were made hypothyroid, the proportion of adult TNI decreased slightly. Thin-filament activity was determined from measurements of the effect of acidic pH on calcium activation of myofibrillar ATPase activity. Sensitivity to acidic pH was measured by the magnitude of shift in pCa50 (-log of half-maximally activating molar Ca2+) between pH 7.0 and 6.5. Euthyroid rats displayed developmental increases in pH sensitivity. At 7, 14, and 28 days of development, shifts in pCa50 were 0.11, 0.38, and 0.43 units, respectively. Hypothyroid rats displayed less pH sensitivity with pCa50 shifts of 0.07, 0.21, and 0.15 units at 7, 14, and 28 days of development. Adult hypothyroid rats displayed a 0.38-unit shift in pCa50, whereas euthyroid adults displayed a 0.44-unit shift. Our results indicate that pH sensitivity and expression of cardiac TNI are influenced by developmental stage and hormonal status.

Topics: Adenosine Triphosphatases; Aging; Animals; Animals, Newborn; Calcium; Heart; Hypothyroidism; Myofibrils; Propylthiouracil; Rats; Rats, Inbred Strains; Reference Values; Thyroid Gland; Triiodothyronine; Troponin; Troponin I

The effect of perinatal hypothyroidism on the number and distribution of hippocampal kainic acid binding sites was examined in rats. Timed pregnant Sprague-Dawley rat dams were given water containing either 0.02% propylthiouracil (PTU) or untreated water from gestational day 18 until their litters were weaned at postnatal day 31. The offspring were sacrificed at 31 or 120 days of age, blood samples collected and their brains frozen. In the 31-day-old rats, serum thyroxine, serum triiodothyronine, total body weight and whole brain weight all indicated that the PTU-treated rats were hypothyroid. Hippocampal kainic acid binding was analyzed in sections of dorsal and ventral hippocampal formation by in vitro 3H-vinylidene kainic acid (VKA) autoradiography. Compared to the untreated controls, specific 3H-VKA binding was reduced by 43% in the ventral hippocampal formation stratum lucidum of 31-day-old PTU-treated rats. Specific 3H-VKA binding was not different in the dorsal hippocampal formation. Saturation of 3H-VKA binding studies indicated that the decrease-induced by PTU treatment--in ventral hippocampal 3H-VKA binding was due to a reduction in the total number of 3H-VKA binding sites. At 120 days of age, 3 months after the cessation of the PTU treatment, serum thyroid hormone levels were not different than those of controls, indicating a recovery of thyroid hormone function after the perinatal PTU treatment. However, specific 3H-VKA binding remained significantly reduced in the ventral hippocampal formation of 120-day-old rats.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Animals, Newborn; Autoradiography; Densitometry; Female; Hippocampus; Hypothyroidism; Kainic Acid; Pregnancy; Propylthiouracil; Rats; Rats, Inbred Strains; Receptors, Kainic Acid; Receptors, Neurotransmitter; Thyroxine; Triiodothyronine

The purpose of this study was to determine the effect of thyroid status on the Na,K-ATPase alpha isoforms and beta in rat heart, skeletal muscle, kidney, and brain at the levels of mRNA, protein abundance, and enzymatic activity. Northern and dot-blot analysis of RNA (euthyroid, hypothyroid, and triiodothyronine-injected hypothyroids = hyperthyroids) and immunoblot analysis of protein (euthyroid and hypothyroid) revealed isoform-specific regulation of Na,K-ATPase by thyroid status in kidney, heart, and skeletal muscle and no regulation of sodium pump subunit levels in the brain. In general, in the transition from euthyroid to hypothyroid alpha 1 mRNA and protein levels are unchanged in kidney and skeletal muscle and slightly decreased in heart, while alpha 2 mRNA and protein are decreased significantly in heart and skeletal muscle. In hypothyroid heart and skeletal muscle, the decrease in alpha 2 protein levels was much greater than the decrease in alpha 2 mRNA levels relative to euthyroid indicating translational or post-translational regulation of alpha 2 protein abundance by triiodothyronine status in these tissues. The regulation of beta subunit by thyroid status is tissue-dependent. In hypothyroid kidney beta mRNA levels do not change, but immunodetectable beta protein levels decrease relative to euthyroid, and the decrease parallels the decrease in Na,K-ATPase activity. In hypothyroid heart and skeletal muscle beta mRNA levels decrease; beta protein decreases in heart and was not detected in the skeletal muscle. These findings demonstrate that the euthyroid levels of expression of alpha 1 in heart, alpha 2 in heart and skeletal muscle, and beta in kidney, heart, and skeletal muscle are dependent on the presence of thyroid hormone.

Topics: Animals; Brain; Gene Expression Regulation, Enzymologic; Hypothyroidism; Isoenzymes; Kidney; Macromolecular Substances; Male; Muscles; Myocardium; Nucleic Acid Hybridization; Propylthiouracil; Rats; Rats, Inbred Strains; Reference Values; RNA, Messenger; Sodium-Potassium-Exchanging ATPase; Thyroid Gland; Triiodothyronine

Several in vivo experimental and clinical studies suggest that the production of thymic hormones, such as thymulin (Zn-FTS), is modulated by thyroid hormones. It was not determined in these studies, however whether such modulation is exerted directly on the thymic epithelial cells which synthesize and secrete thymic hormones. In order to discriminate between direct and indirect modulation, the effect of thyroid hormones on the in vitro production of thymulin by whole thymic organ culture, as detected by the rosette inhibition assay, has been investigated. Donors of thymuses were young 6N-propyl-2 thiouracil (PTU)-treated hypothyroid Balb/c mice and normal littermates. Thymuses from hypothyroid mice were shown to produce concentrations in vitro nearly undetectable of thymic hormone, when compared to thymuses from normal mice. The in vitro addition of triiodothyronine (T3) caused a complete recovery of the thymic hormone production by thymuses from hypothyroid mice and an increased synthesis even by normal thymuses over control values. The complete blockade of in vitro thymic hormone production with cycloheximide, which inhibits mRNA and protein synthesis but not thyroid hormone permissive actions, suggests that the T3 induced increment of thymic hormone level in the supernatant is due to de novo synthesis. Furthermore, the number of thymulin-producing cells, as detected by immunofluorescence using a specific antithymulin monoclonal antibody, which is quite low in thymuses from hypothyroid mice, is completely regained after in vitro incubation with T3. These findings support the idea that the modulation of thyroid hormones on thymic endocrine activity is directly exerted at thymic level.

Topics: Animals; Cycloheximide; Fluorescent Antibody Technique; Hypothyroidism; Kinetics; Male; Mice; Mice, Inbred BALB C; Organ Culture Techniques; Propylthiouracil; Thymic Factor, Circulating; Thymus Gland; Thymus Hormones; Triiodothyronine

Two-month-old female Fischer-344 rats were rendered hypothyroid by ingestion of propyl-thiouracyl (PTU) (0.1% in drinking water) and sacrificed 3, 7, 14, and 28 days after the start of PTU administration as well as 3, 7 and 14 days after interruption of a 14-day PTU treatment. Controls received no PTU. The pituitaries were studied by histology, immunohistochemistry, electron microscopy, and immunoelectron microscopy, using the immunogold double-labeling technique. In the course of hypothyroidism, pituitary thyrotrophs had undergone the well-known thyroidectomy change. In addition, a contingent of growth hormone (GH) cells lost their large secretory granules, enlarged, displayed progressive dilation of rough endoplasmic reticulum, thereby transforming into thyroidectomy cells. These bihormonal thyrosomatotrophs contained gH in their secretory granules and thyrotropin in the dilated rough endoplasmic reticulum as documented by the immunogold double-labeling method for GH and thyrotropin. After discontinuation of PTU treatment, a rapid increase in size, number and GH labeling of secretory granules and simultaneous involution of distended rough endoplasmic reticulum with reduction of thyrotropin labeling took place in thyrosomatotrophs. A practically complete restitution of normal pituitary structure was seen in 2 weeks. Results implicate that, contrary to previously accepted concepts, adenohypophysial cells may not be irreversibly committed to one morphologically recognizable cell line.

Topics: Animals; Cell Differentiation; Cytoplasmic Granules; Endoplasmic Reticulum; Female; Growth Hormone; Hypothyroidism; Immunohistochemistry; Microscopy, Electron; Pituitary Gland, Anterior; Prolactin; Propylthiouracil; Rats; Rats, Inbred F344; Thyroidectomy; Thyrotropin

1. The effects of hyperthyroidism and hypothyroidism on the concentrations of glutamine and other amino acids in the muscle and plasma and on the rates of glutamine and alanine release from incubated isolated stripped soleus muscle of the rat were investigated. 2. Hyperthyroidism decreased the concentration of glutamine in soleus muscle but was without effect on that in the gastrocnemius muscle or in the plasma. Hyperthyroidism also increased markedly the rate of release of glutamine from the incubated soleus muscle. 3. Hypothyroidism decreased the concentrations of glutamine in the gastrocnemius muscle and plasma but was without effect on that in soleus muscle. Hypothyroidism also decreased markedly the rate of glutamine release from the incubated soleus muscle. 4. Thyroid status was found to have marked effects on the rate of glutamine release by skeletal muscle per se, and may be important in the control of this process in both physiological and pathological conditions.

Topics: Alanine; Animals; Glutamine; Hyperthyroidism; Hypothyroidism; Male; Muscles; Propylthiouracil; Rats; Rats, Inbred Strains; Reference Values; Triiodothyronine

We have shown previously that the rat pancreas contains nuclear T3 receptors which exhibit a characteristic maturation pattern during development. To investigate whether these receptors are subjected to autologous regulation by thyroid hormones, the effect of T4 on the binding capacity (Bmax), dissociation constant (Kd), and receptor occupancy were followed in intact rat pups at various ages. Hyperthyroidism (by daily injection of T4 0.1 micrograms/g body wt to intact pups starting 4 days before death at 5, 10, 15, and 20 days of age) increased while hypothyroidism (by propylthiouracil feeding) decreased the total T3 binding capacity during preweaning ages (mean maximal binding capacities as estimated by Scatchard analysis, at 30 C for 14-20 days old eu-, hyper-, and hypothyroid pups: 186, 229, and 129 fmol/mg non-histone protein (NHP). The thyroid conditions also affected the percentage of T3 receptor occupancy but not the affinity of binding (as measured by Kd). Concomitantly, these conditions also caused corresponding changes in pancreatic weights, DNA and protein contents, and the concentrations of amylase, trypsinogen, and lipase. The postnatal developmental retardation induced by 6-n-propyl-2-thiouracil treatment was reversed by T4 replacement. The results suggest that rat pancreatic T3 nuclear receptors during postnatal ages are modulated by T4, and such modulation apparently in turn affects the development of the exocrine enzymes.

Topics: Animals; Animals, Newborn; Cell Nucleus; DNA; Exocrine Glands; Hyperthyroidism; Hypothyroidism; Pancreas; Propylthiouracil; Proteins; Rats; Receptors, Thyroid Hormone; Reference Values; Thyroid Gland; Thyroxine; Weaning

To continue our studies on the influence of T3 on TSH regulation in the Walker 256 carcinoma-bearing rat model of nonthyroidal disease, we measured the effect of T3 on pituitary content of beta TSH mRNA and rat (r) TSH in hypothyroid control (C) and tumor-bearing (T) rats. The effect of T3 on TSH regulation was compared to effects on GH mRNA and rGH in the same animals. mRNA content was normalized to a pool of pituitaries from euthyroid rats (= 1.0). beta TSH mRNA increased 18-fold in both hypothyroid C and T rats and then decreased similarly with increasing T3 infusion to a value of 0.1. GH mRNA content decreased to 0.11 +/- 0.01 in hypothyroid C rats, but to only 0.38 +/- 0.02 in T rats (P less than 0.001). The pituitary contents of GH mRNA and rGH in hypothyroid T rats was significantly greater than those in C rats at all T3 infusion rates. These data together with our previous report of decreased nuclear T3 in T rats suggest that regulation of beta TSH mRNA by T3 is intact in T rats, but occurs at a lower concentration of nuclear T3. In contrast, the GH mRNA response is enhanced, displaying differential regulation of these two T3-responsive gene products in this model of nonthyroidal illness.

Topics: Animals; Carcinoma; Growth Hormone; Hypothyroidism; Male; Neoplasm Transplantation; Pituitary Gland, Anterior; Propylthiouracil; Rats; Rats, Inbred Strains; RNA, Messenger; Thyrotropin; Triiodothyronine

Red blood cell (RBC) zinc (Zn) concentration was measured by atomic absorption spectrophotometry in 28 healthy volunteers, in 46 patients with hyperthyroidism, and in 6 patients with hypothyroidism. The mean (+/- SD) RBC Zn concentration in euthyroid controls was 11.4 +/- 1.5 mg/L RBC, and the normal range defined as the mean +/- 2 SD was 8.5 to 14.3 mg/L RBC. The mean RBC Zn in patients with hyperthyroidism was decreased to 6.4 +/- 1.6 mg/L RBC, and 43 (93%) had low values. The mean RBC Zn in patients with hypothyroidism was not different from that in the controls. There was a significant negative correlation between the concentrations of RBC Zn and those of both plasma thyroxine (T4; r = -0.73) and plasma 3,5,3'-triiodothyronine (T3; r = -0.70). After the treatment of 17 hyperthyroid patients with antithyroid drugs, both mean plasma T4 and T3 levels became normal within 4 weeks, but the normalization of RBC Zn lagged about 2 months behind them. The RBC Zn levels significantly correlated with both the plasma T4 and T3 levels obtained 0, 4, 8, and 12 weeks prior to the RBC sampling, and the highest correlation was observed between the RBC Zn levels and plasma T4 and T3 levels measured 8 weeks previously. These data suggest that RBC Zn concentration in hyperthyroid patients reflects a patient's mean thyroid hormone level over the preceding several months as glycosylated hemoglobin level does in diabetic patients.

Topics: Adult; Erythrocytes; Female; Humans; Hyperthyroidism; Hypothyroidism; Male; Methimazole; Middle Aged; Propylthiouracil; Testosterone; Thyroid Hormones; Thyrotropin; Time Factors; Zinc

The effects of hypothyroidism induced by propylthiouracil (PTU) treatment on growth hormone (GH) and prolactin (PRL) messenger ribonucleic acid (mRNA) levels were analyzed in adult female rat adenohypophyses by in situ hybridization histochemistry and Northern hybridization analyses. Twenty-eight days of PTU treatment produced a significant decrease in GH mRNA levels and a smaller decrease in PRL mRNA determined by both in situ hybridization histochemistry and Northern hybridization analyses. A combined procedure of in situ hybridization histochemistry followed by immunochemistry on the same sections revealed mammosomatotropic cells expressing GH mRNA and PRL protein in the same pituitary cells from all treatment groups. Cells expressing GH mRNA and thyroid-stimulating hormone protein were not detected by this method. Immunochemical staining revealed a decrease in GH cells and an increase in thyroid-stimulating hormone cells in hypothyroid rats. Cells expressing both GH and thyroid-stimulating hormone protein were not detected by immunostaining. These results indicate that hypothyroidism produces significant decreases in GH mRNA and also decreases PRL mRNA and that mammosomatotropic cells can be detected in pituitaries from normal and hypothyroid rats.

Topics: Animals; Female; Growth Hormone; Hypothyroidism; Immunohistochemistry; Nucleic Acid Hybridization; Organ Size; Pituitary Gland; Prolactin; Propylthiouracil; Rats; Rats, Inbred F344; RNA, Messenger; Thyroid Gland; Thyrotropin

Extrathyroidal production of 3,3',5-triiodothyronine from the thyroid secretory product, thyroxine, is catalyzed by tissue-specific iodothyronine 5'-deiodinases. Type I 5'-deiodinase (5'D-I) produces greater than 75% of the T3 found in the circulation and in thyroid hormone-responsive tissues and is most abundant in rat liver and kidney. In this study, we used the bromoacetyl derivatives of T4 (N-bromoacetyl-[125I]L-thyroxine, BrAcT4) and T3 (N-bromoacetyl-[125I]3,3',5-triiodothyronine, BrAcT3) as alkylating affinity labels to identify 5'D-I-related protein(s). BrAcT4 and BrAcT3 rapidly and irreversibly inactivated 5'D-I activity in liver and kidney microsomes. Sodium dodecyl sulfate-polyacrylamide gel electrophoresis of affinity labeled 5'D-I preparations showed that approximately 80% of the affinity label was incorporated into a protein with a Mr of 27,000 (p27). 5'D-I substrates and inhibitors specifically blocked affinity labeling of p27 with a rank order of potency (BrAcT4 greater than BrAcT3 greater than 3,5,3'-triiodothyronine (rT3) approximately flavone EMD 21388 greater than iodoacetate greater than N-acetyl-T4 (NAcT4) greater than N-acetyl-T3 (NAcT3] identical to that determined for inhibition of 5'-deiodination. Hyper- and hypothyroidism-induced increases and decreases in 5'D-I activity, respectively, were matched by comparable changes in the quantity of affinity labeled p27. BrAcT3 was a less effective affinity label for p27 and minor labeling of a new band with 53 kDa was observed. Molecular sieve chromatography of detergent-solubilized 5'D-I showed coincident peaks of p27 and 5'-deiodinating activity with an apparent Mr approximately 51,000. Two-dimensional gel electrophoresis showed that p27 was a single polypeptide with a pI of 6.1. Approximately 2-5 pmol of p27 were present per mg of liver microsomal protein, equal to previous estimates for 5'D-I content. Our results suggest that p27 represents the substrate binding subunit of type I 5'-deiodinase, the enzyme catalyzing the key reaction in the activation of T4 to the thyromimetically active T3.

Topics: Affinity Labels; Animals; Binding Sites; Binding, Competitive; Chromatography, Gel; Hyperthyroidism; Hypothyroidism; Iodide Peroxidase; Isoenzymes; Kidney Cortex; Kinetics; Macromolecular Substances; Male; Microsomes; Microsomes, Liver; Molecular Weight; Propylthiouracil; Rats; Rats, Inbred Lew; Rats, Inbred Strains; Reference Values; Thyroxine

Selenium (Se) deficiency for 5 weeks in rats produced changes in the activity of a number of hepatic, renal and plasma enzymes. In animals whose food intake was restricted to 75% of normal for 2 weeks, Se deficiency produced significant increases in the activity of hepatic cytosolic 'malic' enzyme and mitochondrial alpha-glycerophosphate dehydrogenase (GPD), two enzymes that are particular sensitive to the thyroid-hormone concentrations in tissue. Propylthiouracil-induced hypothyroidism produced significant decreases in 'malic' enzyme and GPD activities. The effect of hypothyroidism on the activity of 'malic' enzyme, GPD and other enzymes studied in liver and plasma was often opposite to that seen in Se deficiency. Glutathione S-transferase (GST) activity was increased by both Se deficiency and hypothyroidism, but in hypothyroid animals further significant increases in GST were produced by Se deficiency. These data suggest that the changes in enzyme expression observed in Se deficiency are not caused by decreased tissue exposure to thyroid hormones.

Topics: Animals; Glutathione Peroxidase; Glycerolphosphate Dehydrogenase; Hypothyroidism; Kidney; Malate Dehydrogenase; Male; Mitochondria, Liver; Organ Size; Oxidoreductases; Propylthiouracil; Rats; Selenium; Thyroid Gland; Thyroxine; Triiodothyronine

To study the physiological regulation of the iodothyronine 5'-deiodinases (I-5'D), we have examined the effects of some thiol blockers and of thyroid status on I-5'D activities both in vitro and in vivo. At low (less than 5 mM) concentrations of dithiothreitol, propylthiouracil (PTU) inhibited I-5'D in the brain, pituitary, and brown adipose tissue (BAT) of hypothyroid rats (which contain predominantly the type II activity); the patterns of inhibition in these tissues were essentially similar, with a Ki of about 174 microM at 250 microM dithiothreitol. Hydroxyethyldisulfide was a strong inhibitor of the type II enzyme, with relatively little effect on the renal enzyme at both high concentrations (micromolar) of T4, i.e. predominantly type I activity, and low concentrations (nanomolar) to T4, i.e. both type I and low Km activity. Preincubation of cerebral microsomes with PTU, followed by removal of excess PTU, resulted in 70% inhibition of I-5'D activity in cerebral microsomes at 5 mM dithiothreitol; the corresponding inhibitions of the renal enzyme at high and low substrate concentrations were 66% and 48%, respectively. Specific binding of PTU to renal and cerebral microsomes was diminished by hydroxyethyldisulfide, but not by T4, suggesting that PTU binding was not dependent on substrate interaction. Administration of PTU in vivo (1 mg/100 g BW, ip; 1 h before killing) resulted in approximately 80% inhibition of I-5'D activity in renal microsomes at high T4, and 50-70% inhibition in pituitary, BAT, and renal microsomes at low T4, but no inhibition was observed in brain microsomes. HPLC analyses revealed a PTU content of 35-65 nmol/g wet wt in the pituitary, BAT, liver, and kidney, but no PTU was detected in the brain, suggesting that PTU may be excluded by the blood-brain barrier. Maintaining hypothyroid rats on 1 microgram T4/100 g BW.day for 5 days enhanced renal type I and low Km I-5'D with restoration of serum T3 to normal levels, although the type II I-5'Ds from all sources were severely depressed. A supraphysiological dose of T4 depressed all three I-5'Ds. The data indicate that the I-5'Ds are regulated in a qualitatively similar fashion.

Topics: Adipose Tissue, Brown; Animals; Brain; Disulfides; Dithiothreitol; Ethanol; Homeostasis; Hypothyroidism; Iodide Peroxidase; Kidney; Microsomes; Pituitary Gland; Propylthiouracil; Rats; Sulfhydryl Reagents; Thyroxine

The efficacy of 131I therapy in achieving euthyroidism has been studied in a group of 264 patients followed for up to 10 yr. One hundred and eighty-six were given a dose adjusted for thyroid size and radioactive iodine uptake (Protocol 1), and a second group received the same dosage followed by antithyroid drug therapy plus potassium iodide for 15 days (Protocol 2). At 10-yr follow-up, 50-60% of patients were euthyroid. 25-29% of patients required 2 doses of 131I, and 4-5% required 3 doses. Fewer patients became hypothyroid when their pretreatment FTI was above the average value. More patients became hypothyroid, if their pretreatment test for antimicrosomal antibodies was positive. Patients who required a second dose of radioactive iodide had a significantly greater chance of having worsening of their ophthalmopathy than those who became hypothyroid after the first dose. Treatment with radioactive iodide under either protocol appears to achieve euthyroidism at 10 yr with an incidence higher than that achieved by antithyroid drugs and comparable to that reported for subtotal thyroidectomy.

Topics: Combined Modality Therapy; Eye Diseases; Female; Graves Disease; Humans; Hypothyroidism; Iodine Radioisotopes; Male; Middle Aged; Potassium Iodide; Propylthiouracil; Thyroid Gland; Thyroxine

Lectin staining has been used to detect mono- and oligosaccharides in normal and hypothyroid developing organs of Corti in the rat. Eight developmental stages were studied (1, 5, 8, 10, 15, 20, 50 and 60 days after birth). Congenital hypothyroidism was induced by oral administration of propylthyouracil to pregnant rats. Labelling of the tectorial membrane with 3 lectins, Ulex europaeus agglutinin-I (UEA-I), Lens culinaris agglutinin (LCA) and Ricinus communis agglutinin-I (RCA-I) showed no significant differences between normal and hypothyroid animals. Staining with peanut agglutinin (PNA) showed that the hypothyroid adult tectorial membrane (but not the normal one) possesses the disaccharide galactose + N-acetyl galactosamine. Phaseolus vulgaris agglutinin-L (PHA-L) labels the whole tectorial membrane in both groups of animals, but the staining is more intense in the hypothyroid one for a narrow band of oligosaccharide located just between the tectorial membrane and the underlying organ of Kölliker. Both soybean agglutinin (SBA) and succinylated wheat germ agglutinin (WGA) stain the tectorial membrane as well as the cytoplasm of the cells constituting the inner portion of the organ of Kölliker; this latter feature disappears in the normal animals about the 8th postnatal day, but it is abnormally preserved until the 60th postnatal day in the hypothyroid ones. In the adult hypothyroid animals, 3 of the lectins (LCA, PHA-L and WGA) stain extracellular conglomerates located under the synaptic pole of the outer hair cells.

Topics: Animals; Hypothyroidism; Lectins; Membrane Glycoproteins; Organ of Corti; Propylthiouracil; Rats

Parameters of the peripheral metabolism of thyroxine (T4) were studied in the early postnatal period. Iopanoic acid (IOP) was administered to newborn rats that were either euthyroid or rendered hypothyroid in utero by propylthiouracil (PTU) or methimazole (MMI) administration to the mothers during gestation and injected with thyroxine on postnatal days 6 and 7. In euthyroid newborn rats given IOP from postnatal day 6, the plasma T4 level increased (+50%) while the plasma 3,3',5'-triiodothyronine (T3) level slightly decreased (-18%). Peripheral deiodination of T4 was also reduced (about -50%) as estimated by thyroid 125I uptake after injection of 125I (3'-5')L-T4. In the newborn rats rendered hypothyroid in utero and given T4 on postnatal days 6 and 7, IOP treatment started on day 4 decreased the constant rate of elimination (-50%), the distribution volume (-43%) and the metabolic clearance (-74%) of plasma T4. The results were the same in PTU- and MMI-treated newborn rats. The differences between newborn and adult animals under IOP treatment are discussed.

Topics: Animals; Animals, Newborn; Hypothyroidism; Iopanoic Acid; Methimazole; Propylthiouracil; Rats; Rats, Inbred Strains; Thyroxine; Triiodothyronine

The influence of altered thyroid state is investigated on plasma apolipoprotein-A-I (apo-A-I), apo-B, and apo-E levels and on apo-A-I, apo-A-II, apo-B, apo-E, hepatic triglyceride lipase (HTGL), and low density lipoprotein (LDL) receptor mRNA levels in rat liver and intestine. Plasma total cholesterol and triglycerides are unchanged in hyperthyroid rats. Liver apo-A-I mRNA levels increase 3-fold, whereas intestinal apo-A-I mRNA levels remain constant. Plasma apo-A-I levels almost double after L-T4. Liver apo-B and apo-E and intestinal apo-B mRNA levels are not influenced by L-T4, but plasma apo-B and apo-E decrease significantly. In the liver, apo-A-II mRNA levels decrease, whereas LDL receptor mRNA levels increase more than 50%. HTGL mRNA is not influenced by L-T4. N-Propyl-thiouracil-induced hypothyroidism does not influence plasma triglycerides, but plasma cholesterol levels nearly double. Liver and intestinal apo-A-I mRNA levels and plasma apo-A-I concentrations remain constant after propylthiouracil treatment. Accompanying the increase in plasma apo-B, liver and intestinal apo-B mRNA concentrations rise by approximately 100% and 40%, respectively. Plasma apo-E increases nearly 2-fold, but liver, apo-A-II mRNA rises, whereas HTGL and LDL receptor mRNA levels decrease 20% and nearly 50%, respectively. In conclusion, thyroid hormones regulate rat apo-A-I and apo-A-II gene expression in opposite directions. Furthermore, the LDL receptor is regulated at the mRNA level, whereas HTGL gene expression is relatively resistant to alterations in thyroid status.

Topics: Animals; Apolipoproteins; Gene Expression Regulation; Hyperthyroidism; Hypothyroidism; Intestinal Mucosa; Lipase; Lipids; Liver; Male; Nucleic Acid Hybridization; Propylthiouracil; Rats; Rats, Inbred Strains; Receptors, LDL; RNA, Messenger; Thyroxine

Hepatic hilar denervation, hepatic vagotomy or sham operation were performed in hypothyroid rats. Activities of hepatic lipase were measured nine days after surgery. Sham operation in itself was associated with a decrease of hepatic lipase activity by about 40% compared with non-operated animals. Both hilar denervation and hepatic vagotomy were associated with increased hepatic lipase activity (40% and 35%, compared with sham-operated animals). Liver contents of norepinephrine were reduced by about 90% after hilar denervation, whereas hepatic vagotomy did not affect norepinephrine levels. No major changes in lipids and lipoproteins were noted.

Topics: Animals; Cholesterol; Cholesterol, HDL; Denervation; Hypothyroidism; Lipase; Lipids; Lipoproteins; Liver; Male; Norepinephrine; Propylthiouracil; Rats; Rats, Inbred Strains; Vagotomy

In this study we used propylthiouracil (PTU), a thyroid hormone-inhibiting compound, to render +/+, wv/+, and wv/wv embryos hypothyroid in order to test if the appearance of external granule layer (EGL) cell death in the weaver cerebellum is affected by alteration of granule cell development. At birth, the number of EGL cells in the PTU-treated cerebellum was reduced, compared to control animals, by 50%. Also, the amount of cell death was reduced in the PTU-treated wv/wv cerebellum. As adults, no differences were seen between PTU-treated and untreated mutant or normal cerebella. If the hypothyroid treatment that results in a 50% decrease in EGL cell number is due to an extension of cell cycling time, then the expression of the weaver phenotype of cell death likely follows granule cell exit from the cell cycle.

Topics: Animals; Cell Count; Cerebellum; Hypothyroidism; Mice; Mice, Inbred C57BL; Mice, Neurologic Mutants; Propylthiouracil; Thyroid Hormones

Three consecutive injections of 12.5 X 10(-10) and 25 X 10(-10) moles/g of L-thyroxine (T4) or a single injection of L-triiodothyronine (T3) at 7.5 X 10(-10) moles/g to Singi fish caused an increase in liver protein and RNA contents, whereas similar injections of 50 X 10(-10) moles/g of T4 or 75 X 10(-10) moles/g of T3 caused a fall in these cellular constituents in liver. Treatments of Singi fish with thiourea (1 mg/ml) for 30 days caused a fall in the protein and RNA contents in liver which were restored to the euthyroid control level by a single injection of 7.5 X 10(-10) moles/g of T3 or three consecutive injections of T4 at 12.5 X 10(-10) moles/g dose. Administration of T4 (12.5 X 10(-10) moles/g, three consecutive injections) along with 6N-2-propylthiouracil (PTU) at 20 micrograms/g of b. w. in six consecutive injections to the thiourea treated (hypothyroid) fish failed to cause any change in hepatic protein and RNA contents in comparison to only PTU-treated hypothyroid fish, but a single injection of 7.5 X 10(-10) moles/g of T3 to the PTU-treated hypothyroid fish increased these cellular constituents of liver. A dose-dependent biphasic nature of thyroid hormone action, a higher potency of T3 than T4 and the probable 'prohormone' nature of T4 have been documented in case of Singi fish in the present experiments.

Topics: Animals; DNA; Fishes; Hypothyroidism; Liver; Nucleic Acids; Propylthiouracil; Proteins; RNA; Thyroxine; Triiodothyronine

We present evidence based on equilibrium and non-equilibrium binding studies, as well as on immunological techniques, that of the two rat specific thyroid-hormone-binding proteins, i.e., thyroxine-binding globulin (TBG) and thyroxine-binding prealbumin (TBPA), TBG but not TBPA is regulated by the thyroid hormones (TH). Hypothyroidism, induced from the day of birth by daily treatment with propylthiouracil (PTU-rats), leads to dramatic and sustained increases of the TH-binding abilities of the sera measured at equilibrium, whereas hyperthyroidism, induced by treatment with thyroxine (T4-rats), leads to the decrease of these abilities. Polyacrylamide gel electrophoresis and isoelectrofocalisation of radioiodinated T4-labelled sera, together with immunoassay of TBPA, demonstrate that both effects are due to TBG, the levels of which rise in PTU-rats and decline in T4-rats, while TBPA levels do not respond to either depletion or excess of the thyroid hormones. TBG rather than TBPA appears as the key thyroid-hormone-binding protein of the rat, inasmuch as it alone expresses a regulatory function of the thyroid hormones at protein synthesis level.

Topics: Aging; Animals; Hyperthyroidism; Hypothyroidism; Kinetics; Propylthiouracil; Rats; Rats, Inbred Strains; Thyroxine; Thyroxine-Binding Proteins; Triiodothyronine

Glycolytic activity of five brain areas in the rat was studied under two hypothyroid states: (1) induced by low-iodine diet from weaning, and (2) induced by propylthiouracil. The areas studied were the anterior cortex, amygdala, hypothalamus, septum and hippocampus. A low-iodine diet induced a decrease of pyruvate kinase activity in three region and of phosphofructokinase in the hippocampus, while hexokinase increased in both the amygdala and septum. Propylthiouracil treatment produced an increase in hexokinase activity in the hypothalamus and septum, and a decrease in the anterior cortex, while phosphofructokinase decreased significantly in the hippocampus. No significant changes of lactate dehydrogenase activity were observed. The correlation between the results and type of hypothyroidism is discussed.

Topics: Animals; Brain; Hexokinase; Hypothyroidism; Iodine; L-Lactate Dehydrogenase; Male; Phosphofructokinase-1; Phosphotransferases; Propylthiouracil; Pyruvate Kinase; Rats; Rats, Inbred Strains; Thyroxine; Triiodothyronine

1. Rats (4 weeks old) were made hypothyroid by treatment with propylthiouracil and a low-iodine diet for a further period of 4 weeks. Synaptosomal membranes, myelin and 105,000 g soluble fractions were obtained from six regions of the brain. 2. Hypothyroidism resulted in 2-5-fold increases in membrane-bound 5'-nucleotidase activity in synaptosomal fractions obtained from cerebellum, cortex, striatum and hippocampus. By contrast, myelin 5'-nucleotidase activity was slightly increased only in the medulla oblongata. 3. Hypothyroidism did not change adenosine deaminase activity, but decreased adenosine kinase activity by approx. 40% in soluble fractions obtained from cerebellum, hippocampus, striatum and hypothalamus. 4. It is suggested that these changes in hypothyroidism, in particular the increases in 5'-nucleotidase activity, could enhance the neuromodulatory effect of adenosine to decrease neurotransmitter release.

Topics: 5'-Nucleotidase; Adenosine Deaminase; Adenosine Kinase; Animals; Brain; Hypothyroidism; Male; Nucleoside Deaminases; Nucleotidases; Phosphotransferases; Propylthiouracil; Rats; Rats, Inbred Strains; Synaptosomes

N-bromoacetyl-3,3',5-tri[3'-125I]iodo-L-thyronine was used to label intact heart mitochondria from eu, hypo- and hyperthyroid rats in order to identify proteins involved in T3-regulated mitochondrial processes. The results show strong labeling, competed for by T3 and other analogues, of two proteins with a molecular mass of 48,000 and 49,200 Da. No labeling is seen of the adenine nucleotide translocase, a likely target, neither at 0 degree C, at room temperature, nor after preincubation with the substrates or specific inhibitors. No difference in labeling intensity or distribution is seen in mitochondria from eu-, hypo- or hyperthyroid rats, and the abundance of the adenine nucleotide translocase is unchanged, but five other proteins show differential abundance.

Topics: Affinity Labels; Animals; Hyperthyroidism; Hypothyroidism; Liver; Male; Mitochondria, Heart; Mitochondrial ADP, ATP Translocases; Nucleotidyltransferases; Propylthiouracil; Proteins; Rats; Rats, Inbred Lew; Reference Values; Thyroid Gland; Thyroxine; Triiodothyronine

1. The severity of ventricular arrhythmias induced by coronary artery occlusion and reperfusion has been examined in control rats and animals made hypothyroid by pretreatment with 6-propylthiouracil (PTU). The maximal driving frequency and sensitivity of isolated left atria and papillary muscles to isoprenaline and to phenylephrine in the presence of propranolol, were also examined in tissues from control and hypothyroid animals. 2. Pretreatment with PTU resulted in a potentiation of responses to the alpha-adrenoceptor agonist phenylephrine in both left atria and papillary muscles, while responses to isoprenaline were depressed in left atria but unaltered in papillary muscles from hypothyroid animals. 3. In rats subject to coronary artery occlusion, PTU pretreatment reduced the incidence of ventricular fibrillation during acute myocardial ischaemia and abolished reperfusion-induced ventricular fibrillation. Mortality during myocardial ischaemia and reperfusion was also abolished. Diastolic blood pressure was similar in hypothyroid and control animals, but there was a small reduction in systolic blood pressure and a marked decrease in heart rate in PTU pretreated animals. 4. These results demonstrate that PTU-induced hypothyroidism represents a condition where cardiac alpha-adrenoceptor-mediated responses are enhanced but the severity of ischaemia- and reperfusion-induced arrhythmias is reduced.

Topics: Anesthesia; Animals; Coronary Disease; Hypothyroidism; Isoproterenol; Male; Myocardial Reperfusion Injury; Myocardium; Papillary Muscles; Phenylephrine; Propylthiouracil; Rats; Rats, Inbred Strains; Receptors, Adrenergic, alpha; Ventricular Fibrillation

Thyroid hormone effects on pituitary ACTH have not been well established. Adult male Sprague-Dawley rats were rendered hypo- and hyperthyroid while undergoing treatment with 6-Propylthiouracil (PTU) and L-Thyroxine (T4). At the time of decapitation, plasma values for T4 (micrograms/100 ml) were 3.9 +/- 0.4 in the control, 17.3 +/- 2.2 in the T4 and less than 2 in the PTU treated group; plasma T3 and TSH confirmed hyper- and hypothyroidism in the T4 and PTU treated groups respectively. Plasma immunoassayable ACTH and corticosterone were significantly increased in hyperthyroid and decreased in the PTU treated animals. Pituitaries were removed and incubated in DMEM. After 3 h incubation, ACTH content and secretion to the medium were significantly lower in the PTU group. As expected, pituitary TSH content and secretion were decreased in the T4 treated animals. These data indicate that thyroid hormones influence pituitary-adrenal function by increasing ACTH secretion and consequently corticosterone production.

Topics: Adrenocorticotropic Hormone; Animals; Corticosterone; Culture Techniques; Hyperthyroidism; Hypothyroidism; Male; Pituitary Gland; Propylthiouracil; Radioimmunoassay; Rats; Rats, Inbred Strains; Thyroid Hormones; Thyrotropin; Thyroxine

1. Rats were made hypothyroid by giving them a low-iodine diet with propylthiouracil for 4 weeks, or were made hyperthyroid by injection with tri-iodothyronine (T3) over a 3-day period. 2. Brown adipocytes were isolated from the interscapular depots of these animals or from their euthyroid controls, followed by isolation of mitochondria from the cells. 3. Relative to cell DNA content, hypothyroidism decreased the maximum binding (Bmax.) of [3H]GDP to mitochondria by 50%. T3 treatment increased binding by 37%. 4. These findings, which are discussed in relation to previously observed changes in brown adipose tissue after alteration of thyroid status, suggest that mitochondrial uncoupling for thermogenesis is less or more effective in hypothyroidism or hyperthyroidism respectively.

Topics: Adipose Tissue, Brown; Animals; DNA; Guanine Nucleotides; Guanosine Diphosphate; Hyperthyroidism; Hypothyroidism; Male; Mitochondria; Propylthiouracil; Rats; Rats, Inbred Strains; Triiodothyronine

We assessed the post-natal thyroid function in eight infants of mothers with Graves' disease whose thyroid function at birth was suppressed by maternal ingestion of propylthiouracil during pregnancy. These mothers continued taking propylthiouracil after delivery and breast-fed exclusively (two mothers supplemented their breast milk with a small amount of baby food). The cord free T4 level was slightly but uniformly below the normal range in all eight infants, and the cord TSH level was above the normal in seven infants. The dose of propylthiouracil after delivery ranged from 50 to 300 mg daily, which was equal to, or higher than, that before delivery. All these abnormal values normalized in the infant after birth. Serum samples, from seven of the eight mothers, taken at delivery were examined for TSH receptor antibodies; all were positive. The antibody titre, however, was too low, and/or free T4 and TSH levels were examined too long after delivery, for the antibodies to be the cause of the restoration of the infants' thyroid function. These results assure the safety of breast-feeding for the infants of mothers with Graves' disease taking propylthiouracil.

Topics: Adult; Breast Feeding; Female; Fetal Diseases; Graves Disease; Humans; Hypothyroidism; Infant, Newborn; Maternal-Fetal Exchange; Pregnancy; Propylthiouracil; Thyroid Gland; Thyrotropin; Thyroxine

Mitochondrial L-3-glycerophosphate dehydrogenase (EC 1.1.99.5) is synthesised in bovine kidney (NBL-1) cells treated with uncoupler as a cytosolic precursor with Mr = 76,000 indistinguishable from the mature form. In vitro translation of rat liver mRNA also gives rise to a product of Mr = 76,000 but when this is imported into mitochondria it is processed to a product of Mr = 66,000. L-3-Glycerophosphate dehydrogenase activity and immunoreactive protein are greatly decreased in liver mitochondria from hypothyroid rats. Paradoxically, in vitro translation of the mRNA from such animals gives rise to large amounts of the protein, much greater than that synthesised from euthyroid mRNA and comparable with that produced from hyperthyroid mRNA.

Topics: Animals; Carbonyl Cyanide p-Trifluoromethoxyphenylhydrazone; Cattle; Cell Line; Glycerolphosphate Dehydrogenase; Hypothyroidism; Kidney; Male; Mitochondria; Mitochondria, Liver; NADH Dehydrogenase; Propylthiouracil; Protein Biosynthesis; Protein Processing, Post-Translational; Rats; Rats, Inbred Strains; Reference Values; Submitochondrial Particles; Transcription, Genetic

Male Sprague-Dawley rats were treated for up to 4 weeks with propylthiouracil in a study designed to determine the effects of experimental hypothyroidism on plasma lipoproteins. The distribution of lipid constituents across the plasma lipoprotein spectrum was assessed by size exclusion chromatography and the lipoprotein particle size was assessed by gradient gel electrophoresis. A reduction in the concentration of thyroid hormones was accompanied by changes to plasma lipoproteins within 1 week of commencing treatment with propylthiouracil. These changes progressed for a further week, after which the pattern remained relatively stable for up to 4 weeks of treatment. In the animals treated with propylthiouracil, there was a marked reduction in the concentration of all constituents of very-low-density lipoproteins (VLDL). There was a coincident increase in concentration of all constituents of low-density lipoproteins (LDL), with an increase in LDL triacylglycerol being particularly obvious. There was also a marked and sustained increase in the concentration of cholesterol in high-density lipoproteins (HDL), but in this case, there were no sustained increases in the concentrations of other HDL constituents. There was, however, an appearance of new populations of very large HDL particles comparable to the HDLc which accumulate in the plasma of cholesterol-fed animals.

Topics: Animals; Cholesterol; Chromatography, Gel; Electrophoresis, Polyacrylamide Gel; Hypothyroidism; Lipase; Lipids; Lipoproteins; Lipoproteins, HDL; Lipoproteins, LDL; Liver; Male; Particle Size; Phospholipids; Propylthiouracil; Rats; Rats, Inbred Strains; Triglycerides

Naive rats placed in a plexiglass cylinder from a 15 minute test period show progressive immobility, and retain the immobile response when given a 5-minute retest 24 hours later. In the present study we show that hypothyroidism markedly attenuates the acquisition of the immobile response; that this effect on acquisition is reversed 5-10 minutes after the administration of thyroxine; and that hypothyroid rats treated with a single dose of thyroxine up to 2 hours after the initial test show levels of immobility on re-test indistinguishable from intact rats.

Topics: Administration, Oral; Animals; Behavior, Animal; Hypothyroidism; Injections, Intramuscular; Male; Propylthiouracil; Rats; Rats, Inbred Strains; Thyroid Hormones; Thyroxine; Time Factors; Triiodothyronine

Vasoactive intestinal peptide (VIP) and PRL have been reported to be colocalized in rat lactotropes. To determine whether induced hypothyroidism, known to reduce pituitary PRL concentration, also reduces pituitary concentration of VIP, rats were treated with antithyroid drugs for 3 weeks. Pituitary PRL concentration in male rats (micrograms/mg protein) was markedly reduced by this treatment (9.4 +/- 1.0 vs. 2.3 +/- 0.4 when extracted at pH 1.1, 17.9 +/- 3.0 vs. 3.4 + 0.4 when extracted at pH 7.4, 21.8 +/- 3.3 vs. 6.7 + 1.3 when extracted at pH 10.0). Contrary to expectation, pituitary VIP concentration was markedly increased in hypothyroidism; in males from 169.5 +/- 20.3 to 834.0 +/- 82.2 pg/mg protein, and in females (whose pituitary PRL had been similarly reduced) from 103.1/I +/- 34.1 to 771.6 +/- 100.9 pg/mg protein. Serum PRL was significantly reduced in hypothyroid males (7.4 +/- 1.6 vs. 28.9 +/- 12.2 ng/ml) whereas in females, serum PRL was not significantly altered (41.4 +/- 11.6 vs. 38.8 +/- 14.3 ng/ml). The effect of hypothyroidism was reversed by administration of T4 in physiological doses. The authenticity of pituitary immunoreactive VIP was further established by demonstrating chromatographic patterns by Sephadex G-50 gel exclusion and reverse phase HPLC separations identical to synthetic VIP. Immunohistochemically reactive VIP cells could not be demonstrated in normal pituitaries, but the marked increase in VIP in hypothyroid animals made it possible to visualize a population of VIP immunoreactive stellate cells which appear to be distinct from hypothyroid lactotropes and thyrotropes.

Topics: Animals; Female; Hypothalamus; Hypothyroidism; Male; Pituitary Gland, Anterior; Prolactin; Propylthiouracil; Rats; Rats, Inbred Strains; Reference Values; Triiodothyronine; Vasoactive Intestinal Peptide

We investigated the role of thyroid hormone in the postnatal development of Ca2+ transport activity of sarcoplasmic reticulum in skeletal muscle (m. gastrocnemius-plantaris). With a Ca2+-stat method using the fluorescent dye fura 2 as Ca2+ indicator, we determined the oxalate-supported maximal Ca2+ uptake activity of sarcoplasmic reticulum in whole muscle homogenates from neonatal rats. Expressed per g tissue wet wt, the activity increased nearly 10-fold during the first 8 weeks after birth, following which time a plateau was reached. This development was absent in hypothyroid pups, in which the level of Ca2+ uptake activity remained constant at 10% of the normal adult value for at least 8 weeks. When the mothers were given 0.05% propylthiouracil in the drinking water 1 week before parturition, these pups ceased to grow after 4 weeks, had a reduced muscle protein content and a characteristic cretinous appearance. The effects of hypothyroidism could be reversed by T3 treatment (0.5 micrograms/100 g BW, daily) starting 1 or 6 weeks after birth. Treatment with bovine GH (0.1 or 0.5 IU/100 g BW; daily) starting on day 5 stimulated body growth, particularly of muscle, but was without effect on the failing development of Ca2+ uptake activity. The postnatal rise in citrate synthase and succinate dehydrogenase activities was impaired in the hypothyroid group, but lactate dehydrogenase and creatine kinase activities rose continuously, although at a reduced rate. T3 treatment also reversed these effects of propylthiouracil. At the higher dosage used bovine GH appeared to stimulate the accumulation of creatine kinase. We conclude that the failing postnatal development of sarcoplasmic reticulum Ca2+ transport activity in hypothyroidism is not secondary to the absence of GH, nor is it part of a general, indiscriminate effect, but, rather, that it indicates an absolute requirement of thyroid hormone for this particular aspect of muscle differentiation.

Topics: Animals; Benzofurans; Biological Transport; Calcium; Citrate (si)-Synthase; Creatine Kinase; Cytosol; Female; Fluorescent Dyes; Fura-2; Growth Hormone; Hypothyroidism; L-Lactate Dehydrogenase; Mitochondria; Muscle Development; Muscles; Pregnancy; Propylthiouracil; Rats; Rats, Inbred Strains; Sarcoplasmic Reticulum; Succinate Dehydrogenase; Thyroid Hormones; Triiodothyronine; Weight Gain

We have examined in isolated liver mitochondria the effect of cold exposure on DNA, RNA and protein synthesis in normal, hypothyroid and mildly hyperthyroid rats. In normal rats DNA polymerase activity increased from the first day of cold exposure remaining high up to the fifteenth day. RNA polymerase and protein synthesis were stimulated from the fifth day of cold exposure, maintaining a high level up to the fifteenth day. These activities were related to serum triiodothyronine (T3) levels. Indeed propylthiouracil (PTU) administration to cold-exposed rats drastically depressed the above activities, whereas T3 administration to PTU-treated cold-exposed rats restored them to about the values prevalent in normal cold-exposed rats. The translation products analyzed by gel electrophoresis showed that different effects may be exerted by T3 depending on whether its circulating levels are physiologically or pharmacologically modified. These findings suggest that T3 may be involved in the regulation of the acclimation process by acting, presumably with a permissive role, on those activities which determine a modification of the mitochondrial morphometric features and an increase in mitochondria number and turnover.

Topics: Animals; Cold Temperature; DNA-Directed DNA Polymerase; DNA-Directed RNA Polymerases; DNA, Mitochondrial; Hyperthyroidism; Hypothyroidism; Male; Mitochondria, Liver; Propylthiouracil; Protein Biosynthesis; Rats; Rats, Inbred Strains; RNA; RNA, Mitochondrial; Triiodothyronine

Topics: Adult; Amiodarone; Female; Glucocorticoids; Humans; Hyperthyroidism; Hypothyroidism; Male; Perchlorates; Plasmapheresis; Potassium; Potassium Compounds; Propylthiouracil; Thyroid Hormones; Thyroidectomy; Thyroxine

Previous findings have shown that thyroid hormone markedly increases the speed of diastolic relaxation in the heart. This thyroid hormone-dependent change is also accompanied by an increased Ca2+ pumping ability in the sarcoplasmic reticulum. In an effort to determine the underlying cause of improved Ca2+ transport, mRNA levels of the slow Ca2+-ATPase of the sarcoplasmic reticulum were quantified on Northern blots. In hypothyroid rat hearts, the steady state level of Ca2+-ATPase mRNA was only 36% of control levels, whereas hyperthyroid rat heart mRNA levels were 136% of control. Ca2+-ATPase mRNA responded rapidly to T3, as the mRNA level was significantly increased by 2 h and normalized by 5 h after T3 injection into hypothyroid rats. The well established effect of thyroid hormone on improved myocardial contractility and increased speed of diastolic relaxation may in part relate to specific alterations in the level of the mRNA coding for Ca2+-ATPase, resulting in increased pump units.

Topics: Animals; Calcium-Transporting ATPases; Cloning, Molecular; DNA; Genes; Heart; Hyperthyroidism; Hypothyroidism; Kinetics; Male; Myocardium; Propylthiouracil; Rats; Rats, Inbred Strains; RNA, Messenger; Sarcoplasmic Reticulum; Thyroxine; Transcription, Genetic; Triiodothyronine

The effect of thyroid hormone on atrial natriuretic factor (ANF) production was investigated in hypothyroid, euthyroid, and hyperthyroid rats by measuring levels of ANF mRNA and ANF in myocardium. ANF mRNA was quantitated by dot blot hybridization, and ANF by specific RIA. Relative ANF mRNA concentrations (ANF mRNA to 18S RNA) were determined for right atria, left atria, and ventricular apices. The total chamber content of ANF mRNA was estimated (concentration X total chamber RNA) and used as a measure of each tissue's synthetic capacity. For both atrial tissues, ANF mRNA contents were significantly higher in hyperthyroidism. In right atria, mean ANF mRNA contents in hypothyroidism and hyperthyroidism were 41% and 176%, respectively, of that in euthyroidism (P less than 0.05, by analysis of variance). Left atrial ANF mRNA contents in hypothyroidism and hyperthyroidism were 94% and 272%, respectively, of the euthyroid value (P less than 0.05). In contrast, atrial ANF mRNA concentrations did not differ significantly between thyroid states. In ventricle, ANF mRNA content and concentration were both correlated with serum T4 concentration. Ventricular ANF mRNA contents in hypothyroidism and hyperthyroidism were 31% and 178%, respectively, of that in euthyroidism (P less than 0.02). The concentration of ventricular ANF mRNA was also significantly increased in hyperthyroidism (P less than 0.05). Tissue content of ANF increased in the hyperthyroid right atria and decreased in the hyperthyroid left atria and ventricles. These observations suggest that increased ANF production by both atria and, to a lesser extent, by the ventricles contributes to the higher circulating ANF levels reported in hyperthyroidism. Furthermore, hyperthyroidism is associated with a specific increase in ventricular ANF mRNA expression as has been observed in other conditions causing ventricular hypertrophy.

Topics: Animals; Atrial Natriuretic Factor; Heart Atria; Heart Ventricles; Hyperthyroidism; Hypothyroidism; Male; Myocardium; Propylthiouracil; Rats; Rats, Inbred Strains; Reference Values; RNA, Messenger; Thyroid Gland; Thyroxine; Transcription, Genetic

The changes in met-enkephalin and beta-endorphin contents in the pituitary in PTU-induced hypothyroidism were studied in the rat. After 2 weeks of PTU-treatment, both IR-met-enkephalin and IR-beta-endorphin contents in the pituitary were significantly reduced. Gel filtration chromatography followed by radioimmunoassay showed that the immunoactivities in the peaks of precursors, met-enkephalin, beta-lipotropin and beta-endorphin were all lower in the pituitaries from the PTU-treated rats. In another experiment, some of the PTU-treated rats were injected daily with 500 micrograms T3/kg b.w. In the hypothyroid rats, IR-met-enkephalin and IR-beta-endorphin contents were decreased in both the anterior and neurointermediate lobes. Only the changes in the anterior lobe were reversed by T3 treatment. In conclusion, while the effects on the anterior lobe are probably due to a deficiency in thyroid hormones, the mechanism for the decrease of opioid peptide contents in the neurointermediate lobe is still unclear.

Topics: Animals; beta-Endorphin; Enkephalin, Methionine; Hypothyroidism; Kinetics; Male; Pituitary Gland; Pituitary Gland, Anterior; Pituitary Gland, Posterior; Propylthiouracil; Rats; Rats, Inbred Strains; Triiodothyronine

1. Hypothyroidism was maintained for four weeks in male rats by administration of PTU daily. 2. Hypothyroid rats showed increased behavioural responses to apomorphine, a mixed D1/D2 dopamine receptor agonist, LY 171555, a selective D2 agonist and to SKF 38393, a selective D1 agonist, compared with euthyroid controls. 3. Responses to the selective D1 antagonist, SCH 23390, were decreased, but were increased to the D2 antagonist, haloperidol, in hypothyroid rats. 4. Ligand binding studies showed no significant differences in the affinity and concentration of D1 or D2 receptor sub-types in the striatum of hypothyroid compared with euthyroid rats. 5. However, hypothyroid rats had a greater increase in dopamine stimulated cyclic AMP in the striatum than euthyroid controls. 6. It is concluded that the changes in behavioural sensitivity observed in hypothyroid rats may be associated with these alterations in post-synaptic events.

Topics: 2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine; Animals; Apomorphine; Benzazepines; Brain; Dopamine Antagonists; Ergolines; Haloperidol; Hypothyroidism; Male; Motor Activity; Propylthiouracil; Quinpirole; Rats; Rats, Inbred Strains; Receptors, Dopamine; Reference Values; Stereotyped Behavior; Synapses

In 10-day-old rats made hypothyroid by giving dams propylthiouracil (PTU) in the drinking water since the day of parturition, simultaneous radioimmunoassay (RIA) determinations of basal and stimulated growth hormone (GH) secretion, hypothalamic GH-releasing hormone (GHRH)-like immunoreactivity (LI) content, immunocytochemical localization of somatotrophs, and hypothalamic GHRH-LI-positive structures were performed. The frequency of somatotrophs was also determined. One-day-old hypothyroid rats, whose mothers had been given PTU since the 14th day of pregnancy, were also used for comparison. In 10-day-old hypothyroid rats, pituitary and plasma GH levels and the number of somatotrophs were considerably lower and plasma TSH levels were significantly higher than those in age-matched control rats; however, GHRH-LI titers in the mediobasal hypothalamus and the morphology of GHRH-LI-positive structures were unaltered. In 1-day-old rats the only alteration present, in addition to elevated plasma TSH levels, was a clear-cut decrease in plasma GH levels. An acute challenge with GHRH (20 ng/100 g body wt, sc) or clonidine (15 micrograms/100 g body wt, sc) induced a clear-cut rise in plasma GH levels 15 min postinjection in 10-day-old control rats but failed to do so in age-matched hypothyroid rats. Both compounds failed to rise plasma GH in both hypothyroid and control 1-day-old rats. Taken together these data indicate that in neonatal and infant rats deprivation of thyroid hormones acts primarily to depress pituitary somatotroph function and that possible changes in GHRH-secreting structures represent a later postnatal event.

Topics: Animals; Animals, Newborn; Arcuate Nucleus of Hypothalamus; Clonidine; Growth Hormone; Growth Hormone-Releasing Hormone; Histocytochemistry; Hypothalamus, Middle; Hypothyroidism; Immunoenzyme Techniques; Median Eminence; Pituitary Gland; Propylthiouracil; Rats; Rats, Inbred Strains; Thyrotropin

When TRH was administered every 15 min for 2 hr in euthyroid rats, equivalent modestly supraphysiologic doses of either T4 or T3 suppressed TRH-induced TSH secretion after 45 min. Pretreatment with iopanoic acid blocked the ability of T4 but not of T3 to suppress TRH-induced TSH secretion 2 hr after administration of the respective thyroid hormone. Pretreatment with iopanoic acid also blocked the ability of T4, but not of T3, to depress the elevated basal plasma TSH concentration of hypothyroid rats within 2 hr. Propylthiouracil did not significantly inhibit the ability of T4 to depress TRH-induced TSH secretion and only slightly depressed the ability of T4 to reduce the elevated plasma TSH of hypothyroid rats. Our data support the concept that although equivalent physiologic doses of T4 or T3 inhibit basal or TRH-induced TSH secretion equally rapidly, TSH inhibition produced by T4 is probably dependent on its rapid conversion to T3, either within the pituitary or peripherally. T3 thus seems to be exerting almost all the negative feedback effects on TSH secretion under the conditions of our experiments.

Topics: Animals; Hypothyroidism; Iopanoic Acid; Male; Propylthiouracil; Rats; Thyrotropin; Thyrotropin-Releasing Hormone; Thyroxine; Triiodothyronine

Prior studies have suggested that the lipid composition and lipid fluidity of cellular membranes of various organs are altered in the hypothyroid rat. To date, the effects of hypothyroidism on these parameters have not been examined in rat colonic apical plasma membranes. In the present experiments, male Sprague-Dawley rats were fed a pelleted diet (control group) or the same diet containing 0.1% propylthiouracil (hypothyroid group) for 3 weeks. The lipid composition and lipid fluidity of apical plasma membranes prepared from colonocytes of these two groups of animals were then examined and compared. Membranes prepared from the hypothyroid animals were found to possess a higher level of linoleic acid (18:2) and a lower level of arachidonic acid (20:4) than membranes from control animals. The molar ratio of cholesterol/phospholipid was also lower in hypothyroid membranes secondary to a decreased cholesterol content compared to their control counterparts. Moreover, the lipid fluidity of colonic apical plasma membranes, as assessed by (1) the ratio of excimer to monomer fluorescence intensities of the lipid-soluble fluorophore pyrenedecanoic acid and (2) the anisotropy values of the fluorophore DL-12-(9-anthroyloxy)stearic acid using steady-state fluorescence polarization techniques, was greater in hypothyroid animals. These data, therefore, indicate that alterations in the lipid composition and fluidity of colonic apical plasma membranes can be detected in hypothyroid rats.

Topics: Animals; Arachidonic Acid; Arachidonic Acids; Cell Membrane; Cholesterol; Colon; Decanoic Acids; Fluorescence Polarization; Fluorescent Dyes; Hypothyroidism; Linoleic Acid; Linoleic Acids; Male; Membrane Fluidity; Membrane Lipids; Phospholipids; Propylthiouracil; Rats; Rats, Inbred Strains; Stearic Acids

Young, male ICR mice were given tap water or distilled water containing 200 mg/l propylthiouracil (PTU) and were then infected with 10 plerocercoids of Spirometra erinacei to investigate the effect of plerocercoid infection on thyroid hormone in their hosts. Plerocercoid infection stimulated growth in PTU-induced hypothyroid mice as if they had never received PTU treatment: there were increases in weight in the liver, skeletal muscle, and spleen, as well as enhancement of the head and body length, in spite of a greater decrease in serum T4 levels than was observed in PTU-treated controls. Furthermore, the intact mice infected with plerocercoids showed a decrease in serum T4 levels as well as in the concentration of T4-binding globulin. These observations suggest that the growth stimulation and the decrease in concentrations of serum T4 and T4-binding globulin associated with plerocercoid infection in mice probably resulted from secretion of a growth hormone-like substance produced by plerocercoids of S. erinacei.

Topics: Animals; Body Weight; Cestoda; Cholesterol; Diphyllobothriasis; Growth Substances; Hypothyroidism; Intercellular Signaling Peptides and Proteins; Liver; Male; Mice; Mice, Inbred ICR; Muscle Development; Organ Size; Propylthiouracil; Spirometra; Spleen; Thyroid Gland; Thyroxine; Thyroxine-Binding Proteins; Triglycerides

The effect of T4 on the development of pancreatic glucocorticoid receptors was studied in normal and adrenalectomized rat pups. Daily injection of T4 (0.1 microgram/g BW) to intact pups starting 3 days before death at 10, 15, and 20 days of age resulted in a precocious increase in pancreatic glucocorticoid-binding capacities. Intact pups made hypothyroid by propylthiouracil feeding exhibited lower glucocorticoid-binding capacities in their pancreata. Scatchard analysis demonstrated an increase in the number of glucocorticoid-binding sites in the pancreata of T4-treated intact rats compared to that in normal intact rats. In hypothyroid groups the number of glucocorticoid-binding sites was much lower than that in normal intact rats. The Kd values, however, were unchanged in hypothyroid, hyperthyroid, and control groups. Rat pups who underwent adrenalectomy at 12 days of age had undetectable plasma corticosterone levels and showed an increase in their pancreatic glucocorticoid-binding capacity 3 days after operation. Replacement of corticosterone resulted in a binding level similar to that in the sham-operated group. However, injection of T4 alone to adrenalectomized pups led to a further increase in pancreatic glucocorticoid-binding capacity above that due to adrenalectomy alone. When both T4 and corticosterone were given together to adrenalectomized pups their pancreatic glucocorticoid-binding capacities increased to levels above those in the adrenalectomized group, but lower than those in pups receiving T4 alone. Our results suggest that T4 modulates the development of rat pancreatic glucocorticoid receptors and, at least in part, acts via pathways independent of adrenal function.

Topics: Adrenalectomy; Animals; Corticosterone; Cytosol; Dexamethasone; Hypothyroidism; Pancreas; Propylthiouracil; Rats; Rats, Inbred Strains; Receptors, Glucocorticoid; Thyroxine

Ca2+ accumulation and retention by isolated rat liver mitochondria (RLM), measured with a Ca2+ electrode as aCa, are markedly influenced by thyroid status. RLM from propylthiouracil (PTU)-fed rats took up Ca2+ from a suspending medium (SM) until 10.26 +/- 2.51 (SD) x 10(-5) M Ca2+ had been added (n = 5). RLM from PTU rats given T3 (100 micrograms/kg daily x 6) showed uptake only until 2.37 +/- 0.59 x 10(-5) M Ca2+ had been added (n = 6) and RLM from normal rats showed uptake until 3.69 +/- 0.53 x 10(-5) M (n = 9) Ca2+ was reached. RLM from the three animal groups lowered the aCa in the SM from 9.13 +/- 1.69 x 10(-6) to 4.96 +/- 2.08 x 10(-6) M regardless of hormonal status. The time in minutes that the aCa remained below the initial level in the rat groups was PTU 94.8 +/- 26.2, PTU + T3, 11.5 +/- 3.9, and normal 26.7 +/- 3.8. All differences were significant at the 0.001 level (ANOVA). bGH did not affect Ca2+ handling by RLM from PTU rats. Administered T3 increased RLM alpha-glycerophosphate dehydrogenase activity 24-36 hr before normalizing Ca2+ handling. The thyroid hormone-sensitive system described here adjusts the SM Ca2+ concentration to a level far above cytosolic so that its function may be to regulate intramitochondrial [Ca2+]. The level of intramitochondrial Ca2+ may be of importance in the mechanism of action of thyroid hormone.

Topics: Animals; Biological Transport; Calcium; Calcium Chloride; Electrochemistry; Hypothyroidism; Male; Mitochondria, Liver; Propylthiouracil; Rats; Rats, Inbred Strains; Thyroid Gland; Triiodothyronine

The possible involvement of a deficit of GH and insulin-like growth factor-I (somatomedin C) (IGF-I/SMC) in mediating the effects of propylthiouracil (PTU)-induced hypothyroidism on body and skeletal growth and myelination was studied in the neonatal rat. Myelination (as assessed by 2',3'-cyclic nucleotide 3'-phosphohydrolase (CNP) activity), skeletal growth (as assessed by tail length) and body weight of pups from PTU-treated mothers were significantly retarded compared with normal animals or euthyroid controls. At 20 days after birth, plasma GH in hypothyroid animals was undetectable (less than 10 micrograms/l), pituitary GH content was 1.2% of control, and plasma, liver and kidney IGF-I/SMC concentrations were 63, 68 and 50% of control values respectively. CNP activity in hypothyroid brain was 52% of normal controls but the concentration of IGF-I/SMC was 113-154% of control. Treatment of hypothyroid animals from day 1 with GH (10 mg/kg body weight per day) restored liver and plasma IGF-I/SMC concentrations at 20 days to values above those of normal animals and euthyroid controls. The concentration of IGF-I/SMC was also significantly (P less than 0.001) restored in hypothyroid kidney (79% of normal), but the concentration in brain was unaffected. These observations provide evidence that the GH treatment employed in the present experiments was adequate to restore the deficit. GH treatment had no significant effect on tail length or CNP activity, and only a small (4-24%) effect on body weight at 20 days. Only thyroxine was able fully to restore body weight and substantially restore tail length and CNP activity.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Female; Growth; Growth Hormone; Hypothyroidism; Insulin-Like Growth Factor I; Myelin Sheath; Propylthiouracil; Rats; Rats, Inbred Strains; Thyroxine

The maturation of fibrous astrocytes was studied in the archicortex (hippocampus) of rats rendered hypothyroid by perinatal administration of propylthiouracil (PTU). A decrease in the number of protoplasmic processes and end-feet in fibrous astrocytes from the cortical molecular layer was observed. The diameter of the perikaryon and length of the prolongations were also decreased. In animals rehabilitated after weaning, the diameter of the perikaryon and length of protoplasmic processes returned to normal while that of number of prolongations per astroglial cell remained unchanged. It is postulated that hypothyroidism induced immediately after birth impairs differentiation of astroglia in the archicortex of the rat brain, probably as a response secondary to altered neuronal and capillary development.

Topics: Animals; Astrocytes; Cell Differentiation; Female; Hippocampus; Hypothyroidism; Male; Propylthiouracil; Rats

In the rat, there is a single TSH beta-subunit gene represented by three exons interrupted by two introns. This gene contains two promoters which determines the synthesis of two mRNAs with 5'-untranslated regions that differ by 43 base pairs. This study evaluates the steady state levels of these TSH beta mRNAs in various thyroidal states. Blot hybridization analyses of pituitary mRNA with synthetic probes designed to detect either one or both TSH beta mRNAs were performed. One probe corresponds to 24 bases in the 5'-untranslated region of mRNA1 and a second corresponds to 25 nucleotides in the coding region and detects both mRNA1 and mRNA2. These studies indicate the presence of TSH beta mRNA species of indistinguishable size consistent with the presence of two TSH beta mRNAs that contain slightly different 5'-untranslated regions. Comparison of pituitary RNA obtained from normal and hypothyroid rats reveals that the shorter mRNA (mRNA2) is increased approximately 6- to 8-fold with hypothyroidism while the abundance of the longer mRNA (mRNA1) is relatively unchanged. Treatment of either normal or hypothyroid animals with T3 decreases the abundance of mRNA2 while again mRNA1 is relatively unaffected. Thus, although both mRNAs are detected, only one mRNA is dramatically altered by thyroidal status. Therefore, the single rat TSH beta gene is transcribed into two mRNAs via the use of alternative promoters of which only one is markedly regulated by thyroid hormones.

Topics: Animals; Gene Expression Regulation; Genes; Hypothyroidism; Male; Nucleic Acid Hybridization; Propylthiouracil; Rats; Rats, Inbred Strains; Reference Values; RNA, Messenger; Thyroid Hormones; Thyrotropin; Transcription, Genetic

Plasma and urinary levels of thiobarbituric acid reactive substances (TBAR) were determined in 24 hyperthyroid patients, 19 hypothyroid subjects, 35 controls, and 17 hyperthyroid patients before and after propylthiouracil (PTU) treatment (400 mg/day for 2-3 months), as indexes of lipid peroxidation. These measurements were carried out together with t-butyl hydroperoxide (t-BHP)-induced oxygen uptake and visible chemiluminescence in erythrocytes as functional tests related to the antioxigenic capacity of cells. Hyperthyroid patients exhibited increased levels of plasma and urinary TBAR compared to controls. Erythrocyte suspensions from hyperthyroid patients showed, compared to controls, higher rates of oxygen consumption with shorter induction periods upon addition of t-BHP, together with 142% and 75% increases in basal and t-BHP-induced chemiluminescence, respectively. Levels of TBAR in untreated hyperthyroid patients in plasma (16.2 +/- 1.3 pmol/mg of protein) and urine (15.9 +/- 1.5 nmol/mg of creatinine) were decreased after PTU treatment (Plasma, 9.5 +/- 0.7, p less than 10(-4); urine, 7.8 +/- 0.9, P less than 10(-5) to values not significantly different from those of the control group (plasma, 10.3 +/- 0.6; urine, 7.9 +/- 0.7). Compared to control, elevated rates of oxygen uptake induced by t-BHP, basal and t-BHP-induced chemiluminescence in erythrocyte suspensions from untreated hyperthyroid patients were reverted to normal by PTU, while decreased induction period (T0) values were enhanced. Determination of these lipid peroxidative parameters in hypothyroid patients revealed no significant changes over control values, excepted t-BHP-induced chemiluminescence in erythrocytes that was diminished. These data indicate that hyperthyroidism is associated with a pro-oxidant condition characterized by an enhancement in circulating and urinary lipid peroxidative indexes, which is suppressed by PTU treatment. It is suggested that this condition might reflect an oxidative stress at cellular level in tissues which are target for thyroid hormone action with a calorigenic response.

Topics: Adult; Erythrocytes; Female; Humans; Hyperthyroidism; Hypothyroidism; Kinetics; Lipid Peroxidation; Male; Oxygen Consumption; Propylthiouracil; Reference Values

Topics: Animals; Cholesterol; Fatty Acids; Hypothyroidism; Lipids; Liver; Male; Phospholipids; Propylthiouracil; Rats; Rats, Inbred Strains

Topics: Animals; Disease Models, Animal; Histological Techniques; Hypothyroidism; Liver; Male; Mice; Propylthiouracil

The pharmacokinetic disposition of propylthiouracil (PTU) after a single oral dose was studied in 6 severely hypothyroid patients. Severity of disease, as indicated by thyroid-stimulating hormone concentration, was inversely related to plasma clearance of PTU. There were trends to increased apparent volume of distribution and plasma half-life for PTU as a function of age. The large apparent volume of distribution for PTU in these patients compared to euthyroid and hyperthyroid subjects, after a single drug dose, suggests that hypothyroidism as well as chronic drug ingestion must be considered as possible factors mediating this change.

Topics: Aged; Female; Humans; Hypothyroidism; Male; Middle Aged; Propylthiouracil; Thyroid Function Tests

The reversibility of the effects of propylthiouracil induced neonatal hypothyroidism by daily subcutaneous injections of L-thyroxine (T4) was investigated in the rat. Four groups of rat pups were used in this experiment: Group I (control) received equivalent amounts of saline subcutaneously; Group II (hypothyroid) received propylthiouracil injections daily; Group III (T4-14) are hypothyroid rats who received daily T4 replacement therapy (2.5 micrograms/day) subcutaneously starting on Day 14; Group IV (T4-21) are also hypothyroid rats whose T4 replacement therapy (2.5 micrograms/day) was started on Day 21. The four parameters studied were body length, body weight, brain weight, and cerebellar weight in these four groups of animals at 4, 7, 10, 14, 21, 28, 35, and 42 postnatal days. A minimum of eight animals were studied for each time sequence. The present study clearly indicated the beneficial effect of T4 therapy on the length and body weight of the hypothyroid animals, whether therapy was started at Postnatal Day 14 or 21. In addition, a more important finding of this study was the significant increase in brain and cerebellar weights of T4-treated animals compared to the hypothyroid animals, this beneficial effect being more striking in the T4-14 group when compared to that in the T4-14 animals.

Topics: Animals; Animals, Newborn; Body Weight; Brain; Cerebellum; Hypothyroidism; Organ Size; Propylthiouracil; Rats; Rats, Inbred Strains; Thyroxine

Hypothyroidism was induced in rats by treatment with propylthiouracil through the mother's milk throughout the suckling period followed by surgical thyroidectomy without use of radioiodine. The growth of these animals was considerably retarded and their light-dark discriminative operant learning ability was also significantly decreased. Replacement therapy with thyroxine to maintain its normal serum concentration was effective for continuing normal growth and development of learning ability. Therefore, these hypothyroid rats are a useful model of congenital hypothyroidism. Biochemical studies showed that the inhibition of cerebral Na,K-ATPase and succinic dehydrogenase activities detected in early postnatal life in these hypothyroid rats was transient and that normal activities of these enzymes were later regained in adult rats. However, the activity of 2',3'-cyclic nucleotide 3'-phosphohydrolase and the brain myelin remained low throughout life unless thyroxine was administered. Though a critical correlation between biochemical parameters and learning ability is still uncertain, these results suggest that the formation of myelin in the neonatal period is at least dependent on thyroid hormone and would play an important role in mental development.

Topics: Animals; Body Weight; Brain Chemistry; Conditioning, Psychological; Congenital Hypothyroidism; Disease Models, Animal; Hypothyroidism; Learning; Organ Size; Propylthiouracil; Rats; Rats, Inbred Strains; Thyroidectomy; Thyroxine

Using a DNase I inhibition assay, in the presence or the absence of guanidine hydrochloride (which depolymerizes the actin filaments), developmental changes in total and filamentous actin were determined in the cerebellum of normal and hypothyroid rats. The total actin content per mg protein was not modified by hypothyroidism. As in normal animals, it reached a maximum around the age of 8 days and then decreased until adulthood. In contrast, the proportion of filamentous actin, which increased after the first postnatal week during normal development, was significantly reduced in the thyroid-deficient rats, only reaching normal values at 35 days. Thyroxine treatment for at least 4 days returned the filamentous actin content to normal at 14 days. The present study shows that the morphogenetic action of thyroid hormone is exerted not only on the microtubular apparatus, as previously described, but also in part through a control of actin monomer-polymer equilibrium.

Topics: Actins; Aging; Animals; Cerebellum; Hypothyroidism; Propylthiouracil; Rats; Rats, Inbred Strains; Reference Values

Topics: Adolescent; Adult; Antibodies, Antinuclear; Antithyroid Agents; Autoantibodies; Female; Graves Disease; Humans; Hypothyroidism; Male; Middle Aged; Propylthiouracil

This study was designed to determine if peroxidation of biomembrane lipid and the protective system can be modified by the change in oxidative metabolism induced by thyroid dysfunction. The free radical scavengers (i.e. cuprozinc cytosolic and mangano mitochondrial superoxide dismutases, glutathione peroxidase, and catalase), mitochondrial oxidative marker enzymes (cytochrome c oxidase and fumarase), and lipid peroxide were measured in liver, heart, soleus (slow oxidative), and extensor digitorum longus (fast glycolytic) muscles. Rats were rendered hyper- or hypothyroid for 4 weeks and then killed. Superoxide dismutases were detected by specific RIAs: catalase by polarography, and lipid peroxide by fluorimetry. Hypothyroid rats failed to grow, while hyperthyroid rats had hypertrophied hearts but no growth failure. An increase in lipid peroxide was observed in the soleus and heart muscles of hyperthyroid rats. This was accompanied by an increase in mitochondrial superoxide dismutase and oxidative markers. No such change was observed in either fast glycolytic muscle or liver. Glutathione peroxidase decreased in all tissues of hyperthyroid rats, and there was a parallel decrease in catalase in most tissues. On the other hand, hypothyroidism induced a reduction in oxidative markers and mitochondrial superoxide dismutase in heart and skeletal muscles, but only a marginal change in lipid peroxidation. The cytosolic superoxide dismutase did not change in relation to either oxidative metabolism or lipid peroxidation. These results suggest that the enhanced oxidative metabolism and decreased glutathione peroxidase in hyperthyroidism result in an increase in lipid peroxidation and, in slow oxidative and heart muscle, possible organ damage. No adverse reaction mediated by active oxygen species was found in hypothyroid rat tissues.

Topics: Animals; Catalase; Electron Transport Complex IV; Free Radicals; Fumarate Hydratase; Glutathione Peroxidase; Heart; Hyperthyroidism; Hypothyroidism; Lipid Peroxides; Male; Muscles; Propylthiouracil; Rats; Rats, Inbred Strains; Superoxide Dismutase; Thyroid Diseases; Thyroxine; Triiodothyronine

Hypothyroid rats showed increased behavioral sensitivity to both selective and non-selective dopamine agonists. Ligand binding analysis revealed no differences in concentration or affinity of striatal dopamine receptor subtypes in hypothyroid rats. Measurement of striatal cAMP levels however, indicated that hypothyroid rats showed a greater increase in cAMP production in response to stimulation by dopamine. It is concluded that the changes in behavioural sensitivity observed may be associated with alterations in post-synaptic mechanisms.

Topics: 2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine; Adenylyl Cyclases; Animals; Apomorphine; Behavior, Animal; Benzazepines; Corpus Striatum; Cyclic AMP; Dopamine; Ergolines; Hypothyroidism; Male; Propylthiouracil; Quinpirole; Rats; Rats, Inbred Strains; Receptors, Dopamine; Receptors, Dopamine D1; Receptors, Dopamine D2

The effects of propylthiouracil (PTU) treatment on renal vasopressin sensitive adenylate cyclase in young and adult rats were studied by measuring the binding of tritiated vasopressin and adenylate cyclase activation by vasopressin in kidney medulla plasma membranes. Thyroxine therapy completely corrected the effects of PTU treatment on the vasopressin-adenylate cyclase system. Thus, the abnormalities observed after a such treatment are directly related to thyroid deficiency and not to toxic effects of PTU. The inability of the kidney to normally concentrate urine in developing and adult animals with induced hypothyroidism was mainly related to the reduction of the number of binding sites without significant changes in the basal and guanylyl-imidodiphosphate (Gpp(NH)p)-stimulated adenylate cyclase activities, the apparent dissociation constant (Kbind) of labeled vasopressin from its specific receptor and the apparent activation constant (Kact) of vasopressin for adenylate cyclase. These results also show that thyroid deficiency has more effect on the ontogenesis of receptors than on their turnover, and demonstrate that a normal antidiuretic response occurs at very low receptor occupancy. Since, on the one hand, the hypothyroidism-induced abnormalities in renal medulla responsiveness to vasopressin were reversible and, on the other, only a permanent therapy consisting of two daily physiological doses of thyroxine from birth to the age of sacrifice fully restored them, the responsiveness of developing kidney to thyroid hormones appears to be fundamentally different from that of the CNS.

Topics: Adenylyl Cyclases; Animals; Enzyme Activation; Guanylyl Imidodiphosphate; Hypothyroidism; Kidney; Osmolar Concentration; Propylthiouracil; Rats; Receptors, Angiotensin; Receptors, Vasopressin; Thyroxine; Urine; Vasopressins

Glycolytic metabolism has been assessed by studying a set of key enzymes, in anterior cortex, amygdala, hypothalamus septum and hippocampus, in thyroidectomized rats. The reversibility of the changes induced by the thyroidectomy has been assessed by replacement therapy. In thyroidectomized rats the hexokinase activity was significantly decreased in anterior cortex and hypothalamus. The increase in phosphofructokinase and pyruvate kinase activity was probably due to an increase in cellular energy requirements. Hexokinase activity was best restored by treatment with L-thyroxine (T4) or T4+ propylthiouracil (PTU). The low response of pyruvate kinase activity in all treated animals could suggest that this metabolic step is the least reversible.

Topics: Animals; Animals, Newborn; Brain; Glycolysis; Hexokinase; Hypothyroidism; L-Lactate Dehydrogenase; Male; Phosphofructokinase-1; Potassium Iodide; Propylthiouracil; Pyruvate Kinase; Rats; Rats, Inbred Strains; Thyroidectomy; Thyroxine; Triiodothyronine

The effects of propylthiouracil (PTU) treatment on the plasma vasopressin level, on the number of hepatic (V1) or renal (V2) vasopressin receptors and on the hormone-sensitive adenylate cyclase activity in the kidney of developing rats were studied in parallel. In addition, we investigated the corrective effects of thyroxine therapy on the plasma vasopressin level and parameters related to the liver, and the effects of vasopressin therapy on the parameters related to the kidney. As already reported in the case of the number of V2 receptors and adenylate cyclase activity in the kidney, the deficient plasma vasopressin level in hypothyroid rats was completely corrected by two daily physiological doses of thyroxine given from birth to the age of sacrifice (1 month). Unlike the V1 receptors, the V2 receptors are known to be highly dependent on their specific circulating ligand. Since, first of all, the deficit was similar in the numbers of V1 and V2 receptors in hypothyroid rats, and, secondly, the treatment of hypothyroid rats by two daily physiological doses of long lasting vasopressin was found ineffective to recover the deficit in the number of V2 receptors, it can be concluded that thyroid deficiency directly alters vasopressin receptor biosynthesis in both liver and kidney, instead of acting via the depressed plasma vasopressin level.

Topics: Animals; Congenital Hypothyroidism; Hypothyroidism; Kidney; Liver; Propylthiouracil; Rats; Rats, Inbred Strains; Receptors, Angiotensin; Receptors, Vasopressin; Thyroxine; Vasopressins

Thyrotrophin-releasing hormone (TRH) occurs in high concentrations in the rat ventral prostate and its concentrations is regulated in a positive dose-response manner by testosterone in castrated rats. alpha-Amidation of the tetrapeptide precursor, TRH-Gly, is a rate-limiting step in TRH biosynthesis. To investigate further the hormonal regulation of TRH biosynthesis in prostatic tissue, Sprague-Dawley rats of approximately 250 g were injected s.c. with either physiological saline or 3 mg propylthiouracil (PTU) daily for 5 days. The reproductive tissues were boiled in acetic acid (l mol/l), dried and extracted with methanol. The methanol extracts were measured for TRH immunoreactivity (TRH-IR) and TRH-Gly-IR by radioimmunoassay. Hypothyroidism induced by PTU significantly increased TRH-IR and TRH-Gly-IR levels in prostate and testis and reduced these levels in epididymis but did not affect the serum concentrations of testosterone compared with those of controls. Corresponding changes in TRH and TRH-Gly in the rat prostate were established by high-pressure liquid chromatography. To control for possible pharmacological effects of PTU on TRH biosynthesis, additional experiments were carried out on castrated rats receiving testosterone replacement and treatment with PTU plus methimazole. Treatment with thyroxine (T4) significantly reduced the increase in prostatic TRH levels due to hypothyroidism, despite the drug-induced blockade of the conversion of T4 to tri-iodothyronine. These effects parallel similar observations made in rat spinal cord and pancreas. This study demonstrates that in the male rat reproductive system the levels of TRH and its immediate biosynthetic precursor, TRH-Gly, are regulated by thyroid hormones.

Topics: Animals; Hypothyroidism; Male; Methimazole; Orchiectomy; Propylthiouracil; Prostate; Pyrrolidonecarboxylic Acid; Rats; Rats, Inbred Strains; Testis; Thyroid Hormones; Thyrotropin-Releasing Hormone

Cellular levels of messenger RNA encoding thyrotropin-releasing hormone (TRH) were measured in the paraventricular nucleus of the hypothalamus and the reticular nucleus of the thalamus in male rats after chemical thyroidectomy and thyroid hormone replacement. TRH mRNA levels were measured by quantitative in situ hybridization histochemistry using a 35S-labeled synthetic 48-base oligodeoxynucleotide probe and quantitative autoradiography. Chemical thyroidectomy, produced by the administration of 6-(n-propyl)-2-thiouracil (PrSur), reduced plasma thyroxine below detection limits and significantly increased TRH mRNA in the paraventricular nucleus. Treatment with exogenous L-triiodothyronine (T3) reduced TRH mRNA to the same level in both hypothyroid and euthyroid animals. Neither PrSur treatment nor T3 replacement influenced TRH mRNA levels in the reticular nucleus of the thalamus. Blot hybridization analysis of electrophoretically fractionated total RNA from pituitaries of these animals indicated that thyrotropin-beta mRNA levels were elevated after thyroidectomy and reduced by T3 treatment, showing that the pituitary-thyroid axis was indeed stimulated by PrSur treatment. These results suggest that thyroid hormones are involved, either directly or indirectly, in regulating the biosynthesis of TRH in the thyrotropic center of the hypothalamus.

Topics: Animals; Feedback; Gene Expression Regulation; Hypothalamo-Hypophyseal System; Hypothyroidism; Male; Paraventricular Hypothalamic Nucleus; Propylthiouracil; Rats; Rats, Inbred Strains; RNA, Messenger; Thalamic Nuclei; Thyrotropin-Releasing Hormone; Triiodothyronine

The concentrations of glycogen phosphorylase protein were determined by rocket immunoelectrophoresis in liver extracts from rats that had artificially induced altered hormonal patterns. These levels were compared with measurements of total phosphorylase activity. Minipump-induced chronic hyperglucagonemia and streptozotocin-induced diabetes resulted in 47% and 67% decreases, respectively, in total phosphorylase activity along with corresponding 52% and 68% drop, respectively, in phosphorylase protein levels. Insulin replacement in diabetic rats returned both parameters to control values. Minipump-induced hyperinsulinemia or injection of glucagon antiserum, T3, or propylthiouracil had no effect. The results of this study indicate that conditions which lead to an elevation of the glucagon to insulin molar ratio to values higher than 1.0 cause a significant decrease in the liver phosphorylase protein level.

Topics: Animals; Diabetes Mellitus, Experimental; Glucagon; Hyperthyroidism; Hypothyroidism; Immune Sera; Insulin; Liver; Male; Phosphorylases; Propylthiouracil; Rats; Rats, Inbred Strains; Triiodothyronine

Neonatal hypothyroidism accelerates the postnatal evolution of the adrenal dopamine (DA) content and concentration in the young rat. In 14-day-old control animals, insulin-hypoglycaemia leads to a transient increase in adrenal dopamine content up to 159% above the value in saline-injected animals. This increase is already at its maximum 1 h after insulin administration and lasts 7 h. In the hypothyroid animals, the DA increase evoked by hypoglycaemia is impaired in magnitude (74%) and duration (4 h).

Topics: Adrenal Glands; Animals; Animals, Newborn; Dopamine; Female; Hypoglycemia; Hypothyroidism; Insulin; Male; Propylthiouracil; Rats; Rats, Inbred Strains; Thyroid Gland; Triiodothyronine

Thyroid hormone effects on the developing rat brain were analyzed regarding the nucleic acid contents and the rate of protein synthesis using PTU induced neonatal hypothyroid rat as a model for human congenital hypothyroidism. Significantly reduced amount of total DNA contents per brain and protein/DNA ratio were demonstrated in both cerebrum and cerebellum of the hypothyroid rat after 14 days, suggesting the disturbed cell formation and cell growth in the hypothyroid rat brain. And the maturation of the cerebellum extended later into postnatal life than does that of the cerebrum. Additional evidence by the reduced rate of protein synthesis in the hypothyroids would correlate with these altered morphogenesis. Postmitochondrial supernatant (PMS) obtained from both control and hypothyroid brain homogenate, which was used for the experiment of protein synthesis, contained the same amount of the RNA contents. Therefore the defective protein synthesis might be attributed to the disturbed translational process of the genetic message in protein.

Topics: Animals; Brain; Congenital Hypothyroidism; DNA; Female; Hypothyroidism; Maternal-Fetal Exchange; Nerve Tissue Proteins; Pregnancy; Propylthiouracil; Rats

Several investigations have suggested that a special relationship exists between thyroid function and affective disorders and/or therapeutic response to antidepressants. The present study shows that the reversal by clomipramine, desipramine, imipramine and nialamide of depressive-like behavior in rats (escape deficits produced by previous exposure to uncontrollable stress) was markedly attenuated in hypothyroid rats (propylthiouracil, 0.05% in the drinking water). Conversely, the effect of these same antidepressants was significantly hastened in euthyroid rats given daily triiodothyronine. This supports the notion of intricate thyroid/CNS interactions in the mechanisms of action of antidepressant drugs.

Topics: Animals; Antidepressive Agents; Brain; Clomipramine; Desipramine; Dose-Response Relationship, Drug; Escape Reaction; Hypothyroidism; Imipramine; Male; Nialamide; Propylthiouracil; Rats; Rats, Inbred Strains; Thyroid Gland; Triiodothyronine

Light microscopic morphometric procedures were used in order to examine the effects of propylthiouracil (PTU) on the development of the mesencephalic nucleus of the trigeminal nerve in the duck. A single vascular injection of a 0.2% solution of PTU was administered at a dosage of 2 microliter/gm embryo weight on embryonic day nine (E9). Control embryos received a similar dose of Ringer's solution. The following parameters of cytodifferentiation of cells of the mesencephalic nucleus of V were studied: somal area profiles, nuclear area, and nuclear cytoplasmic ratios. In addition, the frequency of beak clapping was recorded from E16. Significant differences were observed in somal area profiles in the experimental group at E16 and E18 and in nuclear area profiles from E16 through hatching. Beak activity in the experimental embryos was drastically reduced. It is concluded that PTU induces a retardation in the differentiation of cells of the mesencephalic nucleus of V which may lead to behavior deficits as evidenced by reduction of beak activity. These observations provide a basis for the study of interactions between thyroid hormone and specific neuronal systems in the emergence of an adaptive function.

Topics: Animals; Beak; Ducks; Hypothyroidism; Mesencephalon; Neurons; Propylthiouracil; Thyroid Gland; Trigeminal Nuclei

Natural killer (NK) activity of peripheral blood lymphocytes from hyperthyroxinemic patients (Graves' disease or thyroxine (T4)-treated) is severely depressed. In order to study the relationship of thyroid hormone to NK activity, a model for hyperthyroxinemia was induced in mice by addition of T4 to the drinking water. Control mice were hypothyroid (fed propylthiouracil) or normal. Serum T4 levels were elevated (within 2 wk) in mice fed thyroid hormone. Six weeks after initiation of the diets, in vitro NK activity was undetectable in the peripheral blood, spleen, or lung mononuclear cell populations harvested from hyperthyroxinemic mice. Control mice had NK activity within the normal range. Spleen cells from mice fed thyroid hormone and control mice were tested for their ability to release lytic factors (natural killer cytotoxic factors). Lymphoid cells were incubated for 20 hr with unlabeled Yac-1 cells. Supernatants were tested for their capacity to lyse 51Cr-labeled Yac-1 cells in a 20-hr chromium release assay. Unlike controls, supernatants from hyperthyroxinemic spleen cells incubated with Yac-1 targets were unable to lyse 51Cr-Yac-1 cells. The NK cells from the mice fed T4 synthesized lytic factors because nonspecific stimuli, such as 12-O-tetradecanoyl phorbol-13-acetate and the calcium ionophore A23187, induced release of lytic factors capable of lysing Yac-1 targets into the media. These data support the hypothesis that excess thyroid hormone interferes with the triggering mechanism used by NK targets to cause release of lytic molecules from NK cells.

Topics: Animals; Cytotoxicity Tests, Immunologic; Disease Models, Animal; Female; Graves Disease; Hypothyroidism; Interleukin-2; Killer Cells, Natural; Killer Factors, Yeast; Leukocyte Count; Mice; Mice, Inbred C57BL; Propylthiouracil; Proteins; T-Lymphocytes; Thyroxine

The effect of thyroid deficiency on the activity of phosphate-activated glutaminase (the marker for glutamatergic neurons) was studied in different parts of the rat brain at ages 5, 10, 15 and 25 days, and at day 130 following 102 days of rehabilitation. The brain regions investigated were the cerebral cortex, basal forebrain, hippocampus and cerebellum. During normal development, the activity of glutaminase increased relatively earlier in the cerebral cortex and hippocampus than in the cerebellum, while the absolute value reached a much higher level in the hippocampus than in other brain regions. In the basal forebrain, the developmental pattern of glutaminase was bimodal, and the rise in enzyme activity after 15 days coincided with the decrease in the cerebral cortex. These regional developmental changes in glutaminase activity correlated well with known information on the formation of glutamatergic cells and pathways in the brain. Neonatal thyroid deficiency had little effect on the developmental patterns of enzyme activity, the exception being a transient decrease in 10-day-old hypothyroid hippocampus. The present results, together with previous findings, indicate that the effect of thyroid hormone on neural maturation is cell-type specific and the glutamatergic neurons are not the main targets of thyroid hormone action.

Topics: Aging; Animals; Brain; Glutaminase; Hypothyroidism; Propylthiouracil; Rats; Thyroid Hormones

Thyroid hormones are important regulators of GH synthesis and secretion. In this study we have made a detailed examination of the time-course of the effects of hypothyroidism and tri-iodothyronine (T3) replacement in the intact rat on GH gene expression in the anterior pituitary gland. Changes in pituitary cytoplasmic GH messenger (m)RNA levels were compared with total pituitary GH content and serum GH concentration during the development of hypothyroidism and following short-term T3 replacement in vivo. Hypothyroidism was associated with a fall in pituitary GH mRNA levels. Treatment of hypothyroid animals with T3 rapidly stimulated GH mRNA levels to values above those seen in euthyroid controls. The reduction in GH mRNA levels seen during the development of hypothyroidism was accompanied by a fall in serum GH and pituitary GH content, both of which were partially restored by T3 replacement. Thus thyroid hormone replacement in hypothyroidism rapidly stimulates GH mRNA synthesis, which is followed by the gradual restoration of pituitary GH stores and serum GH concentration.

Topics: Animals; Electrophoresis, Agar Gel; Female; Gene Expression Regulation; Growth Hormone; Hypothyroidism; Pituitary Gland; Propylthiouracil; Rats; Rats, Inbred Strains; RNA, Messenger; Triiodothyronine

The effect of hypothyroidism on plasma and erythrocyte membrane lipid components has been investigated. This pathological state is accompanied by a) a cholesterol increase of about 60% in plasma, and at the same time a 22% reduction in erythrocyte membranes; b) 44% and 30% phospholipid level decreases in both plasma and red cell membranes, respectively; and c) almost unaffected phospholipid and fatty acid compositions of both plasma and erythrocyte membranes. All changes were corrected by treatment of the hypothyroid rats with triiodothyronine for two days. These findings suggest that in hypothyroid rats a reduced transfer of cholesterol from plasma to erythrocyte membrane probably takes place. This could explain, at least in part, the increased hematic cholesterol level observed in hypothyroid animals. In red cell membranes, the simultaneous decrease in cholesterol and phospholipid levels does not alter the cholesterol/phospholipid molar ratio, thus avoiding their abnormal function.

Topics: Animals; Cholesterol; Chromatography, High Pressure Liquid; Erythrocyte Membrane; Fatty Acids; Hypothyroidism; Lipids; Male; Phospholipids; Plasma; Propylthiouracil; Rats; Rats, Inbred Strains

The flow rate of portal plasma was measured during hypothalamo-hypophysial portal sampling in the rat using a modified Worthington-Fink technique. In rats rendered hypothyroid with propylthiouracil, there was a significant 140% increase in portal plasma flow. Median eminence stimulation also increased portal plasma flow by 41%. Orchidectomy and adrenalectomy had no effects on plasma flow. Modification of flow rate in the hypothalamo-hypophysial vascular bed may represent a further mechanism involved in the control of pituitary function.

Topics: Adrenalectomy; Animals; Hypothalamo-Hypophyseal System; Hypothyroidism; Male; Orchiectomy; Pituitary Gland; Propylthiouracil; Rats; Rats, Inbred Strains; Regional Blood Flow

The development of the febrile response to E. coli lipopolysaccharide (1.5 micrograms/kg, i.v.) in thyroid-deficient rabbits has been studied. Twenty-eight New Zealand White rabbits weighing 2.1-2.3 kg were used. Hypothyroidism was induced by treatment with propylthiouracil (100 or 200 mg/kg body wt./15 days). Thyroid-deficient animals showed a reduction in the febrile response to lipopolysaccharide, but the effect was significantly different (p less than 0.01) from the control only for rabbits treated with 200 mg/kg of propylthiouracil. Propranolol (2 mg/kg, i.p.) given 30 min before lipopolysaccharide also reduced (p less than 0.01) the fever response in control rabbits. The results of this experiment are consistent with the hypothesis that the reduction in the febrile response of thyroid-deficient rabbits is due to the reduced number of beta-adrenergic receptors, or to a change in the availability of neurotransmitter in thermogenically active tissues, such as brown fat.

Topics: Animals; Body Temperature; Fever; Hypothyroidism; Lipopolysaccharides; Male; Propranolol; Propylthiouracil; Pyrogens; Rabbits

The effect of corticosterone and thyroxine on the development of parietal cells was studied in 20-day-old rats. Either corticosterone or thyroxine injection significantly increased the amount of mitochondria, tubulovesicles, and intracellular canaliculi in normal rat pup parietal cells. However, the ultrastructure of parietal cells did not change when rats were adrenalectomized or made hypothyroid by propylthiouracil (PTU) during the first week of life. Corticosterone had the same effect in hypothyroid rats as in normal rats, increasing the volume fraction of mitochondria and the surface density of tubulovesicles and intracellular canaliculi in the parietal cell. However, thyroxine failed to do so in adrenalectomized animals. When 20-day-old adrenalectomized or hypothyroid rats were challenged with secretagogues, there was no increase in maximal acid output over the basal secretory rate, while normal rats showed a 40-50% increase. We conclude that 1) normal parietal cells respond to additional thyroxine or corticosterone with increases in volume fraction of mitochondria and surface density of tubulovesicles and intracellular canaliculi; 2) the dramatic decreases in acid secretion observed in adrenalectomized or PTU-treated rats are not explained by the morphology of parietal cells that remains normal; 3) the effect of thyroxine on the development of acid secretion is mediated by corticosterone; and 4) unlike chief cells the morphological development of parietal cells does not appear to depend on corticosterone or thyroxine after postnatal day 7.

Topics: Adrenalectomy; Animals; Corticosterone; Hypothyroidism; Microscopy, Electron; Parietal Cells, Gastric; Propylthiouracil; Rats; Rats, Inbred Strains; Thyroxine

This study has examined the karyometric changes within pyramidal neurons of the hippocampus, motor area 6 and visual area 17 in a hypothyroid group of male mice treated with propylthiouracil, with or without interruption of treatment at the 35th postnatal day. Hypothyroidism resulted in decrease of nuclear size in the three areas before puberty and even after puberty in the hippocampus. Where the treatment was continued throughout the experimental period there was a progressive increase of nuclear size in both visual and motor areas.

Topics: Animals; Cell Nucleus; Cerebral Cortex; Hippocampus; Hypothyroidism; Male; Mice; Mice, Inbred Strains; Motor Cortex; Neurons; Propylthiouracil; Visual Cortex

Total L-thyroxine and triiodo-L-thyronine serum concentrations have been measured in 70-day-old male rats under normal conditions (controls) and in rats subjected to several experimental alterations of the thyroid function: hyperthyroidism, hypothyroidism and substitutive treatments. Since some problems appear when standard curves are performed with hormone serum, as consequence of differences in the affinity and inhibitory effects between heterologous proteins at the antigen-antibody reaction, RIA in this work has been carried out with standard curves performed with rat serum maintaining similar protein concentrations in standard and problems. This modification avoids errors by the use of extraction methods and shows a high degree of similarity between standard and problems.

Topics: Animals; Blood Proteins; Hyperthyroidism; Hypothyroidism; Male; Propylthiouracil; Radioimmunoassay; Rats; Thyroidectomy; Thyroxine; Triiodothyronine

The effect of thyroid deficiency on the activity of choline acetyltransferase (ChAT; the marker for cholinergic neurons) was studied in different parts of the rat brain at ages 5, 10, 15 and 25 days, and at day 130 following 102 days of rehabilitation. During normal development, the activity of ChAT increased in the cerebral cortex, hippocampus and basal forebrain, and decreased in the cerebellum. Neonatal thyroid deficiency resulted in a marked retardation of the developmental patterns of the enzyme activity. In the hippocampus the effect diminished with age even during the period of thyroid hormone deprivation, while in the cerebral cortex and cerebellum the enzyme activity was restored to normal only after rehabilitation. In contrast, ChAT activity in the basal forebrain remained persistently reduced in comparison with controls. The results indicate that neonatal thyroid deficiency causes selective irreversible biological damage to subcortical cholinergic neurons.

Topics: Aging; Animals; Choline O-Acetyltransferase; Frontal Lobe; Hypothyroidism; Male; Propylthiouracil; Rats

Adult mice made hypothyroid with propylthiouracil (PTU) lose their sense of smell. This is prevented by daily administration of thyroxine. As thyroxine is necessary for the correct development of the nervous system it may also be necessary for the genesis of new olfactory receptor neurones, a process that continues into adulthood. Adult mice were treated with PTU, injected with [3H]thymidine after 54 days and killed 5 or 15 days later. Microscopic analysis of the olfactory epithelium after autoradiography revealed similar numbers of labelled nuclei in the basal cell layer of the olfactory epithelia of Control and Hypothyroid mice 5 days after injection with [3H]thymidine. This indicated similar rates of basal cell division in the two groups. Fifteen days after [3H]thymidine injection, however, there were fewer labelled nuclei in the receptor cell layer of Hypothyroid mice and the olfactory epithelium was thinner than in Controls. Thyroxine therapy which reversed PTU-induced anosmia also reversed the epithelial effects of PTU treatment. Somewhat unexpectedly, there were no differences between the treatment groups in the average diameter of glomeruli in the olfactory bulb, and no differences in the expression of olfactory marker protein. The results indicate that although hypothyroidism disrupts neural development in the olfactory epithelium, it does not lead to a complete loss of mature receptor neurones.

Topics: Animals; Autoradiography; Cell Nucleus; Central Nervous System; DNA Replication; Epithelial Cells; Hypothyroidism; Male; Mice; Nasal Mucosa; Olfactory Pathways; Propylthiouracil; Smell; Thyroxine; Tritium

The effect of congenital thyroid deficiency upon the postnatal development of the rat kidney has been studied by measuring the nucleic acid, protein and lipid contents, and the area and thickness of the different regions in the organ, i.e. cortex, outer and inner medulla. Thyroid deficiency, induced by daily propylthiouracil treatment, strongly affects the development of the renal cortex. The medulla, and still more its inner part which develops early and partly before the onset of thyroid function, is relatively preserved. These effects are completely corrected by daily thyroxine therapy, excluding a possible toxic effect of the antithyroid drug. Moreover, they are partly reversible after cessation of propylthiouracil treatment.

Topics: Aging; Animals; Congenital Hypothyroidism; DNA; Female; Hypothyroidism; Kidney; Kidney Cortex; Kidney Medulla; Lipid Metabolism; Male; Organ Size; Propylthiouracil; Proteins; Rats; Rats, Inbred Strains; RNA

Sequential changes in thyroid-stimulating antibodies (TSAb) and TSH-binding inhibitor immunoglobulins (TBII) during antithyroid drug treatment were studied in 17 patients with Graves' disease. Before treatment, TSAb and TBII were detected in 17 (100%) and 13 (76.5%) patients, respectively, with a significant correlation between the two activities (r = 0.600, n = 17, P less than 0.02). In 9 patients who became euthyroid as early as after 1-4 months of treatment, the TSAb and TBII activities both gradually decreased, and there was a good correlation between the changes of these activities during treatment. Among the 7 patients in whom small changes in TSAb and TBII activities were observed, 4 showed poor control of the thyrotoxicosis during the whole observation period (7 months-2 years). One patient who showed a marked dissociation between the changes in TSAb and TBII activities developed hypothyroidism, when his TBII became remarkably high. These potent TBII inhibited cAMP production induced by bTSH. These findings indicate that 1) changes in TSAb and TBII activities reflect the clinical course of hyperthyroidism in most patients with Graves' disease, and 2) development of a blocking-type of TBII may induce hypothyroidism in some patients after the treatment.

Topics: Adolescent; Adult; Antithyroid Agents; Female; Graves Disease; Humans; Hypothyroidism; Immunoglobulin G; Immunoglobulins, Thyroid-Stimulating; Male; Methimazole; Middle Aged; Propylthiouracil

An animal model for clinically observed clofibrate (p-chlorophenoxy isobutyrate, CPIB)-induced toxicity has been tested. It is demonstrated that propylthiouracil-induced hypothyroid-hyperlipidemic chick develops severe toxic manifestations following clofibrate administration. Toxic symptoms are characterized by listlessness, drowziness, and extreme muscular weakness. This is associated with elevation of blood urea nitrogen, creatine phosphokinase, uric acid and glutamic oxaloacetic transaminase. Histological examination of muscle specimen from chicks exhibiting toxic syndrome showed degeneration and vacuolization of muscle fibers. The biochemical and histological changes observed are quite similar to those reported in clinical practice in some patients given clofibrate. It is suggested that this chick model could be used to investigate the biochemical basis of clofibrate toxicity.

Topics: Animals; Chickens; Clofibrate; Hyperlipidemias; Hypothyroidism; Male; Muscles; Propylthiouracil

To characterize the nuclear receptor believed to mediate the thyroid hormones' actions on the heart, binding of L-[125I]T3 to extracts of myocardial cell nuclei from normal, propylthiouracil, and T4-treated rats has been investigated. Analysis of in vitro iodothyronine binding to this solubilized nuclear preparation revealed multiple saturable, specific binding sites for T3. High affinity binding for T3 (Kd = 4.2 +/- 1.0 X 10(-10) mol/L), and lower affinity (Kd approximately 10(-8) mol/L) binding activity appeared to be independent (Hill plot slope = 1). The mean maximal binding capacity of the high affinity binding site for T3 in euthyroid rats (84 +/- 8 fmol/mg DNA) was increased by approximately 50% in hypothyroidism (120 +/- 6 fmol/mg DNA) and unchanged in hyperthyroidism (88 +/- 25 fmol/mg DNA). The molecular weight of this T3 binding site is estimated to be 50,000-55,000 daltons. The properties of this solubilized binding activity from rat myocardial nuclei are consistent with its putative role as the biologic thyroid hormone receptor. The increase in binding capacity with hypothyroidism suggest regulation by thyroid hormone of its nuclear receptor in myocardium.

Topics: Animals; Binding, Competitive; Cell Nucleus; Chromatography, Gel; Hydrogen-Ion Concentration; Hyperthyroidism; Hypothyroidism; Kinetics; Male; Myocardium; Propylthiouracil; Radioligand Assay; Rats; Receptors, Cell Surface; Receptors, Thyroid Hormone; Solubility; Temperature; Thyroxine

Cyclic-AMP-dependent protein kinase from the soluble fraction of parotid glands of hypothyroid rats was partially purified. Its isozyme distribution and kinetic properties were similar to those of euthyroid rats. Electrophoresis of 100 microliters portions at 20 mA per slab revealed that an endogenous protein (mol. wt 68,000) was specifically phosphorylated in hypothyroidism; this protein was not found in euthyroid rats. In the presence of cyclic AMP, there was stimulated phosphorylation of euthyroid-soluble proteins with molecular weights of 115,000, 98,000, 57,000, 50,000, 44,000, 33,000 and 19,000, and of proteins from hypothyroid rats with weights of 115,000, 98,000, 60,000, 50,000, 33,000 and 19,000. Tolbutamide reduced incorporation of 32Pi into soluble proteins from both groups. However, cyclic AMP still induced phosphorylation in euthyroid preparations in the presence of tolbutamide, but its effect was markedly reduced in the hypothyroid state. These differences in endogenous protein phosphorylation may have different effects on amylase release induced by beta-adrenergic stimulation.

Topics: Animals; Chromatography, DEAE-Cellulose; Cyclic AMP; Dose-Response Relationship, Drug; Hypothyroidism; Magnesium; Male; Parotid Gland; Phosphoproteins; Phosphorylation; Propylthiouracil; Protein Kinases; Rats; Rats, Inbred Strains

Growth hormone (GH) and the thyroid hormones interact in the hypothalamus, pituitary and peripheral tissues. Thyroid hormone exerts a permissive effect upon the anabolic and metabolic effects of GH, and increases pituitary synthesis of this protein hormone. GH depresses the secretion of thyrotropin and the thyroid hormones and increases the peripheral conversion of thyroxine to triiodothyronine. In the adult male rat experimental hypothyroidism produced by ingestion of propylthiouracil depresses the GH secretory response to GH-releasing hormone in vivo and in vitro, reflecting the lowered pituitary stores of GH in the hypothyroid state. Short term administration of large amounts of thyroxine with induction of the hyperthyroid state does not affect the in vivo GH secretory response to GH-releasing hormone in this animal.

Topics: Animals; Growth Hormone; Growth Hormone-Releasing Hormone; Hyperthyroidism; Hypothyroidism; Male; Pituitary Gland; Propylthiouracil; Rats; Thyroid Hormones; Thyroxine

We have studied the development of thyroid hormone dependence for growth and differentiation of rat skeletal tissues. The radius, tail tip or xiphoid process from 1-day-old rats was transplanted in its entirety under the kidney capsule of euthyroid or hypothyroid (TX) adult syngeneic virgin rats and grown there for 3, 6, 9, 12 or 15 days. Pieces of the sternum or calvarium were treated similarly. Growth of transplanted radius and sternum in TX hosts showed significant retardation by day 3, and that of transplanted calvarium, tail tip and xiphoid showed significant inhibition by day 6 post transplantation. Tissue differentiation of all of the transplants was inhibited in TX hosts and the appearance of epiphyseal ossification centers was significantly delayed. Injection of Propylthiouracil (PTU) in solvent into the neonatal rats from day 1 to day 15 post partum inhibited tail length increase by day 7, and body weight gain by day 9, as compared to the growth of solvent injected littermate pups. Our results indicate that the growth and differentiation of endochondral bones are more dependent on TH levels than are those of membranous bones and cartilage. Endochondral bones develop TH dependence for growth and differentiation before day 4 post partum, while the membranous bones and cartilage develop this dependence at the end of the first week.

Topics: Aging; Animals; Bone and Bones; Bone Development; Bone Transplantation; Hypothyroidism; Propylthiouracil; Rats; Thyroid Hormones; Thyroidectomy

Circulating levels of insulin, glucagon, thyroid hormones as well as lipid levels were determined in an obese strain of chicken and their lean controls. Hepatic and muscle glycogen and lipids were also measured. Obese birds had higher plasma lipids accompanied by significantly higher insulin and lower glucagon levels compared to lean controls. Hepatic and muscle triglycerides were also higher in obese birds. Plasma T4 level was significantly higher in obese but T3 was not different in the two groups. Results suggest that genetically obese birds have significantly increased insulin/glucagon ratios as previously reported in the PTU induced hypothyroid-obese chicks (Horm. Metab. Res. 12: 51, 1980) and this could have causal relationship to hyperlipidemia and obesity observed in these birds.

Topics: Animals; Chickens; Glucagon; Hyperlipidemias; Hypothyroidism; Insulin; Male; Obesity; Propylthiouracil; Thyroid Hormones

Experimental diabetes causes profound alterations in the metabolism of thyroxine (T4), including a decrease in hepatic triiodothyronine (T3) generation from T4 via 5'-deiodination (5'-D). Because 5'-D in brain differs markedly from that in liver, both in enzymatic mechanism and in the response to hypothyroidism, we studied iodothyronine deiodination, in particular T4 to T3 conversion (T4-T3), by incubating 125I T4 with particulate fractions of cerebral cortex (Cx) and cerebellum (Cm) from rats made diabetic by injection of streptozotocin. In nondiabetic thyroidectomized (Tx) rats Cx and Cm T4-T3 activity was increased approximately ten-fold and two-fold, respectively, compared with intact controls. Diabetic Tx rats did not differ from nondiabetic Tx rats in the rate of net T3 production from T4 but the formation of 3,3'-T2 was slightly reduced. Insulin-treated diabetic-Tx rats showed a pattern of T4 metabolism in Cx and Cm virtually identical to that of nondiabetic Tx rats. The rate of T3 degradation, determined in parallel incubations of Cx and Cm with 125I T3, did not differ significantly among the groups, indicating that the observed differences in net T3 production were due to changes in T4 5'-D activity. Intact diabetic rats compared to nondiabetic controls showed no significant changes in T4-T3 either in Cx or in Cm. Administration of T3, 0.8 microgram per 100 g bw per day for 6 days, by constant infusion to intact rats raised T4-T3 in Cx and Cm to levels found in Tx rats. Treatment of intact diabetics with T3 caused qualitatively similar changes, i.e., a hypothyroid response.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Body Weight; Cerebellum; Cerebral Cortex; Diabetes Mellitus, Experimental; Hypothyroidism; Insulin; Iodide Peroxidase; Male; Propylthiouracil; Rats; Rats, Inbred Strains; Thyroxine; Triiodothyronine

We investigated the effect of propylthiouracil (PTU)-induced hypothyroidism and T4-induced hyperthyroidism on the fetal and neonatal rabbit brain insulin receptors (number and affinity) using plasma membranes. PTU administration to the pregnant mothers resulted in low serum-free T4 and normal total T3 concentrations, while T4 therapy to the mothers resulted in high serum-free T4 and high total T3 concentrations in the fetus and neonate. PTU-induced hypothyroidism did not affect the fetal brain insulin receptors, cholesterol content (brain homogenate) or protein content. On the other hand, brain insulin receptor number and total brain cholesterol content decreased in the neonate. T4 therapy at 100 micrograms/kg reversed the serum T4 to the control value and normalized the neonatal brain insulin receptor number and cholesterol content while a higher dose of T4 (200 micrograms/kg) increased the neonatal brain insulin receptor number, cholesterol and protein content. We conclude that altered thyroidal states modulate the brain insulin receptor (number and affinity) in neonatal, but not fetal brain plasma membranes.

Topics: Animals; Blood Glucose; Brain; Cholesterol; Female; Hyperthyroidism; Hypothyroidism; Insulin; Pregnancy; Propylthiouracil; Rabbits; Receptor, Insulin; Thyroxine; Triiodothyronine

We studied the karyometric development of 4 subdivisions of the paraventricular nucleus (rostral, caudal, medial and lateral) and 3 subdivisions of the ventromedial nucleus of the hypothalamus (ventral, central and dorsal) in a hypothyroid group of male albino mice treated with propylthiouracil with or without interruption of the treatment at the 35th postnatal day. Hypothyroidism produces an increase of the nuclear-size values of the paraventricular and ventromedial nuclei, and the continued treatment increases this effect. The caudal and the rostral subdivisions of the paraventricular nucleus show more significant changes of their nuclear sizes compared to the medial and lateral subdivisions. The ventromedial nucleus responds similarly to hypothyroidism in all its subdivisions.

Topics: Animals; Body Weight; Cell Nucleus; Hypothyroidism; Karyometry; Male; Mice; Mice, Inbred Strains; Paraventricular Hypothalamic Nucleus; Propylthiouracil; Time Factors; Ventromedial Hypothalamic Nucleus

Brown adipose tissue (BAT) of hypothyroid rats contains a low Km (type II) iodothyronine 5'-deiodinase (I-5'D) that has been characterized as being insensitive to inhibition by propylthiouracil (PTU), based mainly on observations with homogenates prepared in a medium containing 10 mM dithiothreitol (DTT) and enzymatic assays in the presence of 20 mM DTT in vitro. In the studies reported herein, BAT homogenates from hypothyroid rats prepared in a DTT-free medium were found to contain I-5'D activity at 20 mM DTT, comparable to that in homogenates prepared in a DTT-containing medium, and were activated by submillimolar concentrations of DTT with an EC50 of approximately 0.5 mM. Almost all of the homogenate activities could be accounted for in microsomal preparations. The activity was substantially inhibited by 1 mM PTU. The PTU inhibition was progressively alleviated with increasing concentrations of added DTT and was not seen at DTT concentrations higher than 10 mM. At 250 microM DTT, the Km and maximum velocity values for rT3 and T4 were 2.9 and 1 nM and 70 and 200 fmol/mg protein X h, respectively, with a Ki for PTU of approximately 200 microM. On administration of PTU in vivo (2 mg/100 g BW; 1 h before killing) and subsequent assay at 250 microM DTT, the I-5'D in the homogenates was about 50% inhibited, and the microsomes showed a state of persistent inhibition, with activity levels about 70% of the control value. The data show that BAT type II I-5'D can be substantially activated at submillimolar concentrations of DTT, and this activation is sensitive to inhibition by PTU administered both in vitro and in vivo.

Topics: Adipose Tissue, Brown; Animals; Dithiothreitol; Enzyme Activation; Hypothyroidism; Iodide Peroxidase; Kidney; Kinetics; Male; Microsomes; Propylthiouracil; Rats; Thyroxine; Triiodothyronine, Reverse

Three-dimensional images of blood vessels in thyroid glands from normal, low iodine diet-treated, thyroid-stimulating hormone (TSH)-treated and propylthiouracil (PTU)-treated rats were investigated by use of the corrosion-cast method. The vascular casts made by the injection of methacrylate resin were observed with the scanning electron microscope. In normal animals, each follicle is surrounded by a clearly defined basket-like capillary network, which is generally independent of adjacent networks, though a few anastomoses or common capillaries are sometimes seen. In low iodine diet-treated or TSH-treated animals, the capillaries in the basket-like network become markedly dilated and fuse with one another. Though the vascular casts of PTU-treated animals are similar to those of low iodine diet-treated or TSH-treated ones in some aspects, most basket-like networks become distorted and irregular in shape, and the capillaries are heterogeneously dilated and show many buds, branches and anastomoses. We consider that these peculiar changes in the thyroid of the PTU-treated animals are due not only to the elevation of serum TSH but also to other unknown factors. It is clear that the distribution and morphology of the thyroid capillaries are extremely affected and changed by functional states of the gland.

Topics: Animals; Capillaries; Hyperthyroidism; Hypothyroidism; Male; Microscopy, Electron, Scanning; Propylthiouracil; Rats; Rats, Inbred Strains; Thyroid Gland; Thyrotropin

The effect of hypothyroidism on ischemic acute renal failure was studied in rats. Ten days after thyroidectomy with parathyroid reimplantation, rats underwent right uninephrectomy followed by occlusion of the left renal artery for 60 min. Plasma creatinine was lower in thyroidectomized than control rats 24 hr after ischemia; 1.3 +/- 0.5 vs. 3.2 +/- 0.6 mg%; P less than 0.05. Twenty-four hours after ischemia, inulin clearance was higher in thyroidectomized than control animals (0.40 +/- 0.06 vs. 0.17 +/- 0.03 mliter/min; P less than 0.01), despite an initially lower inulin clearance in thyroidectomized animals (0.81 vs. 1.1 +/- 0.07 mliter/min; P less than 0.05). Administration of the antithyroid drug prophylthiouracil for 14 days also resulted in lower plasma creatinine after ischemia. Kidneys from thyroidectomized animals showed less histologic damage 24 hr after ischemia. Renal cortical content of the lipid peroxidation product malondialdehyde was increased less in thyroidectomy than control kidneys after 60 min ischemia plus 15 min reflow (0.08 +/- 0.02 vs. 0.42 +/- 0.1 nmole/mg protein; P less than 0.005). Renal cortical glutathione content was higher in thyroidectomized animals by approximately 36%, 650 +/- 46 vs. 479 +/- 32 nmole/mg protein (P less than 0.02). In normal rats, glutathione infusion also increased renal cortical glutathione content and resulted in lower plasma creatinine 24 hr after renal artery ischemia. Therefore, hypothyroidism resulted in functional and histologic protection against injury after ischemia. Post-ischemic renal lipid peroxidation was reduced in thyroidectomized animals, perhaps the result of increased scavenging of reactive oxygen species (oxygen free radicals and H2O2) by glutathione.

Topics: Acute Kidney Injury; Animals; Free Radicals; Glutathione; Hypothyroidism; Ischemia; Kidney; Lipid Peroxides; Male; Propylthiouracil; Rats

Thyroid function was tested in mother and her son. The mother was taking propylthiouracil for treatment of hyperthyroidism, and she was breast-feeding. Thyroid function was normal in both.

Topics: Adult; Breast Feeding; Female; Graves Disease; Humans; Hypothyroidism; Infant; Male; Propylthiouracil

Topics: Aging; Animals; Birds; Body Weight; Hypothyroidism; Male; Propylthiouracil; Testis

Topics: Female; Graves Disease; Humans; Hypothyroidism; Infant, Newborn; Maternal-Fetal Exchange; Methimazole; Pregnancy; Pregnancy Complications; Propylthiouracil

Dietary administration of propylthiouracil (0.2%) to male Sprague-Dawley rats for a period of 8 weeks induced hypothyroidism and hypotension in these animals. Resting heart rate, body weight, colonic temperature and serum thyroxine (T4) were significantly lower in the treated hypothyroid rats than in the controls. Time-course study indicates that the maximal depression of these parameters occurred about the eighth week of PTU treatment; except T4 level which declined abruptly about the second week and remained steady thereafter. The mechanism(s) of hypotension is (are) unknown but there seems to be an interrelationship between hypothyroidism-induced hypotension and the parameters monitored, since discontinuation of PTU treatment reversed that trend of the response toward control levels.

Topics: Animals; Blood Pressure; Body Weight; Heart Rate; Hypotension; Hypothermia; Hypothyroidism; Male; Propylthiouracil; Rats; Rats, Inbred Strains; Thyroxine; Time Factors

Propylthiouracil (PTU; 0.05%) was added to the drinking water of rats of various ages and their response was monitored. PTU resulted in reduced body weights in both fetuses and young rats 0-30 days old. Plasma cholesterol levels were elevated and the activities of hepatic 3-hydroxy-3-methyl-glutaryl CoA reductase (HMGCoAR) and 7-alpha-hydroxylase were decreased if PTU was present in the water up to the time of death. However, if no PTU was present for some time before death, this effect was no longer observed. Plasma total carnitine levels were always suppressed by PTU and appeared the most sensitive indicator of PTU action. Intestinal acylcholesterol acyltransferase (ACAT) activity was elevated nearly 5-fold, while intestinal HMGCoAR activity was only slightly and occasionally depressed.

Topics: Aging; Animals; Carnitine; Cholesterol; Cholesterol 7-alpha-Hydroxylase; Female; Fetus; Hydroxymethylglutaryl CoA Reductases; Hypothyroidism; Liver; Maternal-Fetal Exchange; Pregnancy; Propylthiouracil; Rats; Rats, Inbred Strains

Newborn female Long-Evans rats were divided into groups of normal, hypothyroid [0.1% propylthiouracil (PTU) a reversible antithyroid goitrogen in the litter's drinking water], and hypothyroid rehabilitated (PTU water from birth to day 25, normal water thereafter). The rats were tested for several adaptive behavioral tasks between 40 and 90 days of age. At day 50, serum concentration of TSH and thyroid hormones revealed no detectable amounts of T4 and a 10-fold increase in TSH in the hypothyroid rats. At the same age in the rehabilitated animals, TSH levels were still below normal, a deficit fully normalized by day 90. Normal 50-day-old rats responded to pain stress (electric footshocks) by a significant depression of serum T4 and elevation of T3 levels within 10 min of treatment, whereas the rehabilitated animals exhibited an opposite pattern of response, i.e., an increase in the circulating T4 and a decrease in T3. At 50 days of age, both hypothyroid and rehabilitated rats showed decreased exploratory activity and no habituation in the hole-board test, whereas the locomotor activity of the rehabilitated females was significantly higher than that of the normals. No differences were found in the scores of passive avoidance learning (one trial step-through) among the three groups. Similarly, the rate of acquisition of the active one-way conditioned avoidance response (CAR) of the hypothyroid and rehabilitated rats did not differ significantly from that of the controls. However, the hypothyroid rats required significantly more unconditioned stimuli (footshocks) to acquire CAR and showed longer response latency and less intertrial responses. Although the hypothyroid rats showed no extinction of CAR, the rehabilitated rats were capable of extinction to an extent indistinguishable from normal rats. But compared with the normal animals, the rehabilitated rats showed significantly higher intertrial activity during both the acquisition and extinction phases of CAR.

Topics: Animals; Avoidance Learning; Body Weight; Conditioning, Classical; Exploratory Behavior; Extinction, Psychological; Female; Habituation, Psychophysiologic; Hypothyroidism; Learning; Propylthiouracil; Rats; Rats, Inbred Strains; Stress, Physiological; Thyrotropin; Thyroxine; Triiodothyronine

The effect of cold exposure and of PTU and PTU + T3 administration on the protein content and succinic dehydrogenase activity of three mitochondrial populations obtained from rat liver was examined. Our results indicated the following: Succinic dehydrogenase activity increases mainly in the light mitochondrial fraction of cold-exposed rats. PTU administration of cold-exposed animals does not affect the increment in enzyme activity of the heavy fraction but blocks the increment of the light fraction. PTU + T3 administration restores succinic dehydrogenase activity to the values prevalent in normal cold-exposed rats. These findings suggest that thyroid hormone may stimulate the formation of light mitochondria during cold exposure.

Topics: Acclimatization; Animals; Cold Temperature; Hypothyroidism; Male; Mitochondria, Liver; Propylthiouracil; Rats; Rats, Inbred Strains; Succinate Dehydrogenase; Triiodothyronine

Female C57Bl/6J mice were given drinking water containing 0.05% propylthiouracil to induce a hypothyroid condition. Mitochondrial glycerol-3-phosphate dehydrogenase activity, used as an index of hypothyroidism, was 57.1 +/- 4.5 and 29.4 +/- 3.8 nmol/min per mg of protein for control and propylthiouracil-treated animals respectively. Administration of tri-iodothyronine resulted in an approx. 4.5-fold increase in dehydrogenase activity in propylthiouracil-treated animals. A dose-dependent increase in hepatic GSH S-transferase activity in propylthiouracil-treated animals was observed at tri-iodothyronine concentrations ranging from 2 to 200 micrograms/100 g body wt. This increase in transferase activity was seen only when 1,2-epoxy-3-(p-nitrophenoxy)propane was used as substrate for the transferase. Transferase activity with 1-chloro-2,4-dinitrobenzene and 1,2-dichloro-4-nitrobenzene as substrate was decreased by tri-iodothyronine. Administration of actinomycin D (75 micrograms/100 g body wt.) inhibited the tri-iodothyronine induction of transferase activity. Results of these studies strongly suggest that tri-iodothyronine administration markedly affected the activities of GSH S-transferase by inducing a specific isoenzyme of GSH S-transferase and suppressing other isoenzymic activities.

Topics: Animals; Dactinomycin; Enzyme Induction; Epoxy Compounds; Female; Glutathione Transferase; Hypothyroidism; Liver; Mice; Mice, Inbred C57BL; Nitrophenols; Propylthiouracil; Triiodothyronine

Rats were treated with a goitrogen, propylthiouracil (PTU), from 3 days before delivery up to different ages postnatally. Peripheral auditory function was evaluated with the auditory brain-stem response (ABR) technique performed at 200 days of age. All groups of rats exposed consecutively pre- and postnatally to PTU displayed permanent auditory impairment for each stimulus modality used, as revealed by significantly prolonged wave I latencies and elevated thresholds, and the severity of these abnormalities was directly related to the duration of PTU treatment. The only congenitally hypothyroid animals not affected were those treated from 3 days before parturition up to birth and those treated for 10 days beginning at 35 days of age. These data underline the susceptibility of the developing auditory system since, while very brief perinatal PTU exposure resulted in permanent evoked response abnormalities, longer exposure in later life had no effect.

Topics: Animals; Congenital Hypothyroidism; Evoked Potentials, Auditory; Female; Hypothyroidism; Pregnancy; Propylthiouracil; Rats; Rats, Inbred Strains

Measurement of total DNA, RNA, and protein as well as weight of the heart in male rats at 10, 25, 50, and 90 postnatal days revealed that hypothyroidism, as induced by administration from birth of the goitrogen propylthiouracil (PTU), results in highly significant reductions in cardiac cell proliferation and cell growth. These inhibitory effects on hyperplastic and hypertrophic growths were less drastic during the suckling period than during the postweaning period. In the latter period, heart growth of the hypothyroid animals was found to remain at a standstill with regard to all the parameters measured. When, after 25 days of hypothyroidism, PTU treatment was discontinued, the retarded heart showed marked signs of rehabilitation and compensatory development. Indeed, by day 90, total DNA content had essentially compensated for its deficit but total RNA, protein content, and weight, though showing marked compensatory surges (from 80-90% deficit to 20-30%), were not yet fully compensated. The results clearly indicate that the growing heart has a marked ability to be rehabilitated from severe hypothyroid retardation, showing within 2 mo full compensation of cell number and nearly complete compensation of cell growth. It is suggested that rehabilitation of the heart is brought about by physiological restoration not only of the thyroid hormones but also of growth hormone and possibly other thyroid-dependent growth factors.

Topics: Animals; Animals, Newborn; Cell Division; DNA; Heart; Hyperplasia; Hypothyroidism; Male; Myocardium; Organ Size; Propylthiouracil; Proteins; Rats; RNA; Thyroid Hormones; Time Factors

The effect of propylthiouracil (PTU) pretreatment on in vivo and in vitro oxidative drug metabolism was determined in the rat. Whereas pentobarbital sleeping time (PBST) and zoxazolamine paralysis time (ZZPT) were used as indices of in vivo drug metabolizing activity, biotransformation of aminopyrine and aniline by hepatic microsomal preparations were used as indices of in vitro drug metabolizing enzymes activities. PTU pretreatment significantly prolonged both PBST and ZZPT. Whereas PTU did not affect microsomal protein concentration or cytochrome P-450 content, it significantly decreased microsomal cytochrome c reductase and aniline hydroxylase activities. These changes in enzymatic activities were observed in microsomal preparations from either non-fasted or 24-hr fasted rats. Our results suggest that PTU-induced hypothyroidism modifies the metabolism and effectiveness or toxicity of concomitantly administered drugs.

Topics: Aminopyrine; Aniline Compounds; Animals; Biotransformation; Body Weight; Cytochrome P-450 Enzyme System; Hypothyroidism; Liver; Male; Pentobarbital; Propylthiouracil; Rats; Rats, Inbred Strains; Zoxazolamine

The cardiac myofibrillar component of the phosphorylcreatine shuttle mechanism enzymatically couples the functionally significant processes of energy utilization (ATPase) with substrate regeneration by creatine kinase (CK). Both components have isoenzyme forms that are transcriptionally regulated. Propylthiouracil-induced (PTU) hypothyroidism reduced rat cardiac contractile protein ATPase activity by shifting isomyosin predominance from the V1 to the V3 form. However, neither CK specific activity or CK isoenzyme composition was altered by PTU treatment. Thus, myofibrillar components of the phosphorylcreatine shuttle, ATPase and CK, are not coordinately regulated under hypothyroid conditions.

Topics: Adenosine Triphosphatases; Animals; Creatine Kinase; Female; Hypothyroidism; Isoenzymes; Myocardium; Myofibrils; Myosins; Propylthiouracil; Rats; Rats, Inbred Strains

The effect of thyroid status on the postnatal development of the two molecular forms of Na+,K+-ATPase, distinguished kinetically on the basis of their ouabain sensitivity, was examined in rat brain. Hypothyroidism induced by PTU from day 1 postnatally significantly reduced the Na+,K+-ATPase activity in cerebellum (22-30 days) but not forebrain, whereas hyperthyroidism (T4 treatment from day 1) had no effect. The hypothyroidism-induced reduction in cerebellum was reflected by a 20-45% reduction in the activity of the alpha(+) form of Na+,K+-ATPase (high ouabain affinity) against control brains compared to a 60-70% reduction in the activity of the alpha form (low ouabain affinity). These results show that neonatally induced hypothyroidism leads to a selectively greater impairment of the ontogenesis of the activity of cerebellar alpha form of Na+,K+-ATPase. This may possibly reflect a retarded development of a selective cerebellar cell population containing predominantly the alpha form of the enzyme.

Topics: Adenosine Triphosphatases; Animals; Brain; Ca(2+) Mg(2+)-ATPase; Cerebellum; Chemical Phenomena; Chemistry; Diencephalon; Hyperthyroidism; Hypothyroidism; Male; Propylthiouracil; Rats; Sodium-Potassium-Exchanging ATPase; Telencephalon; Thyroxine

The effects of hypothyroidism on glycogen metabolism in rat skeletal muscle were studied using the perfused rat hindlimb preparation. Three weeks after propylthiouracil treatment, serum thyroxine was undetectable and muscle glycogen and Glc-6-P were decreased. Basal and epinephrine-stimulated phosphorylase a and phosphorylase b kinase activities were also significantly reduced, as were epinephrine-stimulated cAMP accumulation and cAMP-dependent protein kinase activity. Conversely, basal and epinephrine-stimulated glycogen synthase I activities were significantly higher while the Ka of the enzyme for Glc-6-P was lower in hypothyroid animals. Propylthiouracil-treated rats also had increased phosphoprotein phosphatase activities towards phosphorylase and glycogen synthase and decreased activity of phosphatase inhibitor 1. beta-Adrenergic receptor binding and basal and epinephrine-stimulated adenylate cyclase activities were reduced in muscle particulate fractions from hypothyroid rats. Administration of triiodothyronine to rats for 3 days after 3 weeks of propylthiouracil treatment restored the altered metabolic parameters to normal. It is proposed that the decreased beta-adrenergic responsiveness of the enzymes of glycogen metabolism in hypothyroid rat skeletal muscle is due to increased activity of phosphoprotein phosphatases and to reduced beta-adrenergic receptors and adenylate cyclase activity.

Topics: Animals; Epinephrine; Glycogen; Hypothyroidism; Kinetics; Male; Muscles; Phosphorylase Kinase; Phosphorylases; Propylthiouracil; Rats; Rats, Inbred Strains; Receptors, Adrenergic, beta; Thyroxine; Triiodothyronine

The binding of 1 alpha,25-dihydroxy (26,27-methyl-[3H]) cholecalciferol ([3H]1,25-(OH)2D3) to its receptor in cytosol of the anterior pituitary cells was examined in hyperthyroid- and hypothyroid rats, as well as in normal rats. The binding capacity increased by 41% in L-Thyroxine-treated hyperthyroid rats and decreased by 49% in propylthiouracil-ingested hypothyroid rats as compared with normal control rats, whereas the affinity of the receptor for [3H]-1,25(OH)2D3 showed no difference among these 3 animal groups. These findings indicate that the number of 1,25(OH)2D3 receptors in the pituitary may be regulated by thyroid hormone, and further suggest that 1,25-(OH)2D3 may play some role in regulating functions of the anterior pituitary.

Topics: Animals; Calcitriol; Centrifugation, Density Gradient; Cytosol; Hyperthyroidism; Hypothyroidism; Male; Pituitary Gland, Anterior; Propylthiouracil; Rats; Receptors, Calcitriol; Receptors, Steroid; Thyrotropin; Thyroxine

The sympathomimetic stimulation of choroid plexus transport and secretion in rat seems to be mediated by beta-adrenergic receptors. In the present report the effect of induced changes in thyroid function on transport mechanisms in the rat choroid plexus was studied. Following induction of hyperthyroidism (treatment with T3 for 10 days) the tissue/medium ratio (T/M) for choline uptake in choroid plexus in vitro decreased significantly by 68%. The Na+-K+-ATPase activity showed a statistically significant increase of about 16%. Also following cervical sympathectomy, T3 caused a reduction of the T/M for choline, to the same level as in the non-sympathectomized animals, while the effect of T3 on the Na+-K+-ATPase activity was changed into a 22% decrease. Hypothyroidism (administration of PTU in the drinking water) had little or no effect on the uptake and accumulation of choline in the choroid plexus. The Na+-K+-ATPase activity was reduced by 40%, in contrast to the stimulating effect of T3. There is, hence, reason to believe that the transport of choline in the choroid plexus is only partly regulated by adrenergic mechanisms acting via Na+-K+-ATPase. The major effect of T3 on the choline uptake may be exerted by a mechanism different from the ATPase activity and not involving adrenergic receptors.

Topics: Animals; Choline; Choroid Plexus; Female; Hyperthyroidism; Hypothyroidism; Propylthiouracil; Proteins; Rats; Rats, Inbred Strains; Sodium-Potassium-Exchanging ATPase; Sympathectomy; Thyroxine; Triiodothyronine

Topics: Animals; Capillaries; Diffusion; Electron Transport Complex IV; Female; Hyperthyroidism; Hypothyroidism; Muscles; Oxidation-Reduction; Oxygen Consumption; Propylthiouracil; Rats; Rats, Inbred Strains

Hypothyroidism was induced in Wistar-Kyoto rats by adding propylthiouracil to the drinking water (0.8 mg/ml). Initial heat, total activity-related heat, and resting heat rate were measured in left ventricular papillary muscle preparations of propylthiouracil-treated and control rats contracting isometrically at 12 beats/min (21 degrees C), using Hill type, planar vacuum-deposited bismuth and antimony thermopiles. In the propylthiouracil preparations, relative to control, time-to-peak tension increased from 288 +/- 27 (mean +/- SD) to 411 +/- 25 msec (P less than 0.001), dp/dtmax decreased from 38.3 +/- 9.5 to 20.4 +/- 3.5 g X mm-2/sec (P less than 0.001), and peak developed tension decreased from 6.11 +/- 1.75 to 4.64 +/- 0.89 g X mm-2 (P less than 0.05). In the propylthiouracil preparations, initial heat was significantly (P less than 0.001) reduced by 27 or 43% when normalized to peak twitch tension or tension-time integral, respectively. In experiments where the papillary muscles were tetanized, the slope of the linear function of total activity-related heat versus tension-time integral was decreased by 43% (P less than 0.001) in the propylthiouracil preparations, indicating an improved economy of isometric tension maintenance. The predominant myosin isoenzyme of the left ventricular wall, as well as the papillary muscle myocardium, was the V3 variety in the propylthiouracil animals, in contrast to V1 in the controls. Myofibrillar actomyosin calcium-magnesium-stimulated adenosine triphosphatase activity was significantly (P less than 0.02) decreased from 55 +/- 18 (control) to 31 +/- 8 nmol inorganic phosphate ion/mg X min (propylthiouracil).(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Actomyosin; Adenosine Triphosphatases; Animals; Body Weight; Ca(2+) Mg(2+)-ATPase; Calcium-Transporting ATPases; Energy Metabolism; Hypothyroidism; Isoenzymes; Isometric Contraction; Myocardial Contraction; Myofibrils; Myosins; Organ Size; Papillary Muscles; Propylthiouracil; Rats; Rats, Inbred WKY

Thyroid surgery in the pediatric age patient accounts for a small minority of all thyroid surgery. Batsakis and Nishiyama reported only 136 patients under the age of 18 who underwent thyroid surgery in 27 years at the University of Michigan. In most series involving the pediatric age group, the majority of thyroid procedures are performed on adolescents. Thyroid surgery in the young child requires special precautions in addition to those routinely associated with thyroidectomy in the adult. The techniques and perioperative management of the pediatric thyroidectomy employed at our institution has evolved as experience is gained. Our experience with five such patients with adequate follow-up will be presented.

Topics: Adenoma; Adolescent; Age Factors; Child; Child, Preschool; Drainage; Female; Follow-Up Studies; Graves Disease; Humans; Hypothyroidism; Iodine; Male; Postoperative Care; Postoperative Complications; Preoperative Care; Propylthiouracil; Thyroid Hormones; Thyroid Neoplasms; Thyroidectomy

The localization of neurons containing immunoreactive thyrotropin-releasing hormone (TRH) was examined in the hypothalamus of intact, propylthiouracil (PTU)-treated, and colchicine-treated adult rats. In intact animals, immunoreactive TRH neurons were occasionally found in the paraventricular and dorsomedial nuclei, and in the anterior and lateral hypothalamic areas. In PTU-treated animals, the cellular appearance of the hypothalamus with the exception of the paraventricular nucleus was almost similar to that of intact animals. In the paraventricular nucleus, only the cells localized in the periventricular and medial parvocellular subdivisions significantly increased in number and became hypertrophic in comparison with intact animals. The distribution of immunoreactive fibers in the hypothalamus was almost equal among the 3 animal groups with the exception of that in the median eminence, in which the fibers were most densely concentrated in intact animals, and most sparse in PTU-treated rats. The fibers projecting into the median eminence were distinguished into the periventricular and lateral pathways, which are derived from the neurons in the periventricular and medial parvocellular subdivisions of the paraventricular nucleus, respectively. Thus, among immunoreactive TRH neurons in the hypothalamus, only those in the periventricular and medial parvocellular subdivisions of the paraventricular nucleus may be involved in the hypothalamic-hypophysial-thyroid axis.

Topics: Animals; Colchicine; Hypothalamus; Hypothyroidism; Male; Organ Size; Propylthiouracil; Rats; Rats, Inbred Strains; Thyroid Gland; Thyrotropin-Releasing Hormone

In order to study the corrective effects of thyroxine (T4) on functional abnormalities induced by congenital hypothyroidism, small doses of T4 were injected to propylthiouracil-treated (PTU-treated) rat pups for 2 consecutive days on selected periods of development (days 3 and 4, 6 and 7, 9 and 10, 12 and 13, 18 and 19). Some animals also received thyroid replacement therapy from days 12 to 17. The animals were tested electrophysiologically on day 30, by recording the compound action potential and the cochlear microphonic from the round window after click and tone burst stimulation. PTU-treated animals given T4 for 2 consecutive days demonstrated both AP and CM threshold shifts. On the contrary, PTU-treated animals given T4 from days 12 to 17 demonstrated a normal CM output of the cochlea, but still showed elevated AP thresholds. These results are discussed with previous data concerning the corrective effects of T4 on cochlear structures in PTU-treated rats previously described.

Topics: Animals; Cochlea; Cochlear Microphonic Potentials; Congenital Hypothyroidism; Evoked Potentials, Auditory; Hypothyroidism; Propylthiouracil; Rats; Rats, Inbred Strains; Reaction Time; Thyroxine

In order to study the corrective effects of thyroxine on the cochlear abnormalities induced by congenital hypothyroidism, small doses of thyroxine were injected in propylthiouracil-treated rat pups for 2 consecutive days during selected periods of development (days 3 and 4, 6 and 7, 9 and 10, 12 and 13, 18 and 19). Some animals also received thyroid replacement therapy from days 12 to 17. Corrective effects of thyroxine on cochlear structures were observed using light microscopy and transmission electron microscopy. The corrective effects not only depended on the period of administration of the hormone, but also on the structure investigated within the organ of Corti. For a given structure, a period of maximal sensitivity to thyroxine exists which corresponds to the period of development during which that structure undergoes its main morphological changes (i.e. from 6 to 13 days for the inner sulcus epithelium, the first postnatal week for the tectorial membrane, from 6 to 10 days for the pillars and the tunnel of Corti, the second and probably a part of the third postnatal week for outer hair cell synaptogenesis).

Topics: Age Factors; Animals; Cochlea; Congenital Hypothyroidism; Hypothyroidism; Microscopy, Electron; Propylthiouracil; Rats; Rats, Inbred Strains; Thyroxine

Studies in vitro have shown that rT3 is a potent and competitive inhibitor of T4 5'-deiodination (5'D). Recent studies in vivo have shown that cerebrocortical (Cx) T4 5'D-type II (5'D-II) activity [propylthiouracil (PTU) insensitive pathway], is reduced by T4 and rT3, the latter being more potent than T3 in Cx 5'D-II suppression. Some other reports had described rT3 production in rat brain as a very active pathway of thyroid hormone metabolism. To examine the possibility that rT3 plays a physiological role in regulating Cx 5'D-II, we have explored rT3 plasma kinetics, plasma to tissue exchange, and uptake by tissues in the rat, as well as the metabolic routes of degradation and the sources of rT3 in cerebral cortex (Cx). Plasma and tissue levels were assessed with tracer [125I]rT3. Two main compartments were defined by plasma disappearance curves in euthyroid rats (K1 = -6.2 h-1 and K2 = -0.75 h-1). In Cx of euthyroid rats, [125I]rT3 peaked 10 min after iv injection, tissue to plasma ratio being 0.016 +/- 0.004 (SE). In thyroidectomized rats, plasma and tissue [125I]rT3 concentrations were higher than in euthyroid rats, except for the Cx that did not change. PTU caused further increases in all the tissues studied, except for the Cx and the pituitaries of thyroidectomized rats. From the effect of blocking 5'D-I with PTU or reducing its activity by making the animals hypothyroid, we concluded that 5'D-I accounts for most of the rT3 clearance from plasma. In contrast, in Cx and pituitary the levels of rT3 seem largely affected by 5'D-II activity. Since the latter results suggest that plasma rT3 does not play a major role in determining rT3 levels in these tissues, we explored the sources of rT3 in Cx using [125I]T4. The [125I]rT3 (T4) to [125I]T4 ratio remained constant at 0.03 from 1 up to 5 h after injection of [125I]T4. From plasma levels of T4 and rT3, Cx concentration was calculated to be 30 pg rT3/g Cx in euthyroid rats, more than 98% locally produced from T4 deiodination. We conclude that rT3 has a very rapid metabolism, mainly attributed to 5'D-I activity, but that 5'D-II could also play a role in certain tissues. Nearly all rT3 present in Cx is locally derived from T4.

Topics: Animals; Cerebral Cortex; Chromatography; Hypothyroidism; Iodine Radioisotopes; Kinetics; Male; Propylthiouracil; Rats; Rats, Inbred Strains; Thyroidectomy; Thyroxine; Tissue Distribution; Triiodothyronine, Reverse

The enzymatic activities of two "key" enzymes of the glycolytic pathway, pyruvate kinase and lactic dehydrogenase, were studied in seven areas of the brain in male adult rats in states of pharmacologically induced hyper and hypothyroidism. The brain areas were: anterior cortex, adenohypophysis, hypothalamus, amygdaline nucleus, septum, hippocampus and cerebellum. In T3 treated animals, pyruvate kinase activity showed significant increase in all the areas studied while lactic dehydrogenase activity decreased. In propyl-thiouracil treated animals these enzyme activities showed no significant variations from those in animals of the control group.

Topics: Animals; Brain; Glycolysis; Hyperthyroidism; Hypothyroidism; L-Lactate Dehydrogenase; Male; Propylthiouracil; Pyruvate Kinase; Rats; Rats, Inbred Strains; Thyroxine; Triiodothyronine

Perinatal thyroid dysfunction in the rat leads to permanent alterations in pituitary TSH secretion in the adult animal. Thus, neonatal hyperthyroidism (NH) and perinatal hypothyroidism (PH) both result in apparent increased pituitary sensitivity to the feedback effects of thyroid hormones in the adult rat. To determine if increased intrapituitary generation of triiodothyronine (T3) might account for these observations, we measured thyroxine (T4) 5'-deiodinase activity in pituitary homogenates of adult NH and PH rats. NH was induced by injecting neonatal rats with 12 daily sc injections of T4 (0.4 microgram/g body weight (BW]. Control rats received vehicle alone. PH was induced by administering 0.05% 6-n-propylthiouracil in the drinking water to pregnant dams from the 16th day of gestation through the 12th day postpartum. Thereafter, a normal water supply was substituted. NH and PH rats were allowed to mature and were sacrificed at 105 days of age. Serum T4, T3, and TSH concentrations were measured by radioimmunoassay. Pituitary T4 5'-deiodinase activity was assessed by the measurement of T3 formation by pituitary homogenates incubated in the presence of 0.65 microM T4 and 100 mM dithiothreitol at 37 degrees C for 90 min. Body weights of adult NH and PH rats were slightly but not significantly decreased compared with control rats. Relative pituitary gland weight (milligrams per 100 g BW) was significantly decreased in adult PH rats (P less than 0.005) but not in adult NH rats. In adult NH rats, serum T4 and T3 concentrations were significantly decreased (P less than 0.01) compared with control rats. Serum TSH concentrations were similar.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Animals, Newborn; Female; Hyperthyroidism; Hypothyroidism; Iodide Peroxidase; Kinetics; Peroxidases; Pituitary Gland; Pregnancy; Propylthiouracil; Rats; Rats, Inbred Strains; Thyroxine

The conversion of T4 to T3 by the anterior pituitary gland appears to be of considerable physiological importance in the control of pituitary function. To determine a possible role of hypothalamic factors in controlling this enzymatic process, iodothyronine 5'-deiodinase (I5'D) activity was studied in rats 6 weeks after homologous transplantation of pituitary (implanted animals) or muscle tissue (sham animals) under the renal capsule. Intrasellar pituitaries remained intact, and serum T3, T4, and TSH levels were similar in both groups. I5'D activity was determined by quantifying T3 production rates in tissue homogenates at T4 concentrations of 0.002-4 microM, and with 20 mM dithiothreitol. Sellar pituitaries from sham and implanted animals displayed similar nonlinear reaction kinetics, suggesting the presence of two enzymatic processes having approximate Michaelis-Menten constant (Km) values of 2 nM and 0.3 microM. Maximum velocity (Vmax) was 51.3 +/- (SE) 4.0 fmol T3/min X mg protein (units) and 40 +/- 6 U for the low and high Km components, respectively. In transplanted pituitary tissue, I5'D activity was markedly altered; the low Km activity was significantly decreased (Km, 6 nM; Vmax, 13.0 +/- 1.1 U; P less than 0.001 compared to sellar pituitaries), whereas the high Km activity was increased 15-fold (Km, 5 microM; Vmax, 620 U). The in vitro addition of 6-n-propyl-2-thiouracil (0.1 mM) inhibited high Km I5'D activity in homogenates of both transplanted pituitary and renal tissue by approximately 50% (P less than 0.001), but had no effect on low Km I5'D activity in either sellar or transplanted pituitaries. In sham and implanted animals rendered hypothyroid by the inclusion of 1 g/dl NaClO4 in their drinking water for 6 weeks, low Km I5'D activity was increased approximately 3-fold in sellar and transplanted pituitary tissue. The levels of activity reached in transplanted tissue, however, were only 20-30% of those noted in sellar pituitary homogenates (P less than 0.001). High Km I5'D activity was estimated to be decreased 55% in transplanted tissue from hypothyroid animals. These studies demonstrate that transplantation of the anterior pituitary gland under the renal capsule in the rat results in marked alterations in two distinct components of pituitary I5'D activity. This suggests that neuroendocrine factors are important in the control of pituitary T4 to T3 conversion. Furthermore, it provides evidence for a unique mechanism whereby the hypothalamu

Topics: Animals; Female; Hypothalamus; Hypothyroidism; Iodide Peroxidase; Kidney; Kinetics; Male; Peroxidases; Pituitary Gland, Anterior; Prolactin; Propylthiouracil; Rats; Thyrotropin; Thyroxine; Triiodothyronine; Weaning

Cockerels and pullets fed with T3 or T4 for 2 weeks showed a decrease in both body weight gain and feed efficiency. The reduction in body weight gain and feed efficiency was dose related in cockerels where T3 or T4 were fed at 0.1, 1.0, and 10.0 ppm levels. T3 and T4 at 0.1 and 1.0 ppm had no significant effects on growth or feed efficiency in pullets, but the 10.0-ppm level of T3 and T4 caused a reduction of -55.24 and -28.18%, respectively, in body weight gain as compared with control birds. T3 was more active than T4 in reducing growth and was toxic when fed at 10.0 ppm both in cockerels and pullets. Both propylthiouracil (PTU)- and methimazole-treated cockerels showed a decrease in rates of gain. T3 and T4 at a dietary level of 0.1 ppm were equipotent in promoting growth in these PTU- and methimazole-treated cockerels, but 10.0 ppm caused a further reduction in body weight gain. Plasma T3 levels were found to be significantly higher in birds that were fed either T3 or T4. Plasma T4 levels were higher in T4-fed birds, but significantly lower in T3-fed birds as compared with controls. Both PTU- and methimazole-treated cockerels had significantly lower plasma T3 and T4 concentrations, but elevated plasma GH concentrations. Dietary T3 and T4 at 1.0 and 10.0 ppm significantly lowered plasma GH concentrations. In summary, these results indicated that T3 was more active than T4 in reducing body weight gain in intact normal birds, but that they were equally potent in promoting growth in PTU- and methimazole-treated hypothyroid birds.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Body Weight; Chickens; Diet; Female; Growth; Growth Hormone; Hypothyroidism; Male; Methimazole; Propylthiouracil; Thyroxine; Triiodothyronine

The effects of altered thyroid states on regeneration in the central nervous system are equivocal. This work was undertaken to examine the influence of propylthiouracil-induced (PTU-induced) pre- and postnatal hypothyroidism on collateral sprouting of noradrenergic (NA) axons in the habenula (Hb), following lesions in the stria medullaris (SM) of the adult rat. Ten pregnant dams were divided into control and PTU-treated groups. Control rats had free access to food and water and the hypothyroid group received, in addition, 0.05% (w/v) of PTU in their drinking water, beginning on day 12 of gestation and continuing post partum through lactation until the offspring were weaned at age 22 days. The pregnant dams received, in addition, daily injections of thyroxine (25 micrograms/kg, ip) and only male pups were used in the study. At weaning the pups were removed from the dams and placed in cages with free access to food and water. The hypothyroid offspring received 0.05% (w/v) PTU in the drinking water until sacrificed at 10 weeks of age. At 6 weeks, some rats in each group received bilateral lesions in the SM and the remainder were sham-operated. All rats were sacrificed 4 weeks after operation. Thus, four groups were formed: 1) control/sham, 2) control/lesion, 3) PTU/sham, 4) PTU/lesion. Sprouting of NA fibers in discrete regions of the Hb was identified by norepinephrine (NE) levels and by fluorescence histochemistry. Blood levels of thyroid stimulating hormone (TSH) were determined. The results show that pre- and postnatal induced chronic hypothyroidism abolished NA sprouting in the partially deafferented Hb. Furthermore, lesions of the SM resulted in a marked decrease in serum TSH levels.

Topics: Adrenergic Fibers; Animals; Diencephalon; Hypothyroidism; Limbic System; Male; Neuronal Plasticity; Propylthiouracil; Rats; Rats, Inbred Strains; Wound Healing

The effects of propylthiouracil (PTU)-induced thyroid deficiency on [14C]acetylcholine synthesis and 14CO2 production from [U-14C]glucose in vitro, by fine prisms of the corpus striatum were investigated in developing rats. Consistent with deficits in choline uptake and choline acetyltransferase activity (Kalaria et al.17), PTU-treatment from two days after birth significantly impaired (27-39%) [14C]acetylcholine synthesis in striatal tissue taken from 3- or 6-week-old animals. In the thyroid-deficient (Tx) animals, 14CO2 production from [14C]glucose was unchanged in incubations in the presence of 5 mM K+ but was significantly reduced (33%) in medium with 31 mM K+ concentration. The addition of 10 mM DL-3-hydroxybutyrate in incubations with 5 mM K+ persistently inhibited 14CO2 production by striatal samples from the Tx rats. The fraction acetylated of [3H]choline accumulated by striatal prisms was unaffected by the PTU-induced thyroid deficiency. These findings suggest the development of fewer cholinergic nerve terminals in striatum during neonatal thyroid deficiency. Cholinergic nerve terminals that develop seem unaffected in their capacity for K+-stimulation and in their ability to acetylate transported [3H]choline.

Topics: 3-Hydroxybutyric Acid; Acetylcholine; Animals; Animals, Newborn; Choline; Corpus Striatum; Glucose; Hydroxybutyrates; Hypothyroidism; In Vitro Techniques; Oxidation-Reduction; Potassium; Propylthiouracil; Rats

Neurogenesis in the motor and mesencephalic nuclei of the trigeminal nerve was examined using autoradiographic techniques. Two groups of pregnant rats (control and experimental) were injected with two successive daily doses of 3H thymidine in an overlapping series starting from day nine of gestation in order to label in their progeny, the dividing precursor of neurons of the motor nucleus and mesencephalic nucleus of the trigeminal nerve. Control group of rats was raised on a standard diet, while the experimental group was made hypothyroid by propylthiouracil (PTU). At postnatal ages ranging between 20-30 days in the pups of both the control group and experimental group, the percentage of cells labelled and the proportion of cells added during each embryonic day were determined quantitatively throughout the rostro-caudal extent for both motor and mesencephalic nuclei. The neurons of the mesencephalic nucleus undergo their final cell divisions between gestational days 9 and 10 (E9 and E10). More than 80% of the population is generated by E10. The neurons of the motor nucleus undergo their final cell divisions between E9 and E11, and nearly 88% of the cells is generated by E11. In the thyroid deficient rats, in both nuclear centers, only 61% of the cells is generated by E12, and labelled cells are observed even as late as E18 and E19. In the hypothyroid state, there is a significant lengthening of the proliferative period. On the basis of absolute datings and duration of neuron production, it is postulated that in normal development, thyroid hormone determines the duration of the proliferative period, and push cells into the differentiative phase by taking them out of the proliferative phase.

Topics: Animals; Animals, Newborn; Body Weight; Female; Histocytochemistry; Hypothyroidism; Litter Size; Mesencephalon; Motor Cortex; Pregnancy; Propylthiouracil; Rats; Thymidine; Trigeminal Nerve; Tritium

Glucose-6-phosphate dehydrogenase activity increases following denervation of rat skeletal muscle. The specificity of this effect to muscle fibre type was studied. Basal activity of the dehydrogenase was higher in soleus, a muscle composed predominantly of type I fibres, than in extensor digitorum longus, a muscle composed predominantly of type IIa and b fibres. The enzymatic activity of the soleus was also greater than that of the red (RQ) and white (WQ) portions of quadriceps muscle (predominantly type IIa and type IIb fibres, respectively). Following denervation, glucose-6-phosphate dehydrogenase increased in extensor digitorum longus and RQ, but not in WQ or the soleus. Following chronic treatment of rats with 3,3',5-triiodothyronine, which converts type I muscle fibres to type II, the dehydrogenase activity increased in both denervated soleus and extensor digitorum longus. It is concluded that the effect of denervation on glucose-6-phosphate dehydrogenase activity is selective for type IIa (fast oxidative-glycolytic) muscle fibres.

Topics: Animals; Glucosephosphate Dehydrogenase; Hyperthyroidism; Hypothyroidism; Male; Muscle Denervation; Muscles; Propylthiouracil; Rats; Triiodothyronine

Cardiovascular alterations in hypo- and hyperthyroidism have been ascribed to changes of noradrenergic neurotransmission. In the present study the influence of thyroid hormones on adrenoceptors in the rat heart was further characterized. The effect of artificial hypothyroidism (induced by feeding 6-propyl-2-thiouracil, PTU) and hyperthyroidism (induced by daily injections of triiodothyronine, T3) on myocardial adrenoceptor binding, catecholamines, some physiological responses, and their interdependence was examined. The density of myocardial beta-adrenergic binding sites (3H-dihydroalprenolol, 3H-DHA) was reduced after PTU (by 38%) and enhanced after T3 treatment (by up to 82%). The increase was dose- and time-dependent and reversible within 4 days. No changes of the affinity of 3H-DHA to its binding sites were observed. Only L-T3 and L-T4 proved to be active, D-T3 and reverse T3 had no effect. The rise in beta-adrenoceptor density caused by T3 was prevented by concomitant administration of cycloheximide, indicating its dependence on protein synthesis. The density of myocardial alpha 1-adrenergic binding sites (3H-prazosin) was significantly reduced in the PTU group (by up to 28%) and even more distinctly by T3 treatment (by up to 50%). KD values remained unaltered. The noradrenaline content and turnover of rat hearts was significantly reduced by T3-induced hyperthyroidism. PTU treatment had no influence on content and turnover of noradrenaline. Plasma noradrenaline as well as adrenaline levels in freely moving rats were increased by PTU treatment 9- and 5-fold, respectively. In T3-injected animals no significant changes were measured. The density of adrenoceptors is known to be inversely correlated with catecholamine levels in several organs. Neither alpha- nor beta-adrenoceptor changes in the myocardium of dysthyroid rats could be attributed to such a homologous regulation, since they still occurred after chemical sympathectomy with 6-hydroxydopamine and adrenalectomy.(ABSTRACT TRUNCATED AT 400 WORDS)

Topics: Animals; Cycloheximide; Decerebrate State; Dihydroalprenolol; Dose-Response Relationship, Drug; Electric Stimulation; Heart Rate; Hyperthyroidism; Hypothyroidism; Male; Myocardium; Norepinephrine; Organ Size; Prazosin; Propylthiouracil; Rats; Rats, Inbred Strains; Receptors, Adrenergic; Time Factors; Triiodothyronine

T4 (0.26 microM) was incubated in 0.1 M phosphate buffer (pH 7.4) containing 10 mM EDTA with homogenates (3-5 mg protein) of various rat tissues and up to 400 mM dithiothreitol (DTT) for 1 h at 37 C; the rT3 generated was measured by RIA of ethanol extracts of the incubation mixture. Among the various tissues of the male rat, homogenates of skin and cerebral cortex were very active in the conversion of T4 to rT3; other tissues demonstrated little or no T4 5-monodeiodinating activity (MA). The tissue content of rT3 was also greatest in these two tissues. The MA in skin increased linearly with incubation period (up to 4 h) and with increasing concentration of protein (up to 5 mg), substrate (up to 10 microM) and DTT (up to 400 mM); its optimal pH was 7.4, and optimal temperature was 37 C. Its Km and maximum velocity approximated 0.29 microM and 9.6 pmol/h X mg protein, respectively, in the presence of 400 mM DTT. There was no appreciable difference in T4 to rT3 MA of skin from different parts of the body. The MA was most abundant in microsomes and least in cytosol. The MA was unaffected by propylthiouracil (up to 25 microM), methimazole (up to 100 microM), sodium salicylate (up to 80 microM), or 8-anilino-1-naphthalene sulfonic acid (up to 75 microM). Ipodate (up to 80 microM) weakly inhibited the MA. T3 and 3,5-diiodothyronine inhibited dermal T4 to rT3 MA in a dose-dependent manner; T3 was 3-12 times more potent than 3,5-diiodothyronine on a molar basis in different experiments. Treatment of euthyroid rats with 3,5-dimethyl-3'isopropylthyronine (45 micrograms/day, ip) for 3 or 5 days significantly increased dermal T4 to rT3 MA. Similar treatment of rats with T4 (100 micrograms/day, ip) or T3 (20 or 80 micrograms/day, ip) did not change with MA appreciably. Hypothyroidism markedly inhibited the MA, and fasting inhibited it modestly. Pregnancy was associated with marked reduction in the MA of skin in the mother [0.30 +/- 0.11 (+/- SE) vs. 7.2 +/- 2.2 ng/h X mg protein; P less than 0.02] and fetus (0.67 +/- 0.075; P less than 0.025).(ABSTRACT TRUNCATED AT 400 WORDS)

Topics: Animals; Dithiothreitol; Fasting; Female; Hydrogen-Ion Concentration; Hyperthyroidism; Hypothyroidism; Male; Microsomes; Pregnancy; Propylthiouracil; Rats; Skin; Temperature; Thyroxine; Time Factors; Tissue Distribution; Triiodothyronine, Reverse

The effect of thyroid status on histamine H1 receptors in adult and developing rat brain was investigated using the (3H) mepyramine binding assay. Hypothyroidism induced by treatment with 6-n-propyl-2-thiouracil resulted in a 31% decrease in the density and total content of adult rat brain (3H) mepyramine binding sites and a significant retardation of the developmental increase in H1 receptor binding in neonates. At 30 days of age, when euthyroid rats reached binding levels of the adult, hypothyroid animals presented reductions of 22 and 39% in (3H) mepyramine bound per unit weight and per brain respectively. In contrast, hyperthyroidism induced by treatment with L-thyroxine did not alter H1 receptor numbers in the adult rat brain but accelerated the developmental increase in (3H) mepyramine bound per unit weight that reached normal adult levels by 21 days of age. The results suggest that thyroid dysfunction during early life and adulthood may cause derangements of the histaminergic system in the brain.

Topics: Age Factors; Animals; Brain Chemistry; Female; Hyperthyroidism; Hypothyroidism; Male; Propylthiouracil; Pyrilamine; Rats; Rats, Inbred Strains; Receptors, Histamine; Receptors, Histamine H1; Thyroxine; Triprolidine

Rats were treated with propylthiouracil (PTU) for 10-day periods beginning at different ages. Daily injections of L-thyroxine (T4) were administered concurrently with PTU to a group of rats which served as one control group. Peripheral auditory function was evaluated by the brainstem response audiometry (BSRA) technique performed at 12, 16, 25 and 120 days of age. PTU treatment significantly increased wave I latency (cochlear nerve compound action potential) in adult rats when administered from 3 days before delivery through 6 days of age, but was without permanent effect (wave I latencies and thresholds) when administered for 10 days starting at 10 days after birth. T4 replacement during the first 10 postnatal days prevented permanent abnormalities. These data suggest that the period of greatest vulnerability to thyroid hormone depletion in the peripheral auditory system extends from at least 3 days before delivery through between 5 and 10 days of age.

Topics: Animals; Animals, Newborn; Auditory Pathways; Brain Stem; Cochlear Nerve; Congenital Hypothyroidism; Evoked Potentials, Auditory; Female; Hypothyroidism; Male; Propylthiouracil; Rats; Rats, Inbred Strains; Thyroid Hormones

Topics: Adult; Aged; Amiodarone; Benzofurans; Female; Humans; Hyperthyroidism; Hypothyroidism; Male; Middle Aged; Propylthiouracil; Thyroid Diseases; Thyroid Function Tests; Thyroid Gland; Thyroxine

It has been suggested that the deficient lipolytic response to catecholamines in hypothyroidism may be due to an increased sensitivity to adenosine and/or increased adenosine levels in this condition. We confirmed that the addition of adenosine deaminase enhanced the lipolytic response of hypothyroid fat cells, but the stimulation was at least as large in euthyroid cells. Adenosine analogs were more potent as antagonists of NA-induced lipolysis in hypothyroid than in euthyroid fat cells, but the difference could be explained by a decreased response to NA. Suspensions of hypothyroid cells accumulated more purine nucleosides (115 +/- 20) than did euthyroid cells (48 +/- 8 pmol/30 min/10(5) cells; p less than 0.01). This difference could not be explained by a lower rate of adenosine elimination, which occurred by three different pathways: uptake followed by phosphorylation, uptake followed by deamination and deamination by the serum albumin preparation. Under certain circumstances the latter pathway is of overwhelming importance. Fat cells from mature rats (460-480 g) behaved similarly as cells from young control rats. Thus, the changes induced by hypothyroidism was not due to a developmental change. The results are discussed in relation to earlier findings on the alterations in catecholamine responsiveness in hypothyroidism. It is concluded that an increased influence of adenosine could possibly explain some aspects of altered catecholamine responsiveness. If it does the mechanism is likely to involve an enhanced amount of adenosine rather than an increased sensitivity to adenosine.

Topics: Adenosine; Adenosine Deaminase; Adipose Tissue; Age Factors; Animals; Hypothyroidism; Inosine; Lipolysis; Male; Norepinephrine; Phosphorylation; Propylthiouracil; Rats; Rats, Inbred Strains; Receptors, Adrenergic, beta

At 14 days of age, hypothyroid and normal rats are rendered hypoglycaemic by insulin injection and the subsequent induction in adrenal tyrosine hydroxylase (TH) is studied. Hypothyroidism impairs both the intensity and the time-course of adrenal TH induction.

Topics: Adrenal Glands; Animals; Enzyme Induction; Female; Hypoglycemia; Hypothyroidism; Insulin; Kinetics; Male; Propylthiouracil; Rats; Thyroid Hormones; Tyrosine 3-Monooxygenase

The structural similarities of the heavy chains (HC) of myosin isolated from atria and ventricles of hyper-, hypo-, and euthyroid rabbits were compared by immunological analysis, by one- and two-dimensional peptide mapping, and by electrophoresis under nondenaturing conditions. Monoclonal and polyclonal antibodies, which are specific for HC alpha of ventricular myosin, cross-reacted equally with the HCs of euthyroid atrial myosin. Our immunological analysis identified multiple epitopes common to euthyroid atrial HC and ventricular HC alpha. One- and two-dimensional gel electrophoretic analysis of peptides produced by partial proteolytic digestion of each type of HC reveal no differences between euthyroid atrial HCs and ventricular HC alpha, whereas marked differences are apparent between atrial HC and ventricular HC beta. Nondenaturing gel electrophoresis separates ventricular myosin from hyper- and hypothyroid rabbits into two forms, V1 and V3, respectively. In euthyroid atria, two isomyosins, A1 and A2, were resolved; with the slower moving A2 isomyosin having the same mobility as that of the V1 isomyosin. After cross-hybridization of light chains of ventricular myosin with euthyroid atrial HCs, only a single band having a mobility identical with that of the V1 isomyosin was seen. Furthermore, atrial myosin HCs isolated from hyper- and hypothyroid rabbits were indistinguishable from euthyroid atrial HC and from ventricular HC alpha by these procedures. We conclude that ventricular HC alpha and atrial HC are indistinguishable proteins, and that the type of HC expressed in the atria is unaffected by the thyroid state of the rabbit.

Topics: Animals; Antibodies, Monoclonal; Epitopes; Heart; Heart Atria; Heart Ventricles; Hyperthyroidism; Hypothyroidism; Myocardium; Myosins; Organ Specificity; Propylthiouracil; Rabbits; Radioimmunoassay; Thyroid Gland; Thyroxine

Kinetic studies of the renin-angiotensin system (RAS) were carried out by measuring plasma renin activity (PRA), plasma renin concentration (PRC) and plasma renin substrate (PRS). Changes in this system were studied during hypothyroidism, after administration of propylthiouracil (PTU), and in thyroidectomized rats. A significant decrease in PRA and PRC was observed in those animals previously treated with PTU. However, a significant increase in PRC, and a decrease in PRS, were found in T animals, but no changes in PRA were observed. In these animals, after daily administration of potassium iodide for 1 week (T + KI), no changes in RAS were observed in comparison with T rats. Nevertheless, administration of daily doses of triiodo-L-thyronine (T + T3) induced a significant increase in PRA, leaving PRC unaltered. In this case the changes in PRA were related to the increase in PRS after T3 treatment. These results suggest that two different mechanisms were involved in renin release, one activated in T rats and the other in pharmacological hypothyroidism.

Topics: Animals; Electrolytes; Hypothyroidism; Male; Potassium Iodide; Propylthiouracil; Rats; Rats, Inbred Strains; Renin; Renin-Angiotensin System; Thyroidectomy; Thyroxine; Triiodothyronine

In order to study the effects of hypothyroidism on the development of microtubules in the cochlea, rat pups were rendered hypothyroid by daily administration of propylthiouracil. Microtubules were studied by immunofluorescence and electron microscopy. The absence of immunostaining of pillar cells with antimicrotubule or antitubulin antibodies was correlated with a retarded morphological development of microtubules within these same structures. The above alterations induced an abnormal development of pillar cells, non-appearance of the tunnel of Corti, and stunted epithelial growth. In contrast, a distinct immunoreaction was observed under the outer hair cells. This was attributed to abnormal persistence of afferent dendrites containing microtubules. The results suggest that, while the effect of thyroid hormone on microtubules in afferent cochlear dendrites could not be demonstrated, thyroid hormone is necessary for the normal development of microtubules in epithelial structures.

Topics: Animals; Cochlea; Fluorescent Antibody Technique; Hair Cells, Auditory; Hypothyroidism; Labyrinth Supporting Cells; Microtubules; Propylthiouracil; Rats; Rats, Inbred Strains

When hypothyroidism is induced surgically in early steps of development in the rat, an increase in serum aldosterone concentration (AC), in absence of changes in plasma renin activity (PRA), is observed. In contrast, in propylthiouracil (PTU) induced hypothyroidism, in adult animals, both AC and PRA decrease. Potassium iodide (KI) or triiodo-L-thyronine (T3) administration to thyroidectomized rats restores AC to normal levels, increasing PRA during the latter treatment. A close relationship between AC and plasma renin concentration (PRC) is observed in these experimental situations. The decrease in urinary aldosterone concentration (ACu), and the relation found between AC/ACu ratio and T3 concentration, suggest that metabolic clearance of aldosterone might be related to peripheric T3 levels in thyroidectomized animals, treated with KI or T3. These observations support the hypothesis, previously reported, which suggests different mechanisms involved in the control of aldosterone and renin release during the two different types of hypothyroidism.

Topics: Aldosterone; Animals; Hypothyroidism; Male; Propylthiouracil; Rats; Rats, Inbred Strains; Renin; Renin-Angiotensin System; Thyroid Hormones; Thyroidectomy

High concentrations of thyrotrophin-releasing hormone (TRH) in the rat pancreas were detected during the first few days of life decreasing thereafter while pancreatic TRH-degrading activity (TRH-DA) absent at birth appeared on day 14 and increased to reach adult values by day 21. This period of life is also remarkable by the low level of circulating thyroid hormones. Since TRH-degrading activity may be thyroid hormone dependent it was of interest to study the effects of thyroid status fluctuations both on TRH-DA and TRH content during the neonatal period. In this study, hypo- and hyperthyroidism were induced by 6-n-propyl-2-thiouracil (PTU) and triiodothyronine (T3) respectively. Pancreatic TRH-DA and TRH concentrations were measured at different ages from birth until day 29, in treated animals and results compared to control age-matched rats. In hypothyroid rats, pancreatic TRH concentrations remained significantly higher after day 16 while TRH-DA was lower during the whole period studied. Following T3 treatment, pancreatic TRH concentrations decreased significantly from day 3 onwards. However, no significant changes were found for TRH-DA except a two-fold increase on day 28. These results suggest that two different mechanisms may account for thyroid hormones action: 1) a direct effect on pancreatic TRH 2) an inductive saturable effect on TRH-DA. Furthermore a fine tuner modulatory role of TRH-DA on TRH concentrations cannot be excluded.

Topics: Age Factors; Animals; Female; Hyperthyroidism; Hypothyroidism; Pancreas; Pregnancy; Propylthiouracil; Radioimmunoassay; Rats; Rats, Inbred Strains; Thyrotropin-Releasing Hormone; Triiodothyronine

High fat, high cholesterol diets do not produce atherosclerotic lesions in some animal species such as the rat; however, when combined with experimentally induced hypothyroidism, such diets do produce lesions. While the diets or hypothyroidism each induce significant alterations in plasma lipoproteins, the combination produces marked hypercholesterolemia. If the atherosclerosis is related to the hyperlipidemia, the combination regimen could be provoking changes in the structure or compositions of lipoproteins which are not noted with either regimen alone. To test this hypothesis, Sprague-Dawley male rats (approximately 250 g) were treated as follows: Diet(a) = chow + 5% lard and 0.3% Na taurocholate; Diet(b) = Diet(a) + 2% cholesterol; Diet(c) = Diet(b) + 0.1% propylthiouracil (PTU). The major findings were as follows. 1) With Diet(b), slow floating very low density lipoprotein (VLDL) (pre-beta) enriched in cholesteryl esters accumulated in plasma and low density lipoprotein (LDL) disappeared from its usual flotation position. 2) With Diet(c), changes in plasma concentration were more marked but were also qualitatively different. More VLDL accumulated, and distribution of VLDL was shifted toward even slower floating cholesteryl ester-rich particles. VLDL had "broad beta" mobility. Also, a beta-migrating intermediate density lipoprotein (IDL) population appeared. 3) Lipoprotein (d less than 1.019 g/ml) and zonal subfractions of d less than 1.019 g/ml lipoproteins (isolated from rats on cholesterol Diet (b] stimulated [3H]oleate incorporation into cholesteryl esters of fibroblasts and macrophages, while the d less than 1.019 g/ml fractions of 5% fat (Diet(a]-fed rats did not. 4) The major finding of this study was that identically prepared d less than 1.019 g/ml fractions of Chol + PTU-treated rats (Diet(c] were approximately 2.5-fold more stimulatory than the lipoproteins of cholesterol-fed rats. The results could not be explained by differences in cholesterol contents of the cholesterol-rich lipoproteins, but significant differences in the apoprotein compositions of the fraction were found which could be important. The most active fractions had higher apoBL/apoBS and apoE/apoC ratios than less active fractions. Thus, the combination regimen of cholesterol and PTU produced changes in lipoprotein structure and composition which enhanced the abilities of the lipoproteins to interact with cells. The results suggest that analysis of lipoprotein-cell interactio

Topics: Animals; Apolipoprotein A-I; Apolipoproteins; Apolipoproteins B; Apolipoproteins E; Cholesterol; Cholesterol, Dietary; Chromatography, Gel; Electrophoresis, Polyacrylamide Gel; Hypothyroidism; Lipoproteins; Lipoproteins, LDL; Lipoproteins, VLDL; Male; Propylthiouracil; Rats; Rats, Inbred Strains; Triglycerides; Ultracentrifugation

Topics: Animals; Female; Hair Cells, Auditory; Hypothyroidism; Microscopy, Electron, Scanning; Propylthiouracil; Rats; Rats, Inbred Strains

Topics: Animals; Female; Hypothyroidism; Pregnancy; Pregnancy Complications; Prenatal Exposure Delayed Effects; Propylthiouracil; Rats; Rats, Inbred Strains

Long-Evans rats and their offspring were made hypothyroid by addition of the antithyroid goitrogen 6-N-propylthiouracil (PTU) to the drinking water (0.1%) from the day of parturition. Serum concentrations of prolactin (PRL), thyroid-stimulating hormone (TSH) and thyroxine (T4) were determined by double radioimmunoassay (RIA). From the fifth postnatal day, body weight of PTU-treated pups was significantly lower than that of control rats, and a strikingly elevated serum TSH level and nondetectable amount of T4 were measured both in PTU-exposed mothers and their offspring at Day 10 postpartum. To test the youngs' suckling capability and the amount of maternal milk production, 10- and 15-day-old normal and PTU-treated pups were separated from their mothers for 4 hr in the morning and then reunited and allowed to suckle. Normal pups gained body weight at the end of both the first and second hour postreunion, while PTU pups gained only during the first hour and lost weight in the second hour of testing. When the pups were exchanged between normal and PTU mothers, opposite results were obtained, indicating that the reduced gain in hypothyroid rats was not due to impaired suckling capability, or insufficient sensory stimulation for milk secretion but to a decreased milk production of PTU mothers. In accordance with this, in lactating hypothyroid rats both the basal (presuckling) level and the suckling-induced rise of serum PRL were found significantly depressed.

Topics: Animals; Animals, Suckling; Female; Hypothyroidism; Lactation; Pregnancy; Prolactin; Propylthiouracil; Rats; Thyrotropin

Symptoms and signs of severe hypothyroidism developed in a young woman at age 15. These symptoms progressed for a year; at age 16, she was found to have a firm goiter, thyroid autoantibodies, very low serum thyroxine and high thyrotropin values, indicating autoimmune thyroiditis with hypothyroidism. She received L-thyroxine, 0.20 mg per day, and was well until age 24 when she became pregnant. In the first trimester, manifestations indicative of hyperthyroidism developed; these were only ultimately recognized immediately after delivery of a 32-week still-born goitrous baby. Despite the discontinuation of thyroxine therapy, the hyperthyroidism persisted and was confirmed as Graves' disease by elevated thyroxine, triiodothyronine, and radioactive iodine uptake values, a diffuse scanning result, and the presence of thyroid-stimulating antibody. The patient was treated with propylthiouracil and became pregnant while receiving that regimen. Later, several months after delivery, the patient was treated with radioactive iodine, ultimately became hypothyroid, and has been treated ever since with thyroxine. She became pregnant again and, because of the continuing high titers of thyroid-stimulating antibody, received propylthiouracil, 100 mg daily, commencing in the third trimester of pregnancy, to avoid probable fetal hyperthyroidism due to the transplacental transfer of thyroid-stimulating antibody. In each of the last two pregnancies, when the infants were born, they seemed normal (because of the transplacental effect of propylthiouracil), but passive-transfer neonatal hyperthyroidism developed in each within 10 days after delivery, ultimately requiring treatment by conventional means. This case illustrates the following points: (1) Hyperthyroidism occasionally develops years after hypothyroidism. (2) In young women, high titers of thyroid-stimulating antibody may produce fetal and neonatal passive-transfer hyperthyroidism even at a time when the mother herself is no longer hyperthyroid; transplacental treatment of the fetus by maternal propylthiouracil ingestion may thus be necessary during the last trimester, but only when there is a high degree of probability that the fetus is at risk. (3) Because the infants had been protected in utero by the placental transfer of propylthiouracil, neonatal hyperthyroidism did not develop until several days after delivery.(ABSTRACT TRUNCATED AT 400 WORDS)

Topics: Adult; Female; Goiter; Graves Disease; Humans; Hypothyroidism; Infant, Newborn; Male; Maternal-Fetal Exchange; Pregnancy; Pregnancy Complications; Propylthiouracil; Thyroxine

Propylthiouracil (PTU) in maximally inhibitory doses for liver and kidney iodothyronine 5'-deiodinase activity (5'D-I), reduces extrathyroidal T4 to T3 conversion by only 60-70% in euthyroid rats. A second pathway of T4 to T3 conversion (5'D-II) has been found in pituitary, central nervous system, and brown adipose tissue. 5'D-II is insensitive to PTU and increases in hypothyroidism, whereas 5'D-I decreases in hypothyroid rats. Thyroxine (T4) and triiodothyronine (T3) kinetics were assessed in euthyroid and thyroidectomized rats by noncompartmental analysis after injecting [125I]T4 and [131I]T3. Neither the volume of distribution nor the rate of fractional removal of plasma T4 was affected by the thyroid status, but the fractional removal rate of T3 was approximately 50% reduced in hypothyroid rats (P less than 0.001). Fractional T4 to T3 conversion was 22% in euthyroid and 26% in hypothyroid rats. In euthyroid rats, sufficient PTU to inhibit liver and kidney 5'D-I greater than 90% reduced serum [125I]T3 after [125I]T4 (results given as percent dose per milliliter X 10(-3) +/- SEM): 4 h, control 16 +/- 2 vs. PTU 4 +/- 1, P less than 0.005, and 22 h, control 6.4 +/- 0.4 vs. PTU 3.6 +/- 0.7, P less than 0.025. In thyroidectomized rats, the same dose of PTU also inhibited 5'D-I in liver and kidney, but had no effect on the generation of serum [125I]T3 from [125I]T4. Similarly, after 1 microgram T4/100 g bw was given to thyroidectomized rats, serum T3 (radioimmunoassay) increased by 0.30 +/- 0.6 ng/ml in controls and 0.31 +/- 0.09 ng/ml in PTU-treated rats. However, when the dose of T4 was increased to 2-10 micrograms/100 g bw, PTU pretreatment significantly reduced the increment in serum T3. T3 clearance was not affected by PTU in hypothyroid rats. The 5'D-II in brain, pituitary, and brown adipose tissue was reduced to less than or equal to 60% of control by 30 micrograms/100 g bw reverse T3 (rT3), an effect that lasted for at least 3 h after rT3 had been cleared. In rT3-pretreated thyroidectomized rats, the generation of [125I]T3 from tracer [125I]T4 was reduced in the serum: 6 +/- 1 vs. 12 +/- 1 X 10(-3)% dose/ml, P less than 0.01, during this 3-h period. We conclude that virtually all the T3 produced from low doses of exogenous T4 given to hypothyroid rats is generated via a PTU-insensitive pathway, presumably catalyzed by the 5'D-II. This is a consequence of the enhanced activity of this low Km enzyme together with the concomitant decrease in the hepatic

Topics: Adipose Tissue; Animals; Brain; Hypothyroidism; Kidney; Kinetics; Liver; Male; Pituitary Gland; Propylthiouracil; Rats; Rats, Inbred Strains; Thyroidectomy; Thyroxine; Triiodothyronine

The effects of neonatal hypothyroidism were examined on the concentrations of cytosol receptors for progestin and estrogen in the cytosols from 10-day old female and male rats. The concentration of cytosol progestin- and estrogen receptors in the 10-day old female and male rats with propylthiouracil-induced hypothyroidism was determined by multiconcentration saturation analysis. Neonatal hypothyroidism markedly depressed the level of progestin receptors in the cortex but not in the hypothalamus-preoptic area (HPOA). There were no differences in the concentration of estrogen receptors in the cortex and HPOA between the control and PTU rats. These results suggest that thyroid hormone may be one of the factors affecting the development of progestin receptors in the cortex. Its significance was discussed in relation to determination of the length of sexual differentiation of the rat brain.

Topics: Animals; Animals, Newborn; Cerebral Cortex; Cytosol; Female; Hypothalamus; Hypothyroidism; Male; Pregnancy; Preoptic Area; Propylthiouracil; Rats; Rats, Inbred Strains; Receptors, Estrogen; Receptors, Progesterone; Sex Factors

Newborn rats of both sexes were treated from birth with the anti-thyroid goitrogen, n-propylthiouracil (PTU) given in the drinking water of the litter (0.1% w/v). One group received the treatment for 25 days, another for 50 days, and a third group for 120 days. The experimental rats showed growth retardation as well as all other classical signs of developmental arrest or delays induced by postnatal hypothyroidism. In order to assess the ability of the hypothyroid animals to recover spontaneously from the retarded state, at days 25, 50 and 120 postnatal the PTU water was replaced with tap water. In each case, within 5-7 days after PTU withdrawal the animals began to show marked compensatory growth accompanied by many signs of behavioral and physiological recovery. In general, the male rats showed higher compensatory growth rates as compared to the females, enabling them to attain significantly higher body weights. However, when growth recovery was followed for up to 6 months it was found that the male rats were unable to attain complete catch-up growth, regardless of the age at which recovery began, while the females of all age groups were able to achieve this goal. In view of the severity of PTU-induced growth retardation, these results suggest significant plasticity of growth processes in the rat, especially in the female. It is suggested that male and female rats recovering from prolonged PTU-induced growth retardation offer a good model system for the study of biochemical, anatomical and physiological aspects of growth recovery and catch-up growth at both the cellular and organismic levels, particularly in relation to the effects of thyroid, growth hormone, and other growth-promoting factors.

Topics: Aging; Animals; Animals, Newborn; Animals, Suckling; Body Weight; Female; Growth Disorders; Hypothyroidism; Male; Propylthiouracil; Rats; Sex Factors; Sexual Maturation; Weaning

Clusters of luminal dense bodies, limited by a triple-layered membrane, were found in all follicle lumina in thyroid glands of mice. After thyroxine treatment the number of luminal dense bodies increased, especially in the periphery of the lumen, where the intraluminal bodies often displayed a striking resemblance to microvilli. In hyperplastic goiters, obtained by feeding mice with propylthiouracil, luminal dense bodies were replaced by intraluminal vesicles. During goiter involution the vesicles were gradually replaced by luminal dense bodies; the presence of intermediate forms suggests that vesicles and dense bodies are basically the same formations. Luminal dense bodies were observed in colloid droplets indicating their removal by endocytosis. As demonstrated by electron-microscopic cytochemistry, luminal dense bodies contain a membrane-bound peroxidase, and electron-microscopic autoradiography after administration of 125I indicate that they possess an iodinating capacity. Our observations on mouse thyroid glands suggest that the luminal dense bodies, which appear as vesicles in hyperplastic glands, are formed by shedding of the apical plasma membrane of the follicle cell. The shedding process might be of importance for the turnover of plasma-membrane material.

Topics: Animals; Autoradiography; Cell Membrane; Hyperthyroidism; Hypothyroidism; Iodine Radioisotopes; Male; Mice; Mice, Inbred Strains; Microscopy, Electron; Propylthiouracil; Thyroid Gland; Thyrotropin; Thyroxine

Studies were designed to determine whether an autoregulation system exists for TSH in the rabbit. For this purpose, a species-specific RIA for rabbit TSH that does not cross-react with human (h) TSH was developed. Hypothyroid animals were studied at varying time periods up to 3 months after either surgical thyroidectomy or propylthiouracil (PTU) treatment. Highly purified hTSH was injected iv at doses of 0 (saline control), 0.1, 0.3, 1,3, and 10 micrograms into unanesthetized rabbits bearing chronically implanted Silastic catheters. Blood samples were obtained at -30, 0, 10, 20, 30, 60, 120, 180, 240, and 300 min and 24 h. Doses between 0.3 and 10 micrograms hTSH produced a prompt fall (10 min) in rabbit TSH in hypothyroid rabbits studied 8-21 days after thyroidectomy. The minimum dose of hTSH that significantly suppressed rabbit TSH was 0.3 micrograms. This dose produced a peak value of hTSH in rabbit serum of 1.3 +/- 0.1 (+/- SEM) ng/ml 10 min after injection, which translates into a bioassay potency of 2.0 microU/ml (close to the physiological level in humans). A dose-response relationship existed between the hTSH dose injected and the duration and magnitude of suppression of rabbit TSH. This response to TSH was specific; 10 micrograms hTSH produced no change in endogenous rabbit serum LH and, conversely, 10 IU hLH produced no change in rabbit serum TSH. In contrast to these striking effects in acute hypothyroid animals, hTSH produced no detectable suppression of rabbit TSH in animals that were hypothyroid for 2-3 months. The sensitivity of the autoregulatory system to the suppressive effects of exogenous hTSH decreased with increasing duration of hypothyroidism; a time-response relationship existed. We conclude that: 1) a sensitive and specific autoregulatory control system for TSH exists in the rabbit; and 2) as the duration of hypothyroidism increases, the sensitivity of the autoregulatory system to the suppressive effects of endogenous TSH changes.

Topics: Animals; Feedback; Humans; Hypothyroidism; Propylthiouracil; Rabbits; Thyroid Gland; Thyroidectomy; Thyrotropin; Thyroxine; Time Factors

Earlier studies have shown larger increments in serum T3 in 2-week-old congenitally hypothyroid rats than in euthyroid controls after injections of small doses of T4. Since hepatic and renal 5'-deiodination of T4 to T3 in vitro (5' D-I) is reduced during the neonatal period and in hypothyroidism, those results suggest that there may be major changes in the distribution and metabolism of T3 or that an alternative enzymatic pathway is the predominant source of extrathyroidally produced T3 in these rats. The alternative pathway, 5' D-II, is a relatively minor source of serum T3 in adult euthyroid rats, but the contribution of this pathway to the extrathyroid T3 pool during the neonatal period and in hypothyroxinemia is not known. Consequently, we studied [125I]T4 and [131I]T3 kinetics and fractional T4 to T3 conversion in 2-week-old euthyroid and hypothyroid rats and then explored the source of circulating T3 by manipulating 5' D-I activity with propylthiouracil and that of 5' D-II with thyroid hormone. The plasma clearance rate of T4 was increased in hypothyroid rats, a difference entirely accounted for by the faster fractional rate of irreversible removal in the hypothyroid pups. Plasma clearance rate of T3 was reduced in hypothyroid rats owing to the reduced volume of distribution of T3. Fractional T4 to T3 conversion was 2- to 3-fold higher in euthyroid or hypothyroid neonates than in adult rats. In euthyroid rats the serum concentration of T4 was 36 +/- 1 (SEM) ng/ml and that of T3 0.61 +/- 0.03 ng/ml, and the production rates were 432 and 159 ng day-1 30 g-1 BW for T4 and T3, respectively. About 80% of the T3 in euthyroid neonates was produced extrathyroidally . These findings are inconsistent with hepatic and renal 5' D-I being the main source of serum T3 in 2-week-old rats. In fact, liver and kidney 5' D-I activities were 40% and 65% of the corresponding adult values in euthyroid neonates, and in hypothyroid pups were further reduced to 15% and 17%. In contrast, 5' D-II, previously reported to be high in central nervous tissue and pituitary, was 7-10-fold higher in brown adipose tissue (BAT) of hypothyroid pups than in that of euthyroid ones.(ABSTRACT TRUNCATED AT 400 WORDS)

Topics: Aging; Animals; Hypothyroidism; Kinetics; Propylthiouracil; Rats; Rats, Inbred Strains; Thyroid Gland; Thyroid Hormones; Thyroxine; Triiodothyronine

This study was designed to investigate the protective effect of PTU pretreatment against acetaminophen hepatotoxicity in rats whose hepatic GSH had been depleted by prior diethylmaleate (DEM) administration. A single injection of DEM depleted hepatic GSH showing lowest level after 90 min in both control and PTU pretreated rats. Triple injection schedule kept the hepatic GSH concentrations consistently very low up to 6 hr. Whereas a toxic dose of acetaminophen administration did not effect SGOT and SGPT levels after 30 hr in PTU pretreated rats given either a single or multiple injections of DEM, the same dose of acetaminophen in the control rats raised these transaminases to a very high level. High activity of transaminases was associated with significant histological hepatic damage. Our results suggest that PTU pretreatment affords significant protection against acetaminophen hepatotoxicity even under conditions when hepatic GSH concentrations have been significantly depleted prior to acetaminophen administration.

Topics: Acetaminophen; Animals; Free Radicals; Glutathione; Hypothyroidism; Liver; Male; Maleates; Propylthiouracil; Rats

The proportion of total, helper and suppressor T lymphocytes among mononuclear cell preparations from blood and spleen of rats made hypo- and hyperthyroid was measured using three monoclonal antibodies specifically directed against total, helper and suppressor T cells. Compared to normal rats, hypothyroid (thyroidectomized or treated with 6-propyl-2-thiouracil (PTU) rats had a decreased proportion of suppressor T cells in the spleen, which produced an increase in the helper/suppressor T cells ratio. The opposite alterations (increased suppressor T cells and decreased ratio) was found in the blood of the same animals. Triiodothyronine (T3) added to PTU in the drinking water prevented these alterations. Animals treated with high doses of T3 for 17 days did not develop any alteration either in the proportions or in the ratio of helper/suppressor T cells. Our results suggest that hypothyroidism but not hyperthyroidism alters the normal balance between helper and suppressor T cells in rats.

Topics: Animals; Antibodies, Monoclonal; Body Weight; Hyperthyroidism; Hypothyroidism; Leukocyte Count; Male; Organ Size; Propylthiouracil; Rats; Rats, Inbred Strains; Spleen; T-Lymphocytes, Helper-Inducer; T-Lymphocytes, Regulatory; Thyroidectomy; Triiodothyronine

In this study we investigated further the antigoitrogenic effect of ClO4 in rats on a low iodine diet (LID) and 6-propyl-2-thiouracil (PTU). The thyroid weight of rats on the mixed goitrogen was initially similar to that of animals on PTU, decreasing to values obtained in rats treated with ClO4 alone by 10 days. Despite the differences in thyroid weight, rats treated during an identical period with PTU or mixed goitrogen develop hypothyroidism to a comparable degree as far as can be assessed by the thyroidal 127I content, plasma T4, T3 and TSH concentrations, and pituitary TSH content. Moreover, it was observed that there were differences in plasma insulin and glucose levels in these hypothyroid animals. The plasma insulin and glucose levels of rats on PTU are comparable to those found in control rats. In rats on mixed goitrogen, both plasma insulin and glucose levels are initially maintained within the normal ranges, and then decline over the subsequent days of treatment. Within the treatment period studied here, plasma insulin and glucose levels were higher for rats on PTU than for animals on ClO4, PTU + ClO4, or thyroidectomized (Th) animals. We have obtained further evidence of the hypothyroid state of rats on these goitrogen regimens based on measurements of pituitary and plasma GH levels and liver mitochondrial alpha-glycerophosphate dehydrogenase (alpha-GPD). The PTU-treatment decreased the liver alpha-GPD activity to a comparable degree to that of mixed goitrogen. Moreover, both PTU + ClO4 and PTU-treatment resulted in a state of hypothyroidism intense enough to induce effects on growth, and plasma and pituitary GH levels comparable to that of Th animals. However, the values for rats on mixed goitrogen appear to be below the PTU data. The present findings appear to be consistent with the view that TSH is not the unique factor determining the size of the resulting goitre. The results are discussed in relation to the hypothesis that: 1) the antigoitrogenic effect of ClO4 could be associated with changes in the ability of the thyroid tissue to bind TSH, or with a step beyond TSH binding, and 2) the different endocrine and metabolic states of rats on PTU or PTU + ClO4, shown by their different plasma insulin, GH and glucose levels, may play an important role in determining the thyroid weight response to TSH.

Topics: Animals; Blood Glucose; Goiter; Growth Hormone; Hypothyroidism; Insulin; Male; Organ Size; Perchlorates; Potassium; Potassium Compounds; Propylthiouracil; Rats; Rats, Inbred Strains; Thyroid Gland; Thyroid Hormones

Postnatal ontogeny of rat liver alpha 1-adrenergic receptor was examined using alpha 1-specific radioligand [3H]prazosin in control and propylthiouracil-treated congenital hypothyroid rats at various ages. Partially purified rat liver membranes prepared by the Neville method had 8-fold purification of 5'-nucleotidase from the crude homogenates from postnatal day 5 to adulthood. [3H]Prazosin binding was typical of an alpha 1-adrenergic receptor, and (-)epinephrine affinity for the [3H]prazosin-binding sites was not altered in the presence of 10(-5) M guanylyl-imidodiphosphate. The receptor density was lower in 5- and 15-day-old rats than in 28-day-old or older rats in both control and hypothyroid groups. (P less than 0.01). At 28-34 days of age, hypothyroid pups had significantly lower alpha 1-receptor density than controls (399 +/- 10 vs. 869 +/- 40 fmol mg protein-1; P less than 0.01). Replacement therapy with daily T4 injection from postnatal days 16-27 restored 54% of the deficit in PTU-treated hypothyroid pups at 28 days. The dissociation constant of [3H] prazosin did not change with advancing age or with different treatment and was consistent at 0.1 nM. These findings indicate that the normal ontogeny of plasma membrane alpha 1-adrenergic receptors is dependent upon thyroid hormone and matures postnatally in rat liver.

Topics: Aging; Animals; Binding, Competitive; Cell Membrane; Female; Hypothyroidism; Kinetics; Liver; Male; Prazosin; Propylthiouracil; Quinazolines; Rats; Rats, Inbred Strains; Receptors, Adrenergic; Receptors, Adrenergic, alpha; Thyroid Gland

We studied the influence of the thyroid hormones on the development of the ability of the adrenal glands to release epinephrine after stimulation by insulin-induced hypoglycaemia in the young rat. In animals rendered hypothyroid from birth, this development is delayed as compared to control rats. Administration of thyroxin to these animals restores the ability of the adrenals to deplete epinephrine. These results may indicate an influence of the thyroid hormones on the development of the functional innervation of the adrenal medulla in the young rat.

Topics: Adrenal Glands; Animals; Blood Glucose; Epinephrine; Female; Hypothyroidism; Insulin; Male; Propylthiouracil; Rats; Thyroxine

The control of weaning was studied in rat pups aged 17-24 days. The influence of two hormones, thyroxine (T4) and corticosterone, and the effect of declining intestinal lactase activity were evaluated. Hypothyroidism was induced by administration of n-propylthiouracil and hyperthyroidism was induced by injection of T4. Hypothyroid pups failed to begin nibbling chow while littermates injected with T4 weaned normally. Two abnormalities resulting from hypothyroidism, hypothermia and stunted incisors, were not responsible for the lack of weaning in hypothyroid pups. Hyperthyroidism did not cause precocious weaning. Glucocorticoid levels were manipulated by both adrenalectomy (ADX) and administration of corticosterone. ADX pups exhibited a delayed pattern of weaning while both ADX pups injected with corticosterone and sham-operated pups weaned normally. Corticosterone injected before its normal developmental surge did not cause precocious weaning. Lactase activity, measured throughout these experiments, did not consistently reflect the degree of weaning progression. We conclude that 1) the hormones, T4 and corticosterone, are necessary for the onset of weaning, but neither is a sufficient stimulus to initiate weaning, and 2) low lactase activity does not initiate weaning.

Topics: Adrenalectomy; Aging; Aldosterone; Animals; beta-Galactosidase; Corticosterone; Female; Hyperthyroidism; Hypothyroidism; Jejunum; Pregnancy; Propylthiouracil; Rats; Rats, Inbred Strains; Thyroxine; Weaning

In order to study the long-term effects of neonatal hypothyroidism on the organ of Corti, rats were given propylthiouracil (PTU) during the first 30 days after birth. Cochlear changes occurring after the cessation of antithyroid treatment were studied by both physiological (brainstem auditory evoked responses: BAERs, electrocochleography) and morphological techniques (transmission and scanning electron microscopy). The first appearance of BAERs was noted between days 37 and 45. Maturation of auditory potentials was achieved within 10-15 days but was incomplete since the animals definitely demonstrated elevated thresholds around 60-70 dB SPL. Morphological results indicated that some structures, like the inner sulcus epithelium, were able to restart maturational processes that had been interrupted during the period of hypothyroidism. However, these maturational changes were considerably limited and rapidLy accompanied by severe degenerative changes involving almost all cochlear structures. Degenerative changes included the deposition of an amorphous substance within the organ of Corti, severe alterations in pillar cells (absence of formation of the tunnel of Corti, distortion of microtubules), severe outer hair cell losses with abnormalities in their innervation (absence of development of efferents and loss of afferent dendrites).

Topics: Aging; Animals; Animals, Newborn; Electrophysiology; Hypothyroidism; Organ of Corti; Propylthiouracil; Rats; Rats, Inbred Strains

Two months after recovery from a perinatal hypothyroidism (PTU), the total amount of pituitary estradiol binding sites (EBS) was still dramatically reduced, but the actual concentration of EBS had returned to control levels.

Topics: Aging; Animals; Animals, Newborn; Female; Hypothyroidism; Pituitary Gland; Pregnancy; Prenatal Exposure Delayed Effects; Propylthiouracil; Rats; Receptors, Estradiol; Receptors, Estrogen

Presented are two case studies which investigate the adverse effects of Graves' disease in pregnant women. Particular attention has been paid to the therapeutic regimen and its implications for the maternal, fetal and neonatal well-being. The first case study illustrates that Graves' disease complicating pregnancy can be treated by bed rest and careful observation of mother and fetus. The first pregnancy of our second case study confirms these results. Her second pregnancy, in which the symptoms of Graves' disease were far more severe, illustrates that it is possible to treat fetal hyperthyroidism by treating the pregnant mother with antithyroid drugs. If great care is taken to avoid overtreatment of the fetus, the treatment with antithyroid drugs is superior to surgical treatment, since surgery completely neglects the problem of fetal hyperthyroidism.

Topics: Abortion, Spontaneous; Adult; Female; Fetal Diseases; Graves Disease; Humans; Hypothyroidism; Intellectual Disability; Pregnancy; Pregnancy Complications; Propylthiouracil

Topics: Aging; Animals; Animals, Newborn; Cell Membrane; Dexamethasone; Female; Fetal Diseases; Hypothyroidism; Liver; Maternal-Fetal Exchange; Pregnancy; Propylthiouracil; Rabbits; Receptor, Insulin

We have studied 5'-deiodination of thyroxine (T(4)) and 3,3',5'-triiodothyronine (rT(3)) in rat pituitary tissue in vitro, with respect to substrate specificity, reaction kinetics, effects of 6-n-propyl-2-thiouracil (PTU), and the time course of effects of thyroid hormone depletion and repletion. Removal of one phenolic iodine or both tyrosyl iodines from the T(4) molecule resulted in compounds that were not deiodinated, but alterations in the alanine side chain had little effect.5'-Deiodination of 2 nM rT(3) by pituitary microsomes from euthyroid rats was inhibited >90% by 1 mM PTU, but was inhibited <10% by 100 nM T(4). The apparent Michaelis constant (K(m)) and maximum velocity (V(max)) for rT(3) at 20 mM dithiothreitol (DTT) were 33 nM and 84 pmol/mg protein per h. This reaction followed ping-pong type reaction kinetics when concentrations of DTT were varied. PTU inhibition was competitive with DTT and uncompetitive with rT(3). In contrast, when pituitary microsomes from hypothyroid rats (21 d postthyroidectomy) were used, deiodination of 2 nM rT(3) was inhibited only 20% by 1 mM PTU and up to 80% by 100 nM T(4). At 20 mM DTT, the apparent K(m) and V(max) in hypothyroid microsomes were 4.7 nM rT(3) and 16 pmol/mg protein per h. T(4) was a competitive inhibitor of PTU-insensitive rT(3) 5'-deiodination (K(i) = 1.3 nM). T(4) 5'-deiodination by hypothyroid microsomes was not affected by PTU, was competitively inhibited by rT(3) (K(i), 1.7 nM), and exhibited sequential type reaction kinetics with DTT as cosubstrate. When T(4) 5'-deiodination was measured in euthyroid and hypothyroid microsomes, respectively, the apparent K(m) and V(max) for T(4) at 20 mM DTT, were 0.9 nM and 0.55 pmol/mg protein per h (euthyroid), and 0.8 nM and 6.9 pmol/mg protein per h (hypothyroid). The T(4) 5'-deiodination rate and the PTU-insensitive, but not total, rT(3) 5'-deiodination rate (i.e. measured in the presence and the absence of 1 mM PTU, respectively) in pituitary homogenates were significantly elevated 24 h after thyroidectomy. PTU-insensitive activity continued to increase until at >/=30 d after thyroidectomy it was 11 times the PTU-insensitive activity in controls. At the latter time, PTU-sensitive rT(3) 5'-deiodinase activity appeared to be decreased. The increase in PTU-insensitive T(4) and rT(3) 5'-deiodination observed 48 h after thyroidectomy was prevented by replacement doses of T(4) or T(3). The PTU-insensitive activity of long term hypothyroid pituitaries was

Topics: Animals; Depression, Chemical; Dithiothreitol; Hypothyroidism; Iodide Peroxidase; Kinetics; Male; Microsomes; Peroxidases; Pituitary Gland, Anterior; Propylthiouracil; Rats; Rats, Inbred Strains; Thyroidectomy; Thyroxine; Triiodothyronine

A group of guinea pigs was rendered hypothyroid using propylthiouracil solution in their drinking water. The animals were hypothyroid for at least 120 days. During this time no change was noted in their hearing thresholds for high-frequency clicks. The audiometric evaluation was performed using brainstem evoked response audiometry.

Topics: Animals; Audiometry, Evoked Response; Guinea Pigs; Hearing Disorders; Hypothyroidism; Propylthiouracil

Thirty-three children with hyperthyroidism, an uncommon condition in childhood, were treated at the Hôpital Ste-Justine in Montreal during the period 1961 to 1974. Of these, 31 underwent medical treatment initially. Fifteen were cured by medical treatment only; the other 18 had to undergo subtotal thyroidectomy. When these two groups were compared the advantage of surgery in the treatment of this disease was clear. There were no major complications postoperatively. Two children became hypothyroid. The mean follow-up was 5 years and 6 months.

Topics: Adolescent; Adult; Child; Female; Follow-Up Studies; Humans; Hyperthyroidism; Hypothyroidism; Male; Propylthiouracil; Thyroidectomy

Newborn rats were rendered hypothyroid during the first post-natal week and then studied as adults. At 80 days of age, groups of control and neonatally treated animals were sacrificed at the peak (13.00 h) and trough (07.00 h) of the serum thyroid stimulating hormone (TSH) circadian rhythm. Both control and treated animals showed the normal peak and trough fluctuation of serum TSH, although the animals made hypothyroid neonatally had serum TSH levels which were less than those of the control animals. Serum thyroxine (T4) levels of control and treated animals were similar at the trough of the serum TSH rhythm (07.00 h), but the (T4) levels of the neonatally hypothyroid animals were significantly lower than those found in the control animals at the peak of the TSH rhythm (13.00 h). The results of this experiment indicate that the central nervous system (CNS) regulation of the circadian pattern of serum TSH is maintained in adult animals made hypothyroid neonatally, and supports the results of previous studies which indicate an enhanced sensitivity of TSH secretion to feedback suppression by thyroid hormones.

Topics: Age Factors; Animals; Animals, Newborn; Circadian Rhythm; Female; Hypothyroidism; Male; Propylthiouracil; Rats; Rats, Inbred Strains; Thyrotropin; Thyroxine

Cholesterol-feeding of hypothyroid Long-Evans rats results in a marked hypercholesterolemia and hepatic secretion of cholesteryl ester and apoE-rich VLDL and LDL which accumulate in the serum compartment (J. Lipid Res. 1981 22: 971-989). The present study segregates the effects of hypothyroidism from the combined effects reported above. Hypothyroidism alone does not result in the secretion of cholesteryl ester-rich lipoproteins by the liver which, in contrast, contains depressed quantities (30%) of triglyceride-rich (71% of lipid mass) VLDL and low levels of LDL which is also triglyceride-rich when compared to the nascent lipoproteins of euthyroid rat livers. The nascent lipoproteins from the hepatic Golgi cisternae and secretory vesicles of hypothyroid rats all had pre-beta or slow pre-beta migration on agarose gel electrophoresis and were very dissimilar in lipid and apoprotein composition from the beta-migrating LDL that accumulates in the sera of these animals and contains 13.8% triglyceride, 51.3% cholesteryl ester, and has an apoB/apoE ratio of 32.7. We conclude that the serum LDL in hypothyroid rats, which contains only apoB100, is not secreted directly by the liver but represents a normal catabolite of triglyceride-rich VLDL that may accumulate due to reduced receptor-mediated clearance rather than an overproduction of its immediate precursor, hepatic VLDL.

Topics: Animals; Apolipoproteins; Cholesterol; Cholesterol Esters; Hypothyroidism; Lipids; Lipoproteins; Lipoproteins, LDL; Lipoproteins, VLDL; Liver; Male; Propylthiouracil; Rats

A woman with hypothyroidism and Graves ophthalmopathy was treated with propylthiouracil during her second pregnancy. This was employed because her first pregnancy resulted in an infant with severe intrauterine growth retardation and neonatal thyrotoxicosis. The antithyroid drug used during the second pregnancy crossed the placenta and treated the infant in utero. The infant was delivered by elective cesarean section at 36 weeks and was a live-born male with appropriate height and weight without evidence of thyrotoxicosis. The therapeutic benefit of propylthiouracil during this second pregnancy seems likely, based on the development of neonatal thyrotoxicosis after 4 days of life and on the presence of high thyroid-stimulating immunoglobulin levels in the mother and the infant.

Topics: Adult; Female; Fetal Diseases; Fetal Growth Retardation; Humans; Hyperthyroidism; Hypothyroidism; Immunoglobulin G; Immunoglobulins, Thyroid-Stimulating; Maternal-Fetal Exchange; Pregnancy; Pregnancy Complications; Propylthiouracil

Appropriate dosage of levothyroxine for the treatment of hypothyroidism is assessed by determining the serum thyroxine (T4) concentration in secondary and tertiary types. In primary hypothyroidism, the optimal thyroid replacement is that which induces a normal thyroid-stimulating hormone level and a normal TSH response to administration of thyrotropin-releasing hormone. Hypothyroidism often occurs in the management of hyperthyroidism. Serial serum TSH measurements help in the early detection of hypothyroidism, whereas serum triiodothyronine (T3) aids in prompt recognition of recurrence of hyperthyroidism.

Topics: Antithyroid Agents; Drug Evaluation; Graves Disease; Humans; Hyperthyroidism; Hypothyroidism; Methimazole; Propylthiouracil; Thyroid Function Tests; Thyroid Hormones; Thyrotropin; Thyrotropin-Releasing Hormone; Thyroxine; Triiodothyronine

Topics: Animals; Dopamine; Hydroxyindoleacetic Acid; Hypothalamus; Hypothyroidism; Male; Norepinephrine; Prolactin; Propylthiouracil; Rats; Serotonin; Serotonin Antagonists; Thyrotropin

Topics: Animals; Animals, Newborn; Brain; DNA; Female; Hypothyroidism; Nerve Tissue Proteins; Oxygen Consumption; Propylthiouracil; Rats; RNA; Triiodothyronine

The effects of thyroid status on the activity of hepatic cAMP phosphodiesterase (PDE) were studied in the rat. Male rats were rendered hyperthyroid by treatment with T3 or hypothyroid by treatment with propylthiouracil. The hepatic particulate low Km PDE was solubilized, and its activity was measured at concentrations of 0.12-1.3 microM cAMP. The Km decreased in hypothyroidism and tended to increase in hyperthyroidism with respect to individual controls. The maximal velocity (Vmax) was unaffected by changes in thyroid status. The increases in Km correlated with increasing plasma T3, whereas the Vmax did not. Concentrations of cAMP increased in the livers from hyperthyroid rats and decreased in those from hypothyroid, in comparison with euthyroid rat livers. The effects of thyroid status on various aspects of hepatic lipid metabolism reported from this laboratory may, in part, have resulted from alterations in hepatic cAMP concentrations. These alterations, may have resulted secondarily from changes in the activity of hepatic PDE by changes in the Km for cAMP with little change in the Vmax.

Topics: 3',5'-Cyclic-AMP Phosphodiesterases; Animals; Cyclic AMP; Hyperthyroidism; Hypothyroidism; Kinetics; Liver; Male; Propylthiouracil; Rats; Rats, Inbred Strains; Triiodothyronine

Topics: Adrenal Medulla; Animals; Female; Heart; Heart Rate; Hypothyroidism; Norepinephrine; Pregnancy; Propylthiouracil; Rats; Rats, Inbred Strains; Receptors, Adrenergic, beta; Sympathetic Nervous System; Synapses

We investigated the development of insulin receptors in membranes of fetal rabbit lung during normal ontogeny and the effect of glucocorticoids and hypothyroidism. Specific binding of 125I-insulin to fetal lung membranes increased progressively to a peak at 29 days gestation, declining by 30 days. Scatchard plots were curvilinear and revealed a progressive increase in receptor numbers (X 10(10)/mg protein) from 129 +/- 7 (mean +/- SE) at 22-24 days to 575 +/- 16 at 29 days, declining to 467 +/- 12 at 30 days, term being approximately 31 days. Affinities did not change throughout gestation and were similar to those of adult lung; receptor numbers in adults were significantly lower than in fetuses at 26-30 days. Epinephrine and PGE1 could evoke a doubling of cAMP production in adult and fetal lung membranes until 29 days. Concomitantly with the fall in fetal insulin receptor number at 30 days, cAMP production in response to epinephrine or PGE1 increased fivefold. Induction of fetal hypothyroidism decreased insulin receptor numbers in the lung of the 28-day fetus by 70% from control (P less than 0.001) without a change in receptor affinity. In contrast, betamethasone administration increased fetal lung insulin receptor numbers by 250% (P less than 0.001) but did not alter their affinity; maternal lung insulin receptors were not altered. Thus, normal ontogeny of the fetal lung insulin receptor is characterized by a progressive increase in number followed by decline immediately before parturition associated with a sharp increase of cAMP responsiveness of the membranes. Hypothyroidism and glucocorticoid exposure can modulate the normal development of the fetal lung insulin receptor.

Topics: Alprostadil; Animals; Betamethasone; Cyclic AMP; Epinephrine; Female; Hypothyroidism; Lung; Organ Size; Pregnancy; Propylthiouracil; Prostaglandins E; Rabbits; Receptor, Insulin

Beta-Adrenergic receptors were identified in membrane fractions of rat lung with the beta-adrenergic antagonists (-)-[3H]-dihydroalprenolol (-)-[3H]DHA) and (+/-)-[125I]-iodohydroxybenzylpindolol ((+/-)-[125I]HYP). Binding capacity (Bmax) for (-)-[3H]DHA increased progressively from 46 +/- 7 on day 18 of gestation to 510 +/- 70 femtomoles . mg-1 protein (mean +/- S.D.) on postnatal day 28, at which time adult Bmax was attained. An increase in (-)-[3H]DHA binding capacity of the lung was observed between postnatal days 15 and 28, during the known period of increased thyroid gland secretory activity, serum triiodothyronine (T3), and thyroxine (T4) concentrations in the rat. We therefore studied lung beta-adrenergic receptors in rat pups made hypothyroid with propylthiouracil (PTU) (in utero and postnatally) compared to normal age-matched control pups and to euthyroid pups which were treated with PTU but were also injected daily with thyroxine (T4-treated). Hypothyroid pups grew nearly normally until postnatal day 15 but grew poorly thereafter; but day 28 somatic and lung weight, lung DNA, and protein were markedly decreased in hypothyroid pups as compared to controls. Pulmonary beta-adrenergic receptors were similar in hypothyroid pups and controls on day 15, but were markedly decreased in hypothyroid pups on day 28 (294 +/- 57 versus 489 +/- 82 femtomoles . mg-1 protein in T4 treated euthyroid controls). Treatment of the hypothyroid pups with T4 on day 25 significantly increased lung beta-adrenergic receptors to near normal concentrations by day 28. We conclude that thyroid hormones or thyroid dependent factors enhance pulmonary beta-adrenergic receptor synthesis and that thyroid hormone is required for the normal postnatal maturation of the beta-adrenergic receptor system in the rat lung.

Topics: Animals; Female; Hypothyroidism; Lung; Pregnancy; Propylthiouracil; Rats; Rats, Inbred Strains; Receptors, Adrenergic; Receptors, Adrenergic, beta; Thyroxine

We studied the effects of thyroid hormones and malnutrition on protein, DNA, and phospholipid content of the developing rat lung during the first month of life. Neonatal hypothyroidism significantly decreases the lung phospholipid content by 30-45% between 5 and 30 days of age whether the results are expressed per milligram DNA or per gram tissue. Administration of thyroxine for 3 days to hypothyroid rats increases significantly (20%) their total phospholipid content, mainly through its preferential effect on phosphatidylcholine (50% increase). Adult animal response to thyroid hormones is markedly different from that observed in young rats for most parameters examined. In malnourished rats, lung tissue phospholipids are decreased per cell but not per unit cell mass after 11 days of age. These results show that hypothyroidism has a specific effect on lung phospholipids during the neonatal period.

Topics: Animals; DNA; Female; Hypothyroidism; Lung; Male; Organ Size; Phosphatidylcholines; Pregnancy; Propylthiouracil; Protein-Energy Malnutrition; Rats; Rats, Inbred Strains; Sphingomyelins

Patients with both exophthalmos and hyperthyroidism were treated with different modes of therapy for their hyperthyroidism. Propylthiouracil followed by surgery, propylthiouracil followed by radioactive iodine, propylthiouracil alone, and radioactive iodine alone were used. Some of the patients became hypothyroid and were made euthyroid with levothyroxine sodium. Based on the mode of therapy and whether or not hypothyroidism occurred, each patient was assigned to one of seven groups and followed up for 18 months or longer. Careful exophthalmometry was performed at six-week intervals in all patients. Though progression of exophthalmos was noted in all groups, the group that received propylthiouracil demonstrated the greatest progression of exophthalmos. In the group receiving sodium iodide l 131 therapy and in the group treated surgically, the rate of progression of exophthalmos was lessened with the development of hypothyroidism. Since these hypothyroid patients were made euthyroid with supplemental levothyroxine, it appeared that loss of thyroid tissue, rather than the hypothyroidism per se, was responsible for the decrease in progression of the exophthalmos. The continued progression of exophthalmos in the propylthiouracil-treated group may be related to effects of propylthiouracil on the immune system.

Topics: Exophthalmos; Graves Disease; Humans; Hyperthyroidism; Hypothyroidism; Iodine Radioisotopes; Propylthiouracil; Thyroidectomy; Thyroxine; Time Factors

The interaction of thyroid status and oleic acid infusion rate on the thermal behavior of the very low density lipoprotein (VLDL) secreted by isolated perfused rat liver was examined. The livers were infused at 37 degrees C with oleate at rates of 0, 83, 166, or 332 mumoles/hr for 4 hours and VLDL was isolated from the perfusate at 12 degrees C. The lipid composition of the VLDL secreted by the perfused liver from hyperthyroid animals was dramatically different from controls at all infusion rates of oleate. Significant changes in the ratio of [phospholipid + cholesterol]/[triglyceride] and in fatty composition of secreted triglycerides occurred. Differential scanning calorimetry of the intact VLDL and extracted triglycerides secreted by euthyroid rats suggested the existence of four thermotropic endothermic transitions centered at -20.5, -14.0, -3.0, and 9.0 degrees C. Both the total enthalpies and the temperatures at which the phase alterations occurred in the triglyceride fraction from VLDL secreted by livers from euthyroid rats were highly dependent on the rate of infusion of oleate. Pretreatment of the rats with triiodothyronine and infusion of 332 mumoles oleate/hr abolished in the intact VLDL the temperature transitions centered at -20.8 and at 10.5 degrees C and decreased the total enthalpy from 8.13 to 38.5 cal/gm. Livers from rats pretreated with propylthiouracil and infused with oleate at 332 mumoles/hr secreted VLDL in which only one transition centered at -5.0 degrees C remained. The total enthalpy was unaffected. At all rates of infusion of oleate, the phase behavior of the intact VLDL or triglycerides extracted from the VLDL was altered by prior treatment of the rats with triiodothyronine or propylthiouracil. The thyroid state of the rat profoundly affected the thermal properties of the VLDL secreted by the perfused liver infused with the unsaturated fatty acid oleate.

Topics: Animals; Calorimetry, Differential Scanning; Chemical Phenomena; Chemistry; Hyperthyroidism; Hypothyroidism; Lipoproteins, VLDL; Liver; Male; Oleic Acid; Oleic Acids; Perfusion; Propylthiouracil; Rats; Rats, Inbred Strains; Thermodynamics; Thyroid Gland; Thyroxine; Triglycerides; Triiodothyronine

1. The role of endogenous glucagon and insulin on the hypolipidemic and glycogenolytic effect of clofibrate was determined in the euthyroid and propylthiouracil (PTU)-induced hypothyroid mice. 2. PTU was fed in diet (0.15%) for 2 weeks and then clofibrate added to diet (0.25%) for 4 weeks. 3. Both PTU and clofibrate significantly increased liver weight but had no effect on kidney weight. PTU significantly decreased plasma triglycerides (TG) and increased cholesterol (Ch). 4. Clofibrate had a significant hypotriglyceridemic effect in both euthyroid and hypothyroid mice but did not affect plasma cholesterol. 5. Clofibrate decreased hepatic glycogen in euthyroid but not in hypothyroid mice. 6. Glucose-6-phosphatase activity was not affected by either PTU or clofibrate. 7. Neither PTU nor clofibrate affected hepatic TG or Ch. 8. Biliary lipid changes due to PTU treatment were reversed by clofibrate administration. 9. Since plasma insulin and glucagon levels were not affected by clofibrate in either euthyroid or hypothyroid mice, our results suggest that the hypotriglyceridemic and glycogenolytic effect of clofibrate is not mediated by changes in circulating insulin and glucagon ratio. 10. Moreover, while the glycogenolytic effect of clofibrate seems to be dependent, the hypotriglyceridemic effect seems to be independent of thyroid hormones.

Topics: Animals; Clofibrate; Glucagon; Glycogen; Hypolipidemic Agents; Hypothyroidism; Insulin; Lipid Metabolism; Liver Glycogen; Male; Mice; Organ Size; Propylthiouracil

Topics: Animals; Catecholamines; Dopamine; Growth Hormone; Hypothalamus; Hypothyroidism; Male; Norepinephrine; Propylthiouracil; Rats; Rats, Inbred Strains; Serotonin; Sodium Glutamate

To determine whether hyperthyroidism or hypothyroidism affected the structure of the very low density lipoprotein (VLDL) secreted by the perfused rat liver, rats were pretreated with 0.9% NaCl, T3, or propylthiouracil. The livers were perfused with 0-332 mumol bovine serum albumin-oleate/h for 4 h. The structure of the secreted VLDL was determined by compositional analysis and the use of the fluorescence probe molecules diphenylhexatriene, trans-parinaric acid, and cis-parinaric acid. Compositional analysis indicated that the VLDL secreted by livers from rats pretreated with T3 had lower unsaturated to saturated fatty acid ratios than did controls, regardless of the amount of oleate infused. Fluorescence polarization of diphenylhexatriene indicated that the interior core lipids of VLDL secreted by livers from T3-treated rats were more rigid than those secreted by livers of euthyroid animals. Arrhenius plots of polarization and corrected fluorescence of diphenylhexatriene and trans-parinaric acid, but not cis-parinaric acid, revealed that characteristic temperatures were shifted 8 to 10 C higher in VLDL secreted by livers from rats pretreated with T3. Treatment of rats for 7 days with propylthiouracil under these mild conditions did not alter the structure or composition of the VLDL secreted by the perfused liver. In summary, the lipid changes in the VLDL secreted by perfused rat livers from hyperthyroid animals were consistent with these VLDL being more rigid particles than those secreted by livers from euthyroid rats, independent of the infusion rate of the FFA.

Topics: Animals; Chemical Phenomena; Chemistry; Fatty Acids; Fluorescence; Hyperthyroidism; Hypothyroidism; In Vitro Techniques; Lipids; Lipoproteins, VLDL; Liver; Male; Oleic Acid; Oleic Acids; Perfusion; Propylthiouracil; Rats; Rats, Inbred Strains; Temperature; Triiodothyronine

Topics: Acetaminophen; Animals; Glutathione; Hyperthyroidism; Hypothyroidism; Liver; Liver Glycogen; Male; Propylthiouracil; Rats; Rats, Inbred Strains; Transaminases; Triiodothyronine

The role of thyroxine (T4) in the ontogeny of serum corticosteroid-binding globulin (CBG) and corticosterone has been studied in the rat. Daily injection of T4 (0.1 micrograms/g body wt) resulted in the precocious appearance of both CBG and corticosterone. A dose-response study revealed an increase in both CBG and corticosterone at thyroxine doses greater than 0.02 micrograms/g body wt. In propylthiouracil-induced hypothyroid pups, the developmental rise of both CBG and corticosterone was suppressed. To determine whether T4 elevation of CBG was mediated by corticosterone, serum CBG was measured in corticosterone-injected pups (10 micrograms/g body wt). No increase in CBG was detected on days 8 and 10. A slight increase, only one-eighth that elicited by T4, occurred on day 12. There was also no synergistic effect between T4 and corticosterone. We conclude that the postnatal increase in serum T4 concentrations cues the developmental rise of both CBG and corticosterone in the rat.

Topics: Aging; Animals; Corticosterone; Female; Hyperthyroidism; Hypothyroidism; Propylthiouracil; Rats; Thyroxine; Transcortin

Rats with diets containing 0.2% propylthiouracil (PTU) throughout gestation had progeny with persistent cyanosis and high neonatal mortality. Histological and histochemical studies failed to reveal lung abnormalities in these pups. Studies of the blood of PTU-fed dams demonstrated that hemoglobin, packed cell volume, and numbers of erythrocytes were significantly reduced. In their 21-day fetal young, erythrocytopenia was accompanied by an elevated mean corpuscular volume and a reduced mean corpuscular hemoglobin concentration. Imprints of marrow from dams and of liver and spleens of the young showed normoblastic erythropoiesis. A granulocytic leucocytosis was present in the blood of the PTU-fed dams, whereas their progeny had a granulocytopenic leucopenia. Tissue concentrations of copper, zinc, manganese, magnesium and iron were determined. The most striking changes observed were the significant elevations of copper in the dams' brain, liver and kidneys. No changes in the concentration of any of the trace minerals were found in the livers of the pups. Food restriction to the dam failed to significantly alter maternal or fetal hematologic or trace element concentrations as compared with controls. It is evident that PTU, when fed to pregnant rats, has demonstrable effects on erythropoiesis, granulocytopoiesis, and maternal trace element distribution. It is not presently known whether these phenomena are interrelated.

Topics: Anemia, Macrocytic; Animals; Birth Weight; Copper; Cyanosis; Diet; Erythrocytes; Erythropoiesis; Female; Hypothyroidism; Leukocyte Count; Magnesium; Male; Manganese; Maternal-Fetal Exchange; Pregnancy; Propylthiouracil; Rats; Trace Elements; Zinc

Lipid and lipoprotein concentrations were studied in 12 hypothyroid and 11 hyperthyroid female subjects, both before and after therapy, and in 27 age matched female controls. Recognized clinical and laboratory criteria established the diagnosis. Lipoproteins, including the sub-fractions of the high density lipoproteins (HDL), were isolated by preparative ultracentrifugation, and the cholesterol (c) and protein (p) contents of each were determined. Total cholesterol, and in particular HDL-c, were elevated in the hypothyroid patients. The low density lipoprotein (LDL) -c/HDL-c ratio was 1.9 in this group, compared to 2.2 in the control group and 1.35 in the hyperthyroid patients. The HDL-2/HDL-3 ratio in the hypothyroid group was 3.75, as compared to 1.75 in the controls and 4.2 in the hyperthyroid group. Plasma triglycerides were moderately elevated in the hypothyroid patients and were significantly reduced in the hyperthyroid group. Total cholesterol was significantly lower in the hyperthyroid group as compared to the control group. Very low density (VLDL) cholesterol and protein were significantly increased and LDL and HDL cholesterol were reduced in the hyperthyroid patients. On rendering the patients euthyroid, most of these changes were reversed. Thyroid function profoundly affects lipoprotein concentration and composition. The change in the plasma HDL concentrations of the hypothyroid group questions the relationship of this group to arteriosclerosis. Therapy partially corrects the abnormalities, but complete correction may be related to duration of therapy.

Topics: Adolescent; Adult; Aged; Cholesterol; Cholesterol, HDL; Female; Humans; Hyperthyroidism; Hypothyroidism; Lipoproteins, HDL; Lipoproteins, HDL2; Lipoproteins, HDL3; Middle Aged; Propylthiouracil; Thyroxine; Triglycerides

The role of the thyroid in the mediation of an estrogen-associated change in thermal balance was studied in thyroidectomized and in propylthiouracil-treated ovariectomized rats. Prior to propylthiouracil treatment, estrogen-treated ovariectomized rats and intact female rats had higher rates of heat production and dry heat loss at -5 degrees C than ovariectomized rats. Heat production of estrogen-treated and intact female rats was well below their rates of dry heat loss without an alteration in the absolute rate of heat loss in the hypothyroid condition. Heat production exceeded heat loss only in the hypothyroid ovariectomized group not receiving estrogen. Ovariectomized rats without estrogen maintained thermal balance, whereas rectal temperatures fell in both intact and estrogen-treated ovariectomized rats during cold exposure. Increased heat loss unbalanced by heat production was also observed in surgically thyroidectomized estrogen-treated ovariectomized rats tested at -5 degrees C. These results suggest that an estrogen-induced increase in heat loss, which is compensated by an increase in heat production in the euthyroid but not the hypothyroid condition, is one mechanism responsible for estrogen-associated changes in thermal balance during cold exposure.

Topics: Animals; Castration; Estradiol; Female; Hypothyroidism; Kinetics; Propylthiouracil; Rats; Rats, Inbred Strains; Water Loss, Insensible

The basal levels of angiotensin I and kinetic parameters of renin-angiotensin system were studied under control, hyper- and hypothyroidism conditions. The serum levels of triiodothyronine (T3) and thyroxine (T4) and plasma angiotensin II have been measured radioimmunoassay. Hyperthyroidism was induced by 5.5 micrograms/200 g of T3 or 100 micrograms/200 g of T4 administration for 12 days, and hypothyroidism by propylthiouracil (PTU) administration of 1 mg/200 g for 12 days. Basal levels of angiotensin I and plasma renin activity (PRA) increased after T3 injection, were not altered by T4 and decreased after PTU administration. T3 and T4 induced an increase in plasma renin concentration (PRC), while PTU induced a decrease in PRC. Plasma renin substrate (PRS) decreased in hyperthyroid rats and was unchanged by experimentally induced hypothyroidism. A good correlation between T3 serum levels and PRA was found, but there was no such correlation between T4 serum levels and PRA.

Topics: Angiotensin I; Angiotensins; Animals; Hyperthyroidism; Hypothyroidism; Kinetics; Male; Propylthiouracil; Rats; Rats, Inbred Strains; Renin-Angiotensin System; Thyroxine; Triiodothyronine

The aim of this study was to examine the temporal and dose characteristics of the corticosteroid-binding globulin (CBG) response to T4 and to determine whether this response is due to stimulation of hepatic biosynthesis of CBG. When n-propylthiouracil (PTU)-induced hypothyroid pups were given a single injection of T4 (0.1 microgram/g BW) on postnatal day 5, 6, or 7, only pups treated on day 7 showed a significant increase in CBG. In a T4 dose-response study conducted with 5- and 8-day-old pups, older pups exhibited maximum CBG concentrations (Rmax) which were 2.5-fold higher than those of younger pups. The D1/2 (dose required to elicit half the maximum response) values were similar at both ages. The effect of T4 withdrawal on serum CBG was also studied in PTU-treated pups. T4 injection on postnatal days 5-19 resulted in a progressive rise in CBG. In pups treated with T4 on days 5-9 and then withdrawn from treatment through day 20, serum CBG showed no further increase but was maintained at an elevated level. Using a liver slice system to assess CBG production in vitro, livers from 14-day-old hyperthyroid pups produced 4.77 ng corticosterone bound/g liver, while livers from euthyroid pups produced no CBG. We conclude: 1) the response of CBG to T4 is a function of the age of the animal; between days 5 and 8 this is due to increased Rmax without any change in sensitivity to T4 (D1/2); 2) T4 is required not only to initiate but also to sustain the developmental increase in CBG; and 3) T4 elicits an increase in circulating CBG by stimulating its synthesis.

Topics: Aging; Animals; Animals, Newborn; Dose-Response Relationship, Drug; Hyperthyroidism; Hypothyroidism; In Vitro Techniques; Liver; Propylthiouracil; Rats; Rats, Inbred Strains; Thyroxine; Transcortin

Between the 4th and 10th days of postnatal life in the rat, serum corticosterone levels were low and basal, while the rate of [3H]thymidine incorporation into lung DNA was maximal. From day 13, serum corticosterone levels began to rise significantly, and the lung [3H]thymidine incorporation rate began to fall dramatically; however, these events were obtunded by propylthiouracil-induced hypothyroidism. When 6- to 8-day-old euthyroid pups were given a single sc injection of 10 micrograms dexamethasone, the rate of DNA synthesis in the lung fell by 96.7% of the initial rate at 24 h. This steroidal effect was blunted in hypothyroid pups and restored by exogenous thyroid hormone. The thyroid status of the pup did not modify the response patterns of lung phosphodiesterase and cytosolic glucocorticoid receptor levels to dexamethasone treatment, although both parameters were influenced by thyroid hormone availability. Radiocholine incorporation into lung phospholipids, which was altered in hypothyroidism, was unaffected by dexamethasone treatment. An in vivo assessment of radiothymidine incorporation into DNA of various tissues in 5-day-old euthyroid pups given 10 micrograms dexamethasone 24 h earlier revealed that of the several tissues in which inhibition of DNA synthesis was demonstrable, the developing lung was the most sensitive to the anti-mitogenic steroidal effect. When considered in the light of existing evidence, these observations suggest that glucocorticoids play an important role in triggering lung cytodifferentiation during the third postnatal week in the rat, and that preconditioning of the lung by thyroid hormone optimizes this developmental effect of glucocorticoids.

Topics: Aging; Animals; Corticosterone; Dexamethasone; DNA; Hypothyroidism; Lung; Propylthiouracil; Rats; Rats, Inbred Strains; Thymidine; Thyroid Hormones

Norepinephrine uptake and turnover rate were measured in the interscapular brown adipose tissue of normal and hypothyroid young rats. At the age of 15 days, hypothyroidism lowers the uptake of norepinephrine. This fact could partially explain why the norepinephrine content of the tissue has previously been found reduced in these animals when compared to controls. In the same animals, the turnover rate of norepinephrine is reduced by 80%. This indicates a decrease of the sympathetic tonus in the tissue.

Topics: Adipose Tissue, Brown; Aging; Animals; Animals, Newborn; Hypothyroidism; Kinetics; Norepinephrine; Propylthiouracil; Rats; Scapula

The effects of propylthiouracil (PTU) on the ontogeny of suckling behavior in rats were examined. The drug was given at two dosage levels of 0.3% and 0.5% respectively mixed with rat diet throughout gestation and suckling. The thyroid glands of treated fetuses and pups and of untreated control animals of the same age groups were monitored by histologic examination. At the behavioral level, the frequency of individual movements of head, forelimbs and mouth was significantly reduced in treated fetuses. The combination movements of head, mouth and forelimbs showed severe deficits both quantitatively and qualitatively for all ages in the experimental group from day 18 of gestation. Hypothyroid pups of dams raised on 0.5% PTU were unable to attach to the nipple of the mother and died within a few days. Pups of dams raised on 0.3% PTU showed longer latencies for nipple attachment, and their gross motor movements of rooting and suckling were greatly impaired. These results have been discussed in relation to the development of suckling behavior to indicate that, during ontogeny, some decisive step in the integration of individual movements takes place in utero from day 18 of gestation. This coincides with the establishment of pituitary thyroid relationship, which is continued through postnatal stages.

Topics: Animals; Body Weight; Female; Gestational Age; Hypothyroidism; Maternal-Fetal Exchange; Motor Activity; Muridae; Pituitary Gland; Pregnancy; Propylthiouracil; Sucking Behavior; Thyroid Hormones

The induction of hypothyroidism in the rat is necessary for the development of pronounced dietary-induced hypercholesterolemia. The nature of nascent lipoproteins secreted by isolated hepatocytes from euthyroid, hypothyroid and hypothyroid, cholesterol-fed rats was investigated to distinguish between these hormonal and dietary effects. Serum total lipids, apolipoproteins, B, E and A-I, were greatly elevated in hypercholesterolemia. In hypothyroidism, serum apolipoproteins B and E were elevated, triacylglycerols were reduced by 65% and free cholesterol was increased by 50%. The total lipid, apolipoprotein B and E, secreted by hypercholesterolemic rat hepatocytes was markedly elevated when compared to normal. Triacylglycerol and phospholipid secretion was slightly increased by hypothyroid rat hepatocytes; however, apolipoprotein B, E and A-I secretion rates were unaffected. Gel filtration of the nascent lipoproteins demonstrated that compared to normal, proportionately more apolipoprotein B and E from hypercholesterolemic rat hepatocytes and apolipoprotein E from hypothyroid rat hepatocytes was secreted as larger lipoproteins. Hypercholesterolemic rat hepatocytes secreted abnormal cholesterol-rich particles even after 24 h of incubation in a lipid-deficient medium. Hypothyroidism alone cannot account for this observation, as hypothyroid rat hepatocytes secreted a triacylglycerol-rich, cholesterol-deficient lipoprotein having a normal nascent lipoprotein lipid composition. These observations are consistent with the hypothesis that in hypothyroidism the accumulation of beta-migrating lipoproteins results from impaired removal of lipoprotein catabolites from the serum, a condition which would only promote hypercholesterolemia in cholesterol feeding where direct synthesis of abnormal lipoproteins occurs.

Topics: Animals; Apolipoproteins; Cholesterol; Cholesterol Esters; Hypercholesterolemia; Hypothyroidism; Lipoproteins; Liver; Male; Phospholipids; Propylthiouracil; Rats; Triglycerides

Topics: Female; Fetus; Graves Disease; Humans; Hyperthyroidism; Hypothyroidism; Immunoglobulin G; Immunoglobulins, Thyroid-Stimulating; Infant, Newborn; Infant, Newborn, Diseases; Pregnancy; Pregnancy Complications; Propylthiouracil; Thyrotropin; Triiodothyronine; Triiodothyronine, Reverse

Topics: Animals; Brain; Clonidine; Hypothyroidism; Kinetics; Male; Membranes; Propylthiouracil; Rats; Rats, Inbred Strains; Receptors, Adrenergic; Receptors, Adrenergic, alpha; Triiodothyronine

Topics: Antithyroid Agents; Carbimazole; Female; Fetus; Humans; Hyperthyroidism; Hypothyroidism; Infant, Newborn; Infant, Newborn, Diseases; Methimazole; Pregnancy; Pregnancy Complications; Propranolol; Propylthiouracil; Thyroid Diseases; Thyroid Gland

The influence of thyroid hormones on the concentration and properties of alpha 1-adrenoceptors in a crude membrane fraction obtained from the rat cerebral cortex was investigated using the [3H]-WB 4101 binding assay. Animals were made hypothyroid by feeding 6-propyl-2-thiouracil for 8 weeks. Hyperthyroidism was induced by triiodothyronine injections (50 microgram/100 g body weight) for 9 days. 1. The binding of [3H]-WB 4101 was saturable and of high affinity in controls as well as in hyper- and hypothyroid animals. The maximal number of binding sites (Bmax), which amounted to 95 fmol/mg protein in control animals, was increased by 27% in cortical membranes from hyperthyroid rats and reduced by 23% in the hypothyroid group. 2. The reduction in [3H]-WB 4101 binding due to 6-propyl-2-thiouracil feeding was reversible by triiodothyronine treatment. 3. Dissociation constants (KD) calculated from saturation experiments (0.25 nM) or kinetic data (0.21 nM) remained unchanged in altered thyroid states. 4. Inhibition of [3H]-WB 4101 binding by adrenergic agonists and antagonists revealed no differences between euthyroid and hypothyroid animals. The higher affinity of prazosin to the binding sites compared with yohimbine indicated that [3H]-WB 4101 predominantly labeled alpha 1-adrenoceptors. It is concluded that thyroid hormones regulate the number of alpha 1-adrenoceptors in membranes of the rat cerebral cortex, leaving their affinities unchanged.

Topics: Animals; Binding Sites; Cerebral Cortex; Dioxanes; Hypothyroidism; Male; Propylthiouracil; Rats; Receptors, Adrenergic; Receptors, Adrenergic, alpha; Thyroid Hormones

Topics: Animals; Circadian Rhythm; Dopamine; Estrogens; Female; Fenclonine; Hypothalamus; Hypothyroidism; Light; Norepinephrine; Pineal Gland; Propylthiouracil; Rats; Reproduction; Serotonin; Testosterone

Propylthiouracil fed to pregnant rats for the last week of gestation to induce maternal and fetal hypothyroidism induced a 3-fold rise in plasma TSH concentration in the newborn pups compared to a 4-fold rise in their mothers. Subcutaneous administration of 1 ng/g BW TRH caused a greater rise in plasma TSH in the hypothyroid pups than in their mothers. These results, in combination with published data, indicate that the apparent independence of pituitary-thyroid function from TRH control during early ontogenesis in the rat is primarily due to delayed maturation of the hypothalamic TRH system.

Topics: Animals; Animals, Newborn; Female; Hypothalamus; Hypothyroidism; Pregnancy; Propylthiouracil; Rats; Thyrotropin; Thyrotropin-Releasing Hormone

Topics: Animals; Dose-Response Relationship, Drug; Hypothyroidism; Male; Pituitary Gland, Anterior; Propylthiouracil; Rats; Thyrotropin; Thyrotropin-Releasing Hormone; Triiodothyronine

Hyperlipidemia associated with hypothyroidism is well documented in man and several animal species. The effect of hypothyroidism on apolipoprotein metabolism in the absence of complicating factors such as high cholesterol or fat content in the diet is virtually unknown. Hypothyroidism was therefore induced in male Sprague-Dawley rats by radiothyroidectomy (RTx-treated) or treatment with propylthiouracil (PTU-treated). Both treatments resulted in an over 90% decrease in circulating thyroid hormone concentrations accompanied by a 50-100% increase in plasma cholesterol and a 20-40% reduction in plasma triglyceride concentrations. Plasma apo E and apo B concentrations increased by 100% in the PTU-treated group and 40-50% in the RTx-group. Apo A-I increased 10 and 30% in the RTx- and PTU-treated rats, respectively, while the concentration of apo A-IV was not altered. A large increase in the low-density (LDL) and high-density lipoprotein (HDL) protein was observed and accompanied by a marked reduction of very low density lipoprotein (VLDL) in the hypothyroid rats. The electrophoretic pattern of plasma lipoproteins in the hypothyroid rats was changed by the appearance of a slow pre-beta band shown to be beta-VLDL. A redistribution of apo B occurred within the lipoprotein fractions. Apo B content in the VLDL fraction decreased and a large increase was noted in LDL. The major portion of the apo E and apo A-I increment was recovered in the HDL and to a lesser degree in LDL. An accumulation of apo E-rich larger HDL particles, resembling HDLc in apolipoprotein composition and distinct from the apo A-I-containing species, was observed by column chromatography. The results presented are consistent with the hypothesis that hypothyroidism in the rat may induce an accelerated production of VLDL catabolic remnants, including LDL, but at the same time reduce the rate of removal of these lipoproteins from the circulation.

Topics: Animals; Apolipoprotein A-I; Apolipoproteins; Apolipoproteins A; Apolipoproteins B; Apolipoproteins E; Hypothyroidism; Lipoproteins; Male; Propylthiouracil; Rats; Thyroxine; Triiodothyronine

Topics: Female; Fetus; Graves Disease; Humans; Hypothyroidism; Infant, Newborn; Infant, Newborn, Diseases; Male; Pregnancy; Pregnancy Complications; Propylthiouracil; Prospective Studies; Thyroid Function Tests; Thyroid Hormones; Thyrotropin

Although hyperprolactinemia and galactorrhea occur in primary hypothyroidism, factors influencing their presence are not well established. To further define these factors, the duration of illness and serum levels of PRL and TSH were investigated in a group of 50 patients with spontaneous (27 females and 7 males) and iatrogenic (16 females) primary hypothyroidism. To test the hypothesis of reduced hypothalamic dopamine content in over long-standing primary hypothyroidism, the percent increase in serum PRL after the administration of metoclopramide, a dopamine blocker (2.5 mg, iv bolus), was studied in 13 women with spontaneous primary hypothyroidism and compared with that in 10 euthyroid women. While 88.2% of the patients with spontaneous primary hypothyroidism were hyperprolactinemia, only 31% of those with iatrogenic disease had elevated PRL levels. Women with spontaneous primary hypothyroidism had a longer duration of illness (72 +/- 12 vs. 6.7 +/- 1.8 months; P less than 0.001) and higher serum TSH (189 +/- 32 vs. 68 +/- 14 microunits/ml; P less than 0.01) and PRL levels (49.8 +/- 5.6 vs. 20.9 +/- 0.8 ng/ml; P less than 0.001) than women with iatrogenic hypothyroidism. A linear correlation existed between PRL and duration of illness (r = 0.53; P less than 0.001), while a logarithmic correlation was found between PRL and TSH levels (r = 0.44; P less than 0.01). Even though the duration of illness and TSH levels were similar in women with spontaneous disease with (n = 7) or without (n = 20) galactorrhea, the former were significantly younger (39.3 +/- 1.8 vs. 56.6 +/- 3 yr; P less than 0.001), and their PRL levels were significantly higher (69.3 +2- 8.9 vs. 42.9 +/- 2.2 ng/ml; P less than 0.001). The PRL response to metoclopramide in women with spontaneous disease was significantly smaller than that in controls (194 +/- 39% vs. 446 +/- 40%; P less than 0.001) and inversely correlated with basal PRL levels (r = -0.55; P less than 0.05). These data indicate that in primary hypothyroidism 1) the duration of illness is important in the development of hyperprolactinemia, 2) galactorrhea is more common in young women with spontaneous disease and high PRL levels, and 3) hypothalamic dopamine appears reduced in spontaneous disease.

Topics: Adolescent; Adult; Aged; Female; Galactorrhea; Humans; Hypothyroidism; Iatrogenic Disease; Lactation Disorders; Male; Metoclopramide; Middle Aged; Pregnancy; Prolactin; Propylthiouracil; Thyroidectomy; Thyrotropin

Changes in the development pattern of cytoplasmic and mitochondrial malate dehydrogenase (decarboxylating; NADP+) activity in the brain of hypothyroid rats and the effect of triiodothyronine on the enzyme activity have been investigated. Hypothyroid rats showed lower malate dehydrogenase activity than controls during the suckling period. Results suggest that thyroid hormones promote the development of malic enzyme in the brain.

Topics: Aging; Animals; Brain; Hypothyroidism; Liver; Malate Dehydrogenase; Propylthiouracil; Rats; Triiodothyronine

Topics: Adrenalectomy; Animals; Arginine Vasopressin; Carboxy-Lyases; Castration; Dehydration; Hormones; Hypothyroidism; Kidney; Male; Mice; Ornithine Decarboxylase; Propylthiouracil

Hypothyroidism was induced in 38-day old male rats by feeding the animals a chow diet supplemented with propylthiouracil (PTU, 0.1% by weight) for 43 days. Wheel activity of PTU animals was not significantly different from that of euthyroid, ad lib feeding controls it was significantly lower when compared to pairfed controls. Body weight was significantly lower than that of euthyroid ad lib controls. After 75 days of PTU discontinuation catch-up growth of PTU animals was not complete: body weight and tibia length were significantly lower in the PTU condition in comparison to euthyroid, ad lib feeding condition. However, no difference existed between the catch-up growth of PTU and pairfed animals. It was suggested that growth arrest observed in early hypothyroidism may be partly due to factors nonspecific to thyroxine absence, such as hypophagia.

Topics: Animals; Body Weight; Bone Development; Hypothyroidism; Male; Motor Activity; Propylthiouracil; Rats

The local growth rate of Morris Hepatoma 44 (generation time, 6 months) was inhibited by 66 to 87%, and host survival was prolonged by 36 to 78% after the induction of hypothyroidism within 2 weeks of tumor implantation by propylthiouracil (0.1% in Purina chow), 131I(1 mCi/100 g body weight i.p.), or surgical thyroidectomy. In additional experiments, we studied the effects of inducing hypothyroidism (131I) at different stages in the natural history of Morris Hepatoma 44 on local and metastatic growth as well as on host survival. Induction of hypothyroidism within 2 weeks of tumor implantation (Group I) reduced local tumor growth as well as the number and size of pulmonary metastases, and prolonged survival by 70 to 80%. Induction of hypothyroidism at 6 weeks postimplantation when tumors were palpable (Group II) inhibited local growth by 39%, reduced the number and size of pulmonary metastases by approximately 80%, and prolonged host survival by 35%. Initiation of 131I treatment at 11 weeks when microscopic pulmonary emboli were present in most animals (Group III) reduced local growth by 19% and the number and size of pulmonary metastases by 72 and 50%, respectively. In this case, survival was prolonged by 17%. We conclude from these results that the local and metastatic growth of Morris hepatoma 44 as well as host survival are thyroid hormone-dependent processes. The mechanisms responsible for these observations remain to be explained.

Topics: Animals; Hypothyroidism; Liver Neoplasms, Experimental; Lung Neoplasms; Male; Neoplasm Metastasis; Propylthiouracil; Rats; Thyroidectomy

Sprague-Dawley rats were fed Purina Lab Chow with or without propylthiouracil (PTU), 0.001%, 0.01% or 0.1% PTU, ad libitum from weaning to vaginal opening. Mean values for all pubertal measurements are included in Tables 1 and 2. Growth rate (mean +/- S.E.) was significantly reduced (Neuman-Keuls test; P less than 0.05 level) in all PTU-fed rats (controls 4.9 +/- 0.1 g/day, 0.001% PTU 4.2 +/- 0.2 g/day, 0.01% PTU 3.4 +/- 0.2 g/day, 0.1% PTU 2.5 +/- 0.1 g/day), while age at vaginal opening in rats fed 0.001% PTU (35.8 +/- 0.6 days) or 0.01% PTU (36.1 +/- 0.9 days) was not significantly different from controls (36.0 +/- 0.6 days). Nevertheless, body weight at vaginal opening was lower in rats fed 0.1% PTU (87.6 +/- 4.7 g) than in controls (113.6 +/- 3.7 g). Pubertal body weight of rats fed 0.1% PTU was also reduced (88.6 +/- 3.7 g) but vaginal opening delayed (40.4 +/- 0.8 days). Proportions of body fat (6.1 - 5.1%), protein (15.0 - 14.1%), and water (72.4 - 71.3%) at vaginal opening were the same in control and PTU groups. Serum T4 was greatly diminished and similar in all 3 PTU groups, 0.2 - 0.3 microgram/100 ml, vs 4.8 +/- 0.2 microgram/100 ml in controls; in rats fed 0.1% and 0.01% PTU, T3 was 0.9 +/- 0.4 ng/100 ml and 0.9 +/- 0.6 ng/100 ml, respectively vs 72.6 +/- 5.6 ng/100 ml in controls, but not significantly reduced in the 0.001% PTU-fed group (60.7 +/- 7.9 ng/100 ml). In a second experiment, a group of weanling rats (pair-fed) was selected in which each member was fed the daily amount of control diet eaten by a corresponding age- and weight-matched 0.01% PTU-fed rat. During the experiment, both groups maintained the same body weight, growth rate, and food intake, however, only 45% (n = 11) of the pair-fed animals had vaginal opening by the time their 0.01% PTU-fed counterparts attained first estrus. Although one of the pair-fed (undernourished) rats attained first estrus, no eggs were found. Despite greatly reduced body weight (105.3 +/- 3.5 g vs controls 127.5 +/- 6.6 g), growth rate (3.5 +/- 0.2 g/day vs controls 5.5 +/- 0.1 g/day) and food intake (13.9 +/- 0.7 g/100g BWt/day vs controls 10.1 +/- 0.3 g/100g BWt/day), the 0.01% PTU-fed rats exhibited vaginal opening (36.9 +/- 0.8 days vs controls 35.6 +/- 1 days) and first estrus (39.6 +/- 0.9 days vs controls 36.4 +/- 1 days) at the usual age. In contrast, pair-fed rats had a lower % fat (4.5 +/- 0.1% vs PTU 6.8 +/- 0.4%) and higher % protein (16.5 +/- 0.3% vs PTU 14.3 +/- 0.3%) at the age when

Topics: Animals; Body Weight; Dose-Response Relationship, Drug; Female; Hypothyroidism; Nutrition Disorders; Prolactin; Propylthiouracil; Rats; Sexual Maturation

Topics: Aging; Animals; Body Weight; Eating; Half-Life; Hypothyroidism; Lipoproteins, LDL; Male; Metabolic Clearance Rate; Propylthiouracil; Rats

The results of medical and surgical therapy were determined in 107 hyperthyroid children. After surgery, 85% of patients were rendered free of hyperthyroidism; however, 62% became hypothyroid. After medical treatment, 30% of patients were euthyroid and 2% became hypothyroid. The relapse rate, however, was higher after medical (22%) than after surgical (9%) therapy. Serious drug-related complications (arthritis-, hepatitis-, and collagen disease-like syndromes) occurred in 14% of patients. Complications occurred in 9% of surgically treated patients, but recurrent laryngeal nerve injury or permanent hypoparathyroidism did not occur. In medically treated patients, both a goiter size less than three times normal prior to treatment and a reduction in goiter size to less than two times normal at the completion of therapy correlated with a successful outcome.

Topics: Adolescent; Arthritis; Chemical and Drug Induced Liver Injury; Child; Child, Preschool; Collagen Diseases; Female; Humans; Hyperthyroidism; Hypothyroidism; Male; Methimazole; Postoperative Complications; Propylthiouracil; Thyroidectomy

Topics: Adolescent; Adult; Aged; Antibodies; Antithyroid Agents; Carbimazole; Female; Follow-Up Studies; Humans; Hyperthyroidism; Hypothyroidism; Iodine; Iodine Radioisotopes; Male; Methimazole; Middle Aged; Propylthiouracil; Recurrence; Thyroid Gland; Thyroidectomy

The influence of thyroid hormone deficiency on beta-adrenoceptors in the rat cerebral cortex was investigated using the 3H-dihydroalprenolol binding assay. The maximal number of binding sites (Bmax) and the dissociation constants (KD) were determined in the brain tissue from euthyroid animals and from rats made hypothyroid by feeding 6-propyl-2-thiouracil. Hypothyroidism resulted in a 37% decrease in beta-adrenoceptor density (Bmax). The dissociation constants (KD) of both groups were not significantly different.

Topics: Animals; Binding Sites; Cerebral Cortex; Dihydroalprenolol; Hypothyroidism; Male; Propylthiouracil; Rats; Receptors, Adrenergic; Receptors, Adrenergic, beta

The role of endogenous glucagon and insulin on the hepatic glycogen and triglyceride storage syndrome in propylthiouracil (PTU)-induced hypothyroidism was investigated in the chick. PTU feeding in the diet resulted in a progressive increase in liver glycogen concentration associated with a concomitant decrease in hepatic glucose-6-phosphatase (G-6-Pase) activity. Plasma glucagon level was significantly decreased and insulin significantly increased after two days of PTU administration. These enzyme and hormone changes were associated with a significant increase in hepatic glucose-6-phosphate (G-6-P) and a decrease in cyclic AMP levels. Although our results do not directly prove, the data does suggest that the hepatic glycogen storage syndrome observed in the PTU-induced hypothyroidism in the chick is mediated through changes in pancreatic glucagon and insulin secretion. The extent of glycogen accumulation was inversely related to G-6-Pase which is a rate limiting glycogenolytic enzyme. A significant increase in the plasma insulin/glucagon ratio, along with a significant decrease in the hepatic cyclic AMP concentration, could most likely also account for the excessive hepatic triglyceride accumulation in the PTU-treated chicks.

Topics: Animals; Blood Glucose; Chickens; Cholesterol; Cyclic AMP; Glucagon; Glucose-6-Phosphatase; Glycogen; Hypothyroidism; Insulin; Liver; Male; Phospholipids; Propylthiouracil; Triglycerides

Topics: Adenylyl Cyclases; Animals; Cyclic AMP; Electric Stimulation; Hypothyroidism; In Vitro Techniques; Isoproterenol; Male; Myocardial Contraction; Myocardium; Phenylephrine; Propylthiouracil; Rats; Sodium Fluoride; Yohimbine

Thyroid hormones are known to influence the noradrenergic neurotransmission in several peripheral organs. In order to find out whether similar changes exist in the central nervous system, we investigated adrenoceptor-mediated responses in the rat brain cortex during propylthiouracil-induced hypothyroidism. In contrast to unchanged basal cAMP levels, the cAMP accumulation following (-)noradrenaline incubation (3 X 10(-6)--3 X 10(-5) M) was significantly reduced in brain slices from hypothyroid animals. The difference between controls and propylthiouracil-fed rats became more pronounced when (-) isoprenaline (3 X 10(-6)--3 X 10(-5) M) was used for selective stimulation of beta-adrenoceptors. Since the cAMP increase mediated via alpha-adrenoceptors was not affected, it may be concluded that thyroid hormone deficiency only impairs the beta-adrenergic transmission. Phosphodiesterase activity remained unaltered suggesting that thyroid hormones influence the beta-adrenoceptors or the adenylate cyclase coupled to it. The sensitivity of presynaptic alpha-adrenoceptors modulating the release of noradrenaline was evaluated using occipital cortical slices preincubated in 3H-noradrenaline. Clonidine inhibited whereas phentolamine enhanced the 3H-overflow induced by electrical stimulation in a dose-dependent manner. No differences could be detected between control- and propylthiouracil-treated animals. Thus presynaptic alpha-adrenoceptors are not affected by hypothyroidism.

Topics: Animals; Cerebral Cortex; Clonidine; Cyclic AMP; Dose-Response Relationship, Drug; Hypothyroidism; In Vitro Techniques; Isoproterenol; Male; Norepinephrine; Phentolamine; Phosphoric Diester Hydrolases; Propylthiouracil; Rats; Receptors, Adrenergic; Receptors, Adrenergic, beta

Multiple serum samples were obtained from six hypothyroid and six hyperthyroid females, 11--17 years of age, over the course of their corrective treatment with L-thyroxine (LT4) and propylthiouracil (PTU), respectively. Sera were assayed for total N-acetyl-beta-hexosaminidase (HEX), the A (heat-labile) and B (heat-stable) isozymes, and total T4. HEX activity (total HEX A) in sera from hypothyroid (< 4 micrograms/dl T4) patients (total HEX: 518 +/- 66 nmol/60 min/ml, mean +/- S.D.; HEX A: 325 +/- 55; n = 5) was significantly lower than that of the euthyroid control group (total HEX: 638 +/- 77 (p < 0.005); HEX A: 420 +/- 76 ( p < 0.01); n = 23); no difference in HEX B levels was noted. Serum samples from patients successfully treated for hypothyroidism via oral administration of LT4 (n = 12) displayed levels of total HEX (722 +/- 113) and HEX A (491 +/- 91) significantly higher than those of the control group (p < 0.01 in both cases); again, no change in levels of HEX B was observed. HEX activity in sera from hyperthyroid (> 13 micrograms/dl T4) individuals (total HEX: 839 +/- 96; HEX A: 540 +/- 74; HEX B: 299 +/- 52; n =20) was significantly higher than that of the control group (p < 0.005 in all cases). The depression of hormone activity to the euthyroid range by PTU was accompanied ay a decrease in enzyme activity to control levels (total HEX: 632 +/- 92; HEX A: 400 +/- 55; HEX B: 232 +/- 52; n = 16). Non-parametric analysis of the data shows highly significance differences between pre- and post-treatment enzyme levels (alpha < 0.001) in both hyper- and hypothyroid groups. Alteration of thyroid status, and specifically T4 level is, therefore, indicated to be a contributing factor in the regulation of serum HEX activity in humans, as evidenced by individual responsiveness to oral administration of this hormone, or inhibitors of its peripheral metabolism.

Topics: Adolescent; beta-N-Acetylhexosaminidases; Child; Female; Hexosaminidase A; Hexosaminidase B; Hexosaminidases; Humans; Hyperthyroidism; Hypothyroidism; Isoenzymes; Propylthiouracil; Thyroxine

Topics: Animals; Blood Glucose; Female; Fetal Resorption; Fetus; Glucose; Homeostasis; Hypothyroidism; Liver; Liver Glycogen; Organ Size; Pregnancy; Pregnancy, Animal; Propylthiouracil; Protein-Energy Malnutrition; Rats

Topics: 9,10-Dimethyl-1,2-benzanthracene; Animals; Body Weight; Female; Hypothyroidism; Mammary Neoplasms, Experimental; Neoplasms, Hormone-Dependent; Propylthiouracil; Rats; Thyroxine; Time Factors; Triiodothyronine

Topics: Animals; Diiodothyronines; Dithiothreitol; Edetic Acid; Hyperthyroidism; Hypothyroidism; Iodide Peroxidase; Kinetics; Liver; Male; NADP; Peroxidases; Propylthiouracil; Rats; Starvation; Thyroidectomy; Thyronines; Triiodothyronine; Triiodothyronine, Reverse

The changes in the developmental pattern of 3-oxo acid CoA-transferase activity in the brain of hypothyroid rats and the effect of triiodothyronine on this enzyme activity have been investigated. Hypothyroid rats showed lower activity than controls during the suckling period. However, higher enzyme levels were found in treated rats after weaning in contrast to control animals. The results suggest that thyroid hormones promote the development of enzymes of ketone-body metabolism in the brain.

Topics: Aging; Animals; Animals, Suckling; Body Weight; Brain; Coenzyme A-Transferases; Female; Hypothyroidism; Keto Acids; Organ Size; Pregnancy; Propylthiouracil; Rats; Succinates; Sulfurtransferases; Triiodothyronine

Topics: Acetaminophen; Alanine Transaminase; Animals; Aspartate Aminotransferases; Chemical and Drug Induced Liver Injury; Disease Models, Animal; Glutathione; Hypothyroidism; Liver; Male; Necrosis; Propylthiouracil; Rats; Thyroid Gland; Thyroidectomy

Topics: Animals; Cochlear Microphonic Potentials; Cochlear Nerve; Evoked Potentials, Auditory; Female; Hypothyroidism; Organ of Corti; Pregnancy; Propylthiouracil; Rats; Thyroxine

Topics: Animals; Dose-Response Relationship, Drug; Hypothyroidism; Male; Propylthiouracil; Rats; Thyroidectomy; Thyrotropin; Thyroxine

We studied the noradrenaline content, and monoamine oxidase (MAO) and catechol-O-methyltransferase (COMT) activities in brown adipose tissue (BAT) of normal, hypothyroid, and hyperthyroid developing rat. In the newborn, thyroid hormones are necessary for the increase in noradrenaline content which occurs between 0 and 5 days. Hypothyroidism increases both MAO and COMT activities. Hyperthyroidism decreases MAO activity but not noradrenaline content or COMT activity. In the full-term fetus, hypothyroidism decreases noradrenaline content as in the newborn, and also decreases MAO and COMT activities. It is suggested that thyroid hormones could modulate BAT nonshivering thermogenesis by regulating the level of noradrenaline, the direct mediator of heat production.

Topics: Adipose Tissue, Brown; Aging; Animals; Animals, Newborn; Catechol O-Methyltransferase; Female; Hyperthyroidism; Hypothyroidism; Male; Monoamine Oxidase; Norepinephrine; Pregnancy; Propylthiouracil; Rats; Thyroxine

Topics: Animals; Body Weight; Cholesterol; Fasting; Female; Hyperthyroidism; Hypothyroidism; Male; Propylthiouracil; Rats; Species Specificity; Thyroid Gland; Thyroxine; Triglycerides

Topics: Animals; Female; Hyperthyroidism; Hypothyroidism; Kinetics; Prolactin; Propylthiouracil; Rats; Thyroid Gland; Thyroxine

In order to assess the effects of perinatal hypothyroidism or hyperthyroidism on the development of an integrated behavioral response, we tested hypothyroid, hyperthyroid, and control pups, as well as pups receiving thyroxine replacement therapy, for the development of the home orientation response. Hypothyroidism was induced in the pups by feeding the pregnant or lactating female a diet of .2% propylthiouracil from Day 15 of gestation to Day 22 postpartum. Pups receiving replacement therapy and pups made hyperthyroid were injected daily with thyroxine, starting at birth. The ability of the pups to initiate and maintain locomotion toward the nest was assessed between Days 4 and 22. Hyperthyroid, control, and replacement therapy pups behaved very similarly on the task, showing a peak in the percentage of pups homing between Days 12 and 16. Hypothyroid pups showed a delay in the peak percentage until Day 20, although the percentage of pups was similar to that found in other treatments. An integrated behavioral response can be delayed by hypothyroidism and still emerge apparently intact at a later age.

Topics: Animals; Female; Hyperthyroidism; Hypothyroidism; Motor Activity; Orientation; Pregnancy; Propylthiouracil; Rats; Social Environment; Thyroxine

Studies of the effect on feedback mechanisms in nycthemeral fluctuation of plasma TSH and of its sex-related variation were carried out on normally fed (Purina) and propylthiouracil (PTU) treated rats. Plasma TSH concentration of purina fed rat was significantly higher in males than in females (M = 96 +/- 14, F = 49 +/- 3 microunits/ml, P less than 0.01). Plasma T4 concentration also showed a high tendency in males compared to females (M = 7.4 +/- 0.5, F = 5.8 +/- 1.0 micrograms/dl, 0.05 less than P less than 0.1) but the statistical difference was not significant. Plasma TSH demonstrated a typical periodicity characterized by a zenith at 1200 hr and a nadir at 1800 hr as in the previous reports. Plasma TSH concentrations rose apparently after the diet was switched to the one containing 0.15% of PTU. On the other hand, plasma T4 concentrations decreased to the very low levels following PTU administration. Concerning to the nycthemeral fluctuation and its sex related variation following PTU administration, nycthemeral fluctuation in male rats disappeared rapidly, whereas it was preserved in female rats. These facts showed that it kept more persistent fluctuation in female rats than in male rats under the high plasma TSH levels. Furthermore, female rats showed higher concentration of plasma TSH after PTU treatment compared to male rats. These results suggest that the nycthemeral fluctuation of plasma TSH was abolished or masked by the feedback mechanism of hypothalamo-pituitary-thyroid axis and there was a sex-related difference.

Topics: Animals; Circadian Rhythm; Corticosterone; Feedback; Female; Hypothyroidism; Male; Propylthiouracil; Rats; Sex Factors; Thyrotropin; Thyroxine

This study was undertaken to determine the effects of propylthiouracil-induced thyroid deficiency on a) the capacity of muscle homogenates to oxidize [2-14C]pyruvate and [U-14C]palmitate and b) glycogen depletion during exercise in liver and in fast-oxidative-glycogenolytic (FOG), fast-glycogenolytic (FG), and slow-oxidative (SO) muscle. Relative to the rates for normal rats, oxidation with pyruvate was reduced by 53, 68, and 58%, and palmitate by 40, 50, and 48% in FOG, FG, and SO muscle, respectively (P less than 0.05). Normal rats ran longer than thyroid-deficient rats at 26.7 m/min (87 +/- 8 vs. 37 +/- 5 min). After 40 min of running (22 m/min), the amount of glycogen consumed in normal FOG, FG, and SO muscle and in liver amounted to only 23, 12, 66, and 52%, respectively, of that for their thyroid-deficient counterparts. Also, normal rats maintained higher plasma free fatty acid levels than thyroid-deficient rats during both rest and exercise (P less than 0.05). These findings suggest that thyroid deficiency causes a reduced potential for FFA utilization in skeletal muscle that enhances its consumption of glycogen, thereby limiting endurance capacity.

Topics: Animals; Blood Glucose; Citrate (si)-Synthase; Fatty Acids, Nonesterified; Female; Glycogen; Hexokinase; Hypothyroidism; Malate Dehydrogenase; Muscles; Physical Exertion; Propylthiouracil; Rats; Respiration

The survival of rats acclimatized to either 5 degrees C or 30 degrees C, treated or not with propylthiouracil (P.T.U.), was determined at 40 degrees C. Changes in metabolic rate and rectal temperature were followed throughout exposure. Total water loss was estimated at the end of the experiment. The survival time of rats accclimatized to 5 degrees C was less than that of rats acclimatized to 30 degrees C, and that of controls was less than that of treated animals. The differences reported seem to be independent of heat transfer capacities, which are similar in all treatment conditions and possibly limited by the experimental set up. A high thermogenic rate would appear to limit resistance to heat under conditions where external heat stress approaches heat transferability, such that the animal's temperature overcomes the lethal threshold, and leads to heat stroke. Results of P.T.U. treatment suggest the involvement of thyroid hormones in heat stress-induced thermogenesis and in cellular lability to elevated internal temperatures.

Topics: Adaptation, Physiological; Animals; Body Temperature Regulation; Body Water; Cold Temperature; Hot Temperature; Hypothyroidism; Propylthiouracil; Rats; Time Factors

Recent evidence indicates that the paraventricular nucleus of the hypothalamus (PVN) contains both neurons that produce thyrotropic releasing hormone (TRH) and neurons that are destroyed or disconnected by the knife cuts that produce hypothalamic hyperphagia and obesity. This, and other evidence, suggested linkage between thyroid regulation and appetite control. As predicted, hyperthyroidism potentiated and hypothyroidism tempered the weight gains of knife cut rats. However, these effects were due entirely to increased and decreased, respectively, linear growth, not to differences in the degree of obesity. Enhanced linear growth and elevated growth hormone levels are a minor component of the enhanced weight gain of hypothalamically knife cut rats. Most of the weight gain is due to fat deposition. Only the enhanced linear growth and growth hormone aspect appear to possibly be mediated via the thyroid. In addition, obesifying knife cuts did not reduce goiterogenesis in PTU treated rats, as would be expected if the elaboration of TRH were blocked by obesifying knife cuts. Thus, neither TRH nor thyroxine is involved in the etiology of hypothalamic obesity.

Topics: Animals; Body Weight; Brain; Hyperthyroidism; Hypothalamus; Hypothyroidism; Male; Obesity; Paraventricular Hypothalamic Nucleus; Propylthiouracil; Rats

Mevalonate, an essential intermediate in cholesterol synthesis, is metabolized either to cholesterol or, by the shunt pathway, to CO2. Previous investigations have demonstrated that the kidneys are the chief site of circulating mevalonate metabolism and that sex hormones as well as insulin markedly influence circulating mevalonate metabolism. The present study examined in rats the influence of thyroid hormone status on mevalonate metabolism in vivo and in vitro. L-thyroxine administration increased renal conversion of circulating mevalonate to cholesterol, 41% in the females and 22% in the males. Conversely, hypothyroidism induced by 6 N propyl-2-thiouracil reduced renal conversion of circulatng mevalonate to cholesterol by 45% in females and 27% in males; thyroid hormone replacement in these animals returned cholesterogenesis in the kidneys to supranormal levels. Neither L-thyroxine nor hypothyroidism altered circulating mevalonate conversion to cholesterol in the liver or carcass. In vitro studies confirmed the in vivo observations. Changes in thyroid hormone produced only minor changes in the shunt pathway of mevalonate metabolism. This study demonstrates that the major effect of the thyroid hormone on the metabolism of circulating mevalonate is to alter the conversion of mevalonate to cholesterol, an effect localized solely to the kidneys.

Topics: Animals; Bone and Bones; Cholesterol; Female; Hypothyroidism; Kidney; Liver; Male; Mevalonic Acid; Propylthiouracil; Rats; Sex Factors; Thyroxine

Thyroid hormones play an important role in growth and development. Therefore, we investigated the effects of neonatal hypo- and hyperthyroidism on pituitary GH content in the rat. In control rats, pituitary GH content increased from 4.16 +/- 0.34 at 2 days to 43.7 +/- 4.2 microgram/gland (mean +/- SE) at 15 days of age, with a t 1/2 of increment of 3.48 +/- 0.40 days. Between 18-60 days of age, pituitary GH content increased from 56.9 +/- 4.0 to 300 +/- 28 microgram/gland, with a t 1/2 of 18.2 +/- 1.5 days. The administration of T3 had no significant effect on the pituitary GH content of these animals. In neonatal hypothyroid rats, pituitary GH content was significantly lower than that of controls at 2 days of age (P < 0.01) and decreased from 8 days on, with a t 1/2 of 3.71 +/- 0.25 days. However, 24 h after the administration of T3 (100 microgram/100 g BW), pituitary GH content was significantly increased in these animals. Similarly, the administration of T3 (0.4 microgram/100 g BW) to 14-day-old hypothyroid rats restored the pituitary GH content to 70-80% of normal after 5 days of therapy. Conversely, hyperthyroidism induced in 14-day-old normal or hypothyroid rats resulted in a significant decrease in their pituitary GH contents after 5 days of treatment. Therefore, the present results indicate that during the neonatal period, thyroid hormones play a primary role in the control of GH accumulation in the pituitary. Furthermore, the lack of increase in pituitary GH content after the administration of T3 during development might suggest that the rate of formation of GH is already maximum during this period of life in the rat, or, alternatively, that the pituitary nuclear T3 receptors are near full saturation during development. Finally, a generally similar effect of T3 on pituitary GH response was observed in the neonatal rat as well as in the adult animal.

Topics: Aging; Animals; Animals, Newborn; Growth Hormone; Hyperthyroidism; Hypothyroidism; Pituitary Gland; Propylthiouracil; Rats; Triiodothyronine

The turnover of cytochrome c was determined in the three skeletal-muscle fibre types of adult male rats by a kinetic analysis that followed the time course of cytochrome c content change. Confirming evidence was obtained with double-labelling studies using delta-aminolaevulinate. Cytochrome c turnover was most rapid in the low-oxidative fast-twitch white fibre [t1/2 (half-life) about 4 days], slowest in the high-oxidative fast-twitch red fibre (t1/2 9-10 days) and relatively rapid in the high-oxidative slow-twitch red fibre (t1/2 5-6 days). Thus cytochrome c turnover does not strictly conform to either the appearance (i.e. red or white) or the contractile characteristics (i.e. fast or slow) of the muscle fibres. The synthesis rates needed to maintain the corresponding cytochrome c concentrations, however, were similarly high in the two mitochondria-rich red fibre types. These data illustrate that both the synthesis and degradation processes are important in establishing the cytochrome c concentrations that distinguish the different skeletal-muscle fibre types.

Topics: Aminolevulinic Acid; Animals; Cytochrome c Group; Half-Life; Hypothyroidism; Kinetics; Muscles; Physical Exertion; Propylthiouracil; Rats; Thyroidectomy

Adrenoceptor-mediated responses of the cardiovascular system during propylthiouracil-induced hypothyroidism were investigated. Interfering nervous reflexes could be circumvented by using pithed rats. Cardiac beta-adrenoceptor-mediated acceleration of heart rate following electrical stimulation or injection of noradrenaline and isoprenaline was markedly diminished even after 2 weeks of treatment. This loss of beta-sensitivity prevented the study of possible changes of presynaptic regulatory adrenoceptors in this test model. Taking the increase in diastolic blood pressure after application of alpha-agonists as index of the sensitivity of vascular alpha-adrenoceptors we found these to have been desensitized in the hypothyroid state. According to these results the lack of thyroid hormones exerted a similar effect on cardiac beta- and on vascular alpha-adrenoceptors.

Topics: Animals; Atropine; Blood Pressure; Bupranolol; Clonidine; Disease Models, Animal; Electric Stimulation; Heart Rate; Hypothyroidism; Isoproterenol; Male; Norepinephrine; Phenylephrine; Propylthiouracil; Rats; Receptors, Adrenergic; Receptors, Adrenergic, alpha; Receptors, Adrenergic, beta; Spinal Cord; Tubocurarine

1. The effect of propylthiouracil (PTU)-induced hypothyroidism on carbohydrate and lipid metabolism was studied in the chick embryo. 2. A single dose of PTU (250 micrograms/embryo) was administered on day 11 and embryos sacrificed on day 20 of incubation. 3. Thyroid glands were significantly enlarged (6 fold) by PTU administration. 4. Increased thyroid weight was associated with growth retardation and decreased plasma thyroxine levels. 5. Plasma glucose level was lower and phospholipids were significantly higher in the hypothyroid embryo. 6. Liver lipid concentrations in the control and hypothyroid embryos were not different but were significantly higher in both groups when compared to previously reported values in the young chick. 7. In contrast to PTU treatment after hatching, liver glycogen levels were not increased in the hypothyroid chick embryo. This was attributed to the high lipid nutrient condition of the chick embryo since a high lipid diet in the young chick decreased hepatic glycogen accumulation significantly.

Topics: Animals; Blood Glucose; Body Weight; Carbohydrate Metabolism; Chick Embryo; Cholesterol; Glucose-6-Phosphatase; Hypothyroidism; Lipid Metabolism; Liver; Organ Size; Phospholipids; Propylthiouracil; Thyroid Gland; Triglycerides

In two separate experiments, treatment of C3H/He mice bearing transplantable mammary adenocarcinomas (C3HBA) with a regimen of 6-propylthiouracil (PTUra) and 5-fluorouracil (FUra) plus chloroquine phosphate (CP) resulted in complete remissions of 77 and 65%, respectively. Treatment with PTUra alone resulted in 41% remissions in experiment 1 and 35% remissions in experiment 2. None of the nontreated control mice in either experiment had spontaneous remissions, and all controls died in each experiment. The principal effect was apparently due to the treatment with PTUra, inasmuch as most of the tumors disappeared during the 21-day treatment period. This observation indicated that the proper timing of the thyroid treatment with PTUra was crucial to achieve the best results. The combined FUra+CP regimen augmented the effects of the thyroid treatment and resulted in an increase in remissions.

Topics: Adenocarcinoma; Animals; Chloroquine; Drug Therapy, Combination; Female; Fluorouracil; Hypothyroidism; Mammary Neoplasms, Experimental; Mice; Mice, Inbred C3H; Propylthiouracil; Remission, Spontaneous

To study the possible mechanisms involved in growth retardation associated with hypothyroidism, serum T4, GH, the GH-dependent somatomedin, insulin-like growth factor (IGF), and its carrier protein (CP) were measured in hypothyroid rats and their age-matched controls. Three groups of rats were studied: infant, immature, and adult. Marked hypothyroidism (serum T4, less than 1 microgram/dl) was produced in experimental animals by providing them with drinking water containing 0.05% propylthiouracil. Infant and immature hypothyroid rats weighed markedly less than normal controls and had significantly reduced serum levels of GH, IGF, and CP. Normal adult rats, treated with propylthiouracil for 60 days, also weighed considerably less than control animals and exhibited a significant drop in serum GH, IGF, and CP during this period. The administration of bovine GH to hypothyroid adult rats for 7 days did not restore either IGF or CP levels to normal, indicating that their decrease in serum was, in part, a direct result of hypothyroidism per se. These results indicate that serum levels of GH, IGF, and CP are at least partly under thyroid hormone control. Furthermore, these studies suggest that the growth retardation associated with hypothyroidism may be mediated through somatomedin activity.

Topics: Aging; Animals; Body Weight; Carrier Proteins; Female; Growth Disorders; Growth Hormone; Hypothyroidism; Male; Nonsuppressible Insulin-Like Activity; Propylthiouracil; Rats; Somatomedins; Thyroxine

Hypothyroidism was induced in neonatal Sprague-Dawley rats by adding propylthiouracil to the lactating female's food and water. Behavioral evaluation on a 6-item battery occurred from 70 to 114 days of age. Results indicated long-lasting behavioral changes in the neonatal hypothyroid animals characterized by increased activity and decreased performance on avoidance and escape learning. Serum thyroxine levels were reduced in the hypothyroid animals throughout the 120-day period. Experimental animals also had fewer synaptic contacts in the cerebellar cortex when analyzed at 90 days of age.

Topics: Animals; Animals, Newborn; Behavior, Animal; Body Weight; Cerebellar Cortex; Female; Hypothyroidism; Male; Nerve Fibers; Propylthiouracil; Rats; Synapses; Thyroxine

Topics: Animals; Chromium; Chromium Radioisotopes; Hyperthyroidism; Hypothyroidism; Male; Propylthiouracil; Rats; Thyroidectomy; Thyroxine; Time Factors

The survival of Buffalo rats brearing Morris Hepatoma 7800 was increased significantly (23 to 31%) after induction of hypothyroidism by propylthiouracil (PTU) (0.1% in Purina rat chow) or 131I. The concentration of PTU used was in the optimal range as 0.03% PTU was less effective than 0.1%, while 0.4% PTU appeared to be toxic. Exogenous thyroxine (8 microgram/kg body weight) reversed the effects of PTU and actually shortened survival. Because food consumption and body weights of hypothyroid rats were decreased, the survival of pair-fed controls was studied and found to be the same as in untreated controls. We conclude that the hypothyroid state increases the survival of rats bearing Morris Hepatoma 7800. We have not yet been able to define any anatomical or biochemical parameters which may be responsible for this effect.

Topics: Animals; Body Weight; Hypothyroidism; Liver Neoplasms, Experimental; Neoplasms, Hormone-Dependent; Organ Size; Propylthiouracil; Rats; Thyroid Gland; Thyroxine; Time Factors

Thyroid disease is often accompanied by changes in the concentrations of serum lipids and lipoproteins. To evaluate the hepatic contribution to the serum abnormalities in thyroid disease, we examined fatty acid metabolism in perfused livers from pair-fed rats made hypothyroid with propylthiouracil (PTU) or made hyperthyroid by treatment with triiodothyronine (T(3)). The animals treated with T(3) became hyperphagic, depending on dose of drug and duration of hyperthyroidism. It was necessary, therefore, for appropriate controls, that food intake of T(3)-treated rats be restricted to quantities consumed by euthyroid rats. Animals treated with PTU for 2 wk became hypophagic, and therefore, food consumption of controls was restricted to that eaten by rats receiving PTU. Dependent on dose of T(3) and duration of treatment, the output of triglyceride and glucose was diminished, whereas output of ketone bodies was increased by livers from hyperthyroid animals. In contrast, livers from PTU-treated animals secreted increased amounts of triglyceride and glucose, whereas ketogenesis was diminished. The best models for study proved to be animals treated with either 10 mug T(3)/100 g body wt per d or 1 mg PTU/100 g body wt per d for 7 d. Under these conditions, all animals consumed the same quantity of food as did the euthyroid rats, but continued to display the metabolic alterations outlined above. The effects of PTU on hepatic metabolism were readily reversible by simultaneous administration of T(3). It is clear from these data that the thyroid status of the rat regulates hepatic triglyceride formation and secretion, and ketogenesis.

Topics: Animals; Dose-Response Relationship, Drug; Eating; Fatty Acids, Nonesterified; Glucose; Hyperthyroidism; Hypothyroidism; Ketone Bodies; Lipid Metabolism; Liver; Male; Propylthiouracil; Rats; Time Factors; Triglycerides; Triiodothyronine

Serum thyroxine levels peak earlier and are significantly higher in audiogenic seizure-susceptible DBA/2J mice than in seizure-resistant C57BL/6J mice during early postnatal life. The seizure susceptibility of DBA/2J mice is suppressed by administration of an antithyroid drug or by radiothyroidectomy, while the seizure susceptibility of C57BL/6J mice is enhanced by treatment with excess thyroxine.

Topics: Acoustic Stimulation; Animals; Hyperthyroidism; Hypothyroidism; Mice; Mice, Inbred Strains; Propylthiouracil; Seizures; Thyroxine

The growth rate of Morris Hepatoma No. 44 (generation time, 6 mo) was inhibited after the induction of hypothyroidism by Propylthiouracil (PTU) (0.1% in Purina Chow), I131 (1 mCi/100 g body wt i.p.), or surgical thyroidectomy. After 11 wk of treatment, hepatoma weight was 66%, 87%, and 75% (after correction for total body wt) relative to controls in PTU-fed, I131 injected, and thyroidectomized rats, respectively. In each case, exogenous thyroxine (T4) (8 microgram/kg body wt i.p.) reversed these inhibitory effects, while T4 administered to euthyroid rats stimulated hepatoma growth. The degree of growth-inhibition achieved with PTU was not observed in pair-fed rats. In addition, after correction for differences in body weight, the sex of the tumor-bearing rats did not influence the response to PTU. Pretreatment with PTU for 2 wk before implantation did not give any added advantage over the effects of PTU administered approximately 10 days after implantation. Serum levels of triiodothyronine (T3) and T4, as well as the concentration of various biochemic parameters, were determined at the time of death. These results suggest that the growth rate of Morris Hepatoma No. 44 is thyroid hormone dependent.

Topics: Animals; Female; Hypothyroidism; Iodine Radioisotopes; Liver Neoplasms, Experimental; Male; Propylthiouracil; Rats; Sex Factors; Thyroidectomy; Thyroxine; Time Factors; Triiodothyronine

Topics: Arousal; Female; Flicker Fusion; Humans; Hypothyroidism; Male; Middle Aged; Propylthiouracil; Reaction Time; Thyroid Hormones; Thyroxine; Triiodothyronine; Visual Acuity

The management of hyperthyroidism and hypothyroidism in pregnancy is discussed and illustrated with appropriate cases. The dangers of the usage of high doses of antithyroid drugs and of propranolol are described.

Topics: Adult; Carbimazole; Female; Humans; Hyperthyroidism; Hypothyroidism; Pregnancy; Pregnancy Complications; Propranolol; Propylthiouracil; Thyroid Diseases

The treatment of benign forms of thyroid disease is reviewed. Endemic goiter is a public health problem preventable by the addition of iodine to the food or water supply. Endemic and familial goiters are treated with replacement doses of I-thyroxine, as are sporadic colloid goiters and goiters resulting from chronic thyroiditis. Hyperfunctioning autionomous nodules without thyrotoxicosis and cystic nodules require no specific therapy. Prophylaxis against diffuse or nodular goiter after radiation to the head or neck for therapeutic purposes with thyroxine replacement therapy is debatable. All forms of hypothyroidism, including incipient types, require replacement thyroxine therapy, but this should be undertaken cautiously in older patients and in those with evidence of ischemic myocardial disease. Myxedema coma requires vigorous treatment and detailed supervision because of dismal mortality rates. Iodine 131 is the treatment of choice in diffuse toxic goiter, but alternative forms.

Topics: Adolescent; Adult; Female; Goiter; Humans; Hyperthyroidism; Hypothyroidism; Iodine Radioisotopes; Methimazole; Pregnancy; Propylthiouracil; Radiation Dosage; Thyroid Diseases; Thyroxine

1. Oral intubation of glucose is more effective than intraperitoneal injection in inducing the premature appearance of hepatic glucokinase in suckling rats. 2. The inducing effect of glucose is enhanced by treatment of the animals 12 h or more earlier with 1 microgram triiodothyronine/g body weight. 3. Low but significant activities of glucokinase appear at the normal time of development in hypothyroid neonatal rats. Intubation of glucose into 13-day-old and 24-day-old hypothyroid results in the rapid appearance of glucokinase similar to that in normal animals treated likewise. 4. The enhancing effect of thyroid hormones on glucokinase induction by glucose does not necessarily mean that the normal postnatal increase in plasma thyroid hormones is essential for the normal appearance of glucokinase activity at the time of weaning. Other possible explanations are discussed.

Topics: Animals; Animals, Newborn; Blood Glucose; Enzyme Induction; Glucokinase; Hexokinase; Hypothyroidism; Kinetics; Liver; Propylthiouracil; Rats; Thyroxine; Triiodothyronine

Topics: 9,10-Dimethyl-1,2-benzanthracene; Animals; Benz(a)Anthracenes; Female; Hyperthyroidism; Hypothyroidism; Liver; Mammary Neoplasms, Experimental; Prolactin; Propylthiouracil; Rats; Thyroid Gland; Thyroxine

The regulation of adrenergic receptors in rat heart was measured in rats made hyperthyroid by injection with thyroxine and made hypothyroid by addition of propylthiouracil to the drinking water. Hyperthyroid rats display cardiac hypertrophy and a decrease in epididymal fat pad weight. The maximal beta-receptor level of ventricular membranes, as determined by (-)-[3H]dihydroalprenolol binding, was increased 60% by thyroxine treatment and decreased about 30% by propylthiouracil treatment. The affinity of the beta receptor was unchanged after thyroxine or propylthiouracil treatment. The maximal activity of the isoproterenol-stimulated adenylate cyclase (EC 4.6.1.1) varied with thyroid state in a manner parallel to the increase in beta-adrenergic binding sites. Thyroxine treatment also increases by 2-fold the beta receptors in isolated rat fat cells. Propylthiouracil treatment lowered the level of alpha receptors in heart by 30% as measured by [3H]dihydroergocryptine binding, but increased the affinity about 2.5-fold. The highest level of alpha receptors was seen in control hearts. These studies indicate that thyroxine may control the turnover of beta-adrenergic receptors in heart and fat cells and regulate physiological responses in these tissues via a hormone-hormone interplay system. Thyroxine treatment reduced the activity of the membrane-bound Mg2+-ATPase (EC 3.6.1.3) and 5'-mononucleotidase (EC 3.1.3.5) but appears to increase the activity of the (Na+ + K+)ATPase (EC 3.6.1.4).

Topics: Adenosine Triphosphatases; Adenylyl Cyclases; Adipose Tissue; Alprenolol; Animals; Cell Membrane; Dihydroergotoxine; Heart; Hyperthyroidism; Hypothyroidism; Male; Propylthiouracil; Rats; Receptors, Adrenergic; Sympathomimetics; Thyroxine

Injections of triiodothyronine (T(3)) and thyroxine (T(4)) into chronically hypothyroid rats were used to evaluate the contribution of intracellular T(4) to T(3) conversion to nuclear T(3) in pituitary, liver, and kidney, and to correlate the occupancy of pituitary nuclear T(3) receptors with inhibition of thyroid-stimulating hormone (TSH) release. Injection of a combination of 70 ng T(3) and 400 ng T(4)/100 g body wt resulted in plasma T(3) concentrations of 45+/-7 ng/dl (mean+/-SD) and 3.0+/-0.4 mug/dl T(4) 3 h later. At that plasma T(3) level, the contribution of plasma T(3) to the nuclear receptor sites resulted in saturation of 34+/-7% for pituitary, 27+/-5% for liver, and 33+/-2% for kidney. In addition to the T(3) derived from plasma T(3), there was additional T(3) derived from intracellular monodeiodination of T(4) in all three tissues that resulted in total nuclear occupancy (as percent saturation) of 58+/-11% (pituitary), 36+/-8% (liver), and 41+/-11% (kidney), respectively. The percent contribution of T(3) derived from cellular T(4) added 41% of the total nuclear T(3) in the pituitary which was significantly higher than the contribution of this source in the liver (24%) or the kidney (19%). 3 h after intravenous injection of increasing doses of T(3), the plasma T(3) concentration correlated well with both the change in TSH and the nuclear occupancy, suggesting a linear relationship between the integrated nuclear occupancy by T(3) and TSH release rate. The contribution of intrapituitary T(4) to T(3) conversion to nuclear T(3) was accompanied by an appropriate decrease in TSH, supporting the biological relevance of nuclear T(3). Pretreatment of the animals with 6-n-propylthiouracil before T(4) injection decreased neither the nuclear T(3) derived from intrapituitary T(4) nor the subsequent decrease in TSH. These results indicate that intracellular monodeiodination of T(4) contributes substantially to the nuclear T(3) in the pituitary of the hypothyroid rat, and suggest a linear inverse relationship between nuclear receptor occupancy by T(3) in the pituitary and TSH release rate. The data further indicate that T(4) to T(3) monodeiodination is considerably more important as a source of nuclear T(3) in the pituitary than in the liver and kidney. This provides a mechanism whereby the TSH secretion could respond promptly to a decrease in thyroid secretion (predominantly T(4)) before a decrease in plasma T(3) would be expected to lead to significant met

Topics: Animals; Cell Nucleus; Hypothyroidism; Kidney; Liver; Male; Pituitary Gland; Propylthiouracil; Rats; Receptors, Cell Surface; Thyrotropin; Thyroxine; Triiodothyronine

Topics: Animals; Cats; Cyclic AMP; Cyclic GMP; Electric Stimulation; Female; Guinea Pigs; Heart; Hypothyroidism; In Vitro Techniques; Male; Myocardial Contraction; Myocardium; Papillary Muscles; Phenoxybenzamine; Propylthiouracil; Rats; Receptors, Adrenergic; Receptors, Adrenergic, alpha; Time Factors

A tracer dose of [125I]T3 was given iv to normal, thyroidectomized, and propylthiouracil-fed rats and the distribution of radioactivity in serum and liver fractions was studied over 1 h. Total liver homogenate and serum 125I were higher at all times in hypothyroid rats and, in all groups, showed a continuous fall over the period studied. Hepatic nuclear 125I was maximal at 20 min in all and was greater in hypothyroid rats; there was more 125I in the hepatic cytosol of normal rats than in that from either thyroidectomized or propylthiouracil-fed animals. Binding studies with [125I]T3 and purified hepatic neclear preparations in vitro indicated that both the association constant, Ka (1.08-9.0 x 10(9) M-1) and the capacity (500-600 pg/mg DNA) in thyroidectomized and goitrogen-treated rats were similar to those obtained with normal animals. Cytosol, on the other hand, showed a decrease in binding capacity without change in affinity in livers of hypothyroid rats. Analysis of binding data by Hill plots indicated the presence of both positive and negative cooperativity in binding of T3 by rat liver cytosol proteins. In the in vitro experiments, higher serum radioactivity alone could not account for increases in the hepatic nuclear 125I in the hypothyroid rats because cytosol 125I (presumably in dynamic exchange with both blood and nuclei) was less. Consequently, cytosol T3-binding proteins may regulate the free T3 concentration in the cell and, thus influence the distribution of the hormone in other cellular compartments.

Topics: Animals; Cell Nucleus; Cytosol; Hypothyroidism; Liver; Male; Propylthiouracil; Rats; Receptors, Cell Surface; Thyroidectomy; Time Factors; Triiodothyronine

Adipocytes isolated from normal, hypothyroid, and hyperthyroid rats were characterized with respect to their lipolytic activity (assessed by glycerol release) and beta-adrenergic receptors (assessed by binding of (--) [3H]alprenolol). Fat cells from hypo- and hyperthyroid rats showed the same affinity (K = 1.4 X 10(10) M(-1) and binding capacity (N = 1.21 X 10(-13) mol/microgram DNA) toward alprenolol as those from normal animals. Adipocytes from hypothyroid rats were unresponsive to epinephrine in a concentration range of 0.1-10 micron, with moderate responses at higher concentrations; injection of T3 in hypothyroid rats restored lipolytic responsiveness of the adipocytes to normal levels. Quabain (1 mM) inhibited lipolytic responses to epinephrine by 40--45% in normal and hyperthyroid rats; the lipolytic increment due to the hyperthyroid state was uninfluenced by ouabain. The lipolytic refractoriness to epinephrine of hypothyroid adipocytes was restored to normal levels by theophylline (1 mM) or EGTA (1 mM); the theophylline and EGTA effects were not additive, suggesting that they stimulated lipolysis via a common mechanism. Epinephrine-induced lipolysis in all groups was progressively inhibited by increasing concentrations of Ca2+ in the medium. The Ca ionophore, A23187, showed a concentration-dependent inhibitory action. Theophylline (1mM) almost completely overcame the inhibitory action of the ionophore; in the presence of lower concentrations of theophylline, the inhibitory effect of the ionophore was least in hypothyroid and greatest in hyperthyroid fat cells. The findings suggest that the differences in the lipolytic response to epinephrine observed in hyperthyroid, euthyroid, and hypothyroid adipocytes are not due to alterations in the number or affinity of beta-adrenergic receptors nor to a membrane mechanism that might show differential ouabain sensitivity, but may be related to altered cellular Ca2+ concentrations which may indirectly alter cellular phosphodiesterase activity.

Topics: Adipose Tissue; Alprenolol; Animals; Calcimycin; Calcium; Epinephrine; Hyperthyroidism; Hypothyroidism; Kinetics; Lipid Mobilization; Male; Propylthiouracil; Rats; Receptors, Adrenergic, beta; Thyroid Gland; Triiodothyronine

Topics: Animals; Body Weight; Castration; Follicle Stimulating Hormone; Gonadotropin-Releasing Hormone; Hypothyroidism; Luteinizing Hormone; Male; Organ Size; Propylthiouracil; Prostate; Rats; Seminal Vesicles; Testis; Testosterone

A possible extrathyroidal effect of propylthiouracil (PTU) and carbimazole on serum levels of thyroxine (T4), triiodothyronine (T3), 3,3',5'-triiodothyronine (reverse T3) and on thyrotrophin-releasing hormone (TRH) induced thyrotrophin (TSH) release was estimated in 19 patients with severe hypothyroidism treated with T4. During PTU medication a significant decrease in serum T3 from 90 +/- 16 (SD) to 79 +/- 23 ng/100 ml (P less than 0.01) and a reciprocal increase in serum reverse T3 from 51 +/- 14 (SD) to 58 +/- 20 ng/100 ml (P less than 0.025) were found. No significant changes in serum T4, basal serum TSH or response to TRH could be demonstrated. Carbimazole did not change any of the parameters studied.

Topics: Adult; Aged; Carbimazole; Female; Humans; Hypothyroidism; Male; Middle Aged; Propylthiouracil; Thyrotropin; Thyrotropin-Releasing Hormone; Thyroxine; Triiodothyronine

Topics: Humans; Hyperthyroidism; Hypothyroidism; Iodine Radioisotopes; Myocardial Contraction; Propylthiouracil; Thyroid Hormones; Thyrotropin; Thyroxine; Triiodothyronine

Topics: Age Factors; Animals; Cerebellar Cortex; Hyperthyroidism; Hypothyroidism; Male; Propylthiouracil; Rats; Thyroxine

Topics: Animals; Bile; Hyperthyroidism; Hypothyroidism; Lactates; Liver; Male; Oleic Acids; Propylthiouracil; Pyruvates; Rats; Thyroxine

Topics: Aging; Animals; Animals, Newborn; Brain; Hyperthyroidism; Hypothyroidism; Propylthiouracil; Rats; Serotonin; Synaptosomes; Thyroid Gland; Triiodothyronine

Chronic dietary administration of theophylline (0.625, 1.25 or 2.50 g/kg food) for 7--9 weeks prevented the decrease in resting oxygen consumption, heart rate and systolic blood pressure characteristically observed in rats treated simultaneously with either of the antithyroid drugs, aminotriazole (ATZ; 0.25 g/kg food) or propylthiouracil (1.0 g/kg food). However, theophylline failed to restore both the food intake and growth rate of hypothyroid rats to that of euthyroid controls. Measurements of 131I uptake by the thyroid gland, thyroid acinar cell height and protein-bound iodine failed to reveal an effect of theophylline in either control or hypothyroid animals although theophylline increased thyroid to body weight ratio in both groups. Thus, the restoration of rate of oxygen consumption, heart rate and systolic blood pressure of hypothyroid rats to that of euthyroid controls was apparently not exerted through an increase in thyroid activity. The reduction in rate of oxygen consumption, heart rate and systolic blood pressure, generally associated with lack of thyroid hormone, appear more likely to be associated with reduced responsiveness to catecholamines in the hypothyroid rats. The results suggest that an increase in the half-life of cAMP by administration of theophylline to hypothyroid rats returned these functions to the level of euthyroid controls.

Topics: Amitrole; Animals; Blood Pressure; Body Weight; Diet; Drug Evaluation, Preclinical; Growth; Heart Rate; Hypothyroidism; Iodine; Male; Oxygen Consumption; Propylthiouracil; Rats; Theophylline; Thyroid Gland

Topics: Animals; Animals, Newborn; Cerebellum; DNA; Female; Hypothyroidism; Maternal-Fetal Exchange; Methyltransferases; Pregnancy; Propylthiouracil; Rats; Thymidylate Synthase

Topics: Animal Population Groups; Animals; Animals, Suckling; Hypothyroidism; Jejunum; Propylthiouracil; Rats; Sucrase; Thyroxine

Treatment of rats with propylthiouracil for the first 30 days of postnatal life drastically retards the ontogenesis of D-amino acid oxidase in the brain stem and cerebellum. There is a marked terminal deficit of D-AAO in both the brain stem (--64%) and cerebellum (--67%) at 94 days (adults) despite the near euthyroid status at this age. If initiated early enough, thyroxine replacement therapy reverses the effects of PTU on the development of D-AAO. Hyperthyroidism significantly accelerates the development of D-AAO in both brain stem and cerebellum. Nonetheless, animals treated with thyroxine the first month of life display a net deficit of cerebellar D-AAO content in adulthood. The results are discussed in terms of the localization of D-AAO in cell types especially sensitive to thyroid hormone: (1) a cell type which is among the last to derive from the external germinal zone in the developing cerebellum, and which in the adult is located adjacent to the Purkinje cell soma; and (2) mossy fiber neurons and cerebellar glomeruli.

Topics: Animals; Animals, Newborn; Brain Stem; Cerebellum; D-Amino-Acid Oxidase; Female; Hyperthyroidism; Hypothyroidism; Male; Propylthiouracil; Rats; Thyroxine

Topics: Antithyroid Agents; Female; Follow-Up Studies; Humans; Hyperthyroidism; Hypothyroidism; Male; Propylthiouracil; Thyroid Function Tests

Sodium dodecyl sulphate (SDS) polyacrylamide gel electrophoresis of the liver cytosol of euthyroid male rats revealed a prominent band (molecular weight, 26 000 daltons), designated Protein II, which was virtually absent in the cytosol of hypothyroid animals. Injection of 500 mug triiodothyronine (T3) per 100 g body weight resulted in a maximal increase in the level of Protein II, reaching 90% of the euthyroidal level 3 days after hormone administration. Concomitant studies with the liver mitochondrial enzyme alpha-glycerophosphate dehydrogenase (alpha-GPD) indicated that this T3 dose also resulted in a maximal enzyme response in this time period. Since we have estimated that 500 mug of T3 will saturate nearly all nuclear T3 binding sites, these results support the concept that the synthesis of both proteins is limited by nuclear binding. Protein II was absent in the liver cytosol of female rats but could be induced in ovariectomized female rats by androgens. Treatment of male rats with oestradiol resulted in disappearance of Protein II. Since administration of testosterone to hypothyroid male rats caused only a minimal increase in the amount of Protein II, the absence of the protein in hypothyroid animals was not due to androgen deficiency. Similarities in the molecular weight and the response to hormonal manipulation of Protein II and of the urinary alpha2uglobulin, previously reported by Roy (1973) raise the possibility that these proteins are the same. The high concentration of Protein II in male rat cytosol and the relative ease in its identification by SDS polyacrylamide gel electrophoresis make it a potentially useful model protein for the study of thyroid hormone action at the cellular level.

Topics: Animals; Castration; Cytosol; Dose-Response Relationship, Drug; Electrophoresis, Polyacrylamide Gel; Estradiol; Female; Glycerolphosphate Dehydrogenase; Hypothyroidism; Liver; Male; Mitochondria, Liver; Molecular Weight; Propylthiouracil; Proteins; Rats; Receptors, Cell Surface; Testosterone; Thyroid Gland; Triiodothyronine

Topics: Animals; Animals, Newborn; Aspartate Carbamoyltransferase; Body Weight; Cerebellum; DNA; Hypothyroidism; Organ Size; Phosphotransferases; Propylthiouracil; Rats; Uridine Kinase

The evolution of monoamine oxidase (MAO) activity towards tryptamine has been studied from birth to 20 days post-natal in the brain and heart of male rats. Hyperthyroidism was induced by thyroxine injections and hypothyroidism by PTU administration. The results are expressed per unit of fresh weight and per unit of protein weight. Cardiac MAO is higher in the hyperthyroid animals than in controls as soon as 5 days following birth; the difference between the 2 groups increases until 20 days. The deficiency in thyroid hormones, on the other hand, was followed by a slight decrease in the cardiac enzyme, this decrease reflecting the general deficit in protein synthesis. Brain MAO is not affected by hyperthyroidism, but a clear deficit follows PTU administration. This deficit is significant beginning at 10 days and the difference between the 2 groups increases up to 20 days. The effects of PTU-induced hypothyroidism can be corrected by thyroxine injections. Except for the decrease in the level of cardiac enzyme in hypothyroid animals, all the effects on MAO activity are independent of the total protein content of both organs.

Topics: Animals; Brain; Heart; Hyperthyroidism; Hypothyroidism; Male; Monoamine Oxidase; Myocardium; Propylthiouracil; Rats; Thyroxine

Topics: Animals; Animals, Newborn; Blood Glucose; Chickens; Glucose; Hypothyroidism; In Vitro Techniques; Intestinal Absorption; Lipid Metabolism; Liver; Oxidation-Reduction; Propylthiouracil; Triglycerides

Topics: Animals; Brain; Hypothyroidism; Isoenzymes; L-Lactate Dehydrogenase; Muscles; Propylthiouracil; Rats

The basal ganglia are presently implicated in learning, and thyroid deficiency induced neonatally is known to affect mentation. The effects of such a deficiency on the developing causate nucleus might be used to provide insight into structure and function of the normal subcortical brain, as well as possible influences of these extrapyramidal structures on mental retardation. Propylthiouracil was added to the diet of lactating rat dams and observations of the developing caudate nuclei of normal hypothyroid rats were made at 8, 14, 20, 30 and 42 days by using various tissue stains and Golgi-Cox preparations. Seven different types of neurons were distinguished in the caudate nucleus. Differences in the size of cell somata and the varying morphology of axons and dendrites were criteria used to make distinctions. Normally, the nucleus acquires cytoarchitectural complexity during the first three postnatal weeks. Within this period, neuron incidence increases in the caudate neuropil with age while the germinal matrix density decreases. Neuron accumulation reaches a plateau after the third week and cell migration is essentially complete at the end of the first postnatal month as shown by computer analysis of Nissl stained cell counts. Branching of cellular processes, attainment of receptor spines and complexity of the fiber network also appeared during this period. Retardation of structural development with thyroid hormone deficiency was shown by decreased numbers of neurons, inhibition of dendritic arborization, decreased numbers of dendritic spines and a reduced complexity of axonal plexuses. Thyroid deficiency delays cell migration during the first three weeks when compared to age-matched normal controls. The lack of thyroid hormone does not appear to influence the size of neuron somata, and the extent of related dendritic fields, nor does hypothyroidism affect a specific cell type population. Generalized disturbances of caudate nuclear morphological maturation are caused by the deficiency. An apparent compensatory process, including a spurt of neural growth and differentiation, takes place in the period between days 14 and 30 in the deficient animals and a seemingly "normal" caudate cytoarchitecture is seen after the third postnatal week. Quantitative data, however, show that this rapid "catch up" process is inadequate. The developmental imperfection of the caudate nucleus which persists might be a part of the underlying substrate for the mental retardation,

Topics: Animals; Animals, Newborn; Biometry; Caudate Nucleus; Cell Count; Computers; Hypothyroidism; Myelin Sheath; Propylthiouracil; Rats; Thyroxine

The jejunal mechanisms for the electrogenic transfer of four neutral amino acids (alanine, leucine, methionine, valine) and for sarcosine were characterised by an electrical method in vitro. The values for apparent Km obtained electrically agree well with those assessed by conventional chemical techniques. Hypothyroidism and/or fasting rats for 3 days induced differential changes in the apparent Km and p.d.max for the various amino acids. These alterations were interpreted as indicating the presence of at least three mechanisms for neutral amino acid transfer and one for sarcosine. In euthyroid rats, only alanine showed changes in apparent Km (decrease) and p.d.max (decrease) after fasting for 3 days. With hypothyroidism the kinetic parameters of electrogenic transfer for alanine, valine and sarcosine were significantly altered while those for leucine and methionine were unaffected.

Topics: Alanine; Amino Acids; Animals; Biological Transport, Active; Fasting; Hypothyroidism; Intestinal Absorption; Intestinal Mucosa; Jejunum; Kinetics; Leucine; Male; Methionine; Propylthiouracil; Rats; Sarcosine; Valine

Propylthiouracil and methimazole are used widely in the treatment of hyperthyroid disorders. The most important complication of the use of these drugs is depression of the neutrophilic granulocyte count. Granulocytopenia occurs in about 4 percent and agranulocytosis occurs in about 0.3 percent of treated patients. Although this depression of the granulocyte count is reversible after the drug is discontinued, serious infection frequently accompanies agranulocytosis and accounts for almost all deaths related to the drugs. It is important to be aware of the clinical features of granulocytopenic reactions due to antithyroid drugs.

Topics: Agranulocytosis; Humans; Hypothyroidism; Methimazole; Propylthiouracil

Male Long-Evans rats 36 to 39 days of age were fed a diet containing 0.1% propylthiouracil (PTU) for 17 to 20 days followed by the resumption of normal diet. Growth rates of body weight and tail length decreased during PTU treatment and increased during recovery; yet only slight catch-up (compensatory) growth occurred in either body weight or tail length. Although serum thyroxine and triiodothyronine concentrations (radioimmunoassay) decreased significantly during PTU treatment, they returned to normal by recovery day 14. Pituitary immunoassayable growth hormone (GH) content and concentration dropped during PTU-feeding. By recovery day 14 there was significant, but incomplete, repletion of the gland. Serum GH during ether anesthesia was increased significantly during PTU treatment; it remained elevated (NS) and showed greater variability during recovery than in controls. Bioassayable serum somatomedin (Sm) activity decreased during PTU treatment in one of two experiments but returned to a normal level by recovery day 7. The addition of PTU to normal rat serum in concentrations used during PTU treatment failed to alter Sm activity. The addition of L-triiodothyronine and/or L-thyroxine to hypothyroid serum also did not alter Sm activity. In vitro and in vivo cartilage sulfate incorporation decreased during PTU treatment but it rose to greater than control values during the recovery period. The difference in sulfate incorporation between treated and control rats was maintained throughout the observation periods. The results indicate that incomplete catch-up growth following transient hypothyroidism is the result of factors other than deficient GH or Sm production. The implications of the persistent changes in cartilage sulfate metabolism are not clear, but these findings during recovery suggest the possibility that a disturbance of intrinsic cartilage function is a limiting factor preventing full catch-up growth after PTU-induced hypothyroidism.

Topics: Animals; Cartilage; Growth Hormone; Hypothyroidism; Male; Pituitary Gland; Propylthiouracil; Rats; Somatomedins; Sulfates; Thyroxine; Triiodothyronine

Topics: Antibody Specificity; Female; Fetal Blood; Humans; Hyperthyroidism; Hypothyroidism; Isomerism; Methimazole; Myocardial Infarction; Pregnancy; Propylthiouracil; Thyroid Hormones; Thyrotropin; Thyroxine; Triiodothyronine

Lipolysis and intracellular levels of cyclic AMP of adipose tissue from man and rat in both hypothyroid and euthyroid states were studied in response to stimulation by catecholamines in vitro. Hypothyroid patients were studied before and after treatment, and were also compared with euthyroid obese controls. The experimental group of rats was rendered hypothyroid by the addition of 2.9 mM-propylthiouracil to their drinking water, and their status confirmed by plasma thyroid function tests. Evidence for alpha-adrenergic receptor activity was found in rat adipose tissue, but was less marked than the pronounced alpha-adrenergic activity in human adipose tissue. Glycerol release from adipose tissue in response to noradrenaline stimulation was less marked in hypothyroidism in both species, and was related to an increased alpha-adrenergic activity. No evidence was found for increased alpha-adrenergic effects on cyclic AMP level in hypothyroid subjects, and little evidence was found in adipose tissue from hypothyroid rats. This discrepancy may be due to the presence of the phosphodiesterase inhibitor, theophylline, in the incubation system. The possible modulatory role of thyroid hormones on receptor and phosphodiesterase activity, and on lipolysis, is discussed.

Topics: Adipose Tissue; Animals; Cyclic AMP; Fatty Acids, Nonesterified; Glycerol; Humans; Hypothyroidism; In Vitro Techniques; Lipid Metabolism; Male; Norepinephrine; Propylthiouracil; Rats; Receptors, Adrenergic; Stimulation, Chemical

Topics: Animals; Cyclic AMP; Hypothyroidism; Isoproterenol; Male; Myocardial Contraction; Myocardium; Perfusion; Phenylephrine; Propranolol; Propylthiouracil; Rats; Time Factors

The effect of hypothyroidism on cerebral and cerebellar synaptosome development has been studied. Neonatal hypothyroidism was induced following addition of 0.3% propylthiouracil to the diet of nursing mothers. Maturation profiles of total synaptosome fraction and specific activities of lactate dehydrogenase, Na+K ATPase, cytochrome c oxidase, and protein were obtained from days 6 to 32 on synaptosomes isolated from Ficoll-sucrose gradients. The greatest changes were found in the total activities of enzymes isolated from the cerebellum. Hypothyroidism induced a retardation of LDH and cytochrome c oxidase in cerebellar synaptosomes, but no change in corresponding specific activities. Maximum rates of 14C-leucine incorporation into cerebellar synaptosome protein was found at 16-20 days, after which a rapid decline occurred to adult levels at 32 days. In neonatal hypothyroidism, synthesis was significantly reduced at 8 and 14 days, but reached control levels or above at 21--32 days. In the cerebrum, maximum rates of 14C-leucine incorporation into synaptosome protein were identified at 8--12 days in normal with a rapid drop to adult levels at approximately 20 days. In neonatal hypothyroidism, peak activities were identified at 14 days and increased activities over control were noted at 14, 20 and 30 days. These observations demonstrate the sensitivity of the developing cerebellar synaptic apparatus to neonatal hypothyroidism, with a protraction in the peak levels of synaptosome protein synthesis in cerebrum and cerebellum.

Topics: Adenosine Triphosphatases; Animals; Animals, Newborn; Cerebellar Cortex; Cerebral Cortex; Electron Transport Complex IV; Hypothyroidism; L-Lactate Dehydrogenase; Leucine; Nerve Tissue Proteins; Potassium; Propylthiouracil; Rats; Sodium; Synaptosomes; Thyroxine

The late consequences of a brief period of perinatal hypothyroidism were studied in the rat by giving propylthiouracil (PTU) prenatally to the mothers and/or neonatally for 5 days to the pups. Perinatal hypothyroidism produced a delay in eye opening, a diminution in weaning weight, a delay in puberty and first estrus, and a prolongation of estrus cycles. The neo-PTU rats usually had a persistently enlarged thyroid gland associated with an elevated pituitary, hypothalamic, and serum thyroid-stimulating hormone (TSH) concentration. The metabolic clearance rate of TSH and response to luteinizing hormone-releasing hormone (LH-RH) were normal. The response to thyrotropin-releasing hormone (TRH) stimulation was significantly blunted in adult neo-PUT males, suggesting secondary or tertiary hypothyroidism. As a result of these studies, serious thought should be given to the possible consequences of antithyroid drug therapy of pregnant women, and certainly all pregnant hypothyroid women should receive full replacement therapy.

Topics: Animals; Animals, Newborn; Body Weight; Endocrine Glands; Female; Fetal Diseases; Hypothyroidism; Luteinizing Hormone; Male; Organ Size; Pregnancy; Pregnancy Trimester, Third; Propylthiouracil; Rats; Thyroid Gland; Thyrotropin; Thyrotropin-Releasing Hormone

Responsiveness to synthetic thyrotropin-releasing hormone (TRH), thyroid suppressibility by triiodothyronine (T3) and the outcome of hyperthyroidism following prolonged therapy with thionamides were studied in a group of 35 patients with toxic diffuse goiter. TRH and T3 suppression tests were performed 10 days to 24 months (mean 4 months) after withdrawal of antithyroid drugs. Nineteen patients were euthyroid and had a normal thyrotropin (TSH) response to TRH, while 4 were recovering from mild hypothyroidism due to overtreatment and had an exaggerated response. No response was observed in 12 patients with recurrent hyperthyroidism. Positive T3 suppression tests were found only in 10 of the 30 cases examined. Peak and net 2 h secretion responses of TSH to TRH exhibited a significant inverse correlation with the levels of serum thyroxine and serum triiodothyronine, but were unrelated to the degree of thyroid suppressibility. Relapse or recurrence of thyrotoxicosis occurred in at least 9 of the 23 patients having no evidence of hyperthyroidism at the time of TRH test. Each of them was found to be responsive to TRH, while the T3 suppression test was negative in 8 and had to be discontinued in one because of thyrotoxic symptoms. The present data indicate that during the early period after completion of a prolonged course of antithyroid drug therapy responsiveness to TRH in toxic diffuse goiter is: a) correlated with circulating thyroid hormones, b) unrelated to the degree of thyroid suppressibility by T3 and c) of little value in predicting the long-term results of treatment.

Topics: Adult; Carbimazole; Female; Humans; Hyperthyroidism; Hypothyroidism; Male; Methimazole; Middle Aged; Propylthiouracil; Radioimmunoassay; Thyrotropin; Thyrotropin-Releasing Hormone; Thyroxine; Time Factors; Triiodothyronine

The inactivation of synthetic [3H]thyrotrophin-releasing hormone (TRH) by plasma was studied in rats treated with propylthiouracil (PTU) alone or with PTU and thyroxine. 48 h after the onset of treatment with thyroxine, the capacity of rat plasma to inactivate [3H]TRH was significantly increased. The percentage of deamidation of TRH to TRH-free acid was increased 2-fold after 4 days of administration of thyroid hormone. The inactivation of TRH by plasma from hypothyroid patients was compared to that obtained from hyperthyroid patients. Extraction of human plasma incubated with [3H]TRH, followed by thin-layer electrophoresis, showed that transformation of [3H[TRH into TRH-free acid was 44% higher in plasma from hyperthyroid than from hypothyroid patients (P less than 0-05). These data suggest that the inactivation process of TRH by blood proteins could be an important factor in the regulation of the hypothalamo-hypophyseal-thyroid axis in rat and man.

Topics: Animals; Blood Proteins; Electrophoresis, Cellulose Acetate; Humans; Hyperthyroidism; Hypothyroidism; Male; Propylthiouracil; Rats; Thyrotropin-Releasing Hormone; Thyroxine

In young Rats made hypothyroid from birth, the activity of monoamine oxidase at 20 days is smaller than controls in brain, heart and kidney. In Rats made hyperthyroid by injections of thyroxine, the activity is lower in brain kidney and liver and is 3.8 times higher in the heart.

Topics: Animals; Animals, Newborn; Brain; Female; Hyperthyroidism; Hypothyroidism; Kidney; Liver; Male; Monoamine Oxidase; Myocardium; Pregnancy; Propylthiouracil; Proteins; Rats; Thyroid Hormones; Thyroxine

The influence of thyroid function on the kinetics of glucose-induced insulin secretion from the isolated perfused rat pancreas has been studied. L-Thyroxine (L-T4) administration did not modify the immediate insulin secretory response of the perfused pancreas to glucose. L-Triiodothyronine (L-T3) treatment as well as propylthiouracil (PTU) treatment decreased the immediate insulin secretory response of the pancreas slightly. Only thyroidectomy (Tx) reduced the immediate secretory response of the pancreas significantly. L-T4 and L-T3 treatment inhibited the late phase of glucose-induced insulin secretion from the isolated perfused rat pancreas, whereas TX and PTU treatment resulted in increased insulin secretion. D-Thyroxine (D-T4) did not affect glucose-induced insulin release from the pancreas. Concomitantly, several parameters indicative of thyroid function were determined in these animals. When changes in body weight, rectal temperature, plasma glucose, plasma cholesterol, and plasma butanol-extractable iodine (BEI) in these rats were compared with the insulin secretory responses, it was evident that experimental hyperthyroidism results in decreased insulin release, whereas experimental hypothyroidism induces increased insulin secretion from the pancreas. The transitions from hypothyroid to euthyroid to hyperthyroid states are accompanied by a steady decrease in glucose-induced insulin release from the rat pancreas. Inhibition of glucose-induced insulin secretion from the pancreas is therefore a specific effect of thyroid hormones.

Topics: Animals; Hyperthyroidism; Hypothyroidism; Insulin; Insulin Secretion; Male; Pancreas; Perfusion; Propylthiouracil; Rats; Thyroid Gland; Thyroid Hormones; Thyroidectomy; Thyroxine; Triiodothyronine

Topics: Animals; Female; Growth Hormone; Hypothyroidism; Male; Mammary Neoplasms, Experimental; Mice; Propylthiouracil

The follicular architecture of the thyroid gland of the rat following experimentally induced states of hypo- and hyperactivity was investigated by scanning electron microscopy and the findings correlated with both light and transmission electron-microscopic observations. By scanning electron microscopy, the microvilli on the apical surfaces of the follicular cells showed the most striking changes; following hypophysectomy, the cells were flattened and the microvilli had decreased in both size and number, whereas following propylthiouracil (PTU) administration the epithelial cells were enlarged, and marked hyperplasia and hypertrophy of the microvilli was present. Of particular interest is that the changes observed following PTU appeared to be identical in short- and long-term PTU-treated rats. Similarly, the heterogeneity of the follicular cells observed within the follicles was maintained under the various experimental conditions. Although the functional significance of these observations is not quite clear, it appears justifiable to assume that a reduction of luminal surface area of the follicular epithelial cell may hinder, whereas an increase may facilitate transport process across the apical cell membrane.

Topics: Animals; Cell Membrane; Epithelial Cells; Epithelium; Hyperthyroidism; Hypophysectomy; Hypothyroidism; Male; Microscopy, Electron; Microscopy, Electron, Scanning; Propylthiouracil; Rats; Thyroid Gland; Time Factors

Administration of propylthiouracil (PTU) to pregnant, third trimester sheep led to decreasing serum thyroxine and increasing serum thyroid-stimulating hormone in both mothers and fetuses. Hypothyroidism appeared more pronounced in the fetuses than in the ewes, and goiter formation was observed in all fetuses exposed to PTU. Concomitant administration of triiodothyronine failed to protect the fetuses from the effects of PTU.

Topics: Animals; Disease Models, Animal; Female; Fetal Diseases; Goiter; Hypothyroidism; Organ Size; Pregnancy; Propylthiouracil; Sheep; Thyroid Gland; Thyrotropin; Thyroxine; Triiodothyronine

Pituitary growth hormone (GH) content and plasma GH response to pentobarbital (PB) of severely hypothyroid rats are markedly decreased compared with euthyroid rats. Both pituitary and plasma GH may be increased by single ip injections of physiologic doses of thyroxine (T4) (1.75 mug/100g BW) or triiodothyronine (T3) (0.2 mug/100g BW). Using this increase in GH of hypothyroid rats to measure the biological effectiveness of single doses of both iodothyronines, we have shown that the administration of 6-propyl-2-thiouracil (PTU) interferes with the activity of T4, but not with that of T3. It is known that deiodination of T4 and of T3 and conversion of T4 to T3 are partially inhibited by PTU. Therefore, it appears that deiodination of T4 is biologically important, whereas deiodination of T3 is not. Data presented here are thus consistent with the hypothesis that conversion of T4 to T3 in vivo plays an important role in the expression of T4 activity.

Topics: Animals; Growth Hormone; Hypothyroidism; Male; Pentobarbital; Propylthiouracil; Rats; Thyroidectomy; Thyroxine; Triiodothyronine

The effect of thyroid status on plasma and tissue levels of labeled nonextractable iodine (NEI) derived from the metabolism of radioiodothyronines was examined in the rat. Concentrations of radioiodoprotein were substantially elevated in plasma, kidney, and liver in thyroidectomized animals 72 h postinjection of [125I]triiodothytonine ([125I]T3). Similarly, total rat concentrations of radioactive NEI were increased (52%) 72 h after injection of [125I]T3. NE125I concentrations from [125I]T3 in plasma, kidney, and liver were diminished progressively in thyroidectomized animals maintained on increasing doses of thyroxine replacement, demonstrating that iodoprotein levels were inversely related to thyroid state. The plasma disappearance rate of radioiodoprotein from [125I]T3 was markedly slowed in hypothyroid animals and accelerated in intact controls rendered hyperthyroid with daily injections of T4, 8 mug/100 g BW. Propylthiouracil (PTU) treatment of thyroidectomized rats maintained on T4, 2 mug/100 g BW per day resulted in increased NE125I from [125E]T3 in plasma, kidney, and liver. The results of the foregoing investigations suggest that thyroid hormone regulates levels of iodothyronine-derived iodoproteins by influencing the rate of degradation of iodoproteins. Moreover, the observed elevation of iodoprotein levels in T4-maintained thyroidectomized animals after PTU administration appears consistent with the modification of thyroid status due to the peripheral antithyroxine effect of PTU.

Topics: Animals; Body Weight; Hyperthyroidism; Hypothyroidism; Iodine Radioisotopes; Iodoproteins; Kidney; Liver; Male; Propylthiouracil; Rats; Thyroid Gland; Thyroid Hormones; Thyroidectomy; Thyroxine; Triiodothyronine

The rate of disappearance of antipyrine from the plasma is a useful indicator for the in vivo capacity of mixed function oxidation. The half-life of antipyrine was measured before and after treatment in three hypothyroid and three hyperthyroid children, aged three months to 14 years, in order to examine the effect on drug metabolism of thyroid disorders in children. The half-life of antipyrine decreased in all three hypothyroid subjects and increased in all three hyperthyroid subjects after treatment. The mean half-life decreased from 34.5 h to 8.6 h after treatment of the hypothyroid subjects and increased from 6.1 to 10.1 h after treatment of the hyperthyroid subjects. The mean metabolic clearance rate of antipyrine increased from 11.7 to 25 ml/h in the hyothyroid patients while in the hyperthyroid children there was a decrease from 43 to 25 ml/h. The apparent volume of distribution did not change significantly in the treatment, thus changes in the half-life of antipyrine were most likely attributable to alterations in the metabolic clearance rate of antipyrine.

Topics: Adolescent; Antipyrine; Child; Child, Preschool; Half-Life; Humans; Hyperthyroidism; Hypothyroidism; Infant; Methimazole; Propylthiouracil; Thyroidectomy; Thyrotropin; Thyroxine; Time Factors

Biosynthesis of phosphatidylcholine, phosphatidylethanolamine, and sphingomyelin was studied in liver endoplasmic reticulum obtained from newly hatched chicks which were made hypothyroid by feeding 0.2% propylthiouracil. In vitro measurements were made of the specific activities of phosphorylcholine-glyceride (cholinephosphotransferase (EC 2.7.8.2), hosphorylethanolamine-glyceride (ethanolamine-phosphotransferase (EC 2.7.8.1)), and phosphorylcholine-ceramide (ceramide cholinephosphotransferase (EC 2.7.8.3)) transferases in control and hypothyroid chick liver for a period of 40 days. The specific activity of all three transferases began to decline after the chicks were on the propylthiouracil-containing diet for 5 days and steadily declined, reaching levels 10-15% of the controls after 15 days. These low levels were maintained for as long as the chicks were on this diet. Administration of L-thyroxine (15 mug/100 g of body weight) to the hypothyroid chicks caused a marked increase in the specific activities of all three transferases, reaching levels similar to those seen in the control chicks in 36-48 h. The specific activities then declined as the chicks were maintained on the diet of propylthiouracil, reaching the former low levels after 120 h. Administration of cycloheximide alone to the hypothyroid chicks caused a rise in the specific activities of the transferases after 24 h approximately equal to that caused by thyroxine alone, while thyroxine and cycloheximide together were no different than either alone. These studies indicate that in some manner circulating thyroxine controls the activities of enzymes involved in the biosynthesis of phosphatidylcholine, phosphatidylethanolamine, and sphingomyelin in chick liver endoplasmic reticulum. There was no evidence that induction of hypothyroidism by propylthiouracil had any effect on the activities of these enzymes in the CNS.

Topics: Animals; Body Weight; Chickens; Hypothyroidism; Lipids; Liver Glycogen; Microsomes, Liver; Organ Size; Phosphatidylcholines; Phosphatidylethanolamines; Phosphotransferases; Propylthiouracil; Sphingomyelins; Thyroxine

From 1959 to 1970, 272 operations for thyrotoxicosis were performed. Most of the patients received anti-thyroid drugs and thyroid hormones preoperatively. The patients were continuously followed up. The primary results with low morbidity and no mortality as well as the long term results with a low rate of recurrence and a relatively high incidence of thyroid substitution are discussed. A safe and effective programme for surgical treatment of thyrotoxicosis is described. Anti-thyroid drugs and thyroid hormones should be administered as the method of choice in preparing these patients for surgery.

Topics: Adolescent; Adult; Aged; Antithyroid Agents; Carbimazole; Child; Female; Goiter; Humans; Hyperthyroidism; Hypocalcemia; Hypothyroidism; Laryngoscopy; Length of Stay; Male; Methimazole; Middle Aged; Paralysis; Postoperative Complications; Preoperative Care; Propylthiouracil; Recurrent Laryngeal Nerve; Thyroxine; Triiodothyronine

The effect of chronic treatment with tyroxine (T4) or propylthiouracile (PTU) on the turnover of norepinephrine (NE), dopamine (DA) and 5-hydroxytryptamine (5-HT) has been studied in various areas of the rat brain (brain stem, hypothalamus, striatum and "rest of the brain"). The turnover of NE and DA was determined by the decay in endogenous levels after inhibition of tyrosine hydroxylase by alpha-methylparatyrosine and the turnover of 5-HT was evaluated by the initial accumulation of endogenous 5-HT after inhibition of monoamine oxydase by pargyline. T4 treatment accelerated the release of DA from the striatum but had no significant effects on NA release in the various cerebral areas : nevertheless the NE endogenous level was significantly reduced in the brain stem. PTU treatment delayed the release of DA and NA only from the "rest of the brain". Concerning 5-HT, the only significant variation was observed in the hypothalamus of PTU-treated rats and implied increased turnover. The possible relations between the changes in cerebral monoamines turnover and the behavioural alterations which are observed in thyroid disfunction are discussed.

Topics: Animals; Brain; Brain Stem; Corpus Striatum; Dopamine; Hyperthyroidism; Hypothalamus; Hypothyroidism; Male; Methyltyrosines; Norepinephrine; Propylthiouracil; Rats; Serotonin; Thyroxine; Tyrosine 3-Monooxygenase

1. It was shown that the development of liver glucokinase in the rat coincided with a peak in the levels of circulating thyroid hormone at about the 16th postnatal day. 2. Administration of thyroid inhibitors blocked the development of the enzyme and administration of thyroid hormone restored activity to normal levels. 3. Glucokinase could be induced prematurely as early as the 2nd postnatal day by the administration of thyroid hormone followed by daily injection of glucose (10 mg/g body weight). 4. Glucocorticoids and corticotropin failed to induce glucokinase activity prematurely. 5. The postnatal increase in circulating thyroid hormone levels together with increased intake of carbohydrate at weaning may be the normal physiological stimulus for induction of this enzyme.

Topics: Adrenocorticotropic Hormone; Animals; Animals, Newborn; Enzyme Induction; Glucocorticoids; Glucokinase; Glucose; Hypothyroidism; Liver; Propylthiouracil; Rats; Thyroid Gland; Thyroxine; Triiodothyronine

Evidence is presented that modulation of the maximum velocity of a particulate low K-m cyclic adenosine 3':5'-monophosphate (cyclic AMP) phosphodiesterase by thyroid hormones is one mechanism for the regulation of the responsiveness of rat epididymal adipocytes to lipolytic agents such as epinephrine and glucagon. Fat cells of propylthiouracil-induced hypothyroid rats are unresponsive to lipolytic agents and the V-max of particulate low K-m cyclic AMP phosphodiesterase of these cells is elevated above normal. In vivo treatment of hypothyroid rats with triiodothyronine restores to control values both the lipolytic response of the fat cells to epinephrine and the V-max of the particulate bound low K-m cyclic AMP phosphodiesterase. No similar correlation is found with the soluble high K-m cyclic AMP phosphodiesterase. The phosphodiesterases of fat cells from normal and hypothyroid rats respond identically in vitro to propylthiouracil, triiodothyronine, methylisobutylxanthine, or theophylline, although the particulate low K-m cyclic AMP phosphodiesterase is inhibited to a greater extent than soluble cyclic guanosine 3':5'-monophosphate phosphodiesterase activity. Protein kinase of fat cells from hypothyroid rats can be stimulated by cyclic AMP to the same total activity as observed in fat cells of normal rats. However, less of the protein kinase in fat cells from hypothyroid rats was in the cyclic AMP-independent form. This shift in the equilibrium of protein kinase forms is consistent with an increased activity of low K-m cyclic AMP phosphodiesterase and probably results from a lowering of the lipolytically significant pool of cyclic AMP.

Topics: Adipose Tissue; Animals; Bucladesine; Cyclic AMP; Cyclic GMP; Epinephrine; Glycerol; Hypothyroidism; Kinetics; Lipid Mobilization; Male; Phosphoric Diester Hydrolases; Propylthiouracil; Protein Kinases; Rats; Theophylline; Thyroid Gland; Thyroid Hormones; Time Factors; Triiodothyronine; Xanthines

Topics: Animals; Animals, Newborn; Cerebellar Cortex; Female; Hypothyroidism; Maternal-Fetal Exchange; Pregnancy; Propylthiouracil; Rats; Synapses

In normal, nonmedicated volunteers and in patients with thyroid disorders the plasma half-lives of antipyrine, propylthiouracil, and methimazole were determined after single oral doses. The plasma half-liver plus or minus S.D. of antipyrine, propylthiouracil, and methimazole were 11.9 plus or minus 1.4 hr, 6.7 plus or minus 1.0 hr, and 9.3 plus or minus 1.4 hr, respectively, in normal volunteers, but were shortened to 7.7 plus or minus 1.2 hr, 4.3 plus or minus 0.7 hr, and 6.9 plus or minus 0.6 hr, respectively, in hyperthyroid patients. In hypothyroid patients the plasma half-lives of these drugs were prolonged to 26.4 plus or minus 4.0 hr, 24.7 plus or minus 34.5 hr, and 13.6 plus or minus 4.8 hr, respectively. Return to the euthyroid state restored plasma half-lives to or toward normal. Alterations in plasma drug half-lives during thyroid dysfunction appear to result mainly from accelerated hepatic microsomal drug metabolism in hyperthyroidism and retarded drug biotransformation during hypothyroidism.

Topics: Adult; Aged; Antipyrine; Biotransformation; Female; Half-Life; Humans; Hyperthyroidism; Hypothyroidism; Kinetics; Male; Methimazole; Middle Aged; Propylthiouracil; Spectrophotometry; Thyroid Diseases; Thyroid Function Tests

The influence of thyroid hormone on serotonin was studied in different regions of the rat brain. Surgical thyroidectomy of adult male rats led to significant increases in the level of serotonin in the hypothalamus but had no effect on this biogenic amine in the brain stem and basal ganglia. Experimental cretinism, induced by daily propylthiouracil treatment starting at birth, caused increased serotonin levels in all brain regions studied. In contrast. neonatal hyperthyroidism, produced by daily administration of L-triiodothyronine from birth, had no effect on the ontogenic patterns of serotonin. The turnover of serotonin, estimated by determining the rate of increase of the amine following administration of the monoamine oxidase inhibitor, pargyline, was decreased in the brains of 30-day-old cretinous rats when compared to their control littermates. The data suggest that thyroid hormone may exert an important regulatory influence on serotonin metabolism in the developing brain.

Topics: Animals; Animals, Newborn; Basal Ganglia; Brain; Brain Stem; Congenital Hypothyroidism; Hyperthyroidism; Hypothalamus; Hypothyroidism; Male; Pargyline; Propylthiouracil; Rats; Serotonin; Thyroid Gland; Thyroid Hormones; Thyroidectomy; Time Factors; Triiodothyronine

1. Oxygen consumption of jejunum removed from either killed or anaesthetized euthytoid, hypothyroid and triiodothyronine (T3)-treated rats was measured polarographically in vitro. 2. Hypothyroidism induced by drinking 6-n-propyl-2-thiouracil depressed jejunal oxygen consumption. 3. Treatment of euthyroid rats with T3 stimulated jejunal oxygen consumption by 39% in the presence of 28 mM glucose and by 23% in its absence. 4. Sodium ions appear to play a major permissive role in the action of T3 on jejunal oxygen uptake. In the presence of sodium, T3 stimulated significantly the oxygen consumption by 23% while in the absence of sodium the stimulation was only 10% which was not significant. The sodium-sensitive oxygen uptake of the jejunum was expanded by 57% after T3 treatment.

Topics: Anesthesia, General; Animals; Glucose; Hypothyroidism; In Vitro Techniques; Intestine, Small; Jejunum; Male; Membrane Potentials; Oxygen; Oxygen Consumption; Partial Pressure; Propylthiouracil; Rats; Sodium; Stimulation, Chemical; Thyroid Gland; Thyroidectomy; Triiodothyronine

Topics: Acid Phosphatase; Alkaline Phosphatase; Animals; Brain; Glucosephosphate Dehydrogenase; Glucuronidase; Hypothyroidism; Lysosomes; Male; Microsomes; Mitochondria; Propylthiouracil; Rats; Synaptosomes; Thyroid Gland; Thyroidectomy; Thyroxine

Topics: Humans; Hyperthyroidism; Hypothyroidism; Iodine Radioisotopes; Methimazole; Propylthiouracil

To determine if propylthiouracil (PTU) inhibited extrathyroidal thyroxine (T4) to triiodothyronine (T3) conversion in man, PTU was administered to T4-treated hypothyroid patients and serial measurements of T4, T3, and thyrotropin (TSH) carried out. All patients had proven thyroidal hypothyroidism and had been receiving 0.1 or 0.2 mg T4 daily for at least 2 mo before study. Hormone measurements were made for 5 consecutive days before and daily during a 7-day treatment period with PTU, 1,000 mg/day. In eight patients receiving 0.1 mg T4 daily, administration of PTU resulted in a prompt fall in mean serum T3 concentrations from 78 plus or minus 6 ng/100 ml (SEM) to 61 plus or minus 3 ng/100 ml after 1 day. The mean serum T3 concentrations ranged from 55 to 60 ng/100 ml during the remainder of the PTU treatment period (P less than 0.01). The mean control serum TSH concentration was 29.6 muU/ml and it increased to a peak of 40 muU/ml on the 5th and 6th days. In five patients receiving 0.2 mg T4 daily, the mean control serum T3 concentration was 84 plus or minus 7 NG/100ML. It fell to 70 plus or minus 5 ng/100 ml after 1 day and 63 plus or minus 7 ng/100 ml after 2 days of PTU administration and thereafter ranged from 6) to 69 ng/100 ml (P LESS THAN 0.01). Serum TSH concentrations did not increase. No changes in serum T4 concentrations were found in either group. In five patients who received 100 mg methimazole (MMI) daily for 7 days there were no changes in serum T4, T3, or TSH concentrations. These results indicate that PTU, but not MMI, produces a prompt and sustained, albeit modest, reduction in serum T3 concentrations in patients whose sole or major source of T3 is ingested T4. These findings most likely result from inhibition of extrathyroidal formation of T3 from T4.

Topics: Administration, Oral; Adult; Aged; Depression, Chemical; Female; Humans; Hypothyroidism; Male; Methimazole; Middle Aged; Propylthiouracil; Thyroid Neoplasms; Thyroidectomy; Thyroiditis, Autoimmune; Thyrotropin; Thyroxine; Triiodothyronine

The isoenzymes of lacticdehydrogenase of cerebral cortex, investigated by starch gel electrophoresis, are changed during pre and neonatal thyroidectomies in relation to these factors: a) dose of the drug (131I or Propylthiouracil), b) date of gestation, c) the age of the animal (with a maximal modification at the 17th-18th day). They retain an enzymatic pattern like the fetal pattern, showing the retardation of the developing central nervous system.

Topics: Age Factors; Animals; Animals, Newborn; Cerebral Cortex; Electrophoresis, Starch Gel; Female; Hypothyroidism; Iodine Radioisotopes; Isoenzymes; L-Lactate Dehydrogenase; Male; Propylthiouracil; Rats; Thyroid Gland; Thyroidectomy

The heparin-releasable LP lipase activity of BAT (brown adipose tissue), and the TG (triglyceride) content of plasma were determined in normal and hypothyroid rats during early post-natal development. The TG content of plasma increased sharply after the onset of suckling and decreased during the weaning period in normal rats, while it stayed at a high level in hypothyroid rats. LP lipase activity was maximal during the perinatal period and decreased later, being practically undetectable in one month old control animals; in contrast, LP lipase activity was still present in cretin rats at this age. The effects of several forms of treatment were also tested in weaned rats: a high-fat diet was not able to maintain the high LP lipase activity of suckling rats, but the activity was high if the animals were bred at a cold temperature. Thyroxine injections had no effect. These results are discussed in terms of the possible factors regulating the LP lipase activity in BAT.

Topics: Adipose Tissue, Brown; Animals; Animals, Newborn; Cold Temperature; Dietary Fats; Female; Heparin; Hypothyroidism; Lactation; Lipoprotein Lipase; Pregnancy; Propylthiouracil; Rats; Thyroxine; Triglycerides

Topics: Adult; Asthma; Female; Graves Disease; Humans; Hypothyroidism; Infant; Male; Potassium Iodide; Propylthiouracil; Thyroxine

Topics: Animals; Biological Assay; Body Weight; Depression, Chemical; Female; Growth Hormone; Hypothyroidism; Iodine Radioisotopes; Male; Microscopy, Electron; Pituitary Gland; Propylthiouracil; Radioimmunoassay; Rats; Sex Factors; Thyroid Function Tests; Thyroidectomy; Thyrotropin; Thyroxine

Topics: Antithyroid Agents; Congenital Hypothyroidism; Female; Goiter; Humans; Hyperthyroidism; Hypothyroidism; Infant; Infant, Newborn; Infant, Newborn, Diseases; Infant, Premature, Diseases; Iodine Radioisotopes; Long-Acting Thyroid Stimulator; Male; Maternal-Fetal Exchange; Methimazole; Pregnancy; Pregnancy Complications; Propylthiouracil; Thyroid Function Tests; Thyroid Hormones; Thyrotropin; Thyroxine; Twins

Topics: Animals; Collagen; Hydroxyproline; Hypophysectomy; Hypothyroidism; Larva; Metamorphosis, Biological; Methimazole; Pituitary Gland; Propylthiouracil; Rana pipiens; Tail; Time Factors

Topics: Adipose Tissue; Animals; Bucladesine; Dietary Fats; Epinephrine; Fatty Acids; Hypothyroidism; Lipid Mobilization; Male; Phosphatidylcholines; Phosphatidylethanolamines; Phosphatidylinositols; Phospholipids; Propylthiouracil; Spectrometry, Fluorescence; Thyroxine

Topics: Animals; Female; Hypothyroidism; Luteinizing Hormone; Perchlorates; Pituitary Gland; Propylthiouracil; Rats; Sodium

Topics: Adenylyl Cyclases; Adipose Tissue; Animals; Bucladesine; Cell Membrane; Centrifugation, Density Gradient; Cyclic AMP; Epinephrine; Glucagon; Hypothyroidism; Lipid Metabolism; Lipid Mobilization; Male; Phosphoric Diester Hydrolases; Propylthiouracil; Rats; Theophylline; Triiodothyronine; Tritium

Topics: Adolescent; Adult; Aged; Blood Proteins; Calcium; Carbimazole; Cholesterol; Female; Goiter; Humans; Hypothyroidism; Iodine Radioisotopes; Male; Middle Aged; Perchlorates; Phosphorus; Propylthiouracil; Recurrence; Serum Albumin; Thyroid Gland; Thyroidectomy; Thyrotropin; Thyroxine

Topics: Adenylyl Cyclases; Animals; Body Weight; Carbon Radioisotopes; Cyclic AMP; Depression, Chemical; Diet; Dinitrophenols; Electrophoresis; Growth Hormone; Hypothalamus; Hypothyroidism; In Vitro Techniques; Male; Pituitary Gland; Prolactin; Propylthiouracil; Rats; Stimulation, Chemical; Thyroxine; Triiodothyronine

Topics: Administration, Oral; Age Factors; Animals; Animals, Newborn; Body Weight; Carbon Radioisotopes; Electrophoresis, Polyacrylamide Gel; Estrus; Female; Gonads; Growth Hormone; Hypothyroidism; Injections, Subcutaneous; Labor, Obstetric; Lactation; Leucine; Organ Size; Pituitary Gland; Pregnancy; Prolactin; Propylthiouracil; Rats; Thyroxine; Vagina; Vaginal Smears

Topics: Aging; Animals; Bone Development; Calcification, Physiologic; Cartilage, Articular; Disease Models, Animal; Female; Growth Hormone; Hypothyroidism; Intervertebral Disc; Iodine Radioisotopes; Lumbar Vertebrae; Male; Mice; Mice, Inbred C57BL; Mice, Inbred DBA; Osteosclerosis; Pituitary Diseases; Prolactin; Propylthiouracil; Spinal Osteophytosis

Topics: Animals; Cerebellum; Cerebral Ventricles; Evoked Potentials; Hypothyroidism; Medulla Oblongata; Neural Conduction; Neural Inhibition; Neural Pathways; Olivary Nucleus; Pons; Propylthiouracil; Purkinje Cells; Rats; Rats, Inbred Strains; Reaction Time; Spinal Cord

Topics: Aging; Animals; Animals, Newborn; Cerebellum; Fasting; Hyperthyroidism; Hypothyroidism; Leucine; Nerve Tissue Proteins; Propylthiouracil; Rats; Thyroxine; Time Factors; Tritium

Topics: Administration, Oral; Animals; Blood; Female; Hypothyroidism; Injections, Subcutaneous; Iodine Radioisotopes; Malaria; Male; Mice; Mice, Inbred C3H; Plasmodium berghei; Propylthiouracil; Thyroxine

Topics: Female; Fetus; Humans; Hyperthyroidism; Hypothyroidism; Intelligence Tests; Iodine; Maternal-Fetal Exchange; Methimazole; Patient Care Team; Pregnancy; Pregnancy Complications; Propylthiouracil; Thyroid Gland; Thyrotropin; Thyroxine; Triiodothyronine

Topics: Animals; Biological Transport; Carbon Radioisotopes; Cholesterol; Chromatography, Thin Layer; Feces; Hyperthyroidism; Hypothyroidism; Liver; Male; Microsomes, Liver; Mixed Function Oxygenases; Propylthiouracil; Rats; Thyroid Gland; Thyroxine; Time Factors; Triglycerides

Topics: Age Factors; Animals; Animals, Newborn; Bone Development; Cerebellum; Cholinesterases; Electrophysiology; Hindlimb; Hypothyroidism; Morphogenesis; Propylthiouracil; Purkinje Cells; Rats; Thyroid Gland; Thyroxine

Topics: Age Factors; Animals; Animals, Newborn; Cerebellar Cortex; Cerebellum; Hyperthyroidism; Hypothyroidism; Propylthiouracil; Purkinje Cells; Rats; Rats, Inbred Strains; Thyroxine

Topics: Adolescent; Adult; Aged; Antithyroid Agents; Carbimazole; Female; Graves Disease; Humans; Hyperthyroidism; Hypothyroidism; Iodine Isotopes; Long-Term Care; Male; Middle Aged; Prognosis; Propylthiouracil; Radiotherapy Dosage; Thyroid Function Tests; Triiodothyronine

Topics: Animals; Deafness; Female; Humans; Hypothyroidism; Maternal-Fetal Exchange; Mice; Mice, Inbred C57BL; Organ of Corti; Pregnancy; Propylthiouracil

Topics: Animals; Female; Growth Hormone; Hydrocortisone; Hypothyroidism; Iodine Isotopes; Male; Neoplasms, Experimental; Pituitary Gland; Pituitary Neoplasms; Prolactin; Propylthiouracil; Radioimmunoassay; Rats; Thyroxine; Time Factors

Topics: Adolescent; Female; Goiter; Hemorrhage; Humans; Hyperthyroidism; Hypoparathyroidism; Hypothyroidism; Iodine; Methylthiouracil; Postoperative Care; Postoperative Complications; Potassium Iodide; Preoperative Care; Propylthiouracil; Thyroid Diseases; Thyroidectomy; Thyroiditis; Time Factors; Vocal Cord Paralysis

Topics: Animals; Electrophysiology; Hypothyroidism; Jejunum; Propylthiouracil; Rats; Thyroidectomy; Thyroxine; Triiodothyronine

Topics: Female; Graves Disease; Humans; Hyperthyroidism; Hypothyroidism; Methimazole; Pregnancy; Pregnancy Complications; Propylthiouracil; Thyroid Function Tests; Thyroid Gland; Thyroid Hormones

Topics: Animals; Animals, Newborn; Body Weight; Cell Division; Cerebellum; DNA; Fetus; Hyperthyroidism; Hypothyroidism; Nerve Tissue Proteins; Nutrition Disorders; Organ Size; Propylthiouracil; Rats; RNA; Spectrophotometry, Ultraviolet; Thyroxine

Topics: Animals; Animals, Newborn; Cell Differentiation; Cerebellum; Disease Models, Animal; Hypothyroidism; Microscopy, Electron; Neuroglia; Nutrition Disorders; Propylthiouracil; Rats

Topics: Animals; Animals, Newborn; Cell Differentiation; Cerebellum; Dendrites; Disease Models, Animal; Fetus; Hypothyroidism; Microscopy, Electron; Neuroglia; Propylthiouracil; Purkinje Cells; Rats

Topics: Animals; Animals, Newborn; Cerebellum; Disease Models, Animal; Hypothyroidism; Neuroglia; Propylthiouracil; Rats

Topics: Age Factors; Animals; Centrifugation, Density Gradient; Cerebellum; Hyperthyroidism; Hypothyroidism; Microscopy, Electron; Nerve Tissue Proteins; Nutrition Disorders; Propylthiouracil; Rats; Synaptosomes; Thyroxine

Topics: Abnormalities, Drug-Induced; Age Factors; Animals; Cochlea; Deafness; Disease Models, Animal; Female; Gestational Age; Goiter; Hypothyroidism; Iodine; Male; Mice; Mice, Inbred C57BL; Organ of Corti; Pregnancy; Propylthiouracil; Thyroxine

Topics: Adrenal Glands; Animals; Body Weight; Estrus; Female; Follicle Stimulating Hormone; Hypothyroidism; Luteinizing Hormone; Male; Organ Size; Ovary; Pituitary Gland; Pregnancy; Propylthiouracil; Prostate; Radioimmunoassay; Rats; Seminal Vesicles; Testis; Thyroid Gland; Thyroxine; Uterus

Topics: Albumins; Animals; Antibody Specificity; Binding Sites; Globulins; Humans; Hyperthyroidism; Hypothyroidism; Immune Sera; Iodine Isotopes; Methimazole; Methods; Propylthiouracil; Rabbits; Radioimmunoassay; Thyroid Function Tests; Thyroxine; Thyroxine-Binding Proteins

Topics: Adolescent; Adult; Aged; Antithyroid Agents; Child; Female; Humans; Hyperthyroidism; Hypothyroidism; Iodine; Male; Middle Aged; Organ Size; Postoperative Complications; Preoperative Care; Propylthiouracil; Thyroid Gland; Thyroidectomy; Voice

Topics: Adult; Female; Graves Disease; Humans; Hypothyroidism; Iodine Radioisotopes; Long-Acting Thyroid Stimulator; Propylthiouracil; Thyroid Function Tests; Thyroid Gland; Thyroid Hormones; Thyrotropin; Thyroxine; Time Factors; Triiodothyronine

Topics: Adenosine Triphosphatases; Adrenal Cortex Hormones; Adrenal Insufficiency; Adrenalectomy; Ammonia; Animals; Calcium; Chromatography, Ion Exchange; Growth Hormone; Heart; Hyperthyroidism; Hypophysectomy; Hypothyroidism; Magnesium; Male; Muscle Proteins; Myocardium; Myosins; Pituitary Hormones; Potassium; Propylthiouracil; Rats; Sodium; Sulfhydryl Compounds; Thyroid Hormones; Thyroxine

Topics: Animals; Animals, Newborn; Brain; Cyclic AMP; Female; Galactose; Hexosyltransferases; Hypothyroidism; Myelin Sheath; Phosphoric Monoester Hydrolases; Pregnancy; Propylthiouracil; Rats; Sphingosine; Spinal Cord; Thyroid Hormones; Thyroxine; Time Factors; Triiodothyronine; Uridine Diphosphate Sugars

Topics: Age Factors; Animals; Cell Fractionation; Cerebellar Cortex; Hyperthyroidism; Hypothyroidism; Membranes; Nerve Endings; Nerve Tissue Proteins; Propylthiouracil; Rats; Synapses; Synaptic Vesicles; Synaptosomes; Thyroid Hormones; Thyroxine

Topics: Animals; Chagas Disease; Female; Hypothyroidism; Male; Mice; Mice, Inbred Strains; Propylthiouracil; Trypanosoma cruzi

Topics: Animals; Gonadotropins, Pituitary; Growth Hormone; Hypothyroidism; Male; Microscopy, Electron; Mitosis; Pituitary Gland; Prolactin; Propylthiouracil; Rats; Thyrotropin; Thyroxine; Time Factors

Topics: Age Factors; Animals; Cerebellar Cortex; Hypothyroidism; Methods; Propylthiouracil; Rats; Synapses

Topics: Animals; Animals, Newborn; Cerebellum; Cholinesterases; Hypothyroidism; Propylthiouracil; Purkinje Cells; Rats; Thyroxine

Topics: Animals; Auditory Cortex; Cell Nucleus; Chick Embryo; Cochlea; Cochlear Nerve; Cytoplasm; Ear; Ear Diseases; Ear, Inner; Ear, Middle; Goiter; Hypothyroidism; Propylthiouracil; Thyroid Gland; Thyroxine

Topics: Amino Acids; Animals; Animals, Newborn; Brain; Cerebellum; Cerebral Cortex; Diencephalon; Hyperthyroidism; Hypothyroidism; Leucine; Liver; Microsomes; Mitochondria; Nerve Tissue Proteins; Propylthiouracil; Rats; Subcellular Fractions; Synaptic Vesicles; Thyroidectomy; Thyroxine; Tritium

Topics: Alanine Transaminase; Animals; Body Weight; Chickens; Cholesterol; Comb and Wattles; Hypothyroidism; Iodine Isotopes; Liver; Liver Glycogen; Male; Organ Size; Propylthiouracil; Radiation Effects; Testosterone; Thyroid Gland

Topics: Acclimatization; Altitude; Animals; Erythropoiesis; Female; Heart; Heart Ventricles; Hematocrit; Hypothyroidism; Hypoxia; Myocardium; Organ Size; Polycythemia; Propylthiouracil; Rats; Thyroid Gland; Thyroxine

The number of synapses in the molecular layer of the rat cerebellum is reduced by early hypo-and hyperthyroidism within 30 days. Hypothyroidism retards synaptogenesis after 10 days, while hyperthyroidism accelerates synaptogenesis initially, but by 21 days the number of synapses is reduced. The sensitivity of developing synapses to thyroid hormone may permit analysis of the events triggering synaptogenesis.

Topics: Age Factors; Animals; Animals, Newborn; Cerebellum; Female; Hyperthyroidism; Hypothyroidism; Male; Propylthiouracil; Rats; Synapses; Thyroid Hormones; Thyroxine

Topics: Acetaldehyde; Acetates; Animals; Caproates; Carbon Dioxide; Carbon Isotopes; Citric Acid Cycle; Ethanol; Hyperthyroidism; Hypothyroidism; In Vitro Techniques; Lactates; Liver; Male; Oxidoreductases; Perfusion; Propylthiouracil; Pyrazoles; Pyruvates; Rats; Triiodothyronine

Topics: Acetylcholine; Acyltransferases; Animals; Brain; Carbon Isotopes; Choline; Female; Hypothyroidism; Propylthiouracil; Rats

Topics: Adipose Tissue; Animals; Carboxy-Lyases; Coenzyme A; Glycerol; Hyperthyroidism; Hypothyroidism; Lipid Metabolism; Lipids; Methods; Oxidoreductases; Propylthiouracil; Pyruvate Kinase; Pyruvates; Rats; Triglycerides; Triiodothyronine

Topics: Adult; Aged; Alopecia; Female; Hair; Humans; Hypothyroidism; Iodine Isotopes; Male; Middle Aged; Propylthiouracil; Thyroid Hormones

Topics: Animals; Benz(a)Anthracenes; Benzimidazoles; Female; Hypothyroidism; Mammary Neoplasms, Experimental; Methimazole; Propylthiouracil; Rats; Sulfhydryl Compounds; Thyroid Gland

Topics: Analysis of Variance; Animals; Animals, Newborn; Autoradiography; Body Weight; Cell Differentiation; Cerebellar Cortex; Hyperthyroidism; Hypothyroidism; Organ Size; Propylthiouracil; Rats; Sodium Chloride; Thymidine; Thyroid Hormones; Thyroxine; Tritium

Topics: Animals; Animals, Newborn; Cell Differentiation; Cerebellar Cortex; Dendrites; Hyperthyroidism; Hypothyroidism; Microscopy, Electron; Phosphotungstic Acid; Propylthiouracil; Purkinje Cells; Rats; Sodium Chloride; Synapses; Thyroid Hormones; Thyroxine

Topics: Apgar Score; Bone Diseases, Developmental; Cesarean Section; Electroencephalography; Female; Fetus; Goiter; Graves Disease; Humans; Hypothyroidism; Infant, Newborn; Iodides; Labor Presentation; Male; Maternal-Fetal Exchange; Potassium Iodide; Pregnancy; Pregnancy Complications; Propylthiouracil; Thyroid Function Tests; Thyroid Hormones; Tracheal Stenosis; Triiodothyronine

Topics: Animals; Drug Interactions; Fatty Acids, Nonesterified; Hypothyroidism; Injections, Intramuscular; Injections, Intraperitoneal; Iodine Isotopes; Lipoprotein Lipase; Male; Myocardium; Norepinephrine; Oxygen Consumption; Propylthiouracil; Rats; Reserpine; Time Factors; Triiodothyronine

Topics: Animals; Castration; Female; Hypertrophy; Hypothyroidism; Organ Size; Ovary; Pituitary Gland; Propylthiouracil; Rats; Thyroidectomy

Topics: Adaptation, Physiological; Animals; Body Weight; Cold Temperature; Hot Temperature; Hypothalamo-Hypophyseal System; Hypothyroidism; Iodine Isotopes; Male; Organ Size; Pituitary Gland; Propylthiouracil; Rats; Secretory Rate; Thyroid Function Tests; Thyroid Gland; Thyrotropin

Topics: Adrenergic beta-Antagonists; Antithyroid Agents; Carbimazole; Chemical Phenomena; Chemistry; Humans; Hyperthyroidism; Hypothyroidism; Imidazoles; Iodine Isotopes; Methimazole; Methylthiouracil; Myocardial Infarction; Perchlorates; Potassium; Potassium Iodide; Propranolol; Propylthiouracil; Psychotic Disorders; Thiourea; Thyroxine; Time Factors

Topics: Adult; Amniocentesis; Amniotic Fluid; Female; Fetal Diseases; Graves Disease; Humans; Hypothyroidism; Pregnancy; Propylthiouracil; Thyroid Function Tests; Thyroxine; Triiodothyronine

Topics: Animals; Blood Glucose; Depression, Chemical; Dietary Fats; Female; Gluconeogenesis; Glucose-6-Phosphatase; Growth; Hypothyroidism; Kidney; Liver; Propylthiouracil; Rats; Stimulation, Chemical; Thyroid Gland; Thyroxine

Topics: Animals; Castration; Female; Fluorescent Antibody Technique; Hypothyroidism; Luteinizing Hormone; Pituitary Gland; Propylthiouracil; Rats; Thyroidectomy; Thyrotropin; Thyroxine

Topics: Animals; Calcitonin; Cell Count; Hypophysectomy; Hypothyroidism; Microscopy, Electron; Propylthiouracil; Rats; Thyroid Gland

Topics: Acetaldehyde; Alcohol Drinking; Animals; Ethanol; Hyperthyroidism; Hypothyroidism; Male; Oxygen Consumption; Propylthiouracil; Rats; Triiodothyronine

Topics: Child, Preschool; Female; Humans; Hyperthyroidism; Hypothyroidism; Menstruation; Propylthiouracil; Puberty, Precocious

Topics: Adenosine Triphosphate; Animals; Coenzyme A; Ethanol; Fructose; Hyperthyroidism; Hypothyroidism; Ketone Bodies; Lactates; Liver; Male; Oxidation-Reduction; Propylthiouracil; Pyruvates; Rats; Triiodothyronine

Topics: Animals; Autoradiography; Cytoplasmic Granules; DNA; Hypothyroidism; Male; Mitosis; Periodic Acid; Pituitary Gland; Propylthiouracil; Rats; Staining and Labeling; Thymidine; Thyroidectomy; Thyrotropin; Tritium

Topics: Animals; Antithyroid Agents; Blood Proteins; Body Weight; Goiter; Hypothyroidism; Insulin; Iodine; Male; Methimazole; Organ Size; Perchlorates; Propylthiouracil; Protein Binding; Rats; Rhenium; Thiocyanates; Thyroid Gland; Thyroidectomy; Thyrotropin; Thyroxine

Topics: Animals; Bone and Bones; Bone Resorption; Calcium; Cell Count; Female; Femur; Fetus; Hypercalcemia; Hypothyroidism; Osteoclasts; Parathyroid Glands; Parathyroid Hormone; Pregnancy; Propylthiouracil; Rats

Topics: Age Factors; Animals; Cerebellum; Female; Hypothyroidism; Leucine; Propylthiouracil; Protein Biosynthesis; Rats; Time Factors; Tritium

Topics: Acetoacetates; Animals; Citric Acid Cycle; Coenzyme A; Depression, Chemical; Ethanol; Fasting; Hydroxybutyrates; Hyperthyroidism; Hypothyroidism; Ketone Bodies; Liver; Male; Metabolism; Mitochondria, Liver; NAD; Oxidation-Reduction; Oxygen Consumption; Propylthiouracil; Rats; Sorbitol; Stimulation, Chemical; Thyroid Diseases; Time Factors; Triiodothyronine

Topics: Age Factors; Animals; Cerebellum; Dendrites; Hypothyroidism; Propylthiouracil; Purkinje Cells; Rats; Thyroxine

Topics: Animals; Anthracenes; Breast; Breast Diseases; Breast Neoplasms; Deficiency Diseases; Demography; Estrogens; Female; Hypothyroidism; Iodine; Male; Propylthiouracil; Rats

Topics: Animals; Animals, Newborn; Cerebellum; Hypothyroidism; Leucine; Nerve Tissue Proteins; Propylthiouracil; Rats; Tritium

Topics: Animals; Body Weight; Chickens; Hyperthyroidism; Hypothyroidism; Male; Organ Size; Phosphates; Phosphorus Isotopes; Pituitary Gland; Propylthiouracil; Secretory Rate; Stimulation, Chemical; Testis; Thyrotropin; Thyroxine

Topics: Animals; Animals, Newborn; Biological Assay; Body Weight; Female; Gonads; Hypothyroidism; Male; Organ Size; Pituitary Function Tests; Pituitary Gland; Pregnancy; Propylthiouracil; Rats; Thyroid Function Tests; Thyrotropin

Topics: Animals; Ear, Middle; Hyperthyroidism; Hypothyroidism; Mucous Membrane; Propylthiouracil; Rats

Topics: Age Factors; Aminopyrine; Aniline Compounds; Animals; Benzoates; Benzopyrenes; Biotransformation; Cytochromes; Deficiency Diseases; Hexobarbital; Hypothyroidism; Iodides; Iron; Mice; Microsomes, Liver; Nitrophenols; Propylthiouracil; Riboflavin; Riboflavin Deficiency; Sleep; Time Factors

Topics: Amines; Animals; Brain; Brain Chemistry; Hypothyroidism; Male; Monoamine Oxidase; Norepinephrine; Propylthiouracil; Rats; Serotonin

Topics: Animals; Female; Hyperthyroidism; Hypothalamo-Hypophyseal System; Hypothyroidism; Male; Propylthiouracil; Radiation Injuries, Experimental; Rats; Thyroid Gland; Thyroxine

Topics: Animals; Animals, Newborn; Cell Differentiation; Cerebellar Cortex; Dendrites; Disease Models, Animal; Growth Hormone; Hypothyroidism; Propylthiouracil; Purkinje Cells; Rats

Topics: Animals; Body Weight; Ethanol; Hyperthyroidism; Hypothyroidism; Liver; Male; Organ Size; Oxidation-Reduction; Oxygen Consumption; Propylthiouracil; Rats; Sorbitol; Thyroid Diseases; Triiodothyronine