methimazole 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

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

In the treatment of pregnant patients with Graves' disease, propylthiouracil is preferred over methimazole in early pregnancy because of a possible teratogenicity of methimazole. Methimazole is preferable to propylthiouracil in other time of pregnancy on the basis of severe liver dysfunction occasionally caused by propylthiouracil. Fetal hypothyroidism can be avoided when maternal free T4 levels are maintained at or above the upper normal limit for non-pregnant subjects. However, maternal free T4 should be kept normal for pregnant reference range when pregnancy complications develop. Fetal hypothyroidism in this setting will not affect the infant's development as long as mothers are euthyroid and the infants recover from hypothyroid state within a short time after birth. In hypothyroid women, 1-T4 dose often needs to be increased in pregnancy. Maternal T4 deficiency in early pregnancy has been suggested to affect normal brain development in the offspring. However, it has recently been shown in iodine rich area that no adverse effect on neuropsychological development was seen irrespective of the severity of maternal T4 deficiency. Insufficient iodine intake in the mother can cause low T4 in pregnancy and also inadequate production of T4 in breast-fed infants when sufficient T4 is essential for normal brain development.

Topics: Female; Graves Disease; Humans; Hypothyroidism; Methimazole; Pregnancy; Pregnancy Complications; Time Factors

Hypothyroidism and hyperthyroidism are associated with maternal and neonatal pregnancy complications. Hypothyroidism should be treated with levothyroxine. Hyperthyroidism requires treatment with propylthiouracil or thiamazole. Subclinical hypothyroidism and thyroid auto-immunity are also associated with maternal and neonatal pregnancy complications. For both subclinical hypothyroidism and thyroid auto-immunity, treatment with levothyroxine has not yet been proven to be effective in preventing complications during pregnancy. For the Dutch population the following reference values for TSH levels during pregnancy may be used: 0.01-4.00 mU/l in the first and second trimesters. Reference values for the third trimester have not reported for this population, but are probably comparable with those of the second trimester.

Topics: Antithyroid Agents; Congenital Hypothyroidism; Female; Humans; Hyperthyroidism; Hypothyroidism; Infant, Newborn; Maternal-Fetal Exchange; Methimazole; Pregnancy; Pregnancy Complications; Pregnancy Outcome; Reference Values; Thyroid Function Tests; Thyrotropin; Thyroxine

Amiodarone is a potent antiarrhythmic drug associated with thyroid dysfunction. Its high iodine content causes inhibition of 5'-deiodinase activity. Most patients remain euthyroid. Amiodarone-induced thyrotoxicosis (AIT) or amiodarone-induced hypothyroidism (AIH) may occur depending on the iodine status of individuals and prior thyroid disease. AIT is caused by excess iodine-induced thyroid hormone synthesis (type I AIT) or by destructive thyroiditis (type II AIT). If the medical condition allows it, discontinuation of the drug is recommended in type I AIT. Otherwise, large doses of thioamides are required. Type II AIT is treated with corticosteroids. Mixed cases require a combination of both drugs. Potassium perchlorate has been used to treat resistant cases of type I AIT but use is limited by toxicity. Thyroidectomy, plasmapheresis, lithium, and radioiodine are used in select cases of AIT. AIH is successfully treated with levothyroxine. Screening for thyroid disease before starting amiodarone and periodic monitoring of thyroid function tests are advocated.

Topics: Amiodarone; Anti-Arrhythmia Agents; Antithyroid Agents; Continuity of Patient Care; Glucocorticoids; Hormone Replacement Therapy; Humans; Hypothyroidism; Iodine Radioisotopes; Methimazole; Perchlorates; Plasmapheresis; Risk Factors; Thyroid Gland; Thyroid Hormones; Thyroidectomy; Thyrotoxicosis; 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

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

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: 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: Age Factors; Animals; Animals, Newborn; Behavior, Animal; Biogenic Amines; Brain; Hyperthyroidism; Hypothyroidism; Iodine Radioisotopes; Lithium; Methimazole; Triiodothyronine; Tryptophan Hydroxylase; Tyrosine 3-Monooxygenase

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

This study aimed to compare the time to achieve euthyroidism and sustained control of hyperthyroidism after treatment with radioactive iodine (RAI) or long-term methimazole (LT-MMI) in patients with post-RAI relapsed hyperthyroidism.. Sixty four patients with recurrence of hyperthyroidism after RAI treatment were randomly assigned to either RAI or LT-MMI treatment. Both groups were followed every 1-3 months in the first year and then every 6 months for a total of 60 months.. In RAI and LT-MMI groups, mean age was 49.0 ± 12.1 and 50.1 ± 14.6 years and time of relapse of hyperthyroidism after previous RAI treatment was 23.2 ± 18.8 and 20.8 ± 17.1 months, respectively. At the end of study, in the LT-MMI group, 31 (97%) and 1 (3%) were euthyroid and hypothyroid, respectively; in the RAI group, 8 (25%) patients were euthyroid, whereas 18 (56%), 3 (9.5%) and 3 (9.5%) had overt hypothyroidism, subclinical hypothyroidism and hyperthyroidism, respectively. Mean time to euthyroidism was 9.4 ± 5.0 months in the RAI group and 3.5 ± 2.8 months in the LT-MMI group (p < 0.001). Patients in the RAI group spent 77.7 ± 14.0 percent and those in the LT-MMI group spent 95.2 ± 5.9 percent of 60 months in the euthyroid state (p < 0.001).. In patients with post-RAI relapse of hyperthyroidism, LT-MMI treatment was superior to radioiodine because of faster achievement of euthyroidism and more sustained control of hyperthyroidism during 60 months of follow-up.

Topics: Adult; Antithyroid Agents; Graves Disease; Humans; Hyperthyroidism; Hypothyroidism; Iodine Radioisotopes; Methimazole; Middle Aged; Neoplasm Recurrence, Local; Thyroid Neoplasms

Structural myocardial abnormalities have been extensively documented in hypothyroidism. Experimental studies in animal models have also shown involvement of thyroid hormones in gene expression of myocardial collagen. This study was planned to investigate the ability of ultrasonic tissue characterization, as evaluated by integrated backscatter (IBS), to early identify myocardial involvement in thyroid dysfunction.. We studied 15 patients with hyperthyroidism (HYPER), 8 patients with hypothyroidism (HYPO), 14 patients with subclinical hypothyroidism (SCH) and 19 normal (N) subjects, who had normal LV systolic function. After treatment, 10 HYPER, 6 HYPO, and 8 SCH patients were reevaluated. IBS images were obtained and analyzed in parasternal short axis (papillary muscle level) view, at left ventricular (LV) posterior wall. The following IBS variables were analyzed: 1) the corrected coefficient (CC) of IBS, obtained by dividing IBS intensity by IBS intensity measured in a rubber phantom, using the same equipment adjustments, at the same depth; 2) cardiac cyclic variation (CV) of IBS--peak-to-peak difference between maximal and minimal values of IBS during cardiac cycle; 3) cardiac cyclic variation index (CVI) of IBS--percentual relationship between the cyclic variation (CV) and the mean value of IBS intensity.. CC of IBS was significantly larger (p < 0.05) in HYPER (1.57 +/- 0.6) and HYPO (1.53 +/- 0.3) as compared to SCH (1.32 +/- 0.3) or N (1.15 +/- 0.27). The CV (dB) (HYPO: 7.5 +/- 2.4; SCH: 8.2 +/- 3.1; HYPER: 8.2 +/- 2.0) and the CVI (HYPO: 35.6 +/- 19.7%; SCH: 34.7 +/- 17.5%; HYPER: 37.8 +/- 11.6%) were not significantly different in patients with thyroid dysfunction as compared to N (7.0 +/- 2.0 and 44.5 +/- 15.1%).. CC of IBS was able to differentiate cardiac involvement in patients with overt HYPO and HYPER who had normal LV systolic function. These early myocardial structural abnormalities were partially reversed by drug therapy in HYPER group. On the other hand, although mean IBS intensity tended to be slightly larger in patients with SCH as compared to N, this difference was not statistical significant.

Topics: Adult; Antithyroid Agents; Diagnosis, Differential; Echocardiography, Doppler; Female; Heart Diseases; Humans; Hyperthyroidism; Hypothyroidism; Male; Methimazole; Middle Aged; Severity of Illness Index; Systole; Thyroxine; Ventricular Function, Left

There are potentially complex interrelationships between thyroid function, leptin, ghrelin, body mass index (BMI), and percentage of body fat (%BF). The goal of this study was to determine if normalization of thyroid status in premenopausal women with hyperthyroidism and hypothyroidism would be associated with changes in serum leptin and ghrelin in the absence of thyroid dysfunction treatment-associated changes in BMI and %BF.. The study was carried out in 47 selected premenopausal women: 17 with hyperthyroidism, 11 with hypothyroidism, and 19 healthy individuals who constituted the control group. Patients with thyroid dysfunction were selected for study if their BMI and %BF did not change after treatment of thyroid dysfunction. Subjects in the control group were selected on the basis of the age, BMI, and the %BF characteristics of the patients with thyroid dysfunction. Concentrations of free thyroxine (fT4), free triiodothyronine (fT3), thyrotropin, leptin, and ghrelin in serum were determined before and after treatment of thyroid dysfunction and in the control group.. Serum leptin concentrations were similar in patients with hyperthyroidism and hypothyroidism before treatment and in normal subjects and did not change significantly after treatment of hyperthyroidism or hypothyroidism. Serum ghrelin concentrations were lower in patients with hyperthyroidism, and higher in patients with hypothyroidism than in the control group (hypothyroidism = 2345 (1157-7015) [median (range)], hyperthyroidism = 1205 (438-2914), control = 2398 (1542-4920), p < 0.05).. In premenopausal women with hyperthyroidism or hypothyroidism, treatment of thyroid dysfunction that is not associated with changes in BMI or %BF does not influence serum leptin but does affect serum ghrelin. Thyroid status itself, in the absence of alterations in the BMI and %BF, has an important influence on circulating ghrelin but not leptin.

Topics: Adolescent; Adult; Antithyroid Agents; Blood Pressure; Body Mass Index; Female; Ghrelin; Humans; Hyperthyroidism; Hypothyroidism; Leptin; Methimazole; Middle Aged; Postmenopause; Thyroxine; Triiodothyronine

Recent studies have indicated the existence of causal links between the endocrine and immune systems and cardiovascular disease. Mannan-binding lectin (MBL), a protein of the innate immune system, may constitute a connection between these fields.. To test whether thyroid hormone regulates MBL levels, we studied eight patients with Graves' hyperthyroidism before and after methimazole therapy, eight healthy subjects before and after short-term experimental hyperthyroidism, and eight hypothyroid patients with chronic auto-immune thyroiditis before and after L-thyroxine substitution.. In all hyperthyroid patients, MBL levels were increased--median (range), 1886 ng/ml (1478-7344) --before treatment and decreased to 954 ng/ml (312-3222) after treatment (P = 0.01, paired comparison: Wilcoxon's signed ranks test). The healthy subjects had MBL levels of 1081 ng/ml (312-1578). Administration of thyroid hormones to these persons induced mild hyperthyroidism and increased MBL levels significantly to 1714 ng/ml (356-2488) (P = 0.01). Two of the eight hypothyroid patients had undetectably low levels of MBL both before and after L-thyroxine substitution. The other six hypothyroid patients had decreased levels of MBL of 145 ng/ml (20-457) compared with 979 ng/ml (214-1533) after L-thyroxine substitution (P = 0.03, paired comparison: Wilcoxon's signed ranks test).. Our data show that thyroid hormone increases levels of MBL. MBL is part of the inflammatory complement system, and this modulation of complement activation may play a role in the pathogenesis of a number of key components of thyroid diseases.

Topics: Adult; Antithyroid Agents; Female; Graves Disease; Humans; Hyperthyroidism; Hypothyroidism; Male; Mannose-Binding Lectin; Mannose-Binding Protein-Associated Serine Proteases; Methimazole; Middle Aged; Single-Blind Method; Thyroid Hormones; Thyroiditis, Autoimmune; Thyroxine; Triiodothyronine

For many years, breast-feeding was forbidden if methimazole (MMI) was being used. However, a few studies have demonstrated the relative safety of MMI. The purpose of this study was to evaluate thyroid function of breast-fed infants whose lactating mothers became hypothyroid while taking methimazole. Between 1990 and 2001, 134 thyrotoxic lactating mothers received MMI while breast-feeding. MMI therapy was initiated between 2-8 months postpartum, 10-30 mg for the first month and 5-10 mg from the second until the twelfth month. In 16 mothers, TSH was increased at the end of one month of MMI therapy (Group 1). Infants of 18 mothers whose serum TSH was normal at the end of the first month were included as controls (Group 2). Mothers and their infants were clinically evaluated and serum T4, T3 and TSH were measured before and at 1, 2, 4, 8 and 12 months after MMI therapy. Serum MMI was measured in 8 infants 2 h after breast-feeding. Mean +/- SD of FT4I and FT3I were not statistically different between the two groups of mothers before MMI therapy. In all 34 mothers thyroid indices decreased one month after MMI therapy; FT4I: Group 1 from 19.8 +/- 4.3 to 6.0 +/- 4.8 (p<0.001) and Group 2 from 20.3 +/- 4.7 to 11.4 +/- 4.1 (p<0.001); FT3I: Group 1 from 602 +/- 56 to 146 +/- 52 (p<0.001) and Group 2 from 562 +/- 42 to 186 +/- 39 (p<0.001). The difference in FT4I, FT3I and TSH (20 +/- 18 vs 2.1 +/- 1.1 mU/l, p<0.001) between the 2 groups was significant at the end of the first month of MMI therapy. There was no significant difference in thyroid function of infants of these two groups one month after MMI therapy and all tests remained within the normal range during 12 months of treatment of their lactating mothers. Serum MMI levels were less than 0.03 in 6 and 0.03 and 0.035 microg/ml in the other 2 infants. The results further indicate the safety of MMI therapy in breast-feeding thyrotoxic women.

Topics: Adult; Antithyroid Agents; Breast Feeding; Chi-Square Distribution; Contraindications; Female; Follow-Up Studies; Humans; Hypothyroidism; Infant; Lactation; Methimazole; Milk, Human; Puerperal Disorders; Retrospective Studies; Thyroid Function Tests; Thyroid Gland; Thyrotoxicosis; Thyrotropin; Thyroxine; Triiodothyronine

Thiourea drugs have been postulated to possess radioprotective property. We studied the effect of adjunctive antithyroid drugs (ATD) and L-thyroxine (L-T4) on the result of radioiodine (RAI) 131I therapy and determined the incidence of hypothyroidism and relapse of hyperthyroidism. One hundred and fifty-nine patients with Graves' disease were randomized prospectively to receive either RAI alone or adjunctive ATD in a form of block-replacement regimen of methimazole (MMI) plus L-T4 for 6 months. The patients were observed for a mean period of 4.6 (range 2-10) years. The incidence of permanent hypothyroidism was studied and the effect of ATD on iodine kinetics was analyzed. The cumulative incidence of hypothyroidism in the ATD group was significantly lower than the RAI group (p = 0.0009), and the difference is accounted by a reduction of early hypothyroidism within 12 months from 20.2 to 3.7% (p = 0.003). The incidence of late hypothyroidism was similar between the two groups. Treatment with ATD did not affect the one dose cure rate with RAI (61.2 vs 55.5%, p = NS), but the time to achieve euthyroidism was significantly earlier with adjunctive ATD (2 vs 8 weeks, p < 0.02). The incidence of relapse within the first year after one dose was also similar between the two groups (38.7 vs 44.5%, p = NS). Comparing the kinetics of the therapeutic dose with a tracer dose, patients receiving MMI were found to be underdosed by 22% (p = 0.003) and the biological half-life was significantly shortened. We conclude that ATD rendered euthyroidism earlier without compromising the one dose cure rate of RAI.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adult; Dose-Response Relationship, Radiation; Drug Therapy, Combination; Female; Graves Disease; Humans; Hypothyroidism; Incidence; Iodine Radioisotopes; Male; Methimazole; Middle Aged; Recurrence; Thyroxine

Radioactive iodine-131 (RAI) has been reported to be associated with a high incidence of development or exacerbation of Graves' ophthalmopathy (GO). This is thought to be associated with a surge of autoantibodies after RAI therapy. The role of methimazole (MMI), which possesses immunomodulatory action, in the prevention of GO was explored by studying 114 patients with Graves' disease. They were assigned randomly to receive either RAI alone or adjunctive antithyroid drugs, which consisted of MMI and L-T4 as a block-replacement therapy for 12 months and were followed for 2 yr. Thirty-five patients (30.7%) had GO at presentation. Twenty-one (18%) patients developed new GO, and six had worsening of preexisting GO. The development of hypothyroidism (P < 0.01) and an elevation of TSH (P < 0.05) were associated with increased risk of development or exacerbation of GO. The chance of development or exacerbation of GO is higher in those with no ophthalmopathy than in those with preexisting GO at presentation (P = 0.002). The incidence of development or exacerbation of GO was similar in the two treatment groups (RAI, 22.8%; adjunctive antithyroid drugs, 23.7%; P = NS). MMI was able to suppress the surge of TSH receptor antibody (TRAB) after RAI, but a surge in TRAB was not of prognostic significance for the development of GO after RAI. Patients who developed or had exacerbation of GO actually had lower TRAB at presentation (P = 0.02). We conclude that hypothyroidism with elevated TSH is an important adverse factor for the development or exacerbation of GO, and MMI was unable to prevent the development or exacerbation of GO after RAI.

Topics: Adult; Aged; Autoantibodies; Eye Diseases; Female; Graves Disease; Humans; Hypothyroidism; Immunoglobulins, Thyroid-Stimulating; Iodine Radioisotopes; Male; Methimazole; Middle Aged; Prognosis; Smoking; Thyrotropin; Thyroxine

Ophthalmopathy caused by Graves' disease may first appear or worsen during or after treatment for hyperthyroidism. It is not known, however, whether choosing to treat hyperthyroidism with antithyroid drugs, iodine-131, or surgery affects the development or aggravation of Graves' ophthalmopathy.. We studied 168 patients with hyperthyroidism caused by Graves' disease, stratified into two age groups--20 to 34 years (54 patients, group 1) and 35 to 55 years (114 patients, group 2). The patients in group 1 were randomly assigned to treatment with methimazole for 18 months or subtotal thyroidectomy, and those in group 2 to either of these two treatments or to iodine-131 therapy. All the patients received thyroxine to avert hypothyroidism, except those treated with iodine-131, who received thyroxine only if hypothyroidism developed. The duration of follow-up was at least 24 months.. Twenty-two patients (13 percent) had infiltrative Graves' ophthalmopathy at randomization. During follow-up, ophthalmopathy developed for the first time in 22 patients (13 percent) and worsened in 8 patients (5 percent). The frequency of the development or worsening of ophthalmopathy was similar among the patients in group 1 (medical therapy, 4 of 27 patients [15 percent]; and surgery, 3 of 27 patients [11 percent]). In group 2, ophthalmopathy developed or worsened in 4 of the 38 patients (10 percent) treated medically, 6 of the 37 patients (16 percent) treated surgically, and 13 of the 39 patients (33 percent) given iodine-131 (P = 0.02 for the comparison between the iodine-131 subgroup and the others combined). The risk of the development or worsening of ophthalmopathy increased as pretreatment serum triiodothyronine concentrations increased.. As compared with other forms of antithyroid therapy, iodine-131 is more likely to be followed by the development or exacerbation of Graves' ophthalmopathy.

Topics: Adult; Female; Follow-Up Studies; Graves Disease; Humans; Hypothyroidism; Iodine Radioisotopes; Male; Methimazole; Middle Aged; Random Allocation; Thyroidectomy; Thyroxine

Little is known about the relationship between hypothyroidism and the parasympathetic nervous system. R-R interval variations revealed by electrocardiogram (ECG) are known to be a useful clinical indicator of abnormalities of parasympathetic nervous system activity. Studies were conducted in hypothyroid patients, and significant reductions in R-R interval variations were observed in patients with primary severe hypothyroidism due to Hashimoto's thyroiditis, and in patients with Graves' disease who became severely hypothyroid during antithyroid drug therapy. R-R interval variations were restored to normal levels in both groups of patients after treatment. The present investigation suggests that in marked hypothyroidism there are hypofunctional abnormalities in the parasympathetic nervous system in association with a reduction in the levels of serum T4 and T3.

Topics: Adult; Electrocardiography; Female; Graves Disease; Heart; Humans; Hypothyroidism; Male; Methimazole; Parasympathetic Nervous System; Thyroid Hormones; Thyroiditis, Autoimmune

We investigated the course of thyroid hormones levels in the serum of hyperthyroid patients acutely treated with amiodarone. Ten patients were treated either with amiodarone, 3 X 400 mg daily for 3 days in addition to methimazole, 3 X 20 mg daily for 10 days (Group I; n = 5) or with a placebo plus methimazole at the same doses (Group II; n = 5). Basal T3, T4 and rT3 serum concentrations were: 297 ng/dl, 16.6 micrograms/dl and 507 pg/dl, respectively in Group I and 377 ng/dl, 17.6 micrograms/dl and 362 pg/dl in Group II (NS). Compared with basal values, the drop in serum T3 concentration became significant on Day 1 in Group I, but not until day 5 in Group II. The decrease in serum T3 concentration was significantly higher in Group I than in Group II from Day 1 to Day 7. In Group I, T4 concentration was significantly lower on Days 2, 4 and 6; the percentage drop in T4 calculated from the areas under the curves was higher and the T3/T4 ratio lower on Days 3-5, 7 and 9; rT3 was higher on Days 4 and 5 and its rise was significant on Days 1, 3 and 4. During the follow-up period a transient rise in T4 and T3 concentrations was observed in two patients in Group I when the methimazole dosage was tapered or stopped because of agranulocytosis. In conclusion, in our hyperthyroid patients, amiodarone in conjunction with methimazole induced a greater fall in T3 and T4 than did methimazole alone.

Topics: Adult; Aged; Aged, 80 and over; Amiodarone; Double-Blind Method; Female; Humans; Hypothyroidism; Methimazole; Middle Aged; Thyroxine; Triiodothyronine

Ten hypothyroid patients with Hashimoto's thyroiditis were treated with methimazole 30 mg in addition to thyroxine 0.15 mg daily. Another 10 hypothyroid patients with Hashimoto's thyroiditis were given thyroxine 0.15 mg alone. After 22 weeks of treatment significant decreases in thyroid microsomal autoantibody titres were observed in both groups (p less than 0.01). There was no difference in the mean change in titre between the two groups. When the patients treated with methimazole were subsequently given thyroxine 0.15 mg alone for a further 22 weeks no additional change in titre was observed. The data suggest that thyroxine, by normalising serum thyroid stimulating hormone concentrations, may reduce the autoantigenic properties of the thyrocytes with a subsequent decrease in autoantibody titres.

Topics: Adult; Autoantibodies; Drug Therapy, Combination; Female; Humans; Hypothyroidism; Male; Methimazole; Microsomes; Middle Aged; Thyroid Gland; Thyroiditis, Autoimmune; Thyroxine; Time Factors

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

Gestational hypothyroidism is a prevalent disorder in pregnant women and also impairs fetal development with relevant outcomes. One of the outcomes of greatest interest has been rodent fear- and anxiety-like behavior. However, the relationship between maternal hypothyroidism and onset of conditioned fear-related responses in offspring remains controversial. Here, we used a well-validated methimazole-induced gestational hypothyroidism to investigate the behavioral consequences in offspring. Dams were treated with methimazole at 0.02% in drinking water up to gestational Day 9. Maternal body weights and maternal behavior were evaluated, and the puppies ware analyzed for weight gain and physical/behavioral development and assigned for the open field and fear conditioning test. Methimazole-induced gestational hypothyroidism induced loss in maternal and litter weight, increases in maternal behavior, and impairs in offspring developmental landmarks in both male and female rodents. Only male offspring enhanced responsiveness to conditioned fear-like behavior in adulthood.

Topics: Animals; Anxiety; Dogs; Fear; Female; Humans; Hypothyroidism; Male; Methimazole; Pregnancy; Prenatal Exposure Delayed Effects; Rodentia

Thyroid hormones (TH) are vital for brain functions, while TH deficiency, i.e. hypothyroidism, induces neurological impairment in children and adults. Cerebellar neuronal apoptosis and motor deficits are crucial events in hypothyroidism; however, the underlying mechanism is less-known. Using a methimazole-treated hypothyroidism rat model, we investigated cerebellar autophagy, growth factor, and apoptotic mechanisms that participate in motor functions. We first identified that methimazole up-regulated cerebellar autophagy, marked by enhanced LC3B-II, Beclin-1, ATG7, ATG5-12, p-AMPKα/AMPKα, and p62 degradation as well as reduced p-AKT/AKT, p-mTOR/mTOR, and p-ULK1/ULK1 in developing and young adult rats. We probed upstream effectors of this abnormal autophagy and detected a methimazole-induced reduction in cerebellar phospho-epidermal growth factor receptor (p-EGFR)/EGFR and heparin-binding EGF-like growth factor (HB-EGF). Here, while a thyroxine-induced TH replenishment alleviated autophagy process and restored HB-EGF/EGFR, HB-EGF treatment regulated AKT-mTOR and autophagy signaling in the cerebellum. Moreover, neurons of the rat cerebellum demonstrated this reduced HB-EGF-dependent increased autophagy in hypothyroidism. We further checked whether the above events were related to cerebellar neuronal apoptosis and motor functions. We detected that comparable to thyroxine, treatment with HB-EGF or autophagy inhibitor, 3-MA, reduced methimazole-induced decrease in Nissl staining and increase in c-Caspase-3 and TUNEL-+ve apoptotic count of cerebellar neurons. Additionally, 3-MA, HB-EGF, and thyroxine attenuated the methimazole-induced diminution in riding time on rota-rod and grip strength for the motor performance of rats. Overall, our study enlightens HB-EGF/EGFR-dependent autophagy mechanism as a key to cerebellar neuronal loss and functional impairments in developmental hypothyroidism, which may be inhibited by HB-EGF and 3-MA treatments, like thyroxine.

Topics: Animals; Autophagy; Cerebellum; Epidermal Growth Factor; ErbB Receptors; Heparin-binding EGF-like Growth Factor; Hypothyroidism; Methimazole; Proto-Oncogene Proteins c-akt; Rats; Thyroxine; TOR Serine-Threonine Kinases

The effectiveness of potassium iodide (KI) (100 mg/day) was evaluated in 504 untreated patients with Graves' hyperthyroidism (GD). Initial response to KI within 180 days, the effect of additional methylmercaptoimidazole (MMI) or radioactive iodine (RI) in resistant or escaped patients, and long-term prognosis were evaluated. Serum fT

Topics: Antithyroid Agents; Graves Disease; Humans; Hyperthyroidism; Hypothyroidism; Iodides; Iodine Radioisotopes; Methimazole; Potassium Iodide; Thyroid Neoplasms; Thyrotropin

Topics: Female; Graves Disease; Humans; Hyperthyroidism; Hypothyroidism; Infant, Newborn; Methimazole; Pregnancy; Pregnancy Complications; Pregnant Women; Thyroid Diseases; Thyroxine

Hypothyroidism is associated with an increased risk of cardiovascular disease and enhanced susceptibility to arrhythmias. In our investigation, we evaluated the potential involvement of late sodium current (I. Male Swiss mice were treated with methimazole (0.1 % w/vol, during 21 days) to induce experimental hypothyroidism before ECG, action potential (AP) and intracellular Ca. The results revealed that hypothyroid animals presented ECG alterations (e.g. increased QTc) with the presence of spontaneous sustained ventricular tachycardia. These changes were associated with depolarized resting membrane potential in isolated cardiomyocytes and increased AP duration and dispersion at 90 % of the repolarization. Aberrant AP waveforms were related to increased Ca. We concluded that animals with hypothyroidism have increased susceptibility to developing arrhythmias and ranolazine, a clinically used blocker of I

Topics: Action Potentials; Animals; Arrhythmias, Cardiac; Caffeine; Dobutamine; Hypothyroidism; Male; Methimazole; Mice; Myocytes, Cardiac; Phenotype; Ranolazine; Sodium

Perinatal hypothyroidism causes long-lasting effects on behavior, including hyperactivity, cognitive delays/deficits, and a reduction in anxiety. Although there is some evidence that hypothyroidism during fetal development in humans has been associated with later autism spectrum disorder diagnosis or autism-like traits, the relationships between early thyroid hormones and social behaviors are largely unknown. Previously, we found that a moderate dose of the hypothyroid-inducing drug methimazole during embryonic and postnatal development dramatically increased juvenile play in male and female rats. The goal of the current study was to determine the extent to which thyroid hormones act in prenatal or postnatal development to organize later social behaviors. Subjects were exposed to methimazole in the drinking water during prenatal (embryonic day 12 to birth), postnatal (birth to postnatal day 23), or pre- and postnatal development; control animals received regular drinking water throughout the experiment. They were tested for play behavior as juveniles (P30-32). We found an interaction between pre- and postnatal methimazole administration such that postnatal hypothyroidism decreased some play behaviors, whereas sustained pre- and postnatal hypothyroidism restored play to control levels. The effects were similar in males and females. To our knowledge, this is the first report of an interaction between pre- and postnatal hypothyroidism on later behavior. The complexity of the timing of these effects may help explain why epidemiological studies have not consistently found a relationship between gestational hypothyroidism and later behavior.

Topics: Animals; Autism Spectrum Disorder; Female; Hypothyroidism; Male; Methimazole; Pregnancy; Prenatal Exposure Delayed Effects; Rats; Thyroid Hormones

Thyroid hormone (TH) is essential for brain development, and hypothyroidism induces cognitive deficits in children and young adults. However, the participating mechanisms remain less explored. Here, we examined the molecular mechanism, hypothesizing the involvement of a deregulated autophagy and apoptosis pathway in hippocampal neurons that regulate cognitive functions. Therefore, we used a rat model of developmental hypothyroidism, generated through methimazole treatment from gestation until young adulthood. We detected that methimazole stimulated the autophagy mechanism, characterized by increased LC3B-II, Beclin-1, ATG7, and ATG5-12 conjugate and decreased p-mTOR/mTOR and p-ULK1/ULK1 autophagy regulators in the hippocampus of developing and young adult rats. This methimazole-induced hippocampal autophagy could be inhibited by thyroxine treatment. Subsequently, probing the upstream mediators of autophagy revealed an increased hippocampal neuroinflammation, marked by upregulated interleukin (IL)-1alpha and beta and activated microglial marker, Iba1, promoting neuronal IL-1 receptor-1 expression. Hence, IL-1R-antagonist (IL-1Ra), which reduced hippocampal neuronal IL-1R1, also inhibited the enhanced autophagy in hypothyroid rats. We then linked these events with hypothyroidism-induced apoptosis and loss of hippocampal neurons, where we observed that like thyroxine, IL-1Ra and autophagy inhibitor, 3-methyladenine, reduced the cleaved caspase-3 and TUNEL-stained apoptotic neurons and enhanced Nissl-stained neuronal count in methimazole-treated rats. We further related these molecular results with cognition through Y-maze and passive avoidance tests, demonstrating an IL-1Ra and 3-methyladenine-mediated improvement in learning-memory performances of the hypothyroid rats. Taken together, our study enlightens the critical role of neuroinflammation-dependent autophagy mechanism in TH-regulated hippocampal functions, disrupted in developmental hypothyroidism.

Topics: Animals; Animals, Newborn; Apoptosis; Autophagy; Cognitive Dysfunction; Hippocampus; Hypothyroidism; Inflammation; Interleukin-1; Memory; Methimazole; Microglia; Microtubule-Associated Proteins; Models, Biological; Neurons; Phosphorylation; Rats, Wistar; Thyroxine; TOR Serine-Threonine Kinases; Triiodothyronine

Összefoglaló. Bevezetés: A tudományos szakirodalomban számos kérdés fogalmazódik meg a pajzsmirigybetegségeket befolyásoló pszichológiai tényezőkről. Kevés tanulmány készült a pajzsmirigybetegségek és a megküzdési stratégiák kapcsolatáról. Célkitűzés: Jelen tanulmányunk célja felmérni a megküzdési stratégiák, a depresszió és a szorongás szintjének változásait a pajzsmirigybetegek (hyperthyreosis és hypothyreosis) esetében a gyógyszeres kezelés (Thyrozol és Euthyrox) hatására. Módszer: A betegeket a szakorvos diagnózisa, illetve a TSH- és fT4-szint alapján hyperthyreosis- (n = 10) és hypothyreosis- (n = 21) csoportba soroltuk. Mindkét csoport tagjait az endokrinológiai kezelés előtt és után pszichológiai felmérésnek vetettük alá. A felmérés során a megküzdési stratégiák felméréséhez a következő skálákat alkalmaztuk: Kognitív Érzelem Szabályozás Kérdőív (Cognitive Emotion Regulation Questionnaire - CERQ), Hobfoll-féle Megküzdési Stratégia Kérdőív (Strategic Approach to Coping Scale - SACS). A Beck Depresszió Kérdőívet (Beck Depression Inventory - BDI-II) alkalmaztuk a depresszió felmérésére, az Állapot- és Vonásszorongás Kérdőívet (State-Trait Anxiety Inventory, Form Y - STAI-Y) a szorongás szintjének felmérésére. Eredmények: A két csoport pszichológiai és laboreredményeit összehasonlítottuk a gyógyszeres kezelés előtt és után. Mind a hyperthyreosisban, mind a hypothyreosisban szenvedő betegeknél magas volt a depresszió és a szorongás szintje. A hyperthyreosisban szenvedő betegeknél a depresszió magasabb. A gyógyszeres kezelés után a depresszió és a szorongás szintje csökkent mindkét csoportban, a megküzdési stratégiák többnyire változatlanok maradtak. Következtetések: Pajzsmirigybetegeknél a kognitív viselkedésbeli pszichoterápiás beavatkozás a gyógyszeres kezelés kiegészítő alternatívája lehet a szorongás és a depresszió szintjének csökkentése és a diszfunkcionális megküzdési stratégiák módosítása szempontjából. Orv Hetil. 2021; 162(7): 262-268.. There is a high interest in the scientific literature in psychological factors that influence the course of thyroid disease. There are a few studies on the link between thyroid disease and coping strategies.. In the present study, we aimed to evaluate the manifestation of depression, anxiety and coping strategies in people with thyroid disease and the impact of endocrinological medication on these psychologic items.. The patients were grouped into two groups, hyperthyroid (n = 10) and hypothyroid (n = 21), according to the diagnosis established by the attending physician, TSH and fT4 level. Patients with hyperthyroidism and hypothyroidism were evaluated before and after endocrinological treatment with the Cognitive Emotion Regulation Questionnaire (CERQ), Strategic Approach to Coping Scale (SACS) for the evaluation of coping strategies, Beck Depression Inventory (BDI-II) for assessing the level of depression, State-Trait Anxiety Inventory, Form Y (STAI-Y) for assessing anxiety. These two groups have been compared.. The psychological and laboratory results of the two groups were compared before and after drug treatment. Both patients with hyperthyroidism and with hypothyroidism had high levels of depression and anxiety. In hyperthyroidism, depression is more severe. Following treatment with Thyrozol and Euthyrox, the level of depression and anxiety decreases in patients with hyper- and hypothyroidism; the coping strategies remained almost unchanged.. Cognitive-behavioral psychotherapeutic intervention could be supplementary to drug treatment in terms of reducing anxiety, depression, and modifying dysfunctional coping strategies for patients with thyroid diseases. Orv Hetil. 2021; 162(7): 262-268.

Topics: Adaptation, Psychological; Antithyroid Agents; Anxiety; Depression; Humans; Hyperthyroidism; Hypothyroidism; Methimazole; Thyroid Diseases; Thyroxine

Topics: Animals; Diabetes Mellitus, Type 2; Ellagic Acid; Glucose; Glycemic Control; Humans; Hypothyroidism; Methimazole; Mice; Mice, Inbred C57BL

Contrary to large multinodular goiters, reports on

Topics: Adult; Aged; Dose-Response Relationship, Radiation; Female; Graves Disease; Humans; Hyperthyroidism; Hypothyroidism; Infant, Newborn; Iodine Radioisotopes; Male; Methimazole; Middle Aged; Pregnancy; Pregnancy Complications; Pregnancy Outcome; Remission Induction; Retrospective Studies; Tomography, X-Ray Computed

Hypothyroidism affects the content of triacylglycerol (TAG), total cholesterol (TC), oxidized lipids, glycogen, and infiltration of immune cells into the ovary and uterus. This study aimed to analyze the impact of hypothyroidism on the lipid content of different regions of the oviduct. Control (n = 6) and hypothyroid (n = 6; 10 mg/kg/day of methimazole in the drinking water for 30 days) adult rabbits were used. In the fimbriae/infundibulum (FIM/INF), ampulla, (AMP), isthmus (IST), and utero-tubal junction (UTJ), the TAG and TC concentrations, presence of oxidized lipid, relative expressions of perilipin A (PLIN A), peroxisome proliferator-activated receptor γ (PPARγ), CAAT/enhancer-binding protein α (C/EBPα), and farnesoid X receptor (FXRα) were analyzed. The content of glycogen and glycans, as well as the infiltration of lymphocytes, were also quantified. In the FIM/INF, hypothyroidism reduced the content of TC, expression of C/EBPα, and presence of glycans while increased the number of intraepithelial lymphocytes. In the AMP and IST-UTJ regions, hypothyroidism increased the content of TAG, oxidized lipids, expression of PPARγ, and glycogen content but decreased the expression of PLIN-A. The FXRα expression in secretory cells of IST-UTJ was higher in the hypothyroid rabbits compared to controls. Additionally, hypothyroidism reduced the C/EBPα expression and the number of intraepithelial lymphocytes in the AMP and IST-UTJ regions, respectively. We demonstrated that the effect of hypothyroidism depends on the oviductal region, possibly associated with different physiological functions specific to each region. These alterations may be related to infertility, tubal disturbances, and ectopic pregnancy observed in hypothyroid women.

Topics: Animals; Antithyroid Agents; Fallopian Tubes; Female; Glycogen; Hypothyroidism; Lipid Metabolism; Lipids; Lymphocytes; Methimazole; Rabbits

Patients suffering from hypothyroidism tend to develop diastolic hypertension. 5-Hydroxytryptamine (5-HT) is an amine that contributes to the maintenance of the blood pressure through central and peripheral 5-HT receptors. Curiously, the hypothyroidism alters the density of the 5-HT receptors in rodent brains.. Analyze the effect of the methimazole-induced hypothyroidism on the peripheral cardiovascular responses elicited by 5-HT.. The vasopressor and tachycardic responses to 5-HT (3-300 μg/kg), and the vasodepressor responses to 5-HT, 5-carboxamidotryptamine (5-CT, 0.001-0.1 μg/kg), isoprenaline (0.03-1 μg/kg) and acetylcholine (ACh, 0.03-3 μg/kg), during an infusion of methoxamine, were determined in pithed hypothyroid rats.. The tachycardic and vasopressor responses to 5-HT and the vasodepressor responses to 5-CT and ACh remained unaffected, the vasodepressor response to 5-HT reduced, and the vasodepressor response to isoprenaline enhanced and reduced at the lowest and highest dose, respectively.. These results suggest that hypothyroidism impairs the vasodepressor response to 5-HT, which could contribute to hypothyroidism-induced hypertension.

Topics: Animals; Cardiovascular Diseases; Hypothyroidism; Male; Methimazole; Rats; Rats, Wistar; Serotonin

Hypothyroidism has been linked to infertility, but the mechanisms underlying infertility-related hypothyroidism have yet to be fully elucidated. Therefore, in this study, effects of hypothyroidism on expression of the proteins related to thyroid hormone function in the uterus, which were thought to play a role implantation, including thyroid hormone receptor (TR), thyroid stimulating hormone receptor (TSHR), retinoic acid receptor (RAR) and extracellular kinase (ERK) were identified. Pregnant female rats were rendered hypothyroid by giving methimazole (MMI), orally. Following hypothyroid induction, rats were grouped into control (non-treated) and received subcutaneous thyroxine at 20, 40, and 80 μg/kg/day for five consecutive days. At Day 6, which is the day of implantation (GD 6), rats were sacrificed and the number of embryo implantation site in the uterus was calculated. Then, uterine horns were harvested and expression of the above proteins and their mRNAs were identified by Western blotting and real-time PCR, respectively. In non-treated hypothyroid pregnant rats, the number of embryo implantation sites decreased as compared to euthyroid and hypothyroid rats receiving thyroxine treatment. Similarly, expression of TRα-1, TRβ-1, TSHR, ERK1/2 and RAR proteins and mRNA in the uterus of non-treated hypothyroid rats also decreased (P < 0.05 when compared to euthyroid and thyroxine-treated hypothyroid rats). In conclusion, downregulated expression of the thyroid hormone related proteins in the uterus at the day of implantation might result in infertility as reported in hypothyroid condition.

Topics: Animals; Down-Regulation; Embryo Implantation; Female; Gene Expression Regulation, Developmental; Hypothyroidism; MAP Kinase Signaling System; Methimazole; Pregnancy; Rats; Rats, Sprague-Dawley; Receptors, Retinoic Acid; Receptors, Thyroid Hormone; Receptors, Thyrotropin; Thyroid Gland; Thyroid Hormones; Thyroxine; Uterus

We investigated the effects of maternal hypothyroidism on forebrain dopaminergic, GABAergic, and serotonergic systems and related behavior in adult rat offspring. Experimental gestational hypothyroidism (EGH) was induced by administering 0.02% methimazole (MMI) to pregnant rats from gestational day 9 to delivery. Neurotransmitter-related protein and gene expression were evaluated in offspring forebrain at postnatal day (P) 120. Exploratory behavior, contextual fear conditioning, locomotion, and 30-day reserpine Parkinson induction were assessed from P75-P120. Protein and gene expression assessments of medial prefrontal cortex showed group differences in dopaminergic, GABAergic, and serotonergic receptors, catabolic enzymes, and transporters. Striatum of MMI offspring showed an isolated decrease in the dopaminergic enzyme, tyrosine hydroxylase. MMI exposure increased GABA and dopamine receptor expression in amygdala. MMI offspring also had decreased state anxiety and poor contextual fear conditioning. We found that baseline locomotion was not changed, but reserpine treatment significantly reduced locomotion only in MMI offspring. Our results indicated that restriction of maternal thyroid hormones reduced dopaminergic, GABAergic, and serotoninergic forebrain components in offspring. Tyrosine hydroxylase deficiency in the striatum may underlie enhanced reserpine induction of Parkinson-like movement in these same offspring. Deficits across different neurotransmitter systems in medial prefrontal cortex and amygdala may underlie decreased state anxiety-like behavior and reduced fear conditioning in offspring, but no changes in trait anxiety-like behavior occurred with maternal MMI exposure. These findings strongly support the hypothesis that adequate delivery of maternal thyroid hormones to the fetus is crucial to the development of the central nervous system critical for emotion and motor regulation.

Topics: Amygdala; Animals; Anxiety; Anxiety Disorders; Disease Models, Animal; Dopamine; Dopaminergic Neurons; Exploratory Behavior; Fear; Female; GABAergic Neurons; Hypothyroidism; Locomotion; Male; Maternal Exposure; Methimazole; Neurotransmitter Agents; Parkinsonian Disorders; Pregnancy; Prenatal Exposure Delayed Effects; Prosencephalon; Rats; Rats, Wistar; Reserpine; Serotonergic Neurons; Thyroid Hormones; Tyrosine 3-Monooxygenase

We report two women who were diagnosed with hypothyroidism due to what was thought to be Hashimoto's thyroiditis 18 and 16 years ago, respectively. They had been euthyroid on stable doses of levothyroxine for many years, and they presented to our clinic with clinically and biochemically overt hyperthyroidism that persisted even after stopping levothyroxine. Immunological and imaging workups were consistent with Graves' disease. Both patients were treated medically and then received definitive treatment. To our knowledge, the intervals for these two conversions are among the longest conversion intervals reported in the medical literature.

Topics: Adrenergic beta-Antagonists; Antithyroid Agents; Female; Graves Disease; Hashimoto Disease; Humans; Hyperthyroidism; Hypothyroidism; Methimazole; Middle Aged; Propranolol; Thyroidectomy; Thyroxine; Treatment Outcome

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

Hypothyroidism is a common disorder that is associated with psychological disturbances such as dementia, depression, and psychomotor disorders. We recently found that chronic treatment with the T-type calcium channel enhancer SAK3 prevents the cholinergic neurodegeneration induced by a single intraperitoneal (i.p.) injection of methimazole (MMI; 75 mg/kg), thereby improving cognition. Here, we evaluated the acute effect of SAK3 on cognitive impairments and its mechanism of action following the induction of hypothyroidism. Hypothyroidism was induced by 2 injections of MMI (75 mg/kg, i.p.) administered once per week. Four weeks after the final MMI treatment, MMI-treated mice showed reduced serum thyroxine (T4) levels and cognitive impairments without depression-like behaviors. Although acute SAK3 (1.0 mg/kg, p.o.) administration failed to ameliorate the decreased T4 levels and histochemical destruction of the glomerular structure, acute SAK3 (1.0 mg/kg, p.o.) administration significantly reduced cognitive impairments in MMI-treated mice. Importantly, the α7 nicotinic acetylcholine receptor (nAChR)-selective inhibitor methyllycaconitine (MLA; 12 mg/kg, i.p.) and T-type calcium channel-specific blocker NNC 55-0396 (25 mg/kg, i.p.) antagonized the acute effect of SAK3 on memory deficits in MMI-treated mice. We also confirmed that acute SAK3 administration does not rescue reduced olfactory marker protein or choline acetyltransferase immunoreactivity levels in the olfactory bulb or medial septum. Taken together, these results suggest that SAK3 has the ability to improve the cognitive decline caused by hypothyroidism directly through activation of nAChR signaling and T-type calcium channels.

Topics: Acetylcholine; Animals; Antithyroid Agents; Benzimidazoles; Calcium Channels, T-Type; Cognitive Dysfunction; Cyclopropanes; Female; Hypothyroidism; Imidazoles; Methimazole; Mice; Naphthalenes; Olfactory Bulb; Signal Transduction; Spiro Compounds

The purinergic system has an important role in the regulation of vascular functions. The interference of thyroid hormones in this system and in cardiovascular events has been studied in recent years. However, the mechanisms involved in vascular, purinergic, and oxidative changes in thyroid disorders are not completely understood. Therefore, the present study aimed to assess purinergic enzyme activity in platelets from rats with hypothyroidism and hyperthyroidism induced, respectively, by continuous exposure to methimazole (MMI) at 20 mg/100 mL or L-thyroxine at 1.2 mg/100 mL in drinking water for 1 month. Results showed that rats exposed to L-thyroxine had a significant decrease in NTPDase activity, wherein ATP hydrolysis was 53% lower and ADP hydrolysis was 40% lower. Moreover, ecto-5'-nucleotidase activity was decreased in both groups, by 39% in the hypothyroidism group and by 52% in the hyperthyroidism group. On the other hand, adenosine deaminase (ADA) activity was increased in hyperthyroidism (75%), and nucleotide pyrophosphatase/phosphodiesterase (NPP) activity was increased in animals with hypothyroidism (127%) and those with hyperthyroidism (128%). Our findings suggest that changes in purinergic enzyme and purine levels could contribute to the undesirable effects of thyroid disturbances. Moreover, oxidative stress and, in particular, a high level of ROS production, showed a causal relation with changes in ectonucleotidase activity and nucleotide and nucleoside levels.

Topics: 5'-Nucleotidase; Adenosine Deaminase; Adenosine Triphosphate; Animals; Antigens, CD; Apyrase; Blood Platelets; Hydrolysis; Hyperthyroidism; Hypothyroidism; Male; Methimazole; Nucleotides; Oxidative Stress; Rats; Rats, Wistar

To determine the impact of hypothyroidism on the bladder and urethral functions as well as in the activation of the pubococcygeous (Pcm) and bulbospongiosus (Bsm) during micturition.. Age-matched control and methimazole-induced hypothyroid female rabbits were used to simultaneously record cystometrograms, urethral pressure, and the reflex activation of Pcm and Bsm during the induced micturition. Urodynamic and urethral variables were measured. Activation or no activation of the Pcm and Bsm during the storage and voiding phases of micturition were categorized as 1 or 0. Significant differences (P ≤ 0.05) between control and hypothyroid groups were determined with unpaired Student-t or Mann-Whitney tests.. One-month induced hypothyroidism increased the residual volume and threshold pressure while the opposite was true for the voided volume, maximal pressure, and voiding efficiency. Urethral pressure was also affected as supported by a notorious augmentation of the urethral resistance, among other changes in the rest of measured variables. Hypothyroidism also affected the reflex activation of the Pcm in the voiding phase of micturition.. Our findings demonstrate hypothyroidism impairs the bladder and, urethral functions, and reflex activation of Pcm and Bsm affecting the micturition in female rabbits.

Topics: Animals; Antithyroid Agents; Electromyography; Female; Hypothyroidism; Methimazole; Pelvic Floor; Pressure; Rabbits; Reflex; Urethra; Urinary Bladder; Urination; Urodynamics

Hypothyroidism is relatively rare etiology of serositis with effusion, but massive pleural effusion is very unusual. This is a report of massive pleural effusion in patient taking methimazole after surgical resection of thyroid-stimulating hormone (TSH)-producing pituitary adenoma (TSHoma). The patient was clinically and biochemically hypothyroid and responded well to discontinuation of methimazole and thyroid hormone replacement therapy. When assessing patients with pleural effusion, we should not rely on laboratory test results alone, as a detailed medical history and thorough physical examination could be more useful.

Topics: Antithyroid Agents; Humans; Hypothyroidism; Male; Methimazole; Middle Aged; Pericardial Effusion; Pituitary Neoplasms; Pleural Effusion; Thyrotropin

Hypothyroxinemia (Hpx) is a thyroid hormone deficiency (THD) condition highly frequent during pregnancy, which although asymptomatic for the mother, it can impair the cognitive function of the offspring. Previous studies have shown that maternal hypothyroidism increases the severity of experimental autoimmune encephalomyelitis (EAE), an autoimmune disease model for multiple sclerosis (MS). Here, we analyzed the immune response after EAE induction in the adult offspring gestated in Hpx. Mice gestated in Hpx showed an early appearance of EAE symptoms and the increase of all parameters of the disease such as: the pathological score, spinal cord demyelination, and immune cell infiltration in comparison to the adult offspring gestated in euthyroidism. Isolated CD4

Topics: Adoptive Transfer; Animals; Biomarkers; Cell Differentiation; Cytokines; Encephalomyelitis, Autoimmune, Experimental; Female; Hypothyroidism; Immunophenotyping; Lymphocyte Activation; Lymphocyte Count; Maternal Exposure; Methimazole; Mice; Myelin Basic Protein; Phenotype; Pregnancy; Pregnancy Complications; Prenatal Exposure Delayed Effects; T-Lymphocyte Subsets; Thyrotropin; Thyroxine

Diabetes and hypothyroidism produce adverse effects on body weight and sexual maturity by inhibiting body growth and metabolism. The occurrence of diabetes is always accompanied with thyroid dysfunction. Thus, it is important to take hypo- or hyper-thyroidism into consideration when exploring the adverse effects caused by diabetes. Previous reports have found hypothyroidism inhibits testicular growth by delaying Sertoli cell differentiation and proliferation. Hence, by establishing a mouse model of diabetes combined with hypothyroidism, we provided evidence that poly glandular autoimmune syndrome affected testicular development and spermatogenesis.. we mimicked polyglandular deficiency syndrome in both immature and prepubertal mice by induction of diabetes and hypothyroidism, which caused decreases in serum concentrations of testosterone and insulin like growth factor 1 (IGF-1). Such reduction of growth factor resulted in inhibition of testicular and epididymal development. Moreover, expressions of Claudin-11 were observed between Sertoli cells and disrupted in the testes of syndrome group mice. We also found reduced sperm count and motility in prepubertal mice.. This mimicry of the diabetes and thyroid dysfunction, will be helpful to better understand the reasons for male infertility in diabetic-cum-hypothyroid patients.

Topics: Animals; Blood Glucose; Blood-Testis Barrier; Body Weight; Claudins; Diabetes Mellitus; Epididymis; Female; Hypothyroidism; Insulin-Like Growth Factor I; Male; Methimazole; Mice, Inbred ICR; Organ Size; Seminiferous Tubules; Sperm Motility; Spermatogenesis; Streptozocin; Testosterone

Insufficient or excessive thyroid hormone (TH) levels during fetal development can cause long-term neurological and cognitive problems. Studies in animal models of perinatal hypo- and hyperthyroidism suggest that these problems may be a consequence of the formation of maladaptive circuitry in the cerebral cortex, which can persist into adulthood. Here we used mouse models of maternal hypo- and hyperthyroidism to investigate the long-term effects of altering thyroxine (T4) levels during pregnancy (corresponding to embryonic days 6.5-18.5) on thalamocortical (TC) axon dynamics in adult offspring. Because perinatal hypothyroidism has been linked to visual processing deficits in humans, we performed chronic two-photon imaging of TC axons and boutons in primary visual cortex (V1). We found that a decrease or increase in maternal serum T4 levels was associated with atypical steady-state dynamics of TC axons and boutons in V1 of adult offspring. Hypothyroid offspring exhibited axonal branch and bouton dynamics indicative of an abnormal increase in TC connectivity, whereas changes in hyperthyroid offspring were indicative of an abnormal decrease in TC connectivity. Collectively, our data suggest that alterations to prenatal T4 levels can cause long-term synaptic instability in TC circuits, which could impair early stages of visual processing.

Topics: Adult; Animals; Animals, Newborn; Antithyroid Agents; Brain Mapping; Disease Models, Animal; Female; Gestational Age; Green Fluorescent Proteins; Humans; Hyperthyroidism; Hypothyroidism; Image Processing, Computer-Assisted; Male; Methimazole; Mice; Mice, Inbred C57BL; Neuroimaging; Pregnancy; Prenatal Exposure Delayed Effects; Synapses; Synapsins; Thalamus; Thyroxine; Time Factors; Transduction, Genetic; Visual Cortex

Perinatal hypothyroidism causes serious damage to auditory functions that are essential for vocalization development. In rat pups, perinatal hypothyroidism potentially affects the development of ultrasonic vocalization (USV) as a result of hearing deficits. This study examined the effect of perinatal hypothyroidism on the development of USVs in rat pups. Twelve pregnant rats were divided into three groups and treated with the anti-thyroid drug methimazole (MMI) via drinking water, from gestational day 15 to postnatal day (PND) 21. The MMI concentration (w/v) was 0% (control group), 0.01% (low-dose group), or 0.015% (high-dose group). After birth, the pups were individually separated from the dam and littermates on PNDs 5, 10, 15, and 20, and their USVs were recorded for 5min. On PNDs 5 and 10, compared with the control group, the low- and high-dose groups exhibited reductions of both frequency-modulated and downward USVs. On PND 15, however, the low- and high-dose groups displayed increases in number, duration, and amplitude of USVs compared with those in the control group. Lower body weights were observed for the low- and high-dose groups than for the control group. Total thyroxine concentrations in plasma were dose-dependently reduced. The onset of auditory functions appeared on PNDs 11-14. Thus, the rat pups were unable to hear externally produced USVs before PND 11. USVs emitted on PNDs 5 and 10 might have been spontaneous and independent of the pups' own or littermate-emitted USVs. The developmental retardation of vocalization-related organs or muscles might underlie the acoustic alterations of USVs on PNDs 5 and 10. The greater number, duration, and amplitude of USVs on PND 15, after which the hearing onset occurred, suggested that the elevation of auditory thresholds occurred as a result of hearing deficits in the low- and high-dose groups. Perinatal hypothyroidism appears to have caused acoustic alterations in the USV development.

Topics: Acoustic Stimulation; Acoustics; Age Factors; Analysis of Variance; Animals; Animals, Newborn; Antithyroid Agents; Body Weight; Disease Models, Animal; Dose-Response Relationship, Drug; Hearing Loss; Hypothyroidism; Methimazole; Rats; Rats, Wistar; Reflex, Startle; Thyroid Hormones; Vocalization, Animal

Alterations in motor functions are well-characterized features observed in humans and experimental animals with thyroid hormone dysfunctions during development. We have previously suggested the implication of the endocannabinoid system in the hyperlocomotor phenotype observed in developmentally induced hypothyroidism in rats. In this work we have further analyzed the implication of endocannabinoids in the effect of hypothyroidism on locomotor activity. To this end, we evaluated the locomotor activity in adult mice lacking the cannabinoid receptor type 1 (CB1R

Topics: 2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine; Animals; Brain; Cannabinoid Receptor Agonists; Disease Models, Animal; Dopamine Agonists; Dopamine Antagonists; Dronabinol; Haloperidol; Hypothyroidism; Imidazoles; Mice, Inbred C57BL; Mice, Knockout; Motor Activity; Perchlorates; Phenotype; Potassium Compounds; Receptor, Cannabinoid, CB1; Receptors, Dopamine D1; Receptors, Dopamine D2

Thyroid hormones are important for the development of the central nervous system. Since the fetal thyroid gland is not functioning until mid-gestation, transport of maternal thyroid hormones across the placenta is essential during the early phases of gestation. Maternal thyroid deficiency has been associated with a higher incidence of neurodevelopmental disorders in the newborns. The relationship between maternal hypothyroidism and the onset of autism spectrum disorders (ASD) in the offspring, however, is still debated. To address this issue, we used a validated animal model of prenatal hypothyroidism based on the administration of the thyroid peroxidase inhibitor methimazole (MMI, 0.02g/100ml in tap water) to rat dams from gestational day 9 up to delivery. The offspring was tested in behavioral tasks during infancy (PNDs 5, 9, 13) and adolescence (PND 35-40) to capture some of the core and associated symptoms of ASD. MMI-exposed pups were able to vocalize as controls when separated from the nest, and showed intact social discrimination abilities in the homing behavior test. At adolescence, the offspring from both sexes did not show an anxious-phenotype in the elevated plus maze and showed intact object recognition. However, MMI-exposed male rats showed increased novelty-directed exploratory behaviors: they solicited their partner to play more and showed more interest for novel rather than familiar objects compared to control rats. Our results show that prenatal MMI-induced hypothyroidism does not cause in the rat offspring behaviors that resemble core and associated ASD symptoms, like deficits in communication and social interaction and anxiety.

Topics: Animals; Anxiety; Autistic Disorder; Disease Models, Animal; Exploratory Behavior; Female; Hypothyroidism; Male; Methimazole; Phenotype; Pregnancy; Pregnancy Complications; Prenatal Exposure Delayed Effects; Rats, Wistar; Recognition, Psychology; Social Behavior; Thyroid Hormones; Vocalization, Animal

Although Graves' disease and systemic sclerosis are both autoimmune disorders, their relationship is rarely reported. We present the case of a Filipino woman with goitre and thyrotoxic signs and symptoms. Diagnosed with Graves' disease at the outpatient clinic, she took antithyroid medications and underwent radioactive iodine ablation with resultant hypothyroidism after 6 months, during which she began to experience skin tightness over the face, neck and fingers. Workup revealed limited cutaneous systemic sclerosis, and the patient improved with methotrexate. This case highlights the increased prevalence of coincident autoimmune disorders in Graves' disease.

Topics: Adult; Antithyroid Agents; Facial Dermatoses; Female; Graves Disease; Hormone Replacement Therapy; Humans; Hypothyroidism; Immunosuppressive Agents; Iodine Radioisotopes; Methimazole; Methotrexate; Neck; Scleroderma, Limited; Thyroxine

Methimazole (MMI) is a first-line therapy used to manage hyperthyroidism and Graves' disease. Despite its therapeutic benefit, chronic MMI administration can lead to hypothyroidism and perturb brain homeostasis in patients, resulting in neuropsychiatric disorders such as depression and cognitive dysfunction. We recently developed the spiroimidazopyridine derivative SAK3 as cognitive enhancer; however, mechanisms underlying its activity remained unclear. Here, we show that SAK3 potentially improves cognitive impairment seen following MMI-induced hypothyroidism. Twenty-four hours after MMI (75 mg/kg, i.p.) treatment, we administered SAK3 (0.1, 0.5 and 1 mg/kg, p.o.) to mice daily for 7 days. MMI treatment alone disrupted olfactory bulb (OB) glomerular structure, as assessed by staining with the olfactory marker protein (OMP), reduced the number of choline acetyl transferase (ChAT)-immunoreactive neurons in medial septum (MS), and significantly impaired cognition. SAK3 (0.5 and 1 mg/kg, p.o.) administration significantly restored the number of cholinergic MS neurons in MMI-treated mice, and SAK3 treatment at a higher dose significantly improved cognitive deficits seen in MMI-treated control mice. Overall, our study suggests that SAK3 treatment could antagonize such impairment in patients with hypothyroidism.

Topics: Animals; Cognition Disorders; Dose-Response Relationship, Drug; Female; Hypothyroidism; Imidazoles; Maze Learning; Methimazole; Mice; Pyridines; Random Allocation; Spiro Compounds

The effectiveness of iodine containing additives on the basis of whey protein and milk protein casein compared to iodized salt in the composition of meat minced semi-finished products for child nutrition was examined in the experiment on laboratory animals. Four variants of the semi-finished products were investigated: 1 - control; 2 - enriched with iodine containing milk protein casein; 3 - enriched with iodine containing whey proteins; 4 - enriched with iodized salt. The semi-finished products were enriched at the level of 15% of the daily norm of iodine requirement for children at the age of 7-12 years. Iodine content in 100 g of product was 20 μkg. Rats (initial body weight 140±20 g, n=80) were divided into five groups (control, intact and three experimental groups). Groups 1 and 5 included the animals fed with a standard vivarium diet throughout the experiment. The rats from groups 2-4 were fed with the iodine enriched diet: group 2 received diet containing semi-finished products No. 2; group 3 sample No. 3 and group 4 - sample No. 4. The first stage of the experiment was aimed at accumulation of iodine in tissues and organs of animals consumed the tested iodine containing additives in the composition of semi-finished products. The second stage of the experiment consisted in simulation of the mercazolilum-induced (50 mg/kg b.w.) hypothyroidism (iodine deficiency) and detection of preventive effects of iodine containing meat semi-finished products in a model of experimental hypothyroidism in rats. The data obtained upon the end of the experiment suggest that the highest effect for correction of iodine deficiency was achieved when using the culinary products enriched with iodine containing whey proteins (sample No. 3): the level of thyroxine (T4) was restored by 98.7% in the animals from group 3 compared to the indices of the intact group, Т3 by 100%, TSH - by 89.3%. This effect was confirmed by the hematological and biochemical blood indexes, as well as the dynamics of their weight change: the level of white blood cells was significantly lower by 28%, granulocytes by 44%, monocytes by 42% compared to control rats; the weight gain of the animals of the 3 group was 20.3%, closer to that of intact animals - 26.4%, while in the control group it was 2.6 %.

Topics: Animals; Cooking; Food Additives; Hypothyroidism; Iodine; Male; Meat Products; Methimazole; Rats; Rats, Wistar

To investigate the effect of methimazole-induced postnatal hypothyroidism on the retinal maturation and to study Sirtuin 2 (SIRT2) level in the hypothyroidic rat retina.. Twenty newborn Wistar albino rat pups were used in this prospective, randomized study. Wistar albino rats, weight 250-300 g, were impregnated (without addition of any drug) and were fed normally. Rat pups were randomly divided into two groups and were fed with breast milk. After weaning till they were 90 days of age, rat pups received the same water as their lactating mothers drank. Group 1 (methimazole (MMI)-induced hypothyroidy group), rats were given MMI-water, whereas, in Group 2, normal tap water. When the pups were 90 days of age, 20 rat pups were decapitated and the eyes were isolated. Eyes were investigated using histological, histomorphometric and immunohistochemistrical techniques.. No histological difference was seen between the groups stained with hematoxylin and eosin. In both groups the retinal layer structures and cells were observed as normal. The examples in the groups had a normal distribution for retinal thickness (pixel) measure. The mean value (mean ± std. deviation) was 554.7 ± 228.4 in the control group and 494.7 ± 129.4 in the hypothyroidy group. There was no significance between the groups in terms of retinal thickness (p = 0.231). However, immunohistochemistry revealed that SIRT2 was weaker stained in the ganglion cell layer and visual cell layer in the hypothyroidy group compared to the control group.. Postnatal hypothyroidism altered the retinal cytoarchitecture and layering which are regulated by thyroid hormones (THs) during retinal maturation in the postnatal period. THs may act by the induction of the SIRT family proteins or through their receptors. Postnatal screenings for THs levels are very important to provide normal retinal development.

Topics: Animals; Animals, Newborn; Antithyroid Agents; Female; Hypothyroidism; Methimazole; Rats, Wistar; Retina; Sirtuin 2

To evaluate the morphometry and thyroid-hormone receptor (TR) expression in pelvic (pubococcygeus, Pcm) and perineal (bulbospongiosus, Bsm) muscles of control and hypothyroid female rabbits.. Hypothyroidism was induced administering 0.02% methimazole in the drinking water for one month. Hematoxylin-eosin stained muscle sections were used to evaluate the fiber cross-sectional area (CSA) and the number of peripheral myonuclei per fiber. Immunohistochemistry was used to calculate the proportion of TR immunoreactive nuclei per fiber. Significant differences were considered at a P ≤ 0.05.. As compared to control rabbits, hypothyroidism increased the averaged fiber CSA and the myonuclei per fiber in the Bsm. Although the myonuclei number per fiber was also increased in the Pcm, the effect concerning the fiber CSA was only observed in a fraction of the Pcm fibers. Both TRα and TRβ were similarly expressed in the Pcm and Bsm. Hypothyroidism increased the expression of the TRα in the Bsm. Meanwhile, the expression of TR isoforms in the Pcm was not altered.. Our findings support that the TR signaling is directly involved in morphometrical changes induced by hypothyroidism in the Pcm and Bsm. The effect of hypothyroidism on the Pcm and Bsm could be related to the different type of fiber and metabolism that these muscles have. Neurourol. Urodynam. 35:895-901, 2016. © 2015 Wiley Periodicals, Inc.

Topics: Anatomy, Cross-Sectional; Animals; Antithyroid Agents; Chinchilla; Female; Hypothyroidism; Immunohistochemistry; Methimazole; Muscle Fibers, Skeletal; Muscle, Skeletal; Pelvic Floor; Rabbits; Receptors, Thyroid Hormone; Thyroid Hormone Receptors alpha; Thyroid Hormone Receptors beta; Urethra

Thyroid hormone and leptin are essential regulators of energy homeostasis. Both hormones stimulate energy expenditure but have opposite effects on appetite. The mechanisms behind food intake regulation in thyroid dysfunctions are poorly understood. It has been shown that hypothyroid rats exhibited impaired leptin anorexigenic effect and signaling in total hypothalamus, even though they were hypophagic. It was hypothesized that hypothyroidism modulates the expression of neuropeptides: orexigenic neuropeptide Y (NPY) and anorexigenic proopiomelanocortin (POMC), independently of inducing nuclei-specific changes in hypothalamic leptin signaling.. Adult male rats were rendered hypothyroid by administration of 0.03% methimazole in the drinking water for 21 days. Protein content of NPY, POMC, and leptin signaling (the signal transducer and activator of transcription 3 [STAT3] pathway) were evaluated by Western blot, and mRNA levels by real time reverse transcription polymerase chain reaction in arcuate (ARC), ventromedial (VMN), and paraventricular (PVN) hypothalamic nuclei isolated from euthyroid (eu) and hypothyroid (hypo) rats. Leptin anorexigenic effect was tested by recording food intake for two hours after intracerebroventricular (i.c.v.) administration of leptin. Statistical differences were considered significant at p ≤ 0.05.. Hypothyroidism was confirmed by decreased serum triiodothyronine, thyroxine, and increased thyrotropin, in addition to increased levels of pro-TRH mRNA in PVN and Dio2 mRNA in the ARC of hypo rats. Hypothyroidism decreased body weight and food intake associated with decreased protein content of NPY and increased content of POMC in the ARC. Conversely, hypothyroidism induced central resistance to the acute anorexigenic effect of leptin, since while euthyroid rats displayed reduced food intake after leptin i.c.v. injection, hypothyroid rats showed no response. Hypothyroid rats exhibited decreased leptin receptor (ObRb) protein content in ARC and VMN but not in PVN nucleus. ObRb protein changes were concomitant with decreased phosphorylated STAT3 in the ARC, and decreased total STAT3 in VMN and PVN. However, hypothyroidism did not affect mRNA levels of Lepr or Stat3 in the hypothalamic nuclei.. Experimental hypothyroidism induced a negative energy balance accompanied by decreased NPY and increased POMC protein content in the ARC, resulting in predominance of anorexigenic pathways, despite central leptin resistance and impairment of the leptin signaling cascade in a nuclei-specific manner.

Topics: Animals; Appetite Regulation; Arcuate Nucleus of Hypothalamus; Disease Models, Animal; Eating; Energy Metabolism; Feeding Behavior; Hypothyroidism; Iodide Peroxidase; Iodothyronine Deiodinase Type II; Leptin; Male; Methimazole; Neuropeptide Y; Paraventricular Hypothalamic Nucleus; Phosphorylation; Pro-Opiomelanocortin; Rats, Wistar; Receptors, Leptin; Signal Transduction; STAT3 Transcription Factor; Thyrotropin-Releasing Hormone; Ventromedial Hypothalamic Nucleus; Weight Loss

To investigate the effect of experimental prenatal and postnatal hypothyroidism (HT) on the craniofacial structure in rats.. Female Wistar albino rats were mated with males for fertilization. Pregnant rats were divided into three groups. Group 1 (methimazole [MMI]-induced prenatal hypothyroidism group) mother rats were given MMI water during and after pregnancy. Group 2 (MMI-induced postnatal hypothyroidism group) mother rats were given MMI water after pregnancy. After the breast-feeding period, group 1 and 2 rat pups received the same water as their lactating mothers drank. Group 3 (control group) pregnant rats and rat pups were given normal tap water. When the rat pups were 90 days of age, lateral cephalometric and posteroanterior films were taken under anesthesia.. Posteroanterior radiographs revealed that palatal, cranial, bizygomatic arch, and bigonial width measurements were significantly shorter in prenatal HT and postnatal HT groups compared to the control group (P < .001). Intragroup comparisons in lateral cephalometric radiographs showed that, nearly all of the comparisons were statistically significant (P < .05), with the exception of the Co-Gn, E-Pg/S-Gn measurements between the prenatal and postnatal HT groups.. Sagittal and transverse measurements showed that untreated HT has detrimental effects on the growth of the maxilla and mandible.

Topics: Animals; Cephalometry; Female; Hypothyroidism; Lactation; Male; Mandible; Maxilla; Methimazole; Pregnancy; Rats; Rats, Wistar

Molecular understanding of lung development is crucial for developing therapies and diagnostic tools. Animal models with altered thyroid hormone signaling provide mechanistic insight into thyroid-dependent neonatal lung disease. Repression of Klf2 (Krüppel-like factor 2), a suggested T3 target gene, is associated with disrupted lung development in mice. Klf2 is proposed to be specifically involved in type I pneumocyte differentiation.. To explore mechanisms of thyroid-dependent lung disease, we studied developing chicken fetuses with experimentally induced hypothyroidism.. Morphology and the expression of a panel of molecules linked to Klf2 were assessed using histology, immunohistochemistry, Western blot and qPCR.. Methimazole injections at E14 hampered lung maturation. The effects of methimazole were evident in several tissue compartments, and impacted on both pneumocyte and vascular differentiation, suggesting cellular and molecular pleiotropy.. Concomitant expression changes in a panel of selected microRNAs regulated by Klf2 suggest importance in lung development. These microRNAs may thus represent potential clinical targets and diagnostic and prognostic tools in thyroid-dependent lung disease.

Topics: Alveolar Epithelial Cells; Animals; Chick Embryo; Embryonic Development; Humans; Hypothyroidism; Kruppel-Like Transcription Factors; Lung; Methimazole; MicroRNAs; Models, Animal; Thyroid Hormones

Subclinical hypothyroidism (SCH) is becoming a global health problem due to its increasing prevalence and potential deleterious effects. However, the molecular mechanisms underlying the lipid metabolic disorders in SCH have not been fully clarified. Additionally, progress in elucidating the exact pathogenesis of SCH has been hampered by the lack of optimized mouse models. Methimazole (MMI) was applied to construct a noninvasive SCH mouse model. Eight-week-old C57BL/6 mice were administrated MMI through the drinking water. After 12 weeks, the MMI-treated mice showed the diagnostic criteria for SCH: increased serum thyrotropin (TSH) levels with constant thyroid hormone levels that persisted for approximately 8 weeks. Notably, SCH mice presented evident lipid metabolic disturbances, including dyslipidemia and hepatic lipid accumulation. Further analysis showed that hepatic endoplasmic reticulum stress (ER stress) was induced in the SCH mice or by the elevation of TSH in vitro, likely via the IRE1α/XBP-1 pathway. Interestingly, when we used 4-phenyl butyric acid to repress ER stress in SCH mice for 4 weeks, dyslipidemia and hepatic lipid accumulation were both significantly alleviated. Our findings indicate that an optimized SCH mouse model could be established using MMI, and ER stress may play a pivotal role in the lipid metabolic abnormalities in SCH.

Topics: Animals; Disease Models, Animal; Endoplasmic Reticulum Stress; Humans; Hypothyroidism; Lipid Metabolism Disorders; Methimazole; Mice; Mice, Inbred C57BL; Phenylbutyrates; Thyroid Hormones; Thyrotropin

The aim of this study was to investigate depression-like behaviors of juvenile rats with congenital and postnatal hypothyroidism.. Twenty-seven newborn rat pups were used. First, 6-month-old Wistar Albino female rats were impregnated. Methimazole (0.025% wt/vol) was given to dam rats from the first day of pregnancy until postnatal 21 days (P21) to generate pups with congenital hypothyroidism (n=8), whereas in the postnatal hypothyroidism group (n=10), methimazole was given from P0 to P21. In the control group (n=9), dam rats were fed ad libitum and normal tap water. Offspring were fed with breast milk from their mothers. The behavioral parameters were measured with the juvenile forced swimming test (JFST). The procedure of JFST consisted of two sessions in two consecutive days: the 15-minute pre-test on day 1 and the 5-minute test on day 2.. Increased immobility and decreased climbing duration were observed in both congenital and postnatal hypothyroidism groups. Decreased swimming duration was detected in the postnatal hypothyroidism group. Both hypothyroidism groups had a lower body weight gain compared with the control group, while the congenital hypothyroidism group had the lowest body weight.. Our results showed that hypothyroidism had negative effects on depression-like behavior as well as on growth and development. Both congenital and postnatal hypothyroidism caused an increase in immobility time in JFST. New studies are required to understand the differing results on depression-like behavior between congenital and postnatal hypothyroidism.

Topics: Analysis of Variance; Animals; Animals, Newborn; Body Weight; Congenital Hypothyroidism; Depression; Female; Hypothyroidism; Male; Methimazole; Motor Activity; Pregnancy; Prenatal Exposure Delayed Effects; Rats, Wistar; Swimming; Thyroxine; Time Factors; Triiodothyronine

Diseases related to thyroid hormones have been extensively studied because affect a large number of individuals, and these hormones participate in the regulation of the whole organism homeostasis. However, little is known about the involvement of purinergic signaling related to oxidative stress in hypothyroidism and possible therapeutic adjuncts for treatment of this disorder. Thus, the present study investigates the effects of quercetin on NTPDase, 5'-nucleotidase and adenosine deaminase activities, platelet aggregation and oxidative profile in platelets of rats with methimazole (MMI)-induced hypothyroidism. Methimazole at a concentration of 20mg/100mL was administered for 90days. From the second month the animals received quercetin 10 or 25mg/kg for 60days. Results showed that: Ecto-5'-nucleotidase activity decreased in methimazole/water group and the treatment with quercetin 25mg/kg decreased NTPDase, 5'-nucleotidase and adenosine deaminase activities. Moreover, platelet aggregation increased in methimazole/water group. Lipid peroxidation increased while superoxide dismutase and catalase activities decreased, but, interestingly, the treatment with quercetin reversed these changes. These results demonstrated that quercetin modulates adenine nucleotide hydrolysis decreasing the ADP formation and adenosine deamination. At the same time quercetin improves the oxidative profile, as well as reduces platelet aggregation, which together with the modulation in the nucleotides levels can contribute to the prevention of platelet disorders.

Topics: Adenine Nucleotides; Adenosine Deaminase; Animals; Antioxidants; Blood Platelets; Catalase; Disease Models, Animal; Dose-Response Relationship, Drug; Hydrolysis; Hypothyroidism; Kinetics; Lipid Peroxidation; Male; Membrane Proteins; Methimazole; Oncogene Proteins; Oxidative Stress; Platelet Aggregation; Platelet Aggregation Inhibitors; Quercetin; Rats, Wistar; Superoxide Dismutase

Oviductal regions show particular histological characteristics and functions. Tubal pathologies and hypothyroidism are related to primary and secondary infertility. The impact of hypothyroidism on the histological characteristics of oviductal regions has been scarcely studied. Our aim was to analyse the histological characteristics of oviductal regions in control and hypothyroid rabbits. Hypothyroidism was induced by oral administration of methimazole (MMI) for 30 days. For both groups, serum concentrations of thyroid and gonadal hormones were determined. Sections of oviductal regions were stained with the Masson's trichrome technique to analyse both epithelial and smooth muscle layers. The percentage of proliferative epithelial cells (anti-Ki67) in diverse oviductal regions was also quantified. Data were compared with Student t-test, Mann-Whitney U-test, or Fischer's test. In comparison with the control group, the hypothyroid group showed: (i) a low concentration of T3 and T4, but a high level of TSH; (ii) similar values of serum estradiol, progesterone and testosterone; (iii) a large size of ciliated cells in the ampulla (AMP), isthmus (IST) and utero-tubal junction (UTJ); (iv) a large size of secretory cells in the IST region; (v) a low percentage of proliferative secretory cells in the fimbria-infundibulum (FIM-INF) region; and (vi) a similar thickness of the smooth muscle layer and the cross-sectional area in the AMP and IST regions. Modifications in the size of the oviductal epithelium in hypothyroid rabbits could be related to changes in the cell metabolism that may impact on the reproductive functions achieved by oviduct.

Topics: Animals; Cell Proliferation; Cell Size; Epithelial Cells; Fallopian Tubes; Female; Hypothyroidism; Methimazole; Muscle, Smooth; Rabbits; Thyrotropin; Thyroxine; Triiodothyronine

Clinical studies have shown that interventional lowering of serum free thyroxine (FT4) may be associated with extended survival in patients with some terminal cancers. The report of success with this approach in glioblastoma multiforme caused involvement of the author (A.H.) in the prospective consultative management of 23 end-stage solid tumor patients in whom hypothyroxinemia was induced to prolong life.. Patients were self-referred or recommended by attending physicians to the author (A.H.) and had advanced cancers of the brain, ovary, lung, pancreas, salivary gland, and breast or had mesothelioma or soft-tissue sarcoma. Hypothyroxinemia was achieved in euthyroid patients by using methimazole, with the addition of 3,3',5-triiodo-L-thyronine (L-T3) to prevent hypothyroidism and suppress endogenous thyrotropin (TSH). In patients with pre-existent primary hypothyroidism, T3 administration was substituted for T4 replacement. Serum FT4 and TSH concentrations were serially monitored to enable adjustments to drug therapy and prevent clinical hypothyroidism. Survival was measured from the date of hypothyroxinemia induction with T3 or methimazole plus T3. Outcomes were compared with the odds of death based on the Surveillance Epidemiology and End Results and American Joint Committee on Cancer databases and literature reports.. The survival time of 83% (19 of 23) of patients exceeded the 20% expected 1-year survival for this hypothyroxinemic, end-stage cancer group. The difference between actual and expected survival was significant.. Although this is an uncontrolled observational experience with frank limitations, compassionate medical induction of hypothyroxinemia should be considered for patients with advanced cancers to whom other avenues of treatment are closed.

Topics: Adult; Aged; Aged, 80 and over; Diazonium Compounds; Female; Humans; Hypothyroidism; Male; Methimazole; Middle Aged; Neoplasms; Survival Analysis; Thyrotropin; Thyroxine; Triiodothyronine

Both developmental and adult-stage hypothyroidism disrupt rat hippocampal neurogenesis. We previously showed that exposing mouse offspring to manganese permanently disrupts hippocampal neurogenesis and abolishes the asymmetric distribution of cells expressing Mid1, a molecule regulated by sonic hedgehog (Shh) signaling. The present study examined the involvement of Shh signaling on the disruption of hippocampal neurogenesis in rats with hypothyroidism. Pregnant rats were treated with methimazole (MMI) at 0 or 200 ppm in the drinking water from gestation day 10-21 days after delivery (developmental hypothyroidism). Adult male rats were treated with MMI in the same manner from postnatal day (PND) 46 to PND 77 (adult-stage hypothyroidism). Developmental hypothyroidism reduced the number of Mid1(+) cells within the subgranular zone of the dentate gyrus of offspring on PND 21, and consequently abolished the normal asymmetric predominance of Mid1(+) cells on the right side through the adult stage. In control animals, Shh was expressed in a subpopulation of hilar neurons, showing asymmetric distribution with left side predominance on PND 21; however, this asymmetry did not continue through the adult stage. Developmental hypothyroidism increased Shh(+) neurons bilaterally and abolished the asymmetric distribution pattern on PND 21. Adult hypothyroidism also disrupted the asymmetric distribution of Mid1(+) cells but did not affect the distribution of Shh(+) hilar neurons. The results suggest that the hippocampal neurogenesis disruption seen in hypothyroidism involves changes in asymmetric Shh(+) neuron distribution in developmental hypothyroidism and altered Mid1 expression in both developmental and adult-stage hypothyroidism.

Topics: Age Factors; Animals; Animals, Newborn; Dentate Gyrus; Disease Models, Animal; Female; Gene Expression Regulation, Developmental; Gestational Age; Hedgehog Proteins; Hypothyroidism; Immunohistochemistry; Male; Methimazole; Neurogenesis; Neurons; Pregnancy; Rats, Sprague-Dawley; Real-Time Polymerase Chain Reaction; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Signal Transduction; Transcription, Genetic

Free circulating extracellular DNA, plasma activities of matrix metalloproteinases in hypothyroid rats, and ultrastructural changes in the myocardium were studied under conditions of experimental hypercholesterolemia. For suppression of thyroid function, the animals received antithyroid drug mercazolyl under conditions of cholesterol diet. Hypercholesterolemia in hypothyroid rats (thyroxine concentration 2-fold below the normal) was paralleled by a pronounced increase of the concentration of free circulating extracellular DNA and total matrix metalloproteinases 2 and 7 activity. These changes were associated with lytic and destructive changes in cardiomyocytes and blood capillary endotheliocytes. Changes in the cardiomyocyte and endotheliocyte ultrastructure were more pronounced in hypothyroid rats.

Topics: Animals; DNA; Hypercholesterolemia; Hypothyroidism; Male; Matrix Metalloproteinase 2; Matrix Metalloproteinase 7; Matrix Metalloproteinases; Methimazole; Myocardium; Rats; Rats, Wistar

Fasting down-regulates the hypothalamus-pituitary-thyroid (HPT) axis activity through a reduction of TRH synthesis in neurons of the parvocellular paraventricular nucleus of the hypothalamus (PVN). These TRH neurons project to the median eminence (ME), where TRH terminals are close to the cytoplasmic extensions of β2 tanycytes. Tanycytes express pyroglutamyl peptidase II (PPII), the TRH-degrading ectoenzyme that controls the amount of TRH that reaches the anterior pituitary. We tested the hypothesis that regulation of ME PPII activity is another mechanism by which fasting affects the activity of the HPT axis. Semiquantitative in situ hybridization histochemistry data indicated that PPII and deiodinase 2 mRNA levels increased in tanycytes after 48 hours of fasting. This increase was transitory, followed by an increase of PPII activity in the ME, and a partial reversion of the reduction in PVN pro-TRH mRNA levels and the number of TRH neurons detected by immunohistochemistry. In fed animals, adrenalectomy and corticosterone treatment did not change ME PPII activity 72 hours later. Methimazole-induced hypothyroidism produced a profound drop in tanycytes PPII mRNA levels, which was reverted by 3 days of treatment with T4. The activity of thyroliberinase, the serum isoform of PPII, was increased at most fasting time points studied. We conclude that delayed increases in both the ME PPII as well as the thyroliberinase activities in fasted male rats may facilitate the maintenance of the deep down-regulation of the HPT axis function, despite a partial reactivation of TRH expression in the PVN.

Topics: Adrenalectomy; Aminopeptidases; Animals; Antithyroid Agents; Corticosterone; Ependymoglial Cells; Fasting; Hypothalamo-Hypophyseal System; Hypothalamus; Hypothyroidism; Iodide Peroxidase; Iodothyronine Deiodinase Type II; Male; Median Eminence; Methimazole; Paraventricular Hypothalamic Nucleus; Protein Precursors; Pyrrolidonecarboxylic Acid; Rats; RNA, Messenger; Thyrotropin-Releasing Hormone; Thyroxine

Investigate the effect of GC-1 on tolerance to exercise in rats with experimental hypothyroidism.. Hypothyroidism was induced with methimazole sodium and perchlorate treatment. Six groups with eight animals were studied: control group (C), hypothyroid group without treatment (HYPO); hypothyroidism treated with physiological doses of tetraiodothyronine (T4) or 10 times higher (10×T4); hypothyroidism treated with equal molar doses of GC-1 (GC-1) or 10 times higher (10×GC-1). After eight weeks, each animal underwent an exercise tolerance test by measuring the time (seconds), in which the rats were swimming with a load attached to their tails without being submerging for more than 10 sec. After the test, the animals were killed, and blood samples were collected for biochemical analysis, and the heart and soleus muscle were removed for weighing and morphometric analysis of the cardiomyocyte.. Hypothyroidism significantly reduced tolerance to exercise and, treatment with GC-1 1× or T4 in physiological doses recover tolerance test to normal parameters. However, high doses of T4 also decreased tolerance to physical exercise. Conversely, ten times higher doses of GC-1 did not impair tolerance to exercise. Interestingly, hypothyroidism, treated or not with T4 in a physiological range, GC-1 or even high doses of GC-1 (10X) did not change cardiomyocyte diameters and relative weight of the soleus muscle. In contrast, higher doses of T4 significantly increased cardiomyocyte diameter and induced atrophy of the soleus muscle.. Unlike T4, GC-1 in high doses did not modify tolerance to physical exercise in the rats with hypothyroidism.

Topics: Acetates; Animals; Exercise Tolerance; Hypothyroidism; Methimazole; Muscle, Skeletal; Myocytes, Cardiac; Perchlorates; Phenols; Rats, Wistar; Sodium Compounds; Swimming; Thyroid Hormone Receptors beta; Thyrotropin; Thyroxine; Triiodothyronine

Subclinical hypothyroidism (SCH) and its associations with atherosclerosis (AS) and cardiovascular disease remain controversial. The purpose of our study was to observe changes in endothelial functioning and hemodynamics in rats with SCH and to determine whether L-thyroxine (L-T4) administration affects these changes.. In total, sixty male Wistar rats were randomly divided into the following three groups with 20 rats each: control euthyroid rats, SCH rats and SCH rats that had been treated with thyroxine (SCH+T4). The SCH rats were induced by administration of 10 mg x kg(-1) x d(-1) methimazole (MMI) once daily by gavage for 3 months. The SCH+T4 rats were administered the same dose of MMI for three months in addition to 2 μg x kg(-1) x d(-1) L-T4 once daily by gavage after 45 days of MMI administration. The control rats received physiological saline via gavage.. The SCH group had significantly higher thyroid-stimulating hormone (TSH), total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), and endothelin (ET) levels and a lower nitric oxide (NO) level than the control and SCH+T4 groups. The tail and carotid artery blood pressures, left ventricular systolic pressure, heart rate and aorta ventralis blood flow were significantly lower in the SCH group than in the control and SCH+T4 groups. ACH treatment caused concentration-dependent relaxation, which was reduced in the SCH arteries compared with the control and SCH+T4 arteries. Histopathological examination revealed the absence of pathological changes in the SCH rat arteries.. These findings demonstrate that L-T4 treatment ameliorates endothelial dysfunction and hemodynamic changes in SCH rats.

Topics: Animals; Aorta; Blood Pressure; Body Weight; Cholesterol; Cholesterol, LDL; Disease Models, Animal; Endothelins; Hemodynamics; Hypothyroidism; Male; Methimazole; Nitric Oxide; Rats; Rats, Wistar; Thyroxine

The role of thyroid hormones in vertebrate development has been well documented for several decades. As hypothyroidism during critical periods of development can cause defects to the development of every major organ system, including brain, eye, and general morphology, we hypothesized that hypothyroidism would affect specific behaviors. To assess this, we treated zebrafish with the hypothyroid drug methimazole (MMI) and examined changes in anxiety, shoaling, vision, and locomotion. Following low-dose MMI exposure for the first 10 days of life, a time of rapid and significant development, larvae were removed from treatment and allowed to develop until 1 month of age. Comparisons between treated and controls took place between 10 and 30 days postfertilization to examine times both during and after treatment. Using the novel tank and startle response tests, we found that anxiety behaviors are significantly increased following MMI treatment. These effects persisted for several days following removal from treatment and indicate a prolonged effect of early hypothyroidism. However, permanent MMI effects on anxiety were not observed, as anxiety behaviors of early treated zebrafish recovered to control levels following 10 days out of treatment. In contrast to the strong link between MMI treatment and anxiety, shoaling and visual behaviors were not significantly affected within our experimental parameters. This indicates that disruption of thyroid system functioning early in life can differentially affect behavior by specifically altering anxiety responses without producing indiscriminate changes to overall behavioral development.

Topics: Animals; Antithyroid Agents; Anxiety; Behavior, Animal; Case-Control Studies; Embryo, Nonmammalian; Hypothyroidism; Methimazole; Thyroid Gland; Zebrafish

Thyroid hormone (TH) through its receptor (TRα/β) influences spatio-temporal regulation of its target gene repertoire during brain development. Though hypothyroidism in WT rodent models of perinatal hypothyroidism severely impairs neurodevelopment, its effect on TRα/β knockout mice is less severe. An explanation to this paradox is attributed to a possible repressive action of unliganded TRs during development. Since unliganded TRs suppress gene expression through the recruitment of histone deacetylase (HDACs) via co-repressor complexes, we tested whether pharmacological inhibition of HDACs may prevent the effects of hypothyroidism on brain development. Using valproate, an HDAC inhibitor, we show that HDAC inhibition significantly blocks the deleterious effects of hypothyroidism on rat cerebellum, evident by recovery of TH target genes like Bdnf, Pcp2 and Mbp as well as improved dendritic structure of cerebellar Purkinje neurons. Together with this, HDAC inhibition also rescues hypothyroidism-induced motor and cognitive defects. This study therefore provides an insight into the role of HDACs in TH insufficiency during neurodevelopment and their inhibition as a possible therapeutics for treatment.

Topics: Animals; Animals, Newborn; Brain-Derived Neurotrophic Factor; Cerebellum; Co-Repressor Proteins; Disease Models, Animal; Female; Histone Deacetylase Inhibitors; Histone Deacetylases; Hypothyroidism; Methimazole; Neurodevelopmental Disorders; Pregnancy; Rats; Rats, Wistar; Thyroid Hormones; Valproic Acid

Available data from in vitro studies show that thyroid hormones (THs) regulate herpes simplex virus (HSV) gene expression and may modulate latency/reactivation of the virus. Whether infectivity of the virus is also affected by THs is not known. Using animal models (in vivo study) and Vero cell culture (in vitro study), we examined the effects of alterations in THs level on HSV-1 infectivity.. Rats were rendered hypo- and hyperthyroid by daily addition of methimazole and l-thyroxine into their drinking water, respectively. Euthyroid animals served as control. All animals were given a single dose of HSV-1 (10(7)TCID50, ip) and sacrificed 3 d later. The spleen of the animals was then removed and viral particles were recovered from the tissue extract through aseptic procedures. Serial dilution of the extracts was prepared and added to Vero cell culture. For the in vitro study, the cultures were pretreated with l-thyroxine and the viral particles were then added. Virus titration was determined by Reed-Muench quantal assay.. The viral load of spleen in hyperthyroid rats was significantly lower (1000-fold) than that of the euthyroid rats. Similarly, in vitro presence of supraphysiologic levels of l-thyroxine in the culture media of Vero cells decreased virus infectivity. Interestingly, hypothyroid animals showed a significant increase (10-fold) in spleen viral load as compared to that of their euthyroid counterparts.. These data clearly show that the HSV-1 infectivity is affected by THs, and suggest that THs or their analogs may have a potential application in prevention and/or treatment of viral infections.

Topics: Animals; Antithyroid Agents; Chlorocebus aethiops; Disease Models, Animal; Herpes Simplex; Herpesvirus 1, Human; Hyperthyroidism; Hypothyroidism; Male; Methimazole; Rats, Sprague-Dawley; Thyroid Gland; Thyroxine; Vero Cells

Hypothyroidism has been associated to psychiatric disorder development and tissue oxidative damage. In this study, we evaluated the effect of diphenyl diselenide supplementation on depressive-like behavior triggered by methimazole exposure in female rats. Additionally, thiobarbituric acid reactive substances (TBARS), reactive oxygen species (ROS) and non-protein thiol (NP-SH) levels were analyzed in cerebral cortex, hippocampus and striatum structures of rats. Monoamine oxidase (MAO) activity was evaluated in total brain. Firstly, female rats received methimazole (MTZ) 20mg/100ml in the drinking water for 30days and were evaluated in open-field and forced swimming tests (FST). In this set of experiments, the rats exposed to MTZ presented a depressive-like behavior, which was evidenced by a significant increase in the immobility time when compared to control group. Thereafter, MTZ-induced hypothyroid rats received either a standard or a diet containing 5ppm of diphenyl diselenide, and then they were evaluated monthly in open-field and FST tests during 3months. No alteration on the locomotor performance was observed among the groups. The depressive-like behavior of hypothyroid rats was blunted by diphenyl diselenide supplementation during all experimental periods. The levels of thyroid hormones remained low in MTZ exposed groups until the end of experimental period. The MTZ group had an increase in TBARS and ROS levels that were restored by diphenyl diselenide supplementation. NP-SH content of cerebral structures was not modified by MTZ exposure and/or diphenyl diselenide supplementation. Diphenyl diselenide supplementation restored the MAO B activity that was decreased in MTZ group. In summary, our results show that hypothyroidism induced by MTZ methimazole triggers a depressive-like behavior in female rats and that dietary diphenyl diselenide was able to reduce this effect.

Topics: Animals; Antidepressive Agents; Benzene Derivatives; Brain; Depression; Female; Hypothyroidism; Immobility Response, Tonic; Lipid Peroxidation; Methimazole; Monoamine Oxidase; Motor Activity; Organoselenium Compounds; Rats; Reactive Oxygen Species; Sulfhydryl Compounds; Thiobarbituric Acid Reactive Substances; Thyroid Hormones

Thyroid hormone levels are implicated in mood disorders in the adult human but the mechanisms remain unclear partly because, in rodent models, more attention has been paid to the consequences of perinatal hypo and hyperthyroidism. Thyroid hormones act via the thyroid hormone receptor (TR) α and β isoforms, both of which are expressed in the limbic system. TR's modulate gene expression via both unliganded and liganded actions. Though the thyroid hormone receptor (TR) knockouts and a transgenic TRα1 knock-in mouse have provided us valuable insight into behavioral phenotypes such as anxiety and depression, it is not clear if this is because of the loss of unliganded actions or liganded actions of the receptor or due to locomotor deficits. We used a hypothyroid mouse model and supplementation with tri-iodothyronine (T3) or thyroxine (T4) to investigate the consequences of dysthyroid hormone levels on behaviors that denote anxiety. Our data from the open field and the light-dark transition tests suggest that adult onset hypothyroidism in male mice produces a mild anxiogenic effect that is possibly due to unliganded receptor actions. T3 or T4 supplementation reverses this phenotype and euthyroid animals show anxiety that is intermediate between the hypothyroid and thyroid hormone supplemented groups. In addition, T3 but not T4 supplemented animals have lower spine density in the CA1 region of the hippocampus and in the central amygdala suggesting that T3-mediated rescue of the hypothyroid state might be due to lower neuronal excitability in the limbic circuit.

Topics: Animals; Anxiety; Conditioning, Classical; Disease Models, Animal; Fear; Hypothyroidism; Male; Methimazole; Mice; Mice, Inbred C57BL; Thyroxine; Triiodothyronine

Hypothyroidism affects neuron population dynamics in the hippocampus of the adult rat, with neuronal damage as the main feature of its effect. This effect is prevented by the blockade of NMDA receptors, which suggests that glutamatergic activity mediates cell death in this condition. Glutamate can also stimulate cell proliferation and survival of newborn neurons, indicating that it can affect different stages of the cell cycle. In this work we measured the expression of specific proteins that control cell proliferation (cycline-D1), cell arrest (p21), damage (p53) or apoptosis (Bax and Bcl2) in the hippocampus of hypothyroid rats treated with the NMDA receptor (NMDAR) blocker MK-801 during the induction of hypothyroidism. The results show that hypothyroidism increases the expression of markers of DNA damage, cell arrest, and apoptosis, but does not affect the marker of cell proliferation. NMDAR blockade prevents the increase on markers of DNA damage and apoptosis, but does not influence cell arrest or cell proliferation. This suggests that hypothyroidism promotes cell death mainly by an excitotoxic effect of glutamate.

Topics: Analysis of Variance; Animals; Antithyroid Agents; Apoptosis; bcl-2-Associated X Protein; Cyclin D1; Cyclin-Dependent Kinase Inhibitor p21; Disease Models, Animal; Dizocilpine Maleate; Excitatory Amino Acid Antagonists; Gene Expression Regulation; Hippocampus; Hypothyroidism; Methimazole; Proto-Oncogene Proteins c-bcl-2; Rats; Tumor Suppressor Protein p53

Myopathy is a known complication of hypothyroidism, commonly characterized by an elevation in Creatine Kinase (CPK) due to increase capillary permeability proportional to the hypothyroid state. Thyroid hormone is important for the expression of fast myofibrillar proteins in the muscle. In hypothyroidism the expression of these proteins are deficient and there is an increase accumulation of slow myofibrillar proteins. A rapid or abrupt descend in thyroid hormones caused by radioiodine therapy after prolonged hyperthyroidism can lead to local hypothyroid state within the muscle tissue, resulting in CPK elevation and hypothyroid myopathy. Hormone replacement leads to resolution of symptoms and normalization of muscle enzymes serum levels.

Topics: Diagnosis, Differential; Edema; Electromyography; Emergencies; Female; Graves Disease; Hormone Replacement Therapy; Humans; Hyperthyroidism; Hypothyroidism; Iodine Radioisotopes; Magnetic Resonance Imaging; Methimazole; Muscle Cramp; Muscle Weakness; Propranolol; Reflex, Abnormal; Thyroid Hormones; Thyroxine; Young Adult

The objective of the present study was to evaluate the effect of quercetin on oxidative stress biomarkers in methimazole (MMI) - induced hypothyroidism male rats. Hypothyroidism was induced by administering MMI at 20 mg/100 ml in the drinking water, for 1 month. After achieved hypothyroidism, rats received orally 10 or 25 mg/kg of quercetin (QT) for 8 weeks. 60 male wistar rats were randomly divided into 6 groups (group I, control; group II, QT10; group III, QT25; group IV, hypothyroid; group V, hypothyroid+QT10; group VI, hypothyroid+QT25). Liver, kidney and serum TBARS levels significantly increased in hypothyroid rats when compared to controls, along with increased protein carbonyl (PCO) in liver and increased ROS levels in liver and kidney tissues. QT10 and QT25 were effective in decreasing TBARS levels in serum and kidney, PCO levels in liver and ROS generation in liver and kidney. MMI - induced hypothyroidism also increased TBARS levels in cerebral cortex and hippocampus that in turn were decreased in rats treated with QT25. Moreover, the administration of QT25 to hypothyroid rats resulted in decreased SOD activities in liver and whole blood and increased liver CAT activity. Liver and kidney ascorbic acid levels were restored with quercetin supplementation at both concentrations. QT10 and QT25 also significantly increased total oxidative scavenging capacity in liver and kidney tissues from hypothyroid rats. These findings suggest that MMI - induced hypothyroidism increases oxidative stress parameters and quercetin administration could exert beneficial effects against redox imbalance in hypothyroid status.

Topics: Animals; Antioxidants; Antithyroid Agents; Biomarkers; Hypothyroidism; Male; Methimazole; Oxidative Stress; Quercetin; Rats; Rats, Wistar

Thyroid hormones are essential for the maturation and functions of the central nervous system. Pain sensitivity is related to the thyroid status. However, information on how thyroid hormones affect pain processing and synaptic transmission in the anterior cingulate cortex (ACC) is limited. Nociceptive threshold and synaptic transmission in the ACC were detected in the experimental hypothyroidism (HT) mice.. HT was induced by methimazole and potassium perchlorate in distilled drinking water for 4 weeks. The threshold of pain perception to hot insults, but not mechanical ones, decreased in hypothyroid mice. After treatment with tri-iodothyronine (T3) or thyroxine (T4) for 2 weeks, thermal pain threshold recovered. Electrophysiological recordings revealed enhanced glutamatergic synaptic transmission and reduced GABAergic synaptic transmission in the ACC. Supplementation with T3 or T4 significantly rescued this synaptic transmission imbalance. In the same model, HT caused the up-regulation of the GluR1 subunit of the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor and NR2B-containing N-methyl-D-aspartate receptors, but it down-regulated γ-aminobutyric acid A receptors in the ACC. Supplementation with T3 or T4 notably recovered the levels of above proteins.. These results suggest that HT promotes hypersensitivity to noxious thermal, and that supplementation with T3 or T4 rescues the imbalance between excitatory and inhibitory transmission in the ACC.

Topics: Animals; Disease Models, Animal; Excitatory Postsynaptic Potentials; Gyrus Cinguli; Hyperalgesia; Hypothyroidism; In Vitro Techniques; Male; Methimazole; Mice; Mice, Inbred C57BL; Pain Threshold; Perchlorates; Potassium Compounds; Receptors, AMPA; Receptors, N-Methyl-D-Aspartate; Synaptic Transmission; Thyroxine; Triiodothyronine; Up-Regulation

Cellular antioxidant signaling can be altered either by thyroid disturbances or by selenium status.. To investigate whether or not dietary diphenyl diselenide can modify the expression of genes of antioxidant enzymes and endpoint markers of oxidative stress under hypothyroid conditions.. Female rats were rendered hypothyroid by continuous exposure to methimazole (MTZ; 20 mg/100 ml in the drinking water) for 3 months. Concomitantly, MTZ-treated rats were either fed or not with a diet containing diphenyl diselenide (5 ppm). mRNA levels of antioxidant enzymes and antioxidant/oxidant status were determined in the cerebral cortex, hippocampus and striatum.. Hypothyroidism caused a marked upregulation in mRNA expression of catalase, superoxide dismutase (SOD-1, SOD-3), glutathione peroxidase (GPx-1, GPx-4) and thioredoxin reductase (TrxR-1) in brain structures. SOD-2 was increased in the cortex and striatum, while TrxR-2 increased in the cerebral cortex. The increase in mRNA expression of antioxidant enzymes was positively correlated with the Nrf-2 transcription in the cortex and hippocampus. Hypothyroidism caused oxidative stress, namely an increase in lipid peroxidation and reactive oxygen species levels in the hippocampus and striatum, and a decrease in nonprotein thiols in the cerebral cortex. Diphenyl diselenide was effective in reducing brain oxidative stress and normalizing most of the changes observed in gene expression of antioxidant enzymes.. The present work corroborates and extends that hypothyroidism disrupts antioxidant enzyme gene expression and causes oxidative stress in the brain. Furthermore, diphenyl diselenide may be considered a promising molecule to counteract these effects in a hypothyroidism state.

Topics: Animals; Antioxidants; Benzene Derivatives; Body Weight; Cerebral Cortex; Corpus Callosum; Disease Models, Animal; Female; Hippocampus; Hypothyroidism; Lipid Peroxidation; Methimazole; NF-E2-Related Factor 2; Organoselenium Compounds; Oxidative Stress; Random Allocation; Rats, Wistar; Reactive Oxygen Species; RNA, Messenger; Sulfhydryl Compounds

The thyroid hormone triiodothyronine (T3) is known to affect energy balance. Recent evidence points to an action of T3 in the hypothalamus, a key area of the brain involved in energy homeostasis, but the components and mechanisms are far from understood. The aim of this study was to identify components in the hypothalamus that may be involved in the action of T3 on energy balance regulatory mechanisms.. Sprague Dawley rats were made hypothyroid by giving 0.025% methimazole (MMI) in their drinking water for 22 days. On day 21, half the MMI-treated rats received a saline injection, whereas the others were injected with T3. Food intake and body weight measurements were taken daily. Body composition was determined by magnetic resonance imaging, gene expression was analyzed by in situ hybridization, and T3-induced gene expression was determined by microarray analysis of MMI-treated compared to MMI-T3-injected hypothalamic RNA.. Post mortem serum thyroid hormone levels showed that MMI treatment decreased circulating thyroid hormones and increased thyrotropin (TSH). MMI treatment decreased food intake and body weight. Body composition analysis revealed reduced lean and fat mass in thyroidectomized rats from day 14 of the experiment. MMI treatment caused a decrease in circulating triglyceride concentrations, an increase in nonesterified fatty acids, and decreased insulin levels. A glucose tolerance test showed impaired glucose clearance in the thyroidectomized animals. In the brain, in situ hybridization revealed marked changes in gene expression, including genes such as Mct8, a thyroid hormone transporter, and Agrp, a key component in energy balance regulation. Microarray analysis revealed 110 genes to be up- or downregulated with T3 treatment (± 1.3-fold change, p<0.05). Three genes chosen from the differentially expressed genes were verified by in situ hybridization to be activated by T3 in cells located at or close to the hypothalamic ventricular ependymal layer and differentially expressed in animal models of long- and short-term body weight regulation.. This study identified genes regulated by T3 in the hypothalamus, a key area of the brain involved in homeostasis and neuroendocrine functions. These include genes hitherto not known to be regulated by thyroid status.

Topics: Animals; Blood Glucose; Body Composition; Body Weight; Eating; Energy Metabolism; Gene Expression Regulation; Homeostasis; Hypothalamus; Hypothyroidism; Male; Methimazole; Rats; Rats, Sprague-Dawley; Triiodothyronine

Thyroid hormones are required for vertebrate development, and disruption of the thyroid system in developing embryos can result in a large range of morphologic and physiologic changes, including in the eye and retina. In this study, our anatomic analyses following low-dose, chronic thyroid inhibition reveal that both methimazole (MMI) exposure and rearing temperature affect eye development in a time- and temperature-dependent fashion. Maximal sensitivity to MMI for external eye development occurred at 65 hr postfertilization (hpf) for zebrafish reared at 28°C, and at 69 hpf for those reared at 31°C. Changes in eye diameter corresponded to changes in thickness of two inner retinal layers: the ganglion cell layer and the inner plexiform layer, with irreversible MMI-induced decreases in layer thickness observed in larvae treated with MMI until 66 hpf at 28°C. We infer that maximal sensitivity to MMI between 65 and 66 hpf at 28°C indicates a critical period of thyroid-dependent eye and retinal development. Furthermore, our results support previous work that shows spontaneous escape from MMI-induced effects potentially due to embryonic compensatory actions, as our data show that embryos treated beyond the critical period generally resemble controls.

Topics: Animals; Antithyroid Agents; Embryo, Nonmammalian; Hypothyroidism; Methimazole; Retina; Temperature; Thyroid Gland; Thyroid Hormones; Zebrafish

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

Prenatal ultrasonography of a pregnant woman with a past history of total thyroidectomy for Graves' disease detected fetal tachycardia, fetal growth restriction and oligohydramnios at 30 weeks gestation. Because a high titer of thyroid-stimulating hormone receptor antibody was noted in maternal serum and the fetal goiter was detected on ultrasonography, fetal hyperthyroidism was strongly suspected and subsequently confirmed with cordocentesis at 31 weeks gestation. After treatment of fetal hyperthyroidism through oral maternal administration of methimazole (MMI) starting at 33 weeks gestation, fetal heart rate and amniotic fluid volume returned to normal ranges. Complete resolution of the fetal goiter was observed at 35 weeks gestation. A male infant was born at 35 weeks 6 days gestation via cesarean section in the absence of thyrotoxic findings; however, cord blood chemical analysis at birth indicated iatrogenic fetal hypothyroidism. In the present report, maternal therapy using MMI to resolve symptoms of fetal thyrotoxicosis, including fetal tachycardia and oligohydramnios, was successfully conducted.

Topics: Antithyroid Agents; Cordocentesis; Female; Fetal Diseases; Goiter; Graves Disease; Humans; Hyperthyroidism; Hypothyroidism; Male; Methimazole; Middle Aged; Neck; Oligohydramnios; Pregnancy; Pregnancy Complications; Pregnancy Outcome; Tachycardia; Thyroidectomy; Thyroxine; Ultrasonography, Doppler, Color; Ultrasonography, Prenatal

Although most patients remain clinically euthyroid, some develop amiodarone-induced hyperthyroidism (HPEAI) or hypothyroidism (HPOAI). The authors present a retrospective analysis of ten patients with amiodarone-induced thyroid dysfunction. Six patients were female and mean amiodarone intake was 17.7 months. HPOIA was more common (six patients). From all the patients with HPEAI, two had type 2, one had type 1, and one had type 3 hyperthyroidism. Symptoms suggestive of thyroid dysfunction occurred in five patients, most of them with HPOAI. In HPEAI, the most frequent symptom was exacerbation of arrhythmia (three patients). Discontinuation of amiodarone and treatment with levothyroxine was chosen in 83.3% of the HPOAI cases, while thyonamide treatment with corticosteroids and without amiodarone was the option in 75% of the HPEAI cases. There were three deaths, all in patients with HPEAI. HPEAI is potentially fatal. The clinical picture may be vague, so the thyroid monitoring is mandatory.

Topics: Aged; Aged, 80 and over; Amiodarone; Anti-Arrhythmia Agents; Antithyroid Agents; Drug Combinations; Female; Glucocorticoids; Humans; Hyperthyroidism; Hypothyroidism; Male; Methimazole; Middle Aged; Retrospective Studies; Thyroxine; Treatment Outcome; Withholding Treatment

Thyroid hormones (THs) are essential for proper brain development in mammals. TH insufficiency during early development causes structural and functional abnormalities in brain leading to cognitive dysfunction. The specific effects of developmental hypothyroidism on attention have not been well characterized in animal models. The present study was conducted to characterize the effects of developmental hypothyroidism on attention in rats, and tested the hypothesis that the hypothyroidism has adverse impacts on attention by means of a visual signal detection task. Pregnant rats were exposed to the anti-thyroid drug, methimazole (0.02% w/v) via drinking water from gestational day 15 through postnatal day (PND) 21 to induce maternal and neonatal hypothyroidism. Male offspring served as subjects for the task started on PND 90. A light stimulus (500 ms, 250 ms or 50 ms) was presented in signal trials and not in blank trials. The offspring were required to discriminate these signal events, and subsequently press the correct lever. The correct response for signal and non-signal events was considered as hit and correct rejection, respectively. The hypothyroid offspring exhibited a decreased hit response for short signals (250 ms and 50 ms) which requires the higher attentional demand. The total number of lever responses during inter-trial interval (ITI) was also increased in the hypothyroid group. The number of lever responses was negatively correlated with a hit response at 50 ms, not at 250 ms. These results suggest that developmental hypothyroidism disrupts signal detection performance via impairment of visual attention and the altered lever response behavior.

Topics: Age Factors; Analysis of Variance; Animals; Animals, Newborn; Antithyroid Agents; Attention; Body Weight; Conditioning, Operant; Female; Hypothyroidism; Male; Methimazole; Perceptual Disorders; Pregnancy; Prenatal Exposure Delayed Effects; Rats; Reaction Time; Reinforcement, Psychology; Signal Detection, Psychological

Methimazole (MMI) is an anti-thyroid drug used in the treatment of chronic hyperthyroidism. There is, however, some debate about its use during pregnancy as MMI is known to cross the mammalian placenta and reach the developing foetus. A similar problem occurs in birds, where MMI is deposited in the egg and taken up by the developing embryo. To investigate whether maternally derived MMI can have detrimental effects on embryonic development, we treated laying hens with MMI (0.03% in drinking water) and measured total and reduced MMI contents in the tissues of hens and embryos at different stages of development. In hens, MMI was selectively increased in the thyroid gland, while its levels in the liver and especially brain remained relatively low. Long-term MMI treatment induced a pronounced goitre with a decrease in thyroxine (T₄) content but an increase in thyroidal 3,5,3'-triiodothyronine (T₃) content. This resulted in normal T₃ levels in tissues except in the brain. In chicken embryos, MMI levels were similar in the liver and brain. They gradually decreased during development but always remained above those in the corresponding maternal tissues. Contrary to the situation in hens, T₄ availability was only moderately affected in embryos. Peripheral T₃ levels were reduced in 14-day-old embryos but normal in 18-day-old embryos, while brain T₃ content was decreased at all embryonic stages tested. We conclude that all embryonic tissues are exposed to relatively high doses of MMI and its oxidised metabolites. The effect of maternal MMI treatment on embryonic thyroid hormone availability is most pronounced for brain T₃ content, which is reduced throughout the embryonic development period.

Topics: Animals; Antithyroid Agents; Biotransformation; Brain; Chick Embryo; Chickens; Egg White; Egg Yolk; Embryonic Development; Female; Gene Expression Regulation, Developmental; Hypothyroidism; Iodide Peroxidase; Kidney; Liver; Methimazole; Organ Size; Oxidation-Reduction; RNA, Messenger; Thyroid Gland; Thyroid Hormones; Tissue Distribution

The EphA5 receptor has recently been known to play an important role in the initiation of the early phase of synaptogenesis, during which irreparable harm would be done to the developing brain in the absence of sufficient thyroid hormone (TH). In the present article, we aimed to analyze the characteristics of EphA5 receptor expression in the brain of congenital hypothyroid rats. The results showed that the levels of the EphA5 receptor were downregulated by TH deficiency in the developing rat brain with remarkable spatial and temporal characteristics. In the hypothyroid rats, the mRNA and protein levels of EphA5 receptor decreased significantly in the hippocampus (27.92-53.26%), cerebral cortex (12.52-47.16%), and cerebellum (8.72-31.69%) compared with those in the normal rats from postnatal day 0 (P0) to P21 (p < 0.01). The expression of EphA5 receptor was highest and declined most as much as 53% in the hippocampus with TH deficiency. At P7, the EphA5 receptor decreased most prominently during all the observed time point.. The EphA5 receptor plays actively in the brain development in congenital hypothyroid rats. Our study highlights the high expression of EphA5 receptor protein in hippocampus and dramatic changes at P7 in condition of TH deficiency, which may provide important basis for further investigations in manipulating congenital hypothyroidism.

Topics: Animals; Antithyroid Agents; Brain; Congenital Hypothyroidism; Disease Models, Animal; Female; Fluorescent Antibody Technique; Gene Expression; Hypothyroidism; Male; Methimazole; Rats; Rats, Sprague-Dawley; Real-Time Polymerase Chain Reaction; Receptor, EphA5; RNA, Messenger; Thyroid Hormones

Thyroid hormones have many effects on cardiovascular function, and deficiency or excess of thyroid hormones can result in cardiac dysfunction. Abnormalities of the cardiovascular system are often identified during examination of hyperthyroid and hypothyroid patients. This article addresses the effects of thyroid hormones on the cardiovascular system and the clinical relevance of the cardiovascular response to thyroid dysfunction. In addition, treatment recommendations are presented.

Topics: Animals; Antithyroid Agents; Cardiovascular Diseases; Cat Diseases; Cats; Dog Diseases; Dogs; Hyperthyroidism; Hypothyroidism; Methimazole; Thyroxine

Neurotoxicity of iodine deficiency-induced hypothyroidism during developmental period results in serious impairments of brain function, such as learning and memory. These impairments are largely irreversible, and the underlying mechanisms remain unclear. In addition to hypothyroidism, iodine deficiency may cause hypothyroxinemia, a relatively subtle form of thyroid hormone deficiency. Neurotoxicity of developmental hypothyroxinemia also potentially impairs learning and memory. However, more direct evidence of the associations between developmental hypothyroxinemia and impairments of learning and memory should be provided, and the underlying mechanisms remain to be elucidated. Thus, in the present study, we investigated the effects of developmental hypothyroxinemia and hypothyroidism on long-term potentiation (LTP), a widely accepted cellular model of learning and memory, in the hippocampal CA1 region. The activation of the phosphatidylinositol 3-kinase (PI3K) signaling pathway - a pathway closely associated with synaptic plasticity and learning and memory - was also investigated. Wistar rats were treated with iodine deficient diet or methimazole (MMZ) to induce developmental hypothyroxinemia or hypothyroidism. The results showed that developmental hypothyroxinemia caused by mild iodine deficiency and developmental hypothyroidism caused by severe iodine deficiency or MMZ significantly reduced the field-excitatory postsynaptic potential (f-EPSP) slope and the population spike (PS) amplitude. Decreased activation of the PI3K signaling pathway was also observed in rats subjected to developmental hypothyroxinemia or hypothyroidism. Our results may support the hypothesis that neurotoxicity of both developmental hypothyroxinemia and hypothyroidism causes damages to learning and memory. Our results also suggest that decreased activation of the PI3K signaling pathway may contribute to impairments of LTP caused by neurotoxicity of both developmental hypothyroxinemia and hypothyroidism.

Topics: Animals; Antithyroid Agents; Blotting, Western; CA1 Region, Hippocampal; Diet; Electric Stimulation; Excitatory Postsynaptic Potentials; Female; Fluorescent Antibody Technique; Hypothyroidism; Immunohistochemistry; Iodine; Long-Term Potentiation; Methimazole; Neurotoxicity Syndromes; Phosphatidylinositol 3-Kinases; Rats; Rats, Wistar; Signal Transduction; Thyrotropin; Thyroxine; TOR Serine-Threonine Kinases; Triiodothyronine

Iodine is essential for the biosynthesis of thyroid hormones, including triiodothyronine and thyroxine. Thyroid hormones are important for central nervous system development. Mild maternal iodine deficiency (ID)-induced hypothyroxinaemia causes neurological deficits and mental retardation of the foetus. However, the detailed mechanism underlying these deficits is still largely unknown. Given that the growth-associated protein of 43 kDa (GAP-43), semaphorin 3A (Sema3A) and the glycogen synthase kinase 3β (GSK3β)/collapsin response mediator protein 2 (CRMP2) pathway are essential for axonal development, we hypothesise that hippocampal axonal growth-related proteins may be impaired, which may contribute to hippocampal axonal growth delay in rat offspring exposed to maternal hypothyroxinaemia. To test this hypothesis, maternal hypothyroxinaemia models were established in Wistar rats using a mild ID diet. Besides a negative control group, two maternal hypothyroidism models were created with either a severe ID diet or methimazole in the water. Our results showed that maternal hypothyroxinaemia exposure delayed offspring axonal growth on gestational day 19, postnatal day (PN) 7, PN14 and PN21. Consistent with this, the mean intensity of hippocampal CRMP2 and Tau1 immunofluorescence axonal protein was reduced in the mild ID group. Moreover, maternal hypothyroxinaemia disrupted expressions of GAP-43 and Sema3A. Furthermore, the phosphorylation of GSK3β and CRMP2 was also affected in the treated offspring, implying a potential mechanism by which hypothyroxinaemia-exposure affects neurodevelopment. Taken together, our data support the hypothesis that maternal hypothyroxinaemia may impair axonal growth of the offspring.

Topics: Animals; Axons; Cell Enlargement; Female; GAP-43 Protein; Gene Expression Regulation, Developmental; Glycogen Synthase Kinase 3; Glycogen Synthase Kinase 3 beta; Hippocampus; Hypothyroidism; Intercellular Signaling Peptides and Proteins; Iodine; Male; Methimazole; Nerve Tissue Proteins; Phosphorylation; Pregnancy; Rats; Semaphorin-3A; tau Proteins

In experiments on sexually mature rats we studied specific cholinergic regulations of the heart and the degree of its structural damage in hypothyroidism, depending on gender and hormone-productive activity of the gonads. Hypothyroidism in sexually mature males and females was modelled with mercazolil intragastric administration (75 mg/kg) daily during 15 days. We also studied the intensity of bradycardia, which occurred in response to electrical stimulation of vagus nerve and intravenous acetylcholine administration. The degree of structural heart damage was assessed by the percentage of damaged cardiomyocytes in the ventricles of myocardium. It was found that one of the mechanisms of bradycardia in merkazolil-induced hypothyroidism is an increase of the sensitivity of sinus node cholinergic receptors and release of more quanta of acetylcholine from stimulated nerves vagus endings, what was more intense in females. The intensity of bradycardia in hypothyroidism was more significant in gonadectomized animals than in individuals with preserved gonads. The mechanisms of its occurrence in males consist of release of greater amount of acetylcholine from the endings of the nerves vagus, and in females it was the result of significant increase of the sensitivity of sinus node cholinergic receptors. Regardless of the gonads activity, structural damage of the myocardium in merkazolil-induced hypothyroidism was more intensive in female rats.

Topics: Acetylcholine; Animals; Bradycardia; Disease Models, Animal; Female; Heart Ventricles; Hypothyroidism; Male; Methimazole; Myocardium; Myocytes, Cardiac; Orchiectomy; Ovariectomy; Rats; Receptors, Cholinergic; Sex Characteristics; Sinoatrial Node; Vagus Nerve; Vagus Nerve Stimulation; Ventricular Function

Thyroid hormone (TH) plays essential roles in normal brain development mainly by regulating gene expression through binding to specific nuclear receptors which serve as transcription factors. Previous studies showed that perinatal deficiency of TH or impairment of its signaling severely affect brain development, especially the development of the γ-aminobutyric acid (GABA) system, but cellular and molecular targets of the hormone are only partly uncovered. In the present study, we focused on the developing rat hippocampus which was confirmed to be one of the regions highly sensitive to TH status, and found two new targets of the hormone among the pre- and post-synaptic components of the GABAergic system. One was glutamic acid decarboxylase 65 (GAD65), the protein level of which was reduced to less than 50% of control in the hippocampus of hypothyroid rats (obtained by administering 0.025% methimazole in drinking water to pregnant dams from gestational day 15 until 4 weeks postpartum) and recovered to control levels by daily thyroxine-replacement after birth. Reduction in GAD65 protein was correlated immunohistochemically with a 37% reduction in the number of GAD65-positive cells as well as a reduction in GAD65-positive processes. In contrast, the other GAD isotype, GAD67, was not affected by TH status. A subpopulation of GABAergic neurons containing parvalbumin was also confirmed to be highly dependent on TH status. The second target of thyroid hormone was neuron-specific K(+)/Cl(-) co-transporter, KCC2, which is responsible for switching of GABA action from excitatory to inhibitory. In the euthyroid hippocampus, a sharp rise of kcc2 expression was observed at postnatal day (PND)10 which was followed by a large increase in KCC2 protein at PND15. This transient rise in kcc2 expression was completely suppressed by hypothyroidism, resulting in nearly 80% reduction in KCC2 protein at PND15. These results indicate that the development of GABAergic terminals and the excitatory to inhibitory maturation of GABA signaling are strongly dependent on TH.

Topics: Age Factors; Animals; Animals, Newborn; Disease Models, Animal; Female; gamma-Aminobutyric Acid; Gene Expression Regulation, Developmental; Glutamate Decarboxylase; Hippocampus; Hypothyroidism; Imidazoles; K Cl- Cotransporters; Male; Parvalbumins; Pregnancy; Rats; Rats, Wistar; Symporters; Thyroid Hormones; Thyroxine

In experiments at 78 adult white outbred male rats were demonstrated that experimental hypothyroidism (injection of 25 mg/kg merkazolil within 20 days) stimulates, while small doses of L-thyroxine (1.5-3.0 μg/kg within 28 days) limit the intensification of lipid peroxidation in the myocardium under short exposure to stressors of a different nature: physical (t 4-5 °C within 30 minutes), chemical (injection of 25% ethanol at a dose of 3.5 g/kg body weight), and emotional (free swimming of rats in the cage within 30 minutes) by influence on the activity of enzymatic (superoxide dismutase and catalase) and non-enzymatic (reduced glutathione) components of the antioxidant system.

Topics: Animals; Antioxidants; Antithyroid Agents; Hypothyroidism; Lipid Peroxidation; Male; Methimazole; Myocardium; Rats; Stress, Physiological

Thyroid hormones play a crucial role in new neuron production and maturation during brain development. Physical exercise is known to promote cell survival and functional recovery after brain injuries. In the present study, we investigated the effects of treadmill exercise on short-term memory, spatial learning ability, neurogenesis, and apoptosis in hypothyroidism rat pups. On the 14th perinatal day, the pregnant rats were divided into two groups: the maternal control group and the maternal methimazole (MMI)-treated group. For the induction of hypothyroidism in rat pups, MMI was added to the drinking water (0.02%, wt/vol), from the 14th prenatal day to the 49th postnatal day. After delivery, the male rat pups born from the maternal control group were assigned into the control group and the control and exercise group. The rat pups born from the maternal MMI-treated group were divided into the hypothyroidism-induction group and the hypothyroidism-induction and treadmill exercise group. The rat pups in the exercise groups were forced to run on a motorized treadmill for 30min once a day, starting on the 22nd postnatal day for 4 weeks. Induction of hypothyroidism during the fetal and early postnatal period showed suppression of neurogenesis and enhancement of apoptosis in the hippocampus. Short-term memory and spatial learning ability were deteriorated in the hypothyroidism rat pups. Treadmill exercise during the postnatal period increased neurogenesis and inhibited apoptosis, and resulted in the improvement of short-term memory and spatial learning ability in the hypothyroidism rat pups.

Topics: Animals; Apoptosis; Female; Hippocampus; Hypothyroidism; Male; Maze Learning; Methimazole; Neurogenesis; Physical Conditioning, Animal; Rats; Rats, Sprague-Dawley; Thyroxine; Triiodothyronine

The aim of this study was to examine whether the relative gene expression of AdipoR1 and AdipoR2 in rat adipose tissue is altered by thyroid hormones, and whether this might relate to their circulating thyroid hormones and adiponectin levels. Hyper- and hypothyroidism were induced by daily oral administration of levothyroxine and methimazole in rats, respectively, over a 42 days period. Real-time PCR analysis was performed to evaluate the changes in AdipoR1 and AdipoR2 mRNA levels in the adipose tissue on days 15, 28, 42, and also 2 weeks after the cessation of treatment. In response to treatment with methimazole, mRNA levels of AdipoR1 and AdipoR2 decreased in the white adipose tissue compared to the euthyroid rats (p < 0.05). This decline was reversible 2 weeks after treatment cessation. The mRNA levels of AdipoR1 and AdipoR2 were increased in the hyperthyroid group of animals compared to euthyroid control (p < 0.05), and its changes were reversible 2 weeks after treatment cessation (P < 0.05). Adiponectin receptors gene expression levels in the adipose tissue of treated animals have positive correlations with thyroid hormones concentrations. Our results suggest that AdipoR1 and AdipoR2 gene expression is regulated by thyroid hormones in hypo- and hyperthyroidism.

Topics: Adiponectin; Animals; Female; Gene Expression Regulation; Hyperthyroidism; Hypothyroidism; Intra-Abdominal Fat; Methimazole; Organ Specificity; Rats; Rats, Sprague-Dawley; Receptors, Adiponectin; RNA, Messenger; Thyroxine; Triiodothyronine

Thyroid hormones modulate the physiology of the hippocampus in humans, where glutamate plays an important role as neurotransmitter. The aim of this work was to study the effect of hypothyroidism on hippocampal glutamate extracellular levels, release, uptake, and synthesis. The effects of PDC (a glutamate transporter inhibitor) and ouabain (a Na(+) /K(+) -ATPase inhibitor) infusion on microdialysate glutamate and aspartate levels of CA3 hippocampal region were evaluated. Animals were assigned to one of the following groups: hypothyroid group (Hyp), receiving methimazole (anantithyroid drug); replacement group (Hyp + T(4) ), receiving antithyroid treatment plus thyroxine; and euthyroid control group (Eut). Dialysate fractions were collected every 15 min to determine basal glutamate levels for 1 hr. Then, PDC (10 mM) or ouabain (100 μM) was infused for 30 min. Results showed lower glutamate and aspartate basal levels in Hyp than in Eut groups. PDC infusion increased amino acids levels in all groups, whereas ouabain infusion increased glutamate and aspartate levels only in the Eut group. The infusion of tetrodotoxin (TTX; a voltage-gated sodium channel inhibitor) prevented the glutamate increase in euthyroid rats. The Hyp + T(4) group showed glutamate levels similar to those found in the Eut group. Additionally, glutaminase activity in hippocampus was lower in the Hyp group than in the Eut or Hyp + T(4) group. Results suggest that high-affinity glutamate transporters are not altered by hypothyroidism; however, decreased hypotyroidism reduced vesicular glutamate release in the CA3-hippocampal region as a consequence of diminished glutamate synthesis.

Topics: Analysis of Variance; Animals; Antithyroid Agents; Aspartic Acid; CA3 Region, Hippocampal; Drug Interactions; Enzyme Inhibitors; Glutamate-Ammonia Ligase; Glutamic Acid; Glutaminase; Hypothyroidism; Male; Methimazole; Microdialysis; Neurotransmitter Uptake Inhibitors; Ouabain; Rats; Rats, Wistar; Synapses; Thyroxine

ALS is commonly associated with a hypermetabolic state. In this study, we assess whether inhibition of this hypermetabolism via the induction of hypothyroidism can forestall disease onset and prolong life in the SOD1-G93A mouse. We treated a cohort of 16 SOD1-G93A mice with methimazole, a potent inhibitor of thyroid hormone synthesis and followed a second group of 23 untreated littermate control animals from approximately five weeks of age onward. Total thyroxine (T4) levels, weights, and rectal temperatures were obtained on a regular basis and animals were sacrificed when they were no longer able to feed themselves. Results revealed that T4 levels were effectively suppressed within two weeks of drug initiation. However, there was no significant difference between the two groups either in terms of clinical disease onset (120.1±9.3 days for treated animals and 116.7±6.3 days for untreated animals) or in terms of survival (131.4±11.7 days for treated animals and 134.0±10.0 days for untreated animals). A correlation analysis between mean T4 levels for each animal versus survival showed that, contrary to our hypothesis, higher T4 levels correlated with longer survival. In conclusion, these studies show that drug-induced hypothyroidism does not alter the disease course in the SOD1-G93A ALS mouse.

Topics: Amyotrophic Lateral Sclerosis; Animals; Antithyroid Agents; Case-Control Studies; Cohort Studies; Disease Models, Animal; Disease Progression; Disease-Free Survival; Hypothyroidism; Metabolism; Methimazole; Mice; Mice, Transgenic; Superoxide Dismutase; Thyroid Gland; Treatment Outcome

This study investigates whether changes in nitric oxide (NO) production participate in the cardiovascular manifestations of hypothyroidism and whether these changes are age-related. Sprague-Dawley rats aged 2 and 18 months old were treated with 0.02% methimazole (wt/vol) during 28 days. Left ventricular function was evaluated by echocardiography. Measurements of arterial blood pressure, heart rate, nitric oxide synthase (NOS) activity and NOS/caveolin-1 and -3 protein levels were performed. Hypothyroidism enhanced the age-related changes in heart function. Hypothyroid state decreased atrial NOS activity in both young and adult rats, associated with a reduction in protein levels of the three NOS isoforms in young animals and increased caveolin (cav) 1 expression in adult rats. Ventricle and aorta NOS activity increased in young and adult hypothyroid animals. In ventricle, changes in NOS activity were accompanied by an increase in inducible NOS isoform in young rats and by an increase in caveolins expression in adult rats. Greater aorta NOS activity level in young and in adult Hypo rats would derive from the inducible and the endothelial NOS isoform, respectively. Thyroid hormones would be one of the factors involved in the modulation of cardiovascular NO production and caveolin-1 and -3 tissue-specific abundance, regardless of age. Hypothyroidism appears to contribute in a differential way to aging-induced changes in the myocardium and aorta tissues. Low thyroid hormones levels would enhance the aging effect on the heart. Age-related changes in NO production participate in the cardiovascular manifestations of hypothyroidism.

Topics: Age Factors; Aging; Analysis of Variance; Animals; Antithyroid Agents; Blood Vessels; Blotting, Western; Caveolin 1; Hypothyroidism; Male; Methimazole; Myocardium; Nitric Oxide; Nitric Oxide Synthase; Rats; Rats, Sprague-Dawley; Thyroid Hormones

Steroid hormones exert profound effects on the development of brain areas controlling complex cognitive function in adulthood. One class, progestins, may contribute by acting on the progestin receptor (PR), which is transiently expressed in a critical layer of developing cortex: the subplate. PR expression in the subplate coincides with the establishment of ongoing cortical connectivity and may play an important organisational role. Identification of the factor(s) that regulate the precise timing of PR expression within subplate may help elucidate the function of PR. Thyroid hormone may interact with hormone response elements within the PR gene. The present study examined the effects of maternal hypothyroidism on levels of PR immunoreactivity (PR-IR) within the foetal subplate. Pregnant rats were made hypothyroid by the administration of methimazole and potassium perchlorate in drinking water. Maternal hypothyroidism significantly decreased PR-IR within the foetal subplate. Using the incorporation of 5-bromo-2'-deoxyuridine (BrDU) during subplate cell neurogenesis (embryonic day 13.5) to determine subplate cell survival in hypothyroid animals, we found that decreases in PR-IR cannot be attributed to significant subplate cell loss but are more likely the result of altered PR expression. Gestational thyroxine replacement to hypothyroid dams prevented the decrease in PR-IR within the subplate. These results identify thyroid hormone as a potential factor in the regulation of PR expression in the developing brain. These results are consistent with the idea that endocrine cross-talk between progesterone and thyroid hormone may be one mechanism by which maternal hypothyroidism alters normal cortical development.

Topics: Animals; Cerebral Cortex; Female; Hypothyroidism; Immunohistochemistry; Methimazole; Perchlorates; Potassium Compounds; Pregnancy; Pregnancy Complications; Radioimmunoassay; Rats; Rats, Sprague-Dawley; Receptors, Progesterone; Thyroxine

Hypothyroidism affects neurogenesis. The present study was performed to clarify the sensitivity of neurogenesis-related cellular responses in the hippocampal dentate gyrus between developmental and adult-stage hypothyroidism. An exposure study of methimazole (MMI) as an anti-thyroid agent at 0, 50, 200 ppm in the drinking water was performed using pregnant rats from gestation day 10 to postnatal day (PND) 21 (developmental hypothyroidism) and adult male rats by setting an identical exposure period from PND 46 through to PND 77 (adult-stage hypothyroidism). Offspring with developmental hypothyroidism were killed at PND 21 or PND 77, and animals with adult-stage hypothyroidism were killed at PND 77. Proliferation and apoptosis were unchanged in the dentate subgranular zone by either developmental or adult-stage hypothyroidism. With regard to precursor granule cells, a sustained reduction of paired box 6-positive stem or early progenitor cells and a transient reduction of doublecortin-positive late-stage progenitor cells were observed after developmental hypothyroidism with MMI at 50 and 200 ppm. These cells were unchanged by adult-stage hypothyroidism. With regard to γ-aminobutyric acid (GABA) ergic interneuron subpopulations in the dentate hilus, the number of parvalbumin-positive cells was decreased and the number of calretinin-positive cells was increased after both developmental and adult-stage hypothyroidism with MMI at 50 and 200 ppm. Fluctuations in GABAergic interneuron numbers with developmental hypothyroidism continued through to PND 77 with 200 ppm MMI. Considering the roles of GABAergic interneuron subpopulations in neurogenesis and neuronal differentiation, subpopulation changes in GABAergic interneurons by hypothyroidism may be the signature of aberrant neurogenesis even at the adult stage.

Topics: Age Factors; Animals; Antithyroid Agents; Apoptosis; Cell Proliferation; Dentate Gyrus; Dose-Response Relationship, Drug; Doublecortin Protein; Female; gamma-Aminobutyric Acid; Hypothyroidism; Male; Methimazole; Neurogenesis; Neurons; Pregnancy; Prenatal Exposure Delayed Effects; Rats; Rats, Sprague-Dawley

Disrupted thyroid hormone function evokes severe physiological consequences in the immature brain. In adulthood, although clinical reports document an effect of thyroid hormone status on mood and cognition, the molecular and cellular changes underlying these behavioural effects are poorly understood. More recently, the subtle effects of thyroid hormone on structural plasticity in the mature brain, in particular on adult hippocampal neurogenesis, have come to be appreciated. However, the specific stages of adult hippocampal progenitor development that are sensitive to thyroid hormone are not defined. Using nestin-green fluorescent protein reporter mice, we demonstrate that thyroid hormone mediates its effects on hippocampal neurogenesis by influencing Type 2b and Type 3 progenitors, although it does not alter proliferation of either the Type 1 quiescent progenitor or the Type 2a amplifying neural progenitor. Thyroid hormone increases the number of doublecortin (DCX)-positive Type 3 progenitors, and accelerates neuronal differentiation into both DCX-positive immature neurones and neuronal nuclei-positive granule cell neurones. Furthermore, we show that this increase in neuronal differentiation is accompanied by a significant induction of specific transcription factors involved in hippocampal progenitor differentiation. In vitro studies using the neurosphere assay support a direct effect of thyroid hormone on progenitor development because neurospheres treated with thyroid hormone are shifted to a more differentiated state. Taken together, our results indicate that thyroid hormone mediates its neurogenic effects via targeting Type 2b and Type 3 hippocampal progenitors, and suggests a role for proneural transcription factors in contributing to the effects of thyroid hormone on neuronal differentiation of adult hippocampal progenitors.

Topics: Animals; Cell Count; Cells, Cultured; Disease Models, Animal; Doublecortin Protein; Gene Expression Regulation, Developmental; Hippocampus; Hyperthyroidism; Hypothyroidism; Male; Methimazole; Mice; Mice, Inbred C57BL; Mice, Transgenic; Molecular Imaging; Neural Stem Cells; Neurogenesis; Promoter Regions, Genetic; Thyrotropin; Thyroxine; Transcription Factors; Triiodothyronine; Up-Regulation

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

The relationship between ischemia-modified albumin (IMA) and thyroid dysfunction remains uncertain. This study aimed to investigate the influence of overt hypothyroidism (Oho), overt hyperthyroidism (Ohe), and their treatments on serum IMA levels.. A total of 35 untreated patients with Ohe, 35 untreated patients with Oho, and 35 control subjects were enrolled in the study. C-reactive protein (CRP), homocysteine (Hcy), IMA, and lipid profiles were measured and evaluated before and after treatment.. CRP, Hcy, and IMA levels and lipid profiles were higher in patients with Oho than in euthyroid or Ohe subjects (p<0.05). Basal IMA levels were reduced after treatments in all patients (p<0.05). In Ohe patients, serum IMA levels were positively correlated with free triiodothyronine (r=0.424, p=0.011) and free thyroxine (r=0.567, p<0.001) levels. In Oho patients, serum IMA levels were inversely correlated with free triiodothyronine (r=-0.555, p=0.001) and free thyroxine (r=-0.457, p=0.006) but positively correlated with anti-thyroid peroxidase antibody, C-reactive protein, and homocysteine levels (p<0.05). Linear regression analyses showed that free triiodothyronine was the most important factor affecting serum IMA levels in Ohe (β=0.694, p=0.019) and in Oho (β=-0.512, p=0.025).. IMA levels are increased in patients with thyroid dysfunction, particularly in overt hypothyroidism. Thyroid dysfunction has a significant impact on the oxidative stress status.

Topics: Adult; Antithyroid Agents; Autoantibodies; Biomarkers; C-Reactive Protein; Case-Control Studies; Cholesterol, HDL; Cholesterol, LDL; Female; Homocysteine; Humans; Hyperthyroidism; Hypothyroidism; Iodide Peroxidase; Male; Methimazole; Middle Aged; Oxidative Stress; Serum Albumin; Serum Albumin, Human; Thyroxine; Triglycerides; Triiodothyronine

Gestational hypothyroidism is a prevalent disorder in pregnant women. We aimed to investigate the impact of experimental gestational hypothyroidism (EGH) on cardiovascular and autonomic nervous systems (ANS) in the offspring of rats. EGH was induced with methimazole (MMI) 0.02% in drinking water from day 9 of gestation until birth. Sixty day old offspring from MMI-treated dams (OMTD, n=13) or water-treated dams (OWTD, n=13) had femoral arteries surgically assessed for the measurements of heart rate (HR), mean (MAP), systolic (SAP) and diastolic arterial pressure (DAP), and spontaneous baroreflex sensitivity (BRS). To investigate the balance of ANS, we established the high (HF) and low frequency (LF) bands of pulse interval (PI) and LF band of SAP spectrum. OMTD had increased MAP (130.2 ± 2.0 vs 108.8 ± 3.0 mmHg, p<0.001), SAP (157.3 ± 2.9 vs 135.7 ± 4.5mm Hg, p<0.001) and DAP (109.7 ± 1.9 vs 88.4 ± 2.6 mmHg, p<0.001) when compared to OWTD, and had lower HR (355.1 ± 8.9 vs 386.8 ± 9.2 bpm, p<0.05). After spectral analysis of PI and SAP, only LF band of SAP spectrum was higher (7.2 ± 0.8 vs 4.0 ± 0.6 mmHg(2), p<0.01) in OMTD under spontaneous condition. Despite bradycardia, EGH promotes spontaneous hypertension in 60 day old offspring, probably due to increased sympathetic modulation of vessels, which is suggested by the higher LF of SAP. These findings suggest a critical role of maternal THs in the development of fetal cardiovascular and autonomic nervous systems.

Topics: Animals; Baroreflex; Blood Pressure; Disease Models, Animal; Female; Heart Rate; Hypertension; Hypothyroidism; Male; Methimazole; Pregnancy; Pregnancy Complications, Cardiovascular; Prenatal Exposure Delayed Effects; Rats; Rats, Wistar

Cytochrome P450 NADPH-reductase (P450R), inducible synthase (iNOS) and xanthine oxidase play an important role in the antracycline-related cardiotoxicity. The expression of P450R and iNOS is regulated by triiodothyronine. The aim of this study was to evaluate the effect of methimazole-induced hypothyreosis on oxidative stress secondary to doxorubicin administration. 48 hours after methimazole giving cessation, rats were exposed to doxorubicin (2.0, 5.0 and 15 mg/kg). Blood and heart were collected 4, 48 and 96 h after the drug administration. Animals exposed exclusively to doxorubicin or untreated ones were also assessed. The hypothyreosis (0.025% of methimazole) significantly increased the doxorubicin effect on the cardiac carbonyl group and they may increase the glutathione level. An insignificant effect of methimazole was noticed in case of the cardiac lipid peroxidation product, the amount of DNA oxidative damages, iNOS and xanthine oxidase-enzymes responsible for red-ox activation of doxorubicin. However, the concentration of P450R was affected by a lower dose of methimazole in rats administered with doxorubicin. Since in rats receiving doxorubicin changes in oxidative stress caused by methimazole were not accompanied by elevation of bioreductive enzymes, it may be concluded that these changes in the oxidative stress were not related to the tested enzymes.

Topics: Animals; Antibiotics, Antineoplastic; Antithyroid Agents; DNA Damage; Doxorubicin; Heart; Hypothyroidism; Male; Methimazole; Myocardium; NADPH-Ferrihemoprotein Reductase; Nitric Oxide Synthase Type II; Oxidative Stress; Rats; Rats, Wistar; Triiodothyronine; Xanthine Oxidase

The osteoporosis associated with human hyperthyroidism has traditionally been attributed to elevated thyroid hormone levels. There is evidence, however, that thyroid-stimulating hormone (TSH), which is low in most hyperthyroid states, directly affects the skeleton. Importantly, Tshr-knockout mice are osteopenic. In order to determine whether low TSH levels contribute to bone loss in hyperthyroidism, we compared the skeletal phenotypes of wild-type and Tshr-knockout mice that were rendered hyperthyroid. We found that hyperthyroid mice lacking TSHR had greater bone loss and resorption than hyperthyroid wild-type mice, thereby demonstrating that the absence of TSH signaling contributes to bone loss. Further, we identified a TSH-like factor that may confer osteoprotection. These studies suggest that therapeutic suppression of TSH to very low levels may contribute to bone loss in people.

Topics: Animals; Bone Density; Bone Diseases, Metabolic; Bone Resorption; Dose-Response Relationship, Drug; Drug Implants; Hormone Replacement Therapy; Hyperthyroidism; Hypothyroidism; Methimazole; Mice; Mice, Inbred C57BL; Mice, Knockout; Osteoporosis; Phenotype; Receptors, Thyrotropin; Signal Transduction; Thyrotropin; Thyroxine

Thyroid hormones are essential for the development of brain. Perinatal hypothyroidism induced by environmental endocrine disrupters is reported to cause cognitive dysfunctions such as attention and memory deficits. The purpose of this study is whether perinatal hypothyroidism causes deficits of shift attention and divided attention in offspring using a target detection task.. Pregnant rats were treated with the anti-thyroid drug methimazole [0.02% (w/v)] from gestational day 15 to postnatal day 21. The offspring received behavioral testing using shift attention and divided attention tasks. The testing of shift attention started with the presentation of one of two targets. A lever was inserted to the same side as the presented target (ipsilateral trial). However, a lever was inserted to the opposite side to the presented target with the probability of 20% (contralateral trial). Next, the testing of divided attention was introduced. The testing started with the presentation of one of the two targets (one-side trial). A lever was inserted to the same side as the presented target. However, both targets were presented (both-side trial) and one of the two levers was inserted with the probability of 20%.. On the contralateral trials in the shift attention task, the untreated rats responded frequently with reaction times of 1.4-1.6 s, whereas the treated rats responded sporadically with a wide range of reaction times of 1.2-7.2 s. This indicates that the treated rats were not able to shift their attention quickly toward the opposite side. When the both-side targets were presented in the divided attention task, the untreated rats responded frequently with the reaction times of 0.6-0.8 s and 1.4-1.6 s. The treated rats responded frequently with reaction times of 0.8-1.0 s and 1.0-6.4 s. Both the untreated and treated rats did not divide their attention toward the both-side targets but probably paid attention to one of the two targets. They responded with the shorter reaction times when the lever was inserted in the same side that they paid attention and responded with longer reaction times when the lever was inserted in the opposite side. We conclude that perinatal hypothyroidism affects shift attention in rats but further researches are necessary to examine whether hypothyroidism affects divided attention.. Perinatal hypothyroidism causes the deficit of shift attention in rats but it was unclear whether hypothyroidism affects divided attention.

Topics: Animals; Antithyroid Agents; Attention; Female; Hypothyroidism; Methimazole; Pregnancy; Rats

Thyroid hormones are essential for normal brain development and very important in the normal functioning of the brain. Thyroid hormones action in the adult brain has not been widely studied. The effects of adult hyperthyroidism are not as well understood as adult hypothyroidism, mainly in hippocampal granular cells. The purpose of the present study is to assess the consequences of adult hormone dysthyroidism (excess/deficiency of TH) on the morphology of dentate granule cells in the hippocampus by performing a quantitative study of dendritic arborizations and dendritic spines using Golgi impregnated material. Hypo-and hyperthyroidism were induced in rats by adding 0.02 percent methimazole and 1 percent L-thyroxine, respectively, to drinking water from 40 days of age. At 89 days, the animals' brains were removed and stained by a modified Golgi method and blood samples were collected in order to measure T4 serum levels. Neurons were selected and drawn using a camera lucida. Our results show that both methimazole and thyroxine treatment affect granule cell morphology. Treatments provoke alterations in the same direction, namely, reduction of certain dendritic-branching parameters that are more evident in the methimazole than in the thyroxine group. We also observe a decrease in spine density in both the methimazole and thyroxine groups.

Topics: Analysis of Variance; Animals; Antithyroid Agents; Disease Models, Animal; Hippocampus; Hyperthyroidism; Hypothyroidism; Male; Methimazole; Neurons; Rats; Rats, Wistar; Silver Staining; Statistics, Nonparametric; Thyroid Hormones; Thyroxine

We evaluated the contribution of the thyroid hormones to the long-term maintenance of feeding behavior and body weight, while distinguishing their direct central effects from those resulting from the metabolic rate in the peripheral tissues.. We assessed the effect of hypothyroidism on the long-term (6 months) regulation of food intake, body weight, and energy expenditure in rats. We then generated the recovery of a euthyroid condition in the brain while maintaining a low T3 availability for the peripheral organs, i.e. a combined condition of central euthyroidism with peripheral hypothyroidism, with the aid of a pharmacological combination.. Hypothyroidism caused a decrease in the daily food intake, body weight, and body temperature. The food intake and body temperature stabilized at a lower value, whereas body weight kept decreasing at a constant rate. The administration of exogenous T4 increased food intake and body-weight gain, but had no effect on body temperature.. The thyroid hormones are necessary for the long-term regulation of energy intake, storage, and expenditure by different mechanisms. The feeding behavior seems to be partially dependent on a direct action of the thyroid hormones on the brain and this effect is independent of the energy expenditure in the peripheral organs. The body weight is closely dependent on the thyroid status and its maintenance seems to involve thyroid action on mechanisms other than feeding and metabolic rate.

Topics: Animals; Antithyroid Agents; Body Temperature; Body Weight; Brain Chemistry; Eating; Energy Metabolism; Hypothalamus; Hypothyroidism; Male; Methimazole; Rats; Rats, Wistar; Thyroxine; Time Factors; Triiodothyronine

It is known that a hypothyroidism-induced hypometabolic state protects against oxidative damage caused by toxins. However, some workers demonstrated that antithyroid drug-induced hypothyroidism can cause cellular damage. Our objective was to determine if methimazole (an antithyroid drug) or hypothyroidism causes cellular damage in the liver, kidney, lung, spleen and heart. Twenty-five male Wistar rats were divided into 5 groups: euthyroid, false thyroidectomy, thyroidectomy-induced hypothyroidism, methimazole-induced hypothyroidism (60 mg/kg), and treatment with methimazole (60 mg/kg) and a T₄ injection (20 μg/kg/d sc). At the end of the treatments (4 weeks for the pharmacological groups and 8 weeks for the surgical groups), the animals were anesthetized with sodium pentobarbital and they were transcardially perfused with 10% formaldehyde. The spleen, heart, liver, lung and kidney were removed and were processed for embedding in paraffin wax. Coronal sections were stained with hematoxylin-eosin. At the end of treatment, animals with both the methimazole- and thyroidectomy-induced hypothyroidism had a significant reduction of serum concentration of thyroid hormones. Only methimazole-induced hypothyroidism causes cellular damage in the kidney, lung, liver, heart, kidney and spleen. In addition, animals treated with methimazole and T₄ showed cellular damage in the lung, spleen and renal medulla with lesser damage in the liver, renal cortex and heart. The thyroidectomy only altered the lung structure. The alterations were prevented by T₄ completely in the heart and partially in the kidney cortex. These results indicate that tissue damage found in hypothyroidism is caused by methimazole.

Topics: Animals; Eosine Yellowish-(YS); Heart; Hematoxylin; Hypothyroidism; Kidney; Liver; Lung; Male; Methimazole; Oxidative Stress; Rats; Rats, Wistar; Spleen; Thyroid Hormones; Thyroidectomy

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

Methimazole is the most widely used antithyroid drug in Europe and North America, but it causes several undesirable side effects, such as hematological dysfunctions and immunosuppression. Our aim in this work was to compare, over a time course, markers of oxidative stress, the redox environment, the antioxidant enzymatic system, and the glutathione cycle in the spleen of rats with methimazole- or thyroidectomy-caused hypothyroidism. We used 70-male Wistar rats divided into four groups: 1) euthyroid; 2) sham thyroidectomy; 3) thyroidectomy-caused hypothyroidism, with parathyroid reimplant; and 4) methimazole-caused hypothyroidism. Five rats of the euthyroid- and methimazole-caused hypothyroidism groups were killed at the end of weeks 1, 2, 3, and 4 after treatment, and 5 rats of the sham thyroidectomy and thyroidectomy-caused hypothyroidism groups were killed at the end of weeks 2, 4, and 8 after the surgical procedure. Each spleen was excised and stored at -70°C until oxidative stress, REDOX environment, and the antioxidant enzymatic-system markers were tested. The histological study showed that only methimazole-induced hypothyroidism caused cell damage. This damage was associated with an increase of oxidative-stress markers that were not compensated for by the antioxidant system. The increase of the glutathione-cycle enzymes was insufficient to prevent oxidative-stress markers. Methimazole causes oxidative stress and cell damage in the spleen, whereas hypothyroidism per se does not cause cell damage in this organ. Therefore, it is necessary to develop new antithyroid drugs without causing oxidative stress and cellular damage.

Topics: Animals; Antithyroid Agents; Biomarkers; Disease Models, Animal; Glutathione; Hypothyroidism; Male; Methimazole; Oxidative Stress; Oxidoreductases; Parathyroid Glands; Rats; Rats, Wistar; Spleen; Thyroid Hormones; Thyroidectomy

Clinical and experimental studies have highlighted the role played by thyroid hormones (TH) in neural and neuro-sensorial development. However, knowledge on TH mechanisms on the developing visual system is still incomplete. To uncover TH actions on the eyes and vision we carried out a microscopical study on the role of TH in the developing retina and optic nerve, in a rat model of controlled TH deficiency (THD). Morphometric and stereological analyses of the retina and optic nerve showed a reduction in the volume of the eye (p<0.001) and optic nerve cross-sectional area (p<0.001), and thinning of the retinal layers (p<0.001). Glial development and myelination was significantly delayed in the THD optic nerves (p<0.001), as compared to controls. The data indicate that TH play an essential role in neuro-retinogenesis. Substitutive TH therapy in critical periods, should be considered in hypothyroidism-related eye disorders as well as neurodegenerative retinal processes.

Topics: Age Factors; Animals; Animals, Newborn; Disease Models, Animal; Embryo, Mammalian; Female; Hypothyroidism; Imidazoles; Male; Microscopy, Electron, Transmission; Optic Nerve; Organ Size; Pregnancy; Rats; Rats, Wistar; Retina; Thyroid Hormones

During pregnancy, changes in maternal physiology influence thyroid status. In addition, maternal thyroid disease can have substantial adverse effects on the fetus. Therefore, evaluating and treating women with thyroid disease during pregnancy requires careful observation and management to ensure favorable pregnancy outcomes. To evaluate thyroid hormone levels during gestation, gestational age-specific values should be used. When hyperthyroidism is treated, the goals of therapy are to achieve a subclinical hyperthyroid state and monitor fetal development. Care must be taken so as not to induce a state of maternal hypothyroidism during pregnancy, since such a diagnosis is also associated with adverse outcomes for both mother and infant.. Consideration should be given to routine screening of pregnant women and all women of childbearing age for thyroid disease.

Topics: Female; Fetus; Graves Disease; Humans; Hyperthyroidism; Hypothyroidism; Infant, Newborn; Infant, Newborn, Diseases; Methimazole; Pregnancy; Pregnancy Complications; Thyroid Diseases; Thyroid Gland; Thyrotoxicosis; United States

Conflicting clinical data on the relationship of panic disorder and thyroid diseases illustrate the need for a simpler approach using animal models. Defensive behaviors evoked by electrical or chemical stimulation of dorsal periaqueductal gray matter (DPAG) have been proposed as a model of panic attack. Therefore, the present study examined the effects of the anti-thyroid agent methimazole (MTZ) either on the panic-like behaviors induced by electrical stimulation of DPAG or the anxiety-like behaviors of rats exposed to the elevated plus-maze (EPM). Male Wistar rats bearing electrodes in the DPAG were stimulated with stepwise increased currents. Rats which displayed galloping at intensities below 60muA were retested following 5- and 10-day treatments with MTZ (0.6mg/kg/day, i.p.) or 10- and 15-day washout periods. MTZ effects on EPM performance were assessed in separate groups. MTZ-treated groups were compared to saline-treated controls. In other experiments, rats were similarly treated with MTZ and the blood was collected for hormone assays. The 10-day treatment with MTZ produced marked increases in the thresholds of exophthalmus (65%), immobility (75%), trotting (63%), galloping (56%), jumping (47%), defecation (114%) and micturition (85%). Effects outlasted the drug discontinuation. In contrast, MTZ had variable effects in the EPM, significantly increasing the open-arm exploration in 5-day treated and 10-day washout groups. Biochemical data revealed a small but significant decrease (13%) in free thyroxine in MTZ-treated groups. Although not significant, thyrotrophin levels showed a 111% increase following the 10-day treatment with MTZ. Selective attenuation by MTZ of DPAG-evoked defensive behaviors supports attenuation of panic attacks in hypothyroidism.

Topics: Animals; Anxiety; Disease Models, Animal; Electric Stimulation; Hypothyroidism; Male; Maze Learning; Methimazole; Panic Disorder; Periaqueductal Gray; Rats; Rats, Wistar; Thyrotropin; Thyroxine

Effects of drug-induced hypothyroidism on myosin heavy chain (MyHC) content and fibre types of fast skeletal muscles were studied in a small marsupial, Antechinus flavipes. SDS-PAGE of MyHCs from the tibialis anterior and gastrocnemius revealed four isoforms, 2B, 2X, 2A and slow, in that order of decreasing abundance. After 5 weeks treatment with methimazole, the functionally fastest 2B MyHC significantly decreased, while 2X, 2A and slow MyHCs increased. Immunohistochemistry using monospecific antibodies to each of the four MyHCs revealed decreased 2b and 2x fibres, and increased 2a and hybrid fibres co-expressing two or three MyHCs. In the normally homogeneously fast superficial regions of these muscles, evenly distributed slow-staining fibres appeared, resembling the distribution of slow primary myotubes in fast muscles during development. Hybrid fibres containing 2A and slow MyHCs were virtually absent. These results are more detailed but broadly similar to the earlier studies on eutherians. We hypothesize that hypothyroidism essentially reverses the effects of thyroid hormone on MyHC gene expression of muscle fibres during myogenesis, which differ according to the developmental origin of the fibre: it induces slow MyHC expression in 2b fibres derived from fast primary myotubes, and shifts fast MyHC expression in fibres of secondary origin towards 2A, but not slow, MyHC.

Topics: Animals; Antibodies, Monoclonal; Electrophoresis, Polyacrylamide Gel; Gene Expression Regulation; Hypothyroidism; Immunohistochemistry; Marsupialia; Methimazole; Muscle Fibers, Fast-Twitch; Myosin Heavy Chains; Protein Isoforms

Infertility associated with congenital and early childhood hypothyroidism is an important reproductive health problem in men. Nevertheless, the exact mechanism underlying hypothyroidism-induced changes in the prostate gland, an androgen-dependent organ that contributes a significant portion of the seminal plasma remains obscure. The present study tested the hypothesis "transient gestational- or neonatal-onset hypothyroidism may have duration dependent and lobe specific effect on androgen receptor (AR) status in the prostate glands of adult rats.". Hypothyroidism was induced in pregnant and lactating rats by feeding 0.05% methimazole (MMI) through drinking water during fetal and neonatal milestones of testicular and prostatic development. Pregnant dams had MMI exposure from 9th day post-coitum (dpc) to 14 dpc (group II) or 21 dpc (group III). Lactating mothers had MMI exposure from day 1 post-partum (dpp) to 14 dpp (group IV) or up to 29 dpp (group V). AR status in the dorsolateral and ventral prostate lobes (DLP and VP) of the pups was assessed by RT-PCR, western blot and radio receptor assay.. AR mRNA expression consistently decreased in the DLP of all groups, whereas it increased in VP of group III and V rats. AR protein consistently decreased in both DLP and VP of all experimental rats. AR nuclear ligand-binding activity diminished in groups II and IV, whereas it increased in groups III and V.. The results obtained support the proposed hypothesis and indicate that an optimum thyroid activity during pre- and neonatal period determines AR status in the prostate glands at adulthood.

Topics: Analysis of Variance; Animals; Animals, Newborn; Blotting, Western; Estradiol; Female; Hypothyroidism; Male; Methimazole; Pregnancy; Prenatal Exposure Delayed Effects; Prostate; Radioimmunoassay; Rats; Rats, Wistar; Receptors, Androgen; Reverse Transcriptase Polymerase Chain Reaction; Testosterone; Thyrotropin; Thyroxine; 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

Thyroid hormones influence brain development through regulation of gene expression mediated by nuclear receptors. Nuclear receptor concentration increases rapidly in the human fetus during the second trimester, a period of high sensitivity of the brain to thyroid hormones. In the rat, the equivalent period is the last quarter of pregnancy. However, little is known about thyroid hormone action in the fetal brain, and in rodents, most thyroid hormone-regulated genes have been identified during the postnatal period. To identify potential targets of thyroid hormone in the fetal brain, we induced maternal and fetal hypothyroidism by maternal thyroidectomy followed by antithyroid drug (2-mercapto-1-methylimidazole) treatment. Microarray analysis identified differentially expressed genes in the cerebral cortex of hypothyroid fetuses on d 21 after conception. Gene function analysis revealed genes involved in the biogenesis of the cytoskeleton, neuronal migration and growth, and branching of neurites. Twenty percent of the differentially expressed genes were related to each other centered on the Ca(2+) and calmodulin-activated kinase (Camk4) pathway. Camk4 was regulated directly by T(3) in primary cultured neurons from fetal cortex, and the Camk4 protein was also induced by thyroid hormone. No differentially expressed genes were recovered when euthyroid fetuses from hypothyroid mothers were compared with fetuses from normal mothers. Although the results do not rule out a specific contribution from the mother, especially at earlier stages of pregnancy, they indicate that the main regulators of thyroid hormone-dependent, fetal brain gene expression near term are the fetal thyroid hormones.

Topics: Animals; Calcium-Calmodulin-Dependent Protein Kinase Type 4; Cells, Cultured; Cerebral Cortex; DNA Primers; Female; Gene Expression Regulation; Humans; Hypothyroidism; Imidazoles; Neurons; Nucleic Acid Hybridization; Oligonucleotide Array Sequence Analysis; Polymerase Chain Reaction; Rats; Rats, Wistar; RNA; Sex-Determining Region Y Protein; Thyroidectomy; Thyrotropin; Triiodothyronine

Thyroid hormones influence brain development through the control of gene expression. The concentration of the active hormone T(3) in the brain depends on T(3) transport through the blood-brain barrier, mediated in part by the monocarboxylate transporter 8 (Mct8/MCT8) and the activity of type 2 deiodinase (D2) generating T(3) from T(4). The relative roles of each of these pathways in the regulation of brain gene expression is not known. To shed light on this question, we analyzed thyroid hormone-dependent gene expression in the cerebral cortex of mice with inactivated Mct8 (Slc16a2) and Dio2 genes, alone or in combination. We used 34 target genes identified to be controlled by thyroid hormone in microarray comparisons of cerebral cortex from wild-type control and hypothyroid mice on postnatal d 21. Inactivation of the Mct8 gene (Mct8KO) was without effect on the expression of 31 of these genes. Normal gene expression in the absence of the transporter was mostly due to D2 activity because the combined disruption of Mct8 and Dio2 led to similar effects as hypothyroidism on the expression of 24 genes. Dio2 disruption alone did not affect the expression of positively regulated genes, but, as in hypothyroidism, it increased that of negatively regulated genes. We conclude that gene expression in the Mct8KO cerebral cortex is compensated in part by D2-dependent mechanisms. Intriguingly, positive or negative regulation of genes by thyroid hormone is sensitive to the source of T(3) because Dio2 inactivation selectively affects the expression of negatively regulated genes.

Topics: Animals; Animals, Newborn; Antithyroid Agents; Cerebral Cortex; Female; Gene Expression Profiling; Gene Expression Regulation, Developmental; Hypothyroidism; Iodide Peroxidase; Iodothyronine Deiodinase Type II; Male; Membrane Transport Proteins; Methimazole; Mice; Mice, Inbred C57BL; Mice, Knockout; Monocarboxylic Acid Transporters; Oligonucleotide Array Sequence Analysis; Pregnancy; Reverse Transcriptase Polymerase Chain Reaction; Symporters; Thyroid Hormones; Thyroxine; Triiodothyronine

To understand the mechanism underlying gestational-onset hypothyroidism-induced male infertility.. Controlled laboratory study.. Research laboratory in a university department of endocrinology.. Wistar rat.. Pregnant rats were exposed to methimazole from embryonic days 9 to 14, 18, and 21, covering specific fetal periods of differentiation and development of male reproductive tract organs.. Fertility of male rats was assessed by testing sperm count, forward motility, and in vivo fertilizing ability. Secretory activity of the epididymis was evaluated by quantifying sialic acid, carnitine, and glycerylphosphorylcholine. Bioavailability of androgens was assessed by quantifying testosterone in serum and testicular interstitial fluid and epididymal 5alpha-reductase activity/mRNA expression. Androgen receptor (AR) status in the epididymis was tested by detecting the expression levels of its mRNA and protein, as well as ligand binding activity. Data were analyzed statistically by one-way analysis of variance.. Gestational exposure to methimazole decreased sperm forward motility, in vivo fertilizing ability, bioavailability of androgens, AR status, and secretory activity of the epididymis in adult rats.. Transient gestational-onset hypothyroidism affects male fertility by impairing posttesticular sperm maturation process in the epididymis, owing to subnormal androgen(s) bioavailability, AR expression, and AR functional activity.

Topics: 3-Oxo-5-alpha-Steroid 4-Dehydrogenase; Animals; Epididymis; Female; Hypothyroidism; Infertility, Male; Male; Methimazole; Pregnancy; Pregnancy Complications; Prenatal Exposure Delayed Effects; Rats; Rats, Wistar; Receptors, Androgen; RNA, Messenger; Sperm Maturation; Sperm Motility; Testis; Thyroid Hormones

Functional consequences of hypothyroidism include impaired learning and memory and inability to produce long-term potentiation (LTP) in hippocampus. Olibanum has been used for variety of therapeutic purposes. In traditional medicine, oilbanum is used to enhance learning and memory. In the present study the effect of olibanum on memory deficit in hypothyroid rats was investigated. Male wistar rats were divided into four groups and treated for 180 days. Group 1 received tap drinking water while in group 2, 0.03% methimazol was added to drinking water. Group 3 and 4 were treated with 0.03% methimazole as well as 100 and 500 mg/kg olibanum respectively. The animals were tested in Morris water maze. The swimming speed was significantly lower and the distance and time latency were higher in group 2 compared with group 1. In groups 3 and 4 the swimming speed was significantly higher while, the length of the swim path and time latency were significantly lower in comparison with group 2. It is concluded that methimazole-induced hypothyroidism impairs learning and memory in adult rats which could be prevented by using olibanum.

Topics: Animals; Behavior, Animal; Boswellia; Disease Models, Animal; Hypothyroidism; Male; Maze Learning; Memory; Memory Disorders; Methimazole; Nootropic Agents; Rats; Rats, Wistar; Reaction Time; Resins, Plant; Swimming; Time Factors

Thyroid hormones (THs) play a crucial role in the development and physiological functioning of different body organs especially the brain. Therefore, the objective of this study was to show the histopathological effects of the different thyroid states on some brain regions (cerebrum and cerebellum) and the skeletal features of their newborns during the postnatal development from the 1st to 3rd week. The female white albino rats were allocated into 3 groups as follows: the experimental hypothyroidism group is induced by 0.02% methimazole (MMI) (w/v) in drinking water, while the experimental hyperthyroidism group is performed by exogenous T4 [from 50 to 200microg/kg body weight intragastric administration beside adding 0.002% T4 (w/v) to the drinking water] from the gestation day 1 to lactation day 21 and control group which received tap water. As well, both maternal hypo- and hyperthyroidism caused some malformation and developmental defects in the cerebellar and cerebral cortex of their newborns along the duration of the experiment. These degenerative symptoms became more prominent and widely spread at the 3rd postnatal week. Concomitantly, there were some degeneration, deformation and severe growth retardation in neurons of these regions in both treated groups throughout the experimental period. Moreover, the skeletal features of these newborns were accelerated in hyperthyroid group while these maturations were delayed partially in hypothyroid ones during the examined periods. These alterations, on both treated groups, were age and dose dependent. Thus, further studies need to be done to emphasize this concept.

Topics: Animals; Antithyroid Agents; Brain; Cell Differentiation; Disease Models, Animal; Female; Humans; Hyperthyroidism; Hypothyroidism; Male; Methimazole; Nerve Degeneration; Neurogenesis; Pregnancy; Prenatal Exposure Delayed Effects; Rats; Thyroxine

The present study was undertaken to assess the effect of selenium (Se) on hypothyroidism induced by methimazole (MMI) in lactating rats and their pups. Rats were randomly divided into four groups of six each: group I served as a negative control which received standard diet; group II received orally MMI (250 mg L -1 ); group II received both MMI (250 mg L -1 , orally) and Se (0.5 mg/kg of diet); group IV served as a positive control and received Se (0.5 mg Na 2 SeO 3 /kg of diet). Treatments were started from the 14th day of pregnancy until postnatal day 14. In the MMI-exposed group, the body weight of 14-day-old pups diminished compared to controls; besides, a hypertrophy of the thyroid glands was observed. Co-administration of Se through the diet restored these parameters to near normal values. In the MMI-treated group, thyroid iodine contents and plasma thyroid hormone levels significantly decreased, while plasma TSH levels increased in pups and their mothers. These biochemical modifications corresponded histologically to closed follicles, increased vascularity and a reduction in colloid volume. Co-treatment with Se ameliorated these parameters. We concluded that the supplementation of Se in diet had beneficial effects on hypothyroidism during a critical period of life.

Topics: Animals; Antithyroid Agents; Feeding Behavior; Female; Humans; Hypertrophy; Hypothyroidism; Lactation; Male; Maternal Exposure; Methimazole; Pregnancy; Rats; Rats, Wistar; Selenium

We investigated protective effects of hypothyroidism on delayed neuronal death, gliosis, lipid peroxidation and Cu,Zn-superoxide dismutase (SOD1) in the gerbil hippocampal CA1 region (CA1) after 5 min of transient cerebral ischemia. The hypothyroidism was induced by 0.025% methimazole treatment. Free triiodothyronine and thyroxine levels were markedly decreased in the hypothyroid group. Four days after ischemia/reperfusion, only a few NeuN-immunoreactive (+) neurons were detected in the CA1 of euthyroid-ischemia (eu-ischemia) group; however, at this time point, the number of NeuN(+) neurons was significantly higher in the hypothyroid-ischemia (hypo-ischemia) group than in the eu-ischemia group. At 5 days postischemia, NeuN(+) neurons were significantly decreased in the hypo-ischemia group: The number of NeuN(+) neurons in this group was similar to that in the eu-ischemia group. Activations of GFAP(+) astrocytes and Iba-1(+) microglia in the CA1 were higher in the eu-ischemia group 3 and 4 days after ischemia/reperfusion. At 5 days postischemia, the activations of both the glial cells in the CA1 were similar between the two groups. 4-Hydroxy-2-nonenal (HNE), a marker for lipid peroxidation, immunoreactivity in the eu-ischemia group was higher than in the hypo-ischemia group; at 5 days postischemia, the immunoreactivity was similar between the two groups. In contrast, SOD1 level was lower in the CA1 of the eu-ischemia group. These results suggest that hypothyroid state does not protect against delayed neuronal death but only delays the neuronal death in the hippocampal CA1 region after transient cerebral ischemia by reducing lipid peroxidation and increasing SOD1.

Topics: Animals; Antithyroid Agents; Brain Ischemia; CA1 Region, Hippocampal; Cell Death; Cytoprotection; Gerbillinae; Gliosis; Hypothyroidism; Lipid Peroxidation; Male; Methimazole; Neurons; Oxidative Stress; Reperfusion Injury; Superoxide Dismutase; Superoxide Dismutase-1

A major problem with antithyroid drug (ATD) therapy in Graves' disease is the high relapse rate. Therefore, clinicians have sought prognostic indicators of permanent remission. Suppression of serum thyrotropin (TSH) when ATD therapy is stopped carries a poor prognosis, but little is known regarding the significance of elevated serum TSH concentrations in the course of ATD therapy. The objective of this study was to determine if elevated serum TSH concentrations during methimazole (MMI) therapy is associated with a favorable long-term prognosis.. We retrospectively studied patients with Graves' disease who were initially on MMI, in whom this drug was stopped because they had undetectable thyroid-stimulating antibodies (TSAbs) or were euthyroid after at least 24 months on MMI treatment. A strategy of high MMI doses plus T4 was not used in these patients. We identified 40 patients with elevated serum TSH concentration (>10 microIU/mL) during MMI therapy (H-TSH group). Eighty-five percent of the H-TSH group had negative tests for TSAb. The H-TSH group was sex- and age-matched with 37 patients who had similar selection criteria, but did not have elevated serum TSH concentration during MMI therapy (N-TSH group). The H-TSH and N-TSH groups were similar in gross thyroid size, percentage of patients with exophthalmos, serum free thyroxine, duration of MMI treatment, TSAb status, duration that their TSAb tests remained negative, and thyroid peroxidase antibody titers. The patients were followed for 24 months after stopping MMI.. In the H-TSH group, MMI-associated hypothyroidism typically occurred after 7-8 months of treatment with daily doses of 10-15 mg MMI. No patient had severe symptoms of hypothyroidism. The percentage of patients in remission at 6, 12, and 24 months after discontinuation of MMI was 90.0, 87.5, and 85.0, respectively, in the H-TSH group and 70.3, 67.6, and 54.1, respectively, in the N-TSH group (p  <  0.05 for the comparison of groups at 6 and 12 months and p  <  0.001 for comparison of the groups at 24 months).. In patients with Graves' disease who are treated with MMI for at least 2 years and become euthyroid, the occurrence of elevated serum TSH concentrations during MMI treatment is a favorable indicator for long-term remission and is independent of multiple other factors including TSAb status, duration of MMI treatment, and gross parameters of goiter size.

Topics: Adult; Antithyroid Agents; Autoantibodies; Exophthalmos; Female; Goiter; Graves Disease; Humans; Hypothyroidism; Immunoglobulins, Thyroid-Stimulating; Male; Methimazole; Middle Aged; Prognosis; Retrospective Studies; Thyrotropin; Thyroxine

Treatment of toxic nodular goiter with ¹³¹I is a first-line therapy for hyperthyroidism. To avoid a thyrotoxic storm, ¹³¹I is usually administered after pretreatment with antithyroid drugs, with thyroid-stimulating hormone (TSH) increase and functional recruitment of inhibited normal tissue. Therefore, both autonomous nodule(s) and normal tissue are irradiated. This may be a reason for late hypothyroidism occurring in 15-25% of patients. This study aimed at assessing different pretreatment modalities with combined methymazole and triiodothyronine, achieving euthyroidism with suppressed TSH.. After diagnosis of autonomously functioning toxic nodule, patients were subjected to thyrostatic medication. Two months later, TSH was checked; if >0.5 mU/L triiodothyronine treatment was associated. After 2 more months, if the TSH level was suppressed, patients received ¹³¹I-therapy. A total of 149 patients were consecutively enrolled, 41 of whom with uninodular and 108 with multinodular goiter. They were evaluated at diagnosis, pretreatment, 3 and 6 months after therapy and at late follow-up (6.8+/-4.2 years; range: 1-22 years).. Administered activity was calculated according to ¹³¹I uptake and gland weight. Methymazole was discontinued 6 days before treatment and T3 was maintained until administration of ¹³¹I-therapy. Euthyroidism was achieved in 88% of patients. At late follow-up, subclinical hypothyroidism was observed in 10 patients (6.7%) and overt hypothyroidism in 5 patients (3.3%). No pathological consequences or side effects of ¹³¹I-therapy were found during the 6.8+/-4.2 year follow-up period.. Treatment of toxic nodular goiter with ¹³¹I-therapy, under combined thyrostatic-thyromimetic treatment is a simple, safe, well-tolerated, and effective procedure.

Topics: Adult; Aged; Aged, 80 and over; Antithyroid Agents; Combined Modality Therapy; Female; Goiter, Nodular; Humans; Hypothyroidism; Iodine Radioisotopes; Male; Methimazole; Middle Aged; Thyrotoxicosis; Time Factors; Triiodothyronine

The thyroid hormone is essential for the proper development of the central nervous system (CNS). Hormone deficiency during CNS development causes neurological abnormalities in the brain. The hippocampus is one of the brain regions vulnerable to hormone deficiency, and the volume of dentate gyrus (DG) and cornu ammonis (CA) are reduced by transient hypothyroidism during CNS development. However, it remains unclear whether transient hypothyroidism specifically reduces the whole hippocampal volume. In the present study, we used magnetic resonance imaging (MRI) to examine the effects of perinatal hypothyroidism on the ratio of hippocampal volume to brain volume as well as brain and hippocampal volumes overall. Perinatal hypothyroidism was induced by adding the anti-thyroid drug, methimazole, to the drinking water of pregnant dams from gestational day 15 to postnatal day 21. The MRI experiment was conducted when the rats were between 7 and 11 months old. The results showed reductions of the hippocampal and brain volume of the treated group. However, the ratio of hippocampal volume to brain volume was comparable between the control and treated groups. These results indicate that perinatal hypothyroidism minimizes the brain as a whole, but does not minimize the hippocampus in particular.

Topics: Animals; Antithyroid Agents; Brain; Female; Hippocampus; Hypothyroidism; Magnetic Resonance Imaging; Male; Maternal-Fetal Relations; Methimazole; Organ Size; Pregnancy; Pregnancy Complications; Rats; Rats, Wistar; Thyroxine; Triiodothyronine

Mutations in the thyroid hormone receptor beta (TR-beta) gene result in resistance to thyroid hormone (RTH). Mutation Delta337T in the TR-beta gene has been shown to have the characteristics of RTH syndrome in mice. The aim of this work was to study the possible involvement of TR-beta receptor in thyroid modulation of ClC-2 in mouse kidney.. Expression of mouse (Delta337T and normal C57BL/6) renal RNA and protein expression were studied by reverse transcriptase-polymerase chain reaction and Western blot, respectively, in mice with hyper- or hypothyroidism. Renal function was studied by analysis of urinary electrolyte excretion. Studies of the ClC-2 promoter region were performed in immortalized renal proximal tubule (IRPT) cells.. In RTH syndrome mice (Delta337T), renal dysfunction was found to be associated with changes in the fractional excretion of sodium (FE(Na)) and chloride (FE(Cl)). ClC-2 chloride channel mRNA and protein expression were found to be decreased by 40% in heterozygous and homozygous mutant mouse kidneys and high levels of plasma thyroid hormone were detected in both groups. Hypothyroidism induced by methimazole decreased the renal expression of ClC-2 in normal mice but not in Delta337T mutant mice. In in vitro studies performed on IRPT cells subjected to thyroid hormone treatment, the promoter region of the ClC-2 chloride channel was stimulated in a dose-dependent manner.. This work emphasizes the importance of thyroid hormone in electrolyte handling along the nephron and suggests its participation in renal ClC-2 gene transcription via the TR-beta receptor pathway.

Topics: Animals; Antithyroid Agents; Chloride Channels; CLC-2 Chloride Channels; Hypothyroidism; Kidney; Male; Methimazole; Mice; Mice, Inbred C57BL; Mutation; Promoter Regions, Genetic; RNA, Messenger; Thyroid Hormone Receptors beta; Thyroid Hormones

MicroRNAs (miRNAs) are extensively involved in diverse biological processes. However, very little is known about the role of miRNAs in mediating the action of thyroid hormones (TH). Appropriate TH levels are known to be critically important for development, differentiation and maintenance of metabolic balance in mammals. We induced transient hypothyroidism in juvenile mice by short-term exposure to methimazole and perchlorate from post natal day (PND) 12 to 15. The expression of miRNAs in the liver was analyzed using Taqman Low Density Arrays (containing up to 600 rodent miRNAs). We found the expression of 40 miRNAs was significantly altered in the livers of hypothyroid mice compared to euthyroid controls. Among the miRNAs, miRs-1, 206, 133a and 133b exhibited a massive increase in expression (50- to 500-fold). The regulation of TH on the expression of miRs-1, 206, 133a and 133b was confirmed in various mouse models including: chronic hypothyroid, short-term hyperthyroid and short-term hypothyroid followed by TH supplementation. TH regulation of these miRNAs was also confirmed in mouse hepatocyte AML 12 cells. The expression of precursors of miRs-1, 206, 133a and 133b were examined in AML 12 cells and shown to decrease after TH treatment, only pre-mir-206 and pre-mir-133b reached statistical significance. To identify the targets of these miRNAs, DNA microarrays were used to examine hepatic mRNA levels in the short-term hypothyroid mouse model relative to controls. We found transcripts from 92 known genes were significantly altered in these hypothyroid mice. Web-based target predication software (TargetScan and Microcosm) identified 14 of these transcripts as targets of miRs-1, 206, 133a and 133b. The vast majority of these mRNA targets were significantly down-regulated in hypothyroid mice, corresponding with the up-regulation of miRs-1, 206, 133a and 133b in hypothyroid mouse liver. To further investigate target genes, miR-206 was over-expressed in AML 12 cells. TH treatment of cells over-expressing miR-206 resulted in decreased miR-206 expression, and a significant increase in two predicted target genes, Mup1 and Gpd2. The results suggest that TH regulation of these genes may occur secondarily via miR-206. These studies provide new insight into the role of miRNAs in mediating TH regulation of gene expression.

Topics: Animals; Cell Line; Gene Expression Profiling; Hypothyroidism; Liver; Methimazole; Mice; Mice, Inbred C57BL; MicroRNAs; Perchlorates; Reproducibility of Results; RNA, Messenger; Thyroid Hormones

Because of its large mass, relatively high metabolic activity and responsiveness to thyroid hormone, skeletal muscle contributes significantly to energy expenditure. Despite the presence of mRNA encoding the type 2 iodothyronine-deiodinase (D2), an enzyme that activates T(4) to T3, very low or undetectable activity has been reported in muscle homogenates of adult humans and mice. With a modified D2 assay, using microsomal protein, overnight incubation and protein from D2 knockout mouse muscle as a tissue-specific blank, we examined slow- and fast-twitch mouse skeletal muscles for D2 activity and its response to physiological stimuli. D2 activity was detectable in all hind limb muscles of 8- to 12-wk old C57/BL6 mice. Interestingly, it was higher in the slow-twitch soleus than in fast-twitch muscles (0.40 ± 0.06 vs. 0.076 ± 0.01 fmol/min · mg microsomal protein, respectively, P < 0.001). These levels are greater than those previously reported. Hypothyroidism caused a 40% (P < 0.01) and 300% (P < 0.001) increase in D2 activity after 4 and 8 wk treatment with antithyroid drugs, respectively, with no changes in D2 mRNA. Neither D2 mRNA nor activity increased after an overnight 4 C exposure despite a 10-fold increase in D2 activity in brown adipose tissue in the same mice. The magnitude of the activity, the fiber specificity, and the robust posttranslational response to hypothyroidism argue for a more important role for D2-generated T(3) in skeletal muscle physiology than previously assumed.

Topics: Animals; Animals, Newborn; Antithyroid Agents; Gene Expression Regulation, Enzymologic; Hypothyroidism; Iodide Peroxidase; Iodothyronine Deiodinase Type II; Male; Methimazole; Mice; Mice, Inbred C57BL; Muscle Fibers, Fast-Twitch; Muscle Fibers, Slow-Twitch; Muscle, Skeletal; RNA, Messenger

Thyroid hormone deficiency during a critical period of development severely affects cognitive functions, resulting in profound mental retardation. Despite the importance of the disorder, the cellular mechanisms underlying these deficits remain largely unexplored. The aim of this study was to examine the effects of the absence of thyroid hormone on the development of the intrinsic properties of CA1 hippocampal pyramidal cells. These cells are known to exhibit different firing patterns during development, being classified as either regular-spiking or burst-spiking cells. Patch-clamp experiments showed that hypothyroid rats presented a larger number of regular-spiking cells at early postnatal age (P9-11). This difference in firing-pattern distribution disappeared at the pre-weanling age (P17-19), when almost every cell displayed bursting behavior in both control and hypothyroid rats. However, when studied in detail, weanling hypothyroid rats presented a smaller number of spikes per burst than did control animals. One of the major factors behind bursting behavior is sustained depolarization following an action potential. In this study, we show that action potential afterdepolarizations of hypothyroid animals registered shorter half-durations than did controls, a fact which could explain the smaller number of action potentials per burst. Additionally, the afterdepolarizations observed on both hypothyroid and control neurons were highly sensitive to low concentrations of nickel, suggesting that a low-threshold Ca(2+) current is key in the generation of spike afterdepolarizations and in the control of the bursting pattern of firing of these neurons. In agreement with this, experiments performed on dissociated hippocampal neurons have shown that this current is significantly depressed in hypothyroid animals. Therefore, we conclude that an alteration of the low-threshold calcium current is the basic factor explaining the differences observed in the firing behavior of hypothyroid animals.

Topics: 6-Cyano-7-nitroquinoxaline-2,3-dione; Action Potentials; Age Factors; Animals; Animals, Newborn; Biophysics; Calcium; Calcium Channels; Disease Models, Animal; Electric Stimulation; Excitatory Amino Acid Antagonists; Female; GABA Antagonists; Hippocampus; Hypothyroidism; In Vitro Techniques; Methimazole; Neurons; Patch-Clamp Techniques; Picrotoxin; Pregnancy; Prenatal Exposure Delayed Effects; Rats; Rats, Wistar; Sodium Channel Blockers; Tetrodotoxin

Severe cognitive impairment follows thyroid hormone deficiency during the neonatal period. The role of nitric oxide (NO) in learning and memory has been widely investigated.. This study aimed to investigate the effect of hypothyroidism during neonatal and juvenile periods on NO metabolites in the hippocampi of rats and on learning and memory. Animals were divided into two groups and treated for 60 days from the first day of lactation. The control group received regular water, whereas animals in a separate group were given water supplemented with 0.03% methimazole to induce hypothyroidism. Male offspring were selected and tested in the Morris water maze. Samples of blood were collected to measure the metabolites of NO, NO2, NO3 and thyroxine. The animals were then sacrificed, and their hippocampi were removed to measure the tissue concentrations of NO2 and NO3.. Compared to the control group's offspring, serum thyroxine levels in the methimazole group's offspring were significantly lower (P<0.01). In addition, the swim distance and time latency were significantly higher in the methimazole group (P<0.001), and the time spent by this group in the target quadrant (Q1) during the probe trial was significantly lower (P<0.001). There was no significant difference in the plasma levels of NO metabolites between the two groups; however, significantly higher NO metabolite levels in the hippocampi of the methimazole group were observed compared to controls (P<0.05).. These results suggest that the increased NO level in the hippocampus may play a role in the learning and memory deficits observed in childhood hypothyroidism; however, the precise underlying mechanism(s) remains to be elucidated.

Topics: Animals; Antithyroid Agents; Female; Hippocampus; Hypothyroidism; Learning Disabilities; Memory Disorders; Methimazole; Nitric Oxide; Nitric Oxide Synthase; Rats; Rats, Wistar; Thyroxine; Time Factors

In experiments on 190 adult male Wistar rats it was established that at chronic stress (the congested housing of animals during 3 months) the status of marginal periodontal tissues and hard dental tissues (degree of gum recession, atrophy of alveolar bone, teeth mobility; enamel acid resistance) depended upon the organism thyroid status: hypothyroidism (intragastric introduction of mercazolil in the of 12 mg/kg body weight during 14 days, then in half dose up to the end of the experiment) increased intensity of stress disturbances whereas small L-thyroxin doses (5-8 μg/kg body weight intragastrally during 28 days after that in half dose) essentially limited them.

Topics: Acids; Animals; Antithyroid Agents; Dental Enamel; Hypothyroidism; Male; Methimazole; Periodontium; Rats; Rats, Wistar; Stress, Psychological; Thyroid Gland; Thyroid Hormones

The time-dependent effects of mild hypothyroidism on endothelial function were assessed in rat mesenteric arteries. Male Wistar rats were treated with methimazole (MMI; 0.003%) or placebo up to 16 wk. Endothelial function of mesenteric small arteries was assessed by pressurized myograph. MMI-treated animals displayed a decrease in serum thyroid hormones, an increment of plasma TSH and inflammatory cytokines, and a blunted vascular relaxation to acetylcholine, as compared with controls. Endothelial dysfunction resulted from a reduced nitric oxide (NO) availability caused by oxidative excess. Vascular-inducible NO synthase (iNOS) expression was up-regulated. S-methylisothiourea (an iNOS inhibitor) normalized endothelium-dependent relaxations and restored NO availability in arteries from 8-wk MMI-animals and partly ameliorated these alterations in 16-wk MMI rats. Similar results were obtained when MMI-induced hypothyroidism was prevented by T(4) replacement. Among controls, an impaired NO availability, secondary to oxidative excess, occurred at 16 wk, and it was less pronounced than in age-matched MMI animals. Both endothelial dysfunction and oxidant excess secondary to aging were prevented by apocynin (nicotinamide adenine dinucleotide phosphate oxidase inhibitor). Mesenteric superoxide production was reduced by S-methylisothiourea and T(4) replacement in MMI animals and abolished by apocynin in controls (dihydroethidium staining). MMI-induced mild hypothyroidism is associated with endothelial dysfunction caused by a reduced NO availability, secondary to oxidative excess. It is suggested that in this animal model, characterized by TSH elevation and low-grade inflammation, an increased expression and function of iNOS, resulting in superoxide generation, accounts for an impaired NO availability.

Topics: Allopurinol; Animals; Ascorbic Acid; Endothelium, Vascular; Enzyme Inhibitors; Hypothyroidism; Male; Mesenteric Arteries; Methimazole; NADPH Oxidases; NG-Nitroarginine Methyl Ester; Nitric Oxide; Nitric Oxide Synthase Type II; Rats; Rats, Wistar; Superoxides; Thyroxine; Vasodilation

The onset of adult hypothyroidism causes neuronal damage in the CA3 hippocampal region, which is attenuated by T(4) administration. We analyzed the expression of molecular proliferation markers (Cyclin D1 and PCNA), cellular damage-arrest (p53 and p21), and apoptosis (Bax/Bcl-2 index) in the hippocampus of hypothyroid (methimazole; 60 mg/kg) or thyroid replaced (T(4), 20 microg/kg; MMI+T(4) or T(3), 20 microg/kg; MMI+T(3)) adult male rats. Histological analysis showed that hypothyroid animals exhibit significant neuronal damage in all regions of the hippocampus accompanied by the triggering of the apoptotic pathway (increases in p53, p21 and the Bax/Bcl-2 index) and no changes in proliferation (Cyclin D1 and PCNA). MMI+T(4) replaced animals were completely protected with no changes in molecular markers. In contrast, MMI+T(3) replaced animals showed partial protection in which, although pro-apoptotic effects remained (increase in the Bax/Bcl-2), proliferative mechanisms were triggered (increase in p53, Cyclin D1 and PCNA expression). Our results indicate that thyroid hormones participate in the maintenance of the hippocampal neuronal population even in adulthood, suggesting that THs have different physiological roles as neuronal survival factors: T(4) prevents the activation of apoptotic pathways, whereas T(3) activates cell differentiation and proliferation mechanisms.

Topics: Animals; Antithyroid Agents; bcl-2-Associated X Protein; Cell Cycle; Cell Cycle Proteins; Cell Proliferation; Cell Survival; Cyclin D1; Cyclin-Dependent Kinase Inhibitor p21; Disease Models, Animal; Hippocampus; Hypothyroidism; Male; Methimazole; Proliferating Cell Nuclear Antigen; Proto-Oncogene Proteins c-bcl-2; Pyramidal Cells; Rats; Rats, Wistar; Thyroid Gland; Thyroid Hormones; Tumor Suppressor Protein p53

We investigated the effects of methimazole, an anti-thyroid drug, on the onset of type 2 diabetes in Zucker diabetic fatty (ZDF) rats. For this, 0.03% methimazole was administered to 7-week-old, pre-diabetic ZDF rats in drinking water for 5 weeks and the animals were sacrificed at 12 weeks of age. Methimazole treatment to ZDF rats significantly reduced blood glucose levels, food intake, body weight, and serum T3 levels. Hepatocytes in ZDF-methi rats were more densely stained with eosin than those in ZDF rats because of low fat accumulation in ZDF-methi hepatocytes. The pancreatic islet in ZDF-methi rats was normal compared to that in ZDF rats. Glucagon, not insulin, immunoreactivity in ZDF-methi rats was significantly higher than that in ZDF-methi rats. These suggest that methimazole treatment may delay the onset of type 2 diabetes in leptin receptor-deficient rats and also suggests that thyroid hormones may be necessary for the onset of diabetes.

Topics: Animals; Antithyroid Agents; Diabetes Mellitus, Type 2; Female; Hepatocytes; Hypothyroidism; Liver; Male; Methimazole; Pancreas; Rats; Rats, Zucker; Receptors, Leptin

Thyroid hormone plays a critical role in mitochondrial biogenesis in two areas of the developing brain, the cerebral cortex and the striatum. Here we analyzed, in the cerebral cortex of neonatal rats, the effect of hypothyroidism on the biogenesis in free and synaptosomal mitochondria by analyzing, in isolated mitochondria, the activity of respiratory complex I, oxidative phosphorylation, oxygen consumption, and the expression of mitochondrial genome. In addition, we studied the effect of thyroid hormone in oxygen consumption in vivo by determining metabolic flow through (13)C nuclear magnetic resonance spectroscopy. Our results clearly show that in vivo, hypothyroidism markedly reduces oxygen consumption in the neural population of the cerebral cortex. This effect correlates with decreased free mitochondria biogenesis. In contrast, no effect was observed in the biogenesis in synaptosomal mitochondria. The parameters analyzed were markedly improved after T(3) administration. These results suggest that a reduced biogenesis and the subsequent reduction of respiratory capacity in free mitochondria could be the underlying cause of decreased oxygen consumption in the neurons of the cerebral cortex of hypothyroid neonates.

Topics: Animals; Cerebral Cortex; Congenital Hypothyroidism; Female; Hypothyroidism; Magnetic Resonance Spectroscopy; Male; Methimazole; Mitochondria; Mitochondrial Proteins; Oxidative Phosphorylation; Oxygen Consumption; Rats; Rats, Wistar

We analyzed the participation of N-methyl-d-aspartate (NMDA) receptors in the neuronal damage caused by adult-onset hypothyroidism. Wistar rats were randomly assigned into four groups. The euthyroid group received tap water. The hypothyroid group received methimazole (60 mg/kg) in their drinking water to induce hypothyroidism. Two more groups of rats received the antithyroid treatment and were injected daily with the NMDA antagonist ketamine (15 mg/kg, sc) or MK-801 (0.5mg/kg, ip). Treatments were administered during 4 weeks. At the end of the respective treatments rats were deeply anaesthetized and perfused intracardially with 0.9% NaCl followed by 4% paraformaldehyde. The brains were removed from the skull, and coronal brain sections (7microm thick) were obtained. Neurons were counted in the CA1, CA2, CA3, and CA4 hippocampal regions differentiating between normal and atrophic cells by an experimenter blind to the treatment. The percentage of neuronal damage found in the MMI group was significantly greater in the hippocampal regions compared to the euthyroid group. In contrast, both NMDA antagonists were able to prevent the neuronal damage secondary to hypothyroidism in all hippocampal regions. Our results suggest that the neuronal damage caused in the hippocampus of adult-onset hypothyroid rats requires activation of NMDA channels.

Topics: Animals; Antithyroid Agents; Cell Count; Dizocilpine Maleate; Hippocampus; Hypothyroidism; Ketamine; Male; Methimazole; Neurons; Random Allocation; Rats; Rats, Wistar; Receptors, N-Methyl-D-Aspartate

We present 4 patients with Graves' disease who developed spontaneous hypothyroidism during follow-up. The two most plausible physiopathologic mechanisms for this development were progressive autoimmune-mediated destruction of the thyroid follicular epithelium and a predominance of blocking antibodies to the thyroid-stimulating hormone (TSH) receptor at the expense of stimulating antibodies in the same patient. Description of these patients not only illustrates the heterogeneous nature of this disease, but also the interrelation among its distinct clinical forms.

Topics: Adult; Aged; Autoantibodies; Disease Progression; Female; Goiter; Graves Disease; Humans; Hypothyroidism; Immunoglobulins, Thyroid-Stimulating; Male; Methimazole; Middle Aged; Receptors, Thyrotropin; Thyroid Hormones; Thyrotoxicosis; Thyroxine

Chronic hypothyroidism is associated with an increased risk for cardiovascular disease attributed, in part, to increased serum cholesterol and atherosclerosis. Decreased hepatic activity of cholesterol 7a-hydroxylase (CYP7A1) is thought to contribute to hypercholesterolemia in hypothyroidism. The endoplasmic reticulum (ER) has been shown to be a central organelle, and it is the location of CYP7A1 in hepatocyte. The aim of the present study was to determine whether the expression of CYP7A1 mRNA and protein could be decreased and whether ER could undergo morphological changes in a rodent model of chronic hypothyroidism induced by methimazole (MMI). Male Wistar rats were treated with MMI (0.04% wt/vol) or regular water for 14 weeks. Hepatic CYP7A1 mRNA was analyzed on quantitative real-time polymerase chain reaction (PCR). Hepatic CYP7A1 protein expression was assessed on western blot. In conjunction with these molecular biological assessments the morphology of ER was evaluated on transmission electron microscopy (TEM). Serum total cholesterol increased significantly compared to controls and was associated with decreased CYP7A1 mRNA and protein, and TEM indicated remarkable dilation of ER in hepatocytes in the chronic hypothyroid rats. These findings suggest that a relationship between the decreased expression of hepatic CYP7A1 mRNA and protein and dilated ER could exist, which may contribute to hypercholesterolemia in chronic hypothyroidism.

Topics: Animals; Blotting, Western; Cholesterol 7-alpha-Hydroxylase; Chronic Disease; Disease Models, Animal; Endoplasmic Reticulum; Gene Expression Regulation, Enzymologic; Hepatocytes; Hypercholesterolemia; Hypothyroidism; Liver; Male; Methimazole; Rats; Rats, Wistar; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger

Neurological deficits in the offspring caused by human maternal hypothyroxinemia are thought to be irreversible. To understand the mechanism responsible for these neurological alterations, we induced maternal hypothyroxinemia in pregnant rats. Behavior and synapse function were evaluated in the offspring of thyroid hormone-deficient rats. Our data indicate that, when compared with controls, hypothyroxinemic mothers bear litters that, in adulthood, show prolonged latencies during the learning process in the water maze test. Impaired learning capacity caused by hypothyroxinemia was consistent with cellular and molecular alterations, including: 1) lack of increase of phosphorylated c-fos on the second day of the water maze test; 2) impaired induction of long-term potentiation in response to theta-burst stimulation to the Schaffer collateral pathway in the area 1 of the hippocampus Ammon's horn stratum radiatum, despite normal responses for input/output experiments; 3) increase of postsynaptic density protein 95 (PSD-95), N-methyl-D-aspartic acid receptor subunit 1, and tyrosine receptor kinase B levels in brain extracts; and 4) significant increase of PSD-95 at the PSDs and failure of this molecule to colocalize with N-methyl-D-aspartic acid receptor subunit 1, as it was shown by control rats. Our findings suggest that maternal hypothyroxinemia is a harmful condition for the offspring that can affect key molecular components for synaptic function and spatial learning.

Topics: Age Factors; Animals; Cognition Disorders; Disks Large Homolog 4 Protein; Female; Hypothyroidism; Imidazoles; Intracellular Signaling Peptides and Proteins; Long-Term Potentiation; Male; Maze Learning; Membrane Proteins; Phosphorylation; Pregnancy; Pregnancy Complications; Prenatal Exposure Delayed Effects; Proto-Oncogene Proteins c-fos; Rats; Rats, Sprague-Dawley; Receptors, N-Methyl-D-Aspartate; Space Perception; Synapses; 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

The effects of hypothyroidism on lipid peroxidation (LP), reactive oxygen species (ROS), and nitric oxide synthase (NOS), levels and expression, in rat brain were examined. Hypothyroidism was induced by administering methimazole in drinking water (60 mg/kg/day). In striatum, motor cortex and cerebellum of hypothyroid rats LP was not modified, whereas LP and ROS increased in amygdala and hippocampus of hypothyroid rats at the third week of treatment with methimazole as compared to euthyroid group values. Regarding NOS participation, only hippocampal constitutive-NOS activity was increased, accompanied by an augmentation in nNOS expression. Results show that hypothyroidism induces selective oxidative stress in both the hippocampus and amygdala, where the nitrergic system is involved.

Topics: Amygdala; Animals; Antithyroid Agents; Body Temperature; Body Weight; Hippocampus; Hypothyroidism; Lipid Peroxidation; Male; Methimazole; Nitric Oxide Synthase Type I; Nitric Oxide Synthase Type III; Oxidative Stress; Rats; Rats, Wistar; Reactive Oxygen Species

Although thyroid hormones are crucial for cerebellar development, and several thyroid hormone-dependent genes are known to be correlated with morphological development of the cerebellum, the precise mechanisms of morphological cerebellar changes in hypothyroidism (HT) remain unknown. To investigate these mechanisms in experimental rat HT induced by the anti-thyroid drug methimazole (MMI-HT rat), we carried out gene expression analysis (sonic hedgehog (Shh), reelin, and Bax) using quantitative real-time PCR. Histological examination revealed cerebellar abnormalities, including reductions in the thickness of the molecular layer and delayed disappearance of the external granular layer (EGL), as well as excess bulges or sublobules in the internal granular layer (IGL). At Postnatal Day (P) 6, Shh expression in MMI-HT rat was comparable to that in controls, thus suggesting that Shh expression was sufficient to form the lobes in the initial phase. However, Shh expression decreased in the later phases, as compared with age-matched controls. This demonstrated that stronger and sustained signaling is necessary for partitioning of the cardinal lobes into lobes and sublobes. Although reelin expression was not clearly different from that in controls, Bax expression decreased at P 15. The attrition of Bax at P 15 as well as Shh in the later phase may be related to irregularities in the IGL and the relatively large numbers of internal granular cells. Taken together, these results suggest that Shh expression is related to the morphological cerebellar changes in experimental hypothyroidism and that sustained signaling by Shh may play a key role in normal development, particularly lobulation, in the cerebellum.

Topics: Animals; bcl-2-Associated X Protein; Cell Adhesion Molecules, Neuronal; Cerebellum; Extracellular Matrix Proteins; Female; Gene Expression Regulation, Developmental; Hedgehog Proteins; Hypothyroidism; Male; Maternal Exposure; Methimazole; Nerve Tissue Proteins; Pregnancy; Prenatal Exposure Delayed Effects; Rats; Reelin Protein; Serine Endopeptidases

Thyroid hormone (TH) deficiency during perinatal life causes a multitude of functional and morphological deficits in the brain. In rats and mice, TH dependency of neural maturation is particularly evident during the first 1-2 weeks of postnatal development. During the same period, synaptic transmission via the inhibitory transmitters glycine and GABA changes from excitatory depolarizing effects to inhibitory hyperpolarizing ones in most neurons [depolarizing-hyperpolarizing (D/H) shift]. The D/H shift is caused by the activation of the K(+)-Cl(-) co-transporter KCC2 which extrudes Cl(-) from the cytosol, thus generating an inward-directed electrochemical Cl(-) gradient. Here we analyzed whether the D/H shift and, consequently, the onset of inhibitory neurotransmission are influenced by TH. Gramicidin perforated-patch recordings from auditory brainstem neurons of experimentally hypothyroid rats revealed depolarizing glycine effects until postnatal day (P)11, i.e. almost 1 week longer than in control rats, in which the D/H shift occurred at approximately P5-6. Likewise, until P12-13 the equilibrium potential E(Gly) in hypothyroids was more positive than the membrane resting potential. Normal E(Gly) could be restored upon TH substitution in P11-12 hypothyroids. These data demonstrate a disturbed Cl(-) homeostasis following TH deficiency and point to a delayed onset of synaptic inhibition. Interestingly, immunohistochemistry demonstrated an unchanged KCC2 distribution in hypothyroids, implying that TH deficiency did not affect KCC2 gene expression but may have impaired the functional status of KCC2. Hippocampal neurons of hypothyroid P16-17 rats also demonstrated an impaired Cl(-) homeostasis, indicating that TH may have promoted the D/H shift and maturation of synaptic inhibition throughout the brain.

Topics: Animals; Antithyroid Agents; Auditory Pathways; Brain Stem; Chlorides; Female; gamma-Aminobutyric Acid; Glycine; Hippocampus; Homeostasis; Humans; Hypothyroidism; K Cl- Cotransporters; Methimazole; Mice; Neurons; Patch-Clamp Techniques; Rats; Rats, Sprague-Dawley; Rats, Wistar; Signal Transduction; Symporters; Synaptic Transmission; Thyroid Hormones

The long-term cardiac effects of amiodarone resemble many aspects of hypothyroidism. The anti-arrhythmic potential of amiodarone may therefore be the result of a drug-induced, local hypothyroid-like condition. To investigate this controversial issue, we compared gene expression profiles in the hearts of rats treated with amiodarone with those of rats with hypothyroidism. Wistar male rats were assigned to 3 groups (n=6-8): Control, systemic hypothyroidism (hypothyroidism) and amiodarone treatment (amiodarone, 150 mg/kg/day, p.o., 4 weeks). Electrocardiogram (ECG) recordings, gene profiling by DNA microarray and Northern blotting were carried out. Amiodarone, like hypothyroidism, caused significant prolongation of RR and QT intervals in ECGs. Microarray analysis of 8435 genes in the left ventricular myocardium revealed a significant similarity in expression profiles between hypothyroidism and amiodarone (R=0.63, p<0.00001). The gene expression profiles of hypothyroidism and amiodarone showed closer correlation when top 100 up-regulated and 100 down-regulated genes in hypothyroidism (total 200 genes) were analyzed (R=0.78, p<0.00001). Northern blots of left ventricular myocardium showed a parallel decrease in mRNAs for myosin heavy chain (MHC)-alpha and a parallel increase for myosin heavy chain (MHC)-beta in hypothyroidism and amiodarone. In the liver and pituitary, in contrast, Northern blots showed quite different changes in the transcripts of the representative T3-responsive genes in the hypothyroidism and amiodarone. In conclusion, long-term treatment with amiodarone causes cardioselective hypothyroid-like alterations in gene expression profiles. The potent anti-arrhythmic activity of amiodarone may be attributable, in part at least, to this unique transcriptional remodeling.

Topics: Amiodarone; Animals; Anti-Arrhythmia Agents; Blotting, Northern; Cluster Analysis; Disease Models, Animal; Electrocardiography; Gene Expression Profiling; Heart; Heart Conduction System; Heart Rate; Heart Ventricles; Hypothyroidism; Liver; Male; Methimazole; Myocardium; Oligonucleotide Array Sequence Analysis; Pituitary Gland; Rats; Rats, Wistar; RNA, Messenger; Time Factors; Transcription, Genetic

Topics: Adult; Antithyroid Agents; Female; Graves Disease; Humans; Hypothyroidism; Methimazole; Nephrosis, Lipoid

Thyroid hormone (T3) deficiency impairs the development of the CNS, particularly myelination. We have previously described an increase in the frequency of morphological abnormalities in the central myelin sheath in a hypothyroidism model, which reinforced the hypothesis of a role for T3 in myelin compaction. However, there are no data concerning the cellular distribution of myelin proteins in hypothyroid animals. In the present work, we describe the distribution of 2',3'-cyclic nucleotide 3'-phosphodiesterase (CNPase), myelin basic protein (MBP) and proteolipid protein (PLP) throughout the central myelin sheath of a hypothyroidism model. We used euthyroid and hypothyroid adult rats at 90 days of age. In order to induce hypothyroid status, animals received 0.02% methimazol from the 19th gestation day onwards. After perfusion with a fixative mixture, small pieces of corpus callosum were obtained, dehydrated and embedded in LR White resin. Ultrathin sections were immunoreacted, using specific antibodies revealed by a secondary antibody coupled to colloidal gold particles of 10nm. Gold particle density per region of myelin sheath for each one of these proteins was obtained. In normal animals, CNPase, PLP and MBP were identified in sites that had already been described in previous studies. In hypothyroid animals, CNPase was identified in the region corresponding to compact lamellae, which normally does not contain this protein, while, in this same region, PLP and MBP immunolabeling were decreased. These results suggest that thyroid hormone deficiency impairs the distribution of the major oligodendrocyte/myelin markers. This effect may justify the reduction in myelin sheath compaction previously demonstrated in a similar model of hypothyroidism.

Topics: 2',3'-Cyclic-Nucleotide Phosphodiesterases; Animals; Antithyroid Agents; Biomarkers; Cell Membrane; Corpus Callosum; Demyelinating Diseases; Hypothyroidism; Methimazole; Microscopy, Immunoelectron; Myelin Basic Protein; Myelin Proteins; Myelin Proteolipid Protein; Myelin Sheath; Oligodendroglia; Rats; Rats, Wistar

Hypothyroidism in humans is associated with incomplete distal renal tubular acidosis, presenting as the inability to respond appropriately to an acid challenge by excreting less acid. Here, we induced hypothyroidism in rats with methimazole (HYPO) and in one group substituted with l-thyroxine (EU). After 4 wk, acid-base status was similar in both groups. However, after 24 h acid loading with NH(4)Cl HYPO rats displayed a more pronounced metabolic acidosis. The expression of the Na(+)/H(+) exchanger NHE3, the Na(+)-phosphate cotransporter NaPi-IIa, and the B2 subunit of the vacuolar H(+)-ATPase was reduced in the brush-border membrane of the proximal tubule of the HYPO group, paralleled by a lower abundance of the Na(+)/HCO(3)(-) cotransporter NBCe1 and a higher expression of the acid-secretory type A intercalated cell-specific Cl(-)/HCO(3)(-) exchanger AE1. In contrast to control conditions, the expression of NBCe1 was increased in the HYPO group during metabolic acidosis. In addition, net acid excretion was similar in both groups. The relative number of type A intercalated cells was increased in the connecting tubule and cortical collecting duct of the HYPO group during acidosis. Thus thyroid hormones modulate the renal response to an acid challenge and alter the expression of several key acid-base transporters. Mild hypothyroidism is associated only with a very mild defect in renal acid handling, which appears to be mainly located in the proximal tubule and is compensated by the distal nephron.

Topics: Acidosis; Ammonium Chloride; Animals; Antithyroid Agents; Bicarbonates; Blotting, Western; Carrier Proteins; Enzyme-Linked Immunosorbent Assay; Hydrogen-Ion Concentration; Hypothyroidism; Kidney; Kidney Tubules, Distal; Kidney Tubules, Proximal; Male; Methimazole; Nephrons; Rats; Rats, Wistar; Sodium-Hydrogen Exchanger 3; Sodium-Hydrogen Exchangers; Thyroid Hormones; Thyrotropin; Triiodothyronine

Insulin receptor substrate-1 (IRS-1) is the main intracellular substrate for both insulin and insulin-like growth factor I (IGF-I) receptors and is critical for cell mitogenesis. Thyrotropin is able to induce thyroid cell proliferation through the cyclic AMP intracellular cascade; however, the presence of either insulin or IGF-I is required for the mitogenic effect of thyroid-stimulating hormone (TSH) to occur. The aim of the present study was to determine whether thyroid IRS-1 content is modulated by TSH in vivo. Strikingly, hypothyroid goitrous rats, which have chronically high serum TSH levels (control, C = 2.31 +/- 0.28; methimazole (MMI) 21d = 51.02 +/- 6.02 ng/mL, N = 12 rats), when treated with 0.03% MMI in drinking water for 21 days, showed significantly reduced thyroid IRS-1 mRNA content. Since goiter was already established in these animals by MMI for 21 days, we also evaluated IRS-1 expression during goitrogenesis. Animals treated with MMI for different periods of time showed a progressive increase in thyroid weight (C = 22.18 +/- 1.21; MMI 5d = 32.83 +/- 1.48; MMI 7d = 31.1 +/- 3.25; MMI 10d = 33.8 +/- 1.25; MMI 14d = 45.5 +/- 2.56; MMI 18d = 53.0 +/- 3.01; MMI 21d = 61.9 +/- 3.92 mg, N = 9-15 animals per group) and serum TSH levels (C = 1.57 +/- 0.2; MMI 5d = 9.95 +/- 0.74; MMI 7d = 10.38 +/- 0.84; MMI 10d = 17.72 +/- 1.47; MMI 14d = 25.65 +/- 1.23; MMI 18d = 35.38 +/- 3.69; MMI 21d = 31.3 +/- 2.7 ng/mL, N = 9-15 animals per group). Thyroid IRS-1 mRNA expression increased progressively during goitrogenesis, being significantly higher by the 14th day of MMI treatment, and then started to decline, reaching the lowest values by the 21st day, when a significant reduction was detected. In the liver of these animals, however, a significant decrease of IRS-1 mRNA was detected after 14 days of MMI treatment, a mechanism probably involved in the insulin resistance that occurs in hypothyroidism. The increase in IRS-1 expression during goitrogenesis may represent an important event associated with the increased rate of cell mitosis promoted by TSH and indicates that insulin and IGF-I are important co-mitogenic factors in vivo, possibly acting through the activation of IRS-1.

Topics: Adaptor Proteins, Signal Transducing; Animals; Goiter; Hypothyroidism; Insulin Receptor Substrate Proteins; Male; Methimazole; Mitosis; Rats; Rats, Wistar; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Thyroid Gland; Thyrotropin

Patients with thyroid diseases have abnormalities of blood coagulation including an alteration of von Willebrand factor (vWF) levels. Because vWF plays an important role in primary hemostasis, we hypothesized that heightened and decreased vWF levels in hyper- and hypothyroidism enhance and decrease platelet plug formation, respectively.. We followed a cohort of 120 patients with overt hyperthyroidism, patients with subclinical and overt hypothyroidism, and euthyroid controls. vWF and in vitro platelet plug formation as collagen-epinephrine-induced closure time (CEPI-CT) were measured at baseline and during therapy with thiamazole or T(4).. Baseline vWF levels were higher in patients with hyperthyroidism and lower in patients with overt hypothyroidism than in controls (P < 0.01). High vWF antigen levels were associated with increased baseline platelet plug formation in patients with hyperthyroidism as compared with controls [114 sec (95% confidence interval, 105-122 sec) vs. 130 sec (120-140 sec), P = 0.01]. After 8 wk of therapy with thiamazole, serum concentrations of T(4) and vWF levels decreased to normal values (P < 0.01 vs. baseline), and CEPI-CT was prolonged as compared with baseline (P < 0.01). During therapy with T(4), vWF levels increased (P < 0.05 vs. baseline) and CEPI-CT was shortened as compared with baseline (P < 0.01).. Hyperthyroidism-induced vWF elevation is associated with enhanced platelet function and therefore shortened CEPI-CT values. These changes may contribute to the higher risk for cardiovascular disease in patients with hyperthyroidism. Platelet plug formation decreases during therapy with thiamazole. Furthermore, CEPI-CT appears to be sensitive to detect acquired von Willebrand disease associated with overt hypothyroidism.

Topics: Adult; Antithyroid Agents; Cohort Studies; Collagen; Epinephrine; Factor VIII; Female; Humans; Hyperthyroidism; Hypothyroidism; Male; Methimazole; Middle Aged; Multivariate Analysis; Platelet Aggregation; Platelet Function Tests; Ristocetin; Thyroxine; Vasoconstrictor Agents; von Willebrand Factor

Cochlear outer hair cells (OHCs) terminally differentiate prior to the onset of hearing. During this time period, thyroid hormone (TH) dramatically influences inner ear development. It has been shown recently that TH enhances the expression of the motor protein prestin via liganded TH receptor beta (TRbeta) while in contrast the expression of the potassium channel KCNQ4 is repressed by unliganded TRalpha1. These different mechanisms of TH regulation by TRalpha1 or TRbeta prompted us to analyse other ion channels that are required for the final differentiation of OHCs. We analysed the onset of expression of the Ca(2+) channel Ca(V)1.3, and the K(+) channels SK2 and BK and correlated the results with the regulation via TRalpha1 or TRbeta. The data support the hypothesis that proteins expressed in rodents prior to or briefly after birth like Ca(V)1.3 and prestin are either independent of TH (e.g. Ca(V)1.3) or enhanced through TRbeta (e.g. prestin). In contrast, proteins expressed in rodents later than P6 like KCNQ4 ( approximately P6), SK2 ( approximately P9) and BK ( approximately P11) are repressed through TRalpha1. We hypothesise that the precise regulation of expression of the latter genes requires a critical local TH level to overcome the TRalpha1 repression.

Topics: Animals; Antithyroid Agents; Cell Differentiation; Cochlea; Hair Cells, Auditory, Inner; Hair Cells, Auditory, Outer; Hypothyroidism; Immunohistochemistry; Ion Channels; Methimazole; Mice; Mice, Knockout; Models, Statistical; Rats; Species Specificity; Thyroid Hormone Receptors alpha; Thyroid Hormone Receptors beta; Thyroid Hormones; Up-Regulation; Vestibule, Labyrinth

Hormone diseases induce changes in the lacrimal gland (LG) and ocular surface (OS). Thyroid hormone (TH) induces cell proliferation and lipid metabolism through the activation of TH receptors. The aim of the present study was to evaluate the location and comparative expression of TH receptor beta-1 (Thrb) in LG of rats with hypothyroidism and in controls and to evaluate the impact of this disease on LG and OS structure and function.. Hypothyroidism was induced in Wistar male rats by the long-term use of tiamazole. Ten weeks later corneal cells were collected for impression cytology (IC). Rats were humanely killed, and tissues were evaluated by immunoperoxidase staining and Western blot for Thrb. The content of malondialdehyde (MDA) and acetylcholine (ACh) in LG was determined by spectrophotometry (n = 5/group in all experiments).. LG weight was significantly lower in hypothyroid rats (P < 0.05). Western blot analysis indicated that LGs express Thrb and that hypothyroidism induces a higher expression of this receptor. IC was significantly different and ACh was significantly lower in hypothyroid rats (P < 0.05).. Chronically reduced levels of TH lead to biochemical and structural changes and modulate the levels of Thrb in LG. These events confirm that LG is a target organ for TH and may facilitate understanding of the mechanism related to dry eye in hypothyroidism.

Topics: Acetylcholine; Animals; Blotting, Western; Conjunctiva; Cornea; Glutathione; Hypothyroidism; Immunoenzyme Techniques; Lacrimal Apparatus; Lipid Peroxidation; Male; Malondialdehyde; Methimazole; Oxidative Stress; Peroxidase; Rats; Rats, Wistar; Thyroid Hormone Receptors beta; Thyroid Hormones

Thyroid-stimulating hormone (TSH) stimulates the synthesis and release of thyroid hormones including triiodothyronine (T3) and thyroxine (T4). Semiquantitative analyses using northern blot and in situ hybridization suggested that TSH gene transcription is upregulated under conditions of hypothyroidism. However, no quantitative analysis of TSH gene expression using real-time polymerase chain reaction (PCR) has been reported. In this study, we quantitated the TSHbeta messenger ribonucleic acid (mRNA) level as well as the TSHbeta heterogeneous nuclear ribonucleic acid (hnRNA) level in the anterior pituitary of hypothyroid rats, by real-time PCR using the LightCycler system. The hnRNA is the primary deoxyribonucleic acid (DNA) transcript, which reflects the transcription rate more reliably than the mRNA because of its short half-life. In the anterior pituitary of rats with methimazol-induced chronic hypothyroidism, both mRNA and hnRNA expression of TSHbeta were upregulated fourfold relative to normal rats (n=4). Our method provides a rapid and accurate measure of gene transcription. In the present report, we described a technique for accurate measurement of TSHbeta hnRNA level.

Topics: Animals; Enzyme-Linked Immunosorbent Assay; Gene Expression Regulation; Hypothyroidism; Male; Methimazole; Rats; Rats, Wistar; Reverse Transcriptase Polymerase Chain Reaction; RNA, Heterogeneous Nuclear; RNA, Messenger; Thyrotropin; Thyroxine; Triiodothyronine

The serum biochemical indexes (level of triiodthyronine, thyroxin, thyrothropic hormone of adenohypophysis, level of cholesterol, triglycerides) and the level of iodine excretion with urine in rats with hypothyrosis corrected by "Iodid-100" and along with excessive intake of chlorine and fluorine ions into the organism had been studied. It has been revealed that hypothyrosis has negative influence on lipid metabolism indexes. "Iodid- 100" usage stabilized hormonal and lipid status. Excessive intake of chlorine and fluorine ions by the organism decreased the effectiveness of iodine containing drugs.

Topics: Animals; Disease Models, Animal; Drug Interactions; Hypothyroidism; Iodides; Iodine; Lipid Metabolism; Male; Methimazole; Rats; Sodium Chloride; Sodium Fluoride; Thyroid Hormones

Thyrotrophin induces proliferation and function in thyroid cells acting through a seven transmembrane G protein-coupled receptor. The proliferative pathways induced by thyrotropin (TSH) in thyrocytes in vivo are not completely understood yet. The aim of this work is to evaluate if Ras can be induced by TSH in rat thyroids, and whether extracellular regulated kinase (ERK) may be involved in the subsequent intracellular signalling cascade. We induced hypothyroidism in Wistar rats by methimazole (MMI) treatment (0.03% in the drinking water for 21 days). A subset of the hypothyroid rats received T4 (1 microg/100 g bw) during the last 10 days of MMI treatment. Hyperthyroidism was induced by subcutaneous injections of T4 (10 microg/100 g bw) during 10 days in another group of rats. Our data show that in the hypothyroid rats there is a clear positive Ras modulation, but a decrease in pERK. In contrast, thyroidal pERK increases in T4-induced hyperthyroidism, but without any change in RAS, although these changes did not reach statistical significance. Thus, while the rat thyroid proliferation induced by TSH may involve an increase in RAS signalling, the subsequent cascade does not involve ERK phosphorilation, which in fact, increases during T4-induced hyperthyroidism.

Topics: Animals; Cell Proliferation; Hyperthyroidism; Hypothyroidism; Male; MAP Kinase Signaling System; Methimazole; Organ Size; Phosphorylation; ras Proteins; Rats; Rats, Wistar; Thyroid Gland; Thyrotropin; Thyroxine

Topics: Adult; Antithyroid Agents; Female; Graves Disease; Humans; Hypothyroidism; Iodine Radioisotopes; Methimazole; Pregnancy; Puerperal Disorders; Thyroiditis, Autoimmune; Thyroxine

To investigate the effect of hypothyroidism on gonadal and adrenal functions in male Japanese quail (Coturnix japonica), hypothyroidism was induced in male adult Japanese quail by daily administration of 2-Mercapto-1-methylimidazole (methimazole) in their drinking water. Four weeks after methimazole treatment, the Japanese quail were sacrificed, and the plasma concentrations of free triiodothyronine (FT3), free thyroxine (FT4), total T3 (TT3), total T4 (TT4), corticosterone, testosterone, LH and immunoreactive (ir) inhibins were measured by radioimmunoassay, the testes and adrenal glands were removed and weighed and the thyroid glands and testes were fixed in 4% paraformaldehyde for histological observation. The results showed that the hypothyroidism induced by methimazole caused a significant decrease in body and testes weight; the plasma levels of FT3, FT4 and TT4 significantly decreased, and the hypothyroid quail possessed a greater number of small follicles and more follicular epithelial cells in the thyroid gland. In addition, hypothyroidism resulted in a significant decrease in the plasma concentrations of corticosterone, LH, testosterone and ir-inhibin. Furthermore, no spermatogenesis was found in the seminiferous tubules of the methimazole treatment groups. These results clearly demonstrate that hypothyroidism caused both gonadal and adrenal disturbances in the adult male Japanese quail.

Topics: Adrenal Glands; Age Factors; Animals; Antithyroid Agents; Body Weight; Coturnix; Hypothyroidism; Male; Methimazole; Organ Size; Testis; Thyroid Hormones

Thyroid hormones are associated with the oxidative and antioxidative status of the organism. Depression of metabolism by hypothyroidism has been reported to decrease oxidant production and thus protect tissues against oxidant damage. The purpose of the present study was to investigate Zn and Cu levels in MMI-induced hypothyroidism and to show whether there is a connection between these trace elements and the oxidant-antioxidant status in experimental hypothyroidism. 3-Nitrotyrosine was measured as a marker of nitro-oxidative stress. In order to examine the antioxidant status of MMI-induced hypothyroidism in rats, GSH and SOD levels were determined as well. Significantly decreased 3-nitrotyrosine, Cu and Zn levels were observed in our experimental model when compared with the controls. On the other hand, GSH and SOD levels remained constant. It may be suggested that Cu and Zn serve as antioxidant molecules and exert their effects in an indirect manner to reduce oxidative stress in experimental hypothyroidism.

Topics: Animals; Antioxidants; Copper; Female; Glutathione; Hypothyroidism; Methimazole; Oxidants; Oxidative Stress; Rats; Rats, Wistar; Superoxide Dismutase; Tyrosine; Zinc

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

Hypothyroidism significantly reduced the mean amplitude and increased the mean frequency of spontaneous rhythmic contractions in 18 day pregnant rat uterus. Nifedipine (10(-12)-10(-9) M) and diltiazem (10(-10)-10(-6) M) caused concentration related inhibition of the myogenic responses of the uterine strips obtained from both pregnant and hypothyroid state. However, nifedipine was less potent (IC50:2.11 x 10(-11) M) in pregnant hypothyroid state as compared to pregnant control (IC50: 3.1 x 10(-12) M). Similarly, diltiazem was less potent (IC50: 3.72 x 10(-9) M) in inhibiting the uterine spontaneous contractions in hypothyroid than in pregnant rat uterus (IC50:5.37 x 10(-10) M). A similar decrease in the sensitivity to nifedipine and diltiazem for reversal of K+ (100 mM)-induced tonic contraction and K(+)-stimulated 45Ca2+ influx was observed with these calcium channel antagonists in uterus obtained from hypothyroid pregnant rats compared to the controls. Nifedipine-sensitive influx of 45Ca(2+)-stimulated either by K+ (100 mM) or by Bay K8644 (1,4-dihydro-2,6-methyl-5-nitro-4-[2'-(trifluromethyl)phenyl]-3-pyridine carboxylic acid methyl ester) (10(-9) M) was significantly less in uterine strips from hypothyroid rats compared to controls. The results suggest that the inhibition of uterine rhythmic contractions may be attributable to a reduction in rat myometrial Ca2+ channel function in the hypothyroid state.

Topics: Animals; Calcium Channel Blockers; Calcium Channels; Diltiazem; Female; Hypothyroidism; Methimazole; Nifedipine; Pregnancy; Pregnancy Complications; Rats; Rats, Sprague-Dawley; Thyroid Hormones; Uterine Contraction; Uterus

We describe two cases of increases in serum creatine kinase (CK) concentrations in children undergoing treatment of Graves' disease with antithyroid medications. Presenting complaints consisted of myalgias and muscle cramping in both patients, and increases in serum CK levels were noted 1 mo after initiation of antithyroid drugs. Both patients were euthyroid at the time of CK elevation. While the mechanisms for this process are not clear, it is likely that the acute decrease of thyroid hormones in tissues following a state of chronic hyperthyroidism may result in relative hypothyroid states and subsequent alterations in CK concentrations.. Although this side effect has been reported in adults, it is a novel finding in children. Clinicians should be aware of the rare potential for elevations in serum CK when initiating treatment for Graves' disease in children.

Topics: Adolescent; Antithyroid Agents; Child; Creatine Kinase; Female; Fructose-Bisphosphate Aldolase; Graves Disease; Humans; Hypothyroidism; Methimazole

The effect of hypothyroidism induced by thiamazole on the toxicity of amitriptyline was studied in chick embryos. Fertilized eggs of White Leghorns were incubated and investigated. 1.2 mg/0.2 ml/egg of thiamazole was injected into the albumen of fertilized eggs on the 9th day of incubation. The control group was given 0.2 ml/egg of physiological saline in the same manner. Amitriptyline at 1 mg/egg was injected into the air sac of fertilized eggs on the 16th day of incubation. Electrocardiograms were recorded 0 to 60 min after the injection. After the injection of amitriptyline into the thiamazole-treated eggs, the heart rate was significantly decreased compared with the untreated eggs. These findings indicate that hypothyroidism induced by thiamazole has a marked influence on the toxicity of amitriptyline in chick embryos.

Topics: Amitriptyline; Animals; Antidepressive Agents, Tricyclic; Antithyroid Agents; Body Weight; Chick Embryo; Electrocardiography; Heart Rate; Hypothyroidism; Methimazole

Hypometabolic state following hypothermia is known to protect tissues from ischemic injury. Hypothyroidism produces a hypometabolic state. The present study was undertaken to investigate the protective effects of hypothyroidism following cerebral ischemia and to ascertain the underlying mechanism. Euthyroid (E) and hypothyroid (H) animals were exposed to a 2 h of middle cerebral artery occlusion followed by 24 h of reperfusion (I/R). Specific enzymatic methods and flowcytometry were used to assess the quantitative changes of molecules involved in neuronal damage as well as in protection. As compared to euthyroid ischemic reperfused (E + I/R) rats, H + I/R rats had insignificant neurological deficit, and smaller area of infarct. H + I/R rats had significantly lower markers of oxidative stress, and lactate dehydrogenase (LDH) activity (a marker for necrosis). Natural antioxidant activity (particularly superoxide dismutase) and integrity of mitochondria (membrane potential) were maintained in H + I/R group but not in E + I/R group. The number of neurons undergoing apoptosis significantly lower in hypothyroid ischemic rats as compared to euthyroid ones. These results suggest that hypothyroid animals face ischemia and reperfusion much better compared to euthyroid animals. A possible explanation could be the decreased oxidative stress and maintained antioxidant activity that finally leads to a decrease in necrosis and apoptosis. These observations may suggest strategies to induce brain-specific downregulation of metabolism that may have implications in the management of strokes in human beings.

Topics: Animals; Brain Infarction; Calcium; Catalase; Cell Death; Disease Models, Animal; Hypothyroidism; Imidazoles; In Situ Nick-End Labeling; Lipid Peroxidation; Male; NADP; Neurologic Examination; Neuroprotective Agents; Nitrites; Oxidative Stress; Rats; Rats, Sprague-Dawley; Reactive Oxygen Species; Reperfusion Injury; Tetrazolium Salts

Topics: Adrenergic beta-Antagonists; Aged; Agranulocytosis; Amiodarone; Anti-Arrhythmia Agents; Antithyroid Agents; Atrial Fibrillation; Chest Pain; Cholangitis; Glucocorticoids; Humans; Hyperthyroidism; Hypothyroidism; Male; Methimazole; Plasmapheresis

The present study aimed to determine the influence of thyroid status on the timing of the pubertal resurgence in gonadotrophin-releasing hormone pulse generator activity [tracked by circulating luteinising hormone (LH) levels] in male rhesus monkeys. Six juvenile monkeys were orchidectomised and then treated with the antithyroid drug, methimazole, from 15-19 months until 36 months of age, at which time thyroxine (T(4)) replacement was initiated. Four additional agonadal monkeys served as controls. Blood samples were drawn weekly for hormonal assessments. Body weight, crown-rump length and bone age were monitored at regular intervals. By 8 weeks of methimazole treatment, plasma T(4) had fallen sharply, and the decline was associated with a plasma thyroid-stimulating hormone increase. In controls, plasma LH levels remained undetectable until the pubertal rise occurred at 29.3 +/- 0.2 months of age. This developmental event occurred in only half of the methimazole-treated animals before 36 months of age when T(4) replacement was initiated. The hypothyroid state was associated with a profound arrest of growth and bone maturation, but increased body mass indices and plasma leptin levels. T(4) replacement in methimazole-treated monkeys was associated with the pubertal rise in LH in the remaining three animals and accelerated somatic development in all six animals. Although pubertal resurgence in LH secretion occurred at a later chronological age in methimazole-treated animals compared to controls, bone age, crown-rump length and body weight at that time did not differ between groups. There were no long-term differences in plasma prolactin between groups. We conclude that juvenile hypothyroidism in male primates causes a marked delay in the pubertal resurgence of LH secretion, probably occasioned at the hypothalamic level. Whether this effect is meditated by an action of thyroid hormone directly on the hypothalamus or indirectly as a result of the concomitant deficit in somatic development remains to be determined.

Topics: Age Factors; Analysis of Variance; Animals; Antithyroid Agents; Body Size; Castration; Growth and Development; Hypothyroidism; Leptin; Luteinizing Hormone; Macaca mulatta; Male; Methimazole; Neurosecretory Systems; Prolactin; Sexual Maturation; Thyrotropin; Thyroxine

Hypothyroidism increases the rate of pregnancy loss. Other manifestations include menstrual disorder, and infertility. Serum levels of gonadotropins are low in hypothyroid patients. Though studies of uterine ultrastructure are well established as approaches to investigating the pathophysiology of infertility, they have scarcely been extended to the study of hypothyroid related infertility. The present study investigates the effect of hypothyroidism on the ultrastructure of uterine epithelium. Three groups of Wistar rats were studied. Two groups were initially made hypothyroid using methimazole, and the third group was an untreated control. One hypothyroid group was given daily injections of thyroxine for six weeks. The uteri were removed in all three groups, and processed for transmission electron microscopy and morphometry. It was found that absolute epithelial cell volume was decreased in hypothyroidism. The volume of the nucleus had decreased though its relative volume in the cell had increased. The height of the luminal epithelium in hypothyroid rats also decreased by (33.8%) as compared with controls. Basement membrane thickness was significantly increased in hypothyroidism. The changes were all substantially abrogated by the administration of thyroxine. This study suggests that thyroid hormones might be importantly concerned in the maintenance of the normal structure of uterine epithelial cells.

Topics: Animals; Antithyroid Agents; Endometrium; Female; Hypothyroidism; Methimazole; Rats; Rats, Wistar; Thyroxine; Uterus

Thionamides are the main therapeutic arsenal for treating hyperthyroidism. Perhaps the first case of a patient who developed a transient pituitary hyperthyroidism after discontinuation of a lengthy intake of a thionamide is reported.. A 48-year-old woman presented with menstrual irregularities when hypothyroidism with pituitary enlargement was detected. She had been undergoing treatment with methimazole for Graves's hyperthyroidism since the age of 34. Three months after discontinuation of methimazole she presented with clinical and laboratory evidence of thyrotoxicosis, with elevated thyroid-stimulating hormone (TSH) levels and blunted response to thyrotropin releasing hormone (TRH). This secondary hyperthyroidism was self-limited and resolved a few months later.. Chronic primary hypothyroidism caused by lengthy use of thionamides can result in pituitary hyperplasia and transient thyrotrope dysfunction.

Topics: Anti-Anxiety Agents; Chronic Disease; Female; Follow-Up Studies; Humans; Hyperthyroidism; Hypothyroidism; Methimazole; Middle Aged; Propranolol; Thyroid Gland; Thyrotoxicosis; Thyrotropin; Thyroxine; Time Factors; Treatment Outcome; Triiodothyronine; Ultrasonography

The low density lipoprotein (LDL) receptor-associated protein (RAP) is an endoplasmic reticulum (ER)-resident molecular chaperone for several LDL receptor family members and it also binds to thyroglobulin (Tg), the thyroid hormone precursor. Disruption of the RAP gene in thyrocytes results in impaired Tg secretion. To gain further insights into the function of RAP in the thyroid, we investigated whether its expression in thyrocytes is regulated by thyroid-stimulating hormone (TSH), a feature common to all proteins involved in thyroid hormone secretion. We found by immunofluorescence that in FRTL-5 cells cultured in the presence of TSH, RAP is expressed intracellularly. The levels of expression increased after exposure to TSH, beginning at 48 hours, in a concentration-dependent manner as observed by immunofluorescence and Western blotting. Expression of RAP was also increased by TSH in primary cultures of human thyrocytes as observed by Western blotting. In hypothyroid mice with high serum TSH, RAP was markedly increased compared with euthyroid mice as observed by immunohistochemistry and Western blotting. Based on these findings, we concluded that RAP is expressed by thyrocytes in a TSH-dependent manner, both in cultured thyroid cells and in vivo.

Topics: Animals; Antithyroid Agents; Blotting, Western; Chlorocebus aethiops; COS Cells; Epithelial Cells; Fluorescent Antibody Technique; Humans; Hypothyroidism; LDL-Receptor Related Protein-Associated Protein; Methimazole; Mice; Perchlorates; Rats; Sodium Compounds; Thyroid Gland; Thyrotropin; Up-Regulation

The influence of thyroid failure on hemostasis has been studied and is still not well understood. These patients have high risk for cardiovascular diseases because of the lipid metabolism and procoagulant agents. But the influence of thyroid failure on hemostasis is controversial. Tissue factor (TF) has an important role in the thromboembolic state. Recent experiments have demonstrated that TF-dependent activation of the coagulation cascade plays an important role in the pathophysiology of intravascular thrombus formation. The purpose of the present study was to investigate the contributions of TF, factor VII:C (FVII:C), factor XII:C (FXII:C), and fibrinogen in experimental hypothyroidism. TF was obtained from the thyroid gland and lung tissue of 10 rats following experimental hypothyroidism induced for 30 d and compared with similar tissue from 10 control rats. Significantly increased TF activities were found in hypothyroid rats. By contrast, FVII:C level was significantly decreased when compared with the control group. In this respect it is interesting to note that a hypercoagulable state due to increased thromboplastic activity may occur. Based on those results, elevated tissue factor activities (TFa) of the patients with low thyroid dysfunction may have another risk factor for cardiovascular diseases.

Topics: Animals; Antithyroid Agents; Factor VII; Factor XII; Female; Fibrinogen; Hemostasis; Hypothyroidism; Lung; Methimazole; Partial Thromboplastin Time; Rats; Rats, Wistar; Statistics, Nonparametric; Thromboplastin; Thyroid Gland; Thyrotropin; Thyroxine; Triiodothyronine

Transport of iodide into thyrocytes, a fundamental step in thyroid hormone biosynthesis, depends on the presence of the sodium-iodide symporter (NIS). The importance of the NIS for diagnosis and treatment of diseases has raised several questions about its physiological control. The goal of this study was to evaluate the influence of thyroid iodine content on NIS regulation by thyrotrophin (TSH) in vivo. We showed that 15-min thyroid radioiodine uptake can be a reliable measurement of NIS activity in vivo. The effect of TSH on the NIS was evaluated in rats treated with 1-methyl-2-mercaptoimidazole (MMI; hypothyroid with high serum TSH concentrations) for 21 days, and after 1 (R1d), 2 (R2d), or 5 (R5d) days of withdrawal of MMI. NIS activity was significantly greater in both MMI and R1d rats. In R2d and R5d groups, thyroid iodide uptake returned to normal values, despite continuing high serum TSH, possibly as a result of the re-establishment of iodine organification after withdrawal of MMI. Excess iodine (0.05% NaI for 6 days) promoted a significant reduction in thyroid radioiodide uptake, an effect that was blocked by concomitant administration of MMI, confirming previous findings that iodine organification is essential for the iodide transport blockade seen during iodine overload. Therefore, our data show that modulation of the thyroid NIS by TSH depends primarily on thyroid iodine content and, further, that the regulation of NIS activity is rapid.

Topics: Animals; Hypothyroidism; Iodine; Male; Methimazole; Rats; Rats, Wistar; Symporters; Thyroid Gland; Thyrotropin; Time Factors

Hypothyroidism was induced by the administration of 0.03% methimazole to drinking water for 1, 2 or 6 weeks to study whether there is a change in adrenoceptor- and muscarinic receptor-mediated blood pressure responses in hypothyroid rats. After 1, 2 and 6 weeks of treatment, the pressor response to norepinephrine was progressively suppressed, and after 6 weeks a significant suppression was observed as compared to control. The depressor response induced by isoprenaline, acetylcholine or sodium nitroprusside was not significantly different between control and hypothyroid rats at any time. The pressor response induced by N(G)-nitro-L-arginine (L-NOARG), an inhibitor of nitric oxide (NO) synthase, was significantly reduced in hypothyroid rats after 1, 2 or 6 weeks of treatment, and the magnitude of the reduction was almost the same for three groups. These results indicated that hypothyroidism causes a time-dependent decrease in pressor responses mediated by alpha-adrenoceptors, but a time-independent decrease in those induced by L-NOARG, and suggest that a progressive decrease in alpha-adrenoceptor-mediated pressor responses occurs in hypothyroidism; however, the decrease in basal NO production and/or release in the peripheral vasculature already occurs in hypothyroid rats at an early stage of the disease.

Topics: Animals; Blood Pressure; Hypothyroidism; Male; Methimazole; Norepinephrine; Rats; Rats, Wistar; Receptors, Adrenergic; Receptors, Muscarinic

To investigate the risk of hypothyroidism after radioiodine (131I) treatment for hyperfunctioning thyroid nodules.. Retrospective analysis of patients treated with 131I for hyperfunctioning thyroid nodules and followed up for a maximum of 20 years.. A total of 346 patients treated with 131I in the years 1975-95, for a single hyperfunctioning nodule.. Hypothyroidism was defined as TSH levels > 3.7 mU/l. Kaplan-Meier survival analysis was used to analyse permanence of euthyroidism after 131I. A stepwise Cox proportional hazard model was used to identify factors influencing the progression to hypothyroidism.. The cumulative incidence of hypothyroidism was 7.6% at 1 year, 28% at 5 years, 46% at 10 years and 60% at 20 years. Age (P < 0.01), 24-th 131I uptake (P < 0.05) and previous treatment with methimazole (MMI, P < 0.1) were associated with a faster progression towards hypothyroidism, while thyroid and nodule size, thyroid status at diagnosis and degree of extranodular thyroid parenchymal suppression had no influence. In hyperthyroid patients with partial parenchymal suppression, however, previous MMI treatment was the most important prognostic factor (P < 0.01).. After 20 years of follow-up, 60% of patients treated with 131I for a single hyperfunctioning nodule are hypothyroid. Factors increasing the risk of hypothyroidism are age, 131I uptake and MMI pretreatment. The prognostic value of this last factor, however, depends on the degree of suppression of the extranodular thyroid parenchyma at the scan.

Topics: Adult; Age Factors; Aged; Antithyroid Agents; Disease Progression; Epidemiologic Methods; Female; Humans; Hyperthyroidism; Hypothyroidism; Iodine Radioisotopes; Male; Methimazole; Middle Aged; Radiation Injuries; Thyroid Gland; Thyroid Nodule; Thyrotropin; Treatment Outcome

The influence of the thyroid hormones on the normal function of the mammalian central nervous system depends on the brain region and on the developmental stage. Adenine nucleotides and their products also affect the brain function; ATP is an excitatory neurotransmitter, and adenosine has inhibitory effects on neurotransmission. Thus, this study aimed to evaluate the effects of hypothyroidism on the hydrolysis of ATP to adenosine in hippocampal and cortical synaptosomes and blood serum of rats during different phases of development. Rats aged 60 and 420 days old were divided into three groups: control, sham-operated and hypothyroid. Hypothyroidism was induced in these rats by thyroidectomy and methimazole (0.05%) added to their drinking water for 14 days. Neonatal hypothyroidism was induced by adding 0.02% methimazole in the drinking water from day 9 of gestation, and continually until 14 days old. Hypothyroidism increased the AMP hydrolysis in both hippocampus and cerebral cortex synaptosomes of rats in all aged tested. In blood serum, thyroid hormones deficiency increased the AMP hydrolysis in 14-day-old rats and the hydrolysis of ATP, ADP and AMP in 60-day-old rats; however, no alteration was observed in 420-day-old rats. Thus, our results suggest the involvement of the 5'-nucleotidase in synaptic function control in hypothyroidism throughout brain development.

Topics: Adenine Nucleotides; Age Factors; Analysis of Variance; Animals; Animals, Newborn; Cerebral Cortex; Hippocampus; Hydrolysis; Hypothyroidism; Male; Methimazole; Rats; Rats, Wistar; Serum; Subcellular Fractions; Synaptosomes

Clinical hypothyroidism is associated with hyperhomocysteinemia, whereas the opposite is seen in hyperthyroidism. The effects of mild thyroid dysfunction on homocysteine concentrations are not known. We performed the following study to investigate this. Total homocysteine, vitamins B6 and B12, folate, fibrinogen, plasminogen activator inhibitor type 1, and lipids were measured in 11 subjects at baseline and after methionine loading. Subjects began methimazole (MMI), 40 mg daily, and were restudied during 2 stages of hypothyroidism. Liothyronine was added and subjects were restudied once thyrotropin normalized. Methimazole was stopped and studies were repeated during 2 stages of hyperthyroidism. Data were analyzed using repeated-measures analysis of variance. Post-methionine homocysteine decreased in each hypothyroid study compared with baseline (28.8+/-10.7, 27.5+/-9.9 vs 34.4+/-9.2 micromol/L, respectively). In addition, both fasting and post-methionine homocysteine decreased in the euthyroid/MMI study arm compared with baseline despite equivalent thyrotropin values (fasting, 7.5+/-3.0 vs 8.8+/-3.5 micromol/L, P<.05; and post-methionine, 27.2+/-10.6 vs 34.4+/-9.2 micromol/L, P<.05, respectively). Fasting homocysteine decreased in the first hyperthyroidism study arm compared with baseline (6.6+/-2.3 vs 8.8+/-3.5 micromol/L, P<.05) and post-methionine homocysteine decreased in both hyperthyroid arms compared with baseline (25.2+/-8.1, 24.2+/-10 vs 34.4+/-9.2 micromol/L, P<.05 respectively). In conclusion, mild thyroid dysfunction changes homocysteine metabolism. Unexpectedly, our results suggest a homocysteine-lowering effect of MMI.

Topics: Adolescent; Adult; Female; Fibrinogen; Folic Acid; Homocysteine; Humans; Hypothyroidism; Lipids; Logistic Models; Male; Methimazole; Methionine; Plasminogen Activator Inhibitor 1; Thyrotropin; Vitamin B 12; Vitamin B 6

The presence of severe neurological symptoms in thyroid diseases has highlighted the importance of thyroid hormones in the normal functioning of the mature brain. Since, ATP is an important excitatory neurotransmitter and adenosine acts as a neuromodulatory structure inhibiting neurotransmitters release in the central nervous system (CNS), the ectonucleotidase cascade that hydrolyzes ATP to adenosine, is also involved in the control of brain functions. Thus, we investigated the influence of hyper-and hypothyroidism on the ATP, ADP and AMP hydrolysis in hippocampal and cortical slices from adult rats. Hyperthyroidism was induced by daily injections of l-thyroxine (T4) 25 microg/100 g body weight, for 14 days. Hypothyroidism was induced by thyroidectomy and methimazole (0.05%) added to their drinking water for 14 days. Hypothyroid rats were hormonally replaced by daily injections of T4 (5 microg/100 g body weight, i.p.) for 5 days. Hyperthyroidism significantly inhibited the ATP, ADP and AMP hydrolysis in hippocampal slices. In brain cortical slices, hyperthyroidism inhibited the AMP hydrolysis. In contrast, hypothyroidism increased the ATP, ADP and AMP hydrolysis in both hippocampal and cortical slices and these effects were reverted by T4 replacement. Furthermore, hypothyroidism increased the expression of NTPDase1 and 5'-nucleotidase, whereas hyperthyroidism decreased the expression of 5'-nucleotidase in hippocampus of adult rats. These findings demonstrate that thyroid disorders may influence the enzymes involved in the complete degradation of ATP to adenosine and possibly affects the responses mediated by adenine nucleotides in the CNS of adult rats.

Topics: 5'-Nucleotidase; Adenine Nucleotides; Adenosine Diphosphate; Adenosine Monophosphate; Adenosine Triphosphatases; Adenosine Triphosphate; Animals; Antigens, CD; Antithyroid Agents; Apyrase; Cerebral Cortex; Hippocampus; Hydrolysis; Hyperthyroidism; Hypothyroidism; Male; Methimazole; Organ Culture Techniques; Rats; Rats, Wistar; Reverse Transcriptase Polymerase Chain Reaction; Thyroidectomy; Thyroxine

To evaluate the ability of the aged rat pituitary to increase TSH secretion in response to major decreases in serum thyroid hormones, hypothyroidism was induced by methimazole in young and old, male and female, Dutch-Miranda and Wistar rats. Before MMI-treatment there were no differences in serum TSH of young and old rats, but serum T(4) was significantly decreased in aged rats from both genders and strains, while serum T(3) was significantly decreased in aged male rats from both strains, and in old Wistar females. MMI treatment significantly decreased serum T(4) and T(3) in all treated animals, and progressively increased serum TSH in both male and female rats, but the increase was significantly smaller in the elder rats. The pituitary TSH content was higher in Wistar than in Dutch-Miranda rats, of both genders, and was not significantly affected by age. MMI treatment decreased the pituitary TSH in both young and old Dutch-Miranda rats, but in the Wistar strain only the old females had a significant decrease. Our results show that the ability of the pituitary thyrotrophs to increase hormonal secretion in response to decreased levels of thyroid hormones is impaired in the old rat, even when the thyroid hormone levels are dramatically reduced.

Topics: Aging; Animals; Antithyroid Agents; Female; Hypothyroidism; Male; Methimazole; Pituitary Gland; Rats; Rats, Inbred Strains; Rats, Wistar; Species Specificity; Thyroid Gland; Thyroid Hormones; Thyrotropin

Topics: Aged; Aged, 80 and over; Antithyroid Agents; Female; Humans; Hypothyroidism; Iatrogenic Disease; Methimazole

Correct positioning of cortical neurons during development depends on the radial migration of the projection neurons and on the coordinated tangential and radial migrations of the subcortically generated interneurons. As previously shown, a transient and moderate maternal deficiency in thyroxin during early corticogenesis alters the radial migration of projection neurons. To determine if a similar effect might also affect tangential migration of medial ganglionic eminence (MGE)-derived neurons at the origin of cortical interneurons, explants of MGE from green fluorescent protein (GFP)-transgenic embryos were implanted into flat cortical mounts from wild-type embryos. The distances covered and the preferential migration (medially) of GFP-MGE neurons from embryos of hypothyroxinemic dams are not affected in their tangential migration into wild-type control cortices. In contrast, when GFP-MGE neurons from embryos of control or hypothyroxinemic dams migrate within cortices from embryos of hypothyroxinemic dams, the GFP-MGE-derived neurons lose their preferential direction of migration, although they still migrate for long distances throughout the cortex. Our results show that maternal hypothyroxinemia alters the tangential migration of GFP-MGE-derived neurons in the neocortex of the progeny and suggest that this alteration is not derived from the migratory neurons themselves but through undefined short- and long-range cues responsible for the guidance of their migration.

Topics: Animals; Brain Mapping; Calbindins; Cell Count; Cell Movement; Cells, Cultured; Cerebral Cortex; Embryo, Mammalian; Female; gamma-Aminobutyric Acid; Green Fluorescent Proteins; Hypothyroidism; Imidazoles; Immunohistochemistry; Male; Median Eminence; Mice; Mice, Inbred ICR; Mice, Transgenic; Neurons; Pregnancy; Prenatal Exposure Delayed Effects; Radioimmunoassay; S100 Calcium Binding Protein G; Thyroid Hormones; Transplants; Tubulin

The kidney is a target organ for thyroid hormone action and a variety of renal transport processes are altered in response to impaired thyroid functions. To investigate the effect of thyroid hormone on the expression of the renal proximal tubular high-affinity-type H(+)-peptide cotransporter (PEPT2) in rats, hypothyroidism was induced in animals by administration of methimazole (0.05%) via drinking water. After 7 weeks of treatment, hypothyroidism was confirmed by determining serum free T(3) and free T(4) concentrations. Northern blotting was used to examine the expression of PEPT2 mRNA in kidney tissues from hypothyroid rats compared to control rats. Hypothyroidism resulted in an increased level of total renal PEPT2 mRNA (121.1+/-3.3% vs. control 100+/-2.8%; p=0.008). The mRNA results were confirmed by immuno-blotting, which demonstrated significantly increased protein levels (162% vs. control 100%; p<0.01). Immunohistochemistry also revealed increased PEPT2 protein levels in the proximal tubules of treated compared to non-treated rats. In summary, PEPT2 is the first proximal tubule transporter protein that shows increased expression in states of hypothyreosis. As PEPT2 reabsorbs filtered di- and tripeptides and peptide-like drugs, the present findings may have important implications in nutritional amino acid homeostasis and for drug dynamics in states of altered thyroid function.

Topics: Animals; Antithyroid Agents; Biological Transport; Blotting, Northern; Gene Expression; Hypothyroidism; Immunohistochemistry; Kidney Tubules, Proximal; Methimazole; Peptides; Rats; RNA, Messenger; Symporters

Thyroid hormones have a dramatic effect on human behavior. However, their role on sexual behavior and performance has seldom been investigated in men.. The objective of this study was to evaluate the prevalence of sexual dysfunctions in patients with hyper- and hypothyroidism and their resolution after normalization of thyroid hormone levels.. We conducted a multicenter prospective study at endocrinology and andrology clinics in university hospitals.. The study included 48 adult men, 34 with hyperthyroidism and 14 with hypothyroidism.. Subjects were screened for hypoactive sexual desire (HSD), erectile dysfunction (ED), premature ejaculation (PE), and delayed ejaculation (DE) on presentation and 8-16 wk after recovery from the thyroid hormone disorder.. In hyperthyroid men, HSD, DE, PE, and ED prevalence was 17.6, 2.9, 50, and 14.7%, whereas in hypothyroid men, the prevalence of HSD, DE, and ED was 64.3% and of PE was 7.1%. After thyroid hormone normalization in hyperthyroid subjects, PE prevalence fell from 50 to 15%, whereas DE was improved in half of the treated hypothyroid men. Significant changes were found in the subdomains of the International Index of Erectile Function; ejaculation latency time doubled after treatment of hyperthyroidism (from 2.4 +/- 2.1 to 4.0 +/- 2.0 min), whereas for hypothyroid men it declined significantly, from 21.8 +/- 10.9 to 7.4 +/- 7.2 (P < 0.01 for both). TSH and thyroid hormone levels normalized rapidly after treatment, and changes in circulating sex steroids partially reflected the changes in SHBG levels.. In summary, most patients with thyroid hormone disorders experience some sexual dysfunctions, which can be reversed by normalizing thyroid hormone levels. Despite the associated changes in sex hormone levels, the high prevalence of ejaculatory disorders and their prompt reversibility suggest a direct involvement of thyroid hormones in the physiology of ejaculation.

Topics: Adrenergic beta-Antagonists; Antithyroid Agents; Benzodiazepines; Drug Therapy, Combination; Ejaculation; Erectile Dysfunction; Follow-Up Studies; Humans; Hyperthyroidism; Hypothyroidism; Libido; Male; Methimazole; Prevalence; Propranolol; Prospective Studies; Sexual Dysfunction, Physiological; Thyroid Hormones; Thyroxine; Treatment Outcome

The effect of the hypothyroidism induced by thiamazole on toxic interactions between propranolol and disopyramide were studied in chick embryos. Fertilized eggs of White Leghorns were incubated and investigated. 1.2 mg/0.2 ml/egg of thiamazole was injected into the albumen of fertilized eggs on the 9th day of incubation. The control group was given 0.2 ml/egg of physiological saline in the same manner. Propranolol at 0.1 mg/egg and disopyramide at 0.3 mg/egg were injected into the air sac of fertilized eggs on the 16th day of incubation. Electrocardiograms were recorded 0 to 60 min after the injection. After the injection of propranolol and disopyramide into the thiamazole treated eggs, the heart rate was significantly decreased compared with the thiamazole untreated eggs. These findings indicate that hypothyroidism induced by thiamazole has a marked influence on the toxic interaction between propranolol and disopyramide in chick embryos.

Topics: Animals; Antithyroid Agents; Body Weight; Chick Embryo; Disopyramide; Drug Interactions; Hypothyroidism; Methimazole; Propranolol

Effects of hypothyroid on hemorheology of patients had widely attracted the attention of researchers during last decade. The present study has been planned with the purpose to determine the effects of experimental hypothyroidism on hemorheological parameters and fibrinogen concentration. To induce experimental hypothyroid methimazole (75 mg/100 g) was added to the fodder of an experimental group rats for 20 d. After experimental duration, plasma and blood viscosity, hematocrit (Hct), hemoglobin, erythrocyte rigidity index, and plasma fibrinogen concentration values of both the control and the experimental group animals were determined and evaluated. The serum T3 and T4 levels of the experimental group were found lower (p < 0.001) but TSH level higher (p < 0.001) than that of the control group. Plasma viscosity and fibrinogen concentration of hypothyroid group were found significantly higher than controls (p < 0.01). Hematocrit and hemoglobin values were also found lower in the experimental group than the control group animals (p < 0.01). However, there was no significant difference found in blood viscosity at the original Hct value but there was a significant increase at standard Hct value (p < 0.01). There was also no change in erythrocyte rigidity index between control and experimental groups. According to these results it may be said that in hypothyroidism, increased fibrinogen concentration may alter the rheological structure of blood by inducing increase in plasma viscosity.

Topics: Animals; Antithyroid Agents; Blood Viscosity; Erythrocytes; Female; Fibrinogen; Hematocrit; Hemoglobins; Hemorheology; Hypothyroidism; Methimazole; Rats; Rats, Sprague-Dawley; Thyroid Hormones

The present work was performed in order to know if mild hypothyroidism in rats modifies the activity of the Na+/K+ -ATPase in different regions of the brain. Male Wistar rats (300-350 g) were randomly divided into three groups: (1) control group (n=8) drank tap water. (2) hypothyroid group (n=8) treated with 60 mg/kg of methimazole in drinking water; and (3) replaced group (n=8) treated with 60 mg/kg of methimazole plus 35 microg/kg of thyroid hormone (T3) in drinking water. After four weeks of treatment, the rats of all groups were sacrificed by decapitation. The cortex, amygdala, hippocampus and cerebellum were dissected and frozen at -70 degrees C until assay. For enzymatic assay, the tissues were homogenized. The Na+/K+ -ATPase activity was determined by quantifying inorganic phosphate after the samples were incubated with ATP in the presence and absence of 1 mM ouabain. The Na+/K+ -ATPase activity is expressed as pmoles Pi/hr/mg protein. The results showed that the Na+/K+ -ATPase activity in the cortex, amygdala and hippocampus, but not in cerebellum, was lower in hypothyroid group than in control group (p<0.05). The co-administration of methimazole and T3 avoided the decrease of Na+/K+ -ATPase activity, except in amygdala. According to the results obtained we concluded that methimazole treatment decreased the Na+/K+- ATPase activity in the brain's regions which are related to seizures onset. That decrement in enzyme activity was avoided with the coadministration of thyroid hormone.

Topics: Animals; Antithyroid Agents; Body Temperature; Brain; Hypothyroidism; Male; Methimazole; Rats; Rats, Wistar; Sodium-Potassium-Exchanging ATPase; Thyroid Hormones

Topics: Adult; Aged; Antithyroid Agents; Female; Goiter; Humans; Hyperthyroidism; Hypothyroidism; Iodine Radioisotopes; Male; Methimazole; Middle Aged; Randomized Controlled Trials as Topic; Recurrence; Thyroid Function Tests; Thyroid Hormones; Treatment Outcome

Thyroid hormones exert significant changes in the metabolism of bile acids. However, in humans, the effect of thyroid hormone on cholesterol 7alpha-hydroxylase (cyp7a), the rate- controlling enzyme in the classical bile acid biosynthetic pathway, remains poorly understood and has been difficult to study directly in vivo. Previous studies from our laboratory have shown that the activity of the human cholesterol 7alpha-hydroxylase gene promoter is repressed by T(3) in cultured cells. Accordingly, we hypothesized that T(3) would negatively regulate human CYP7A1 gene expression in vivo. We tested this hypothesis by inducing hypo- and hyperthyroidism in transgenic mice expressing the human CYP7A1 gene. Hypothyroidism did not affect the abundance of human cyp7a mRNA in transgenic mice. In hyperthyroid male mice, human cyp7a mRNA abundance was decreased. No significant change in cyp7a mRNA abundance was observed in hyperthyroid female mice. Gender differences in the amount of cholesterol and bile acids in gallbladder bile were also observed. The data indicate that thyroid hormone can repress the human CYP7A1 gene in transgenic mice, but this effect is dependent on gender in this in vivo model.

Topics: Animals; Bile; Bile Acids and Salts; Cholesterol; Cholesterol 7-alpha-Hydroxylase; Cholesterol, HDL; Diet; Female; Gallbladder; Gene Expression Regulation; Humans; Hyperthyroidism; Hypothyroidism; Iodine; Male; Methimazole; Mice; Mice, Transgenic; RNA, Messenger; Sex Characteristics; Transfection; Triiodothyronine

To determine the effect of methylimidazole (MMI)-induced hypothyroidism in a newborn rat model of low retinal neovascular (NV) incidence.. Control and MMI-exposed newborn rats were raised either in room air or variable oxygen (40/15) until P14. All groups were then exposed to room air between postnatal day (P)14 and P20. Dams drank either tap water or water containing MMI. Eyes of animals in all groups were enucleated, and retinas were removed and stained with adenosine diphosphatase and analyzed for peripheral avascularity, vascular density, and NV incidence and severity.. In the control group, MMI treatment did not promote the development of retinal NV although a linear relationship (r = 0.99, P < 0.01) was found between increased MMI dose and lower peripheral retinal vascular densities. In all the 40/15 groups, peripheral retinal vascular densities were lower (P < 0.05) than normal and were not a function of MMI dose. Increased MMI dose produced increased retinal incidence of NV (r = 0.99, P < 0.05).. These data are consistent with the notions that thyroid function contributes to normal retinal vascular density and that hypothyroidism can play a permissive role in the development of retinal NV.

Topics: Adenosine Diphosphate; Animals; Animals, Newborn; Antithyroid Agents; Disease Models, Animal; Hyperoxia; Hypothyroidism; Incidence; Methimazole; Oxygen; Rats; Rats, Sprague-Dawley; Retinal Neovascularization; Retinal Vessels; Thyroid Gland

Voltage-dependent anion-selective channel proteins (VDACs) are pore-forming proteins found in the outer mitochondrial membrane of all eukaryotes and in brain postsynaptic membranes. VDACs regulate anion fluxes of a series of metabolites including ATP, thus regulating mitochondrial metabolic functions. Hexokinase binds to porin. The mitochondrially bound hexokinase can greatly increase the rate of aerobic glycolysis. The activities of hexokinase and protein levels of mitochondrial porin were determined in brains of hypothyroid rabbits and in hypothyroid rabbits administered with thyroxine. Proteins were separated by electrophoresis, and the proteins of interest were quantified. Western blotting analysis revealed a significant decrease (approximately 50%) in the relative amount of porin in the hypothyroid compared with euthyroid rabbits. The changes in the developmental pattern of hexokinase activity in the brain of hypothyroid rabbits and the effect of T(4) on this enzyme activity have been investigated. Hypothyroid rabbits showed lower activity than their corresponding age-matched normal neonates. Administration of thyroxine to the hypothyroid neonates at birth abolished the effects of methimazole [1-methyl-2-mercaptoimidazole (MMI)]. These findings apparently indicate that the synthesis of the pore-forming protein and the hexokinase enzymes are under thyroid control during the fetal and the early postnatal period.

Topics: Animals; Animals, Newborn; Blotting, Western; Brain; Dose-Response Relationship, Drug; Female; Hexokinase; Hypothyroidism; Intracellular Membranes; Ion Channels; Lipid Bilayers; Methimazole; Porins; Rabbits; Thyroxine; Voltage-Dependent Anion Channels

Immunocytochemistry using polyclonal anti-type I deiodinase (D1) led to the localization of D1 protein in the internal granule cells of the cerebellum in 1-day-old chicks, which was confirmed by the presence of in vitro D1 activity. Western blot analysis of hepatic and cerebellar extracts revealed a band of 27 kDa. In hypothyroid embryos D1 was expressed in both the internal and external granule cell layer and the signal diminished with more severe hypothyroidism, which is in agreement with the expected downregulation of D1 activity during hypothyroidism. In accordance with the protein data, hypothyroidism resulted in the downregulation of cerebellar D1 mRNA. Finally, histological stainings confirmed that the lack of staining in the external germinal layer of 1-day-old euthyroid chicks was due to the fact that migration of immature granule cells from the external towards the internal layer was completed at this stage while cell migration was retarded in hypothyroid animals.

Topics: Animals; Blotting, Western; Cell Movement; Cerebellum; Chickens; Down-Regulation; Hypothyroidism; Iodide Peroxidase; Methimazole; Neurons; RNA, Messenger; Staining and Labeling

Activation of cell-mediated immunity by soluble interleukin-2 receptor alpha (sIL-2Ralpha) release is well documented. The aim of this study was to measure serum concentrations of sIL-2Ralpha in patients with autoimmune and non-autoimmune thyroid disorders in different stages of thyroid function, before and after administration of l-thyroxine (l-T4) and its discontinuation as well as before and during methimazole administration.. The study included 80 females: 16 with Graves' disease, 15 with Hashimoto's thyroiditis and subclinical hypothyroidism, 14 with Hashimoto's thyroiditis with fibrosis and clinical hypothyroidism, 20 after subtotal thyroidectomy following nodular non-toxic goitre and 15 healthy controls. Patients were examined at two different time points. Serum concentrations of sIL-2Ralpha were measured with the use of enzyme immunoassay technique.. Souble IL-2Ralpha serum concentration increased in patients with untreated Graves' disease and decreased after methimazole treatment. In Hashimoto's thyroiditis, the sIL-2Ralpha level was within the normal range, in Hashimoto's thyroiditis with clinical hypothyreosis it was low and after l-T4 administration it increased in both patient groups. After thyroidectomy, patients treated with l-T4, had increased levels of sIL-2Ralpha which decreased after discontinuation of therapy. There were a significant positive correlation between sIL-2Ralpha and free thyroxine in patients with (i). Graves' disease both before and after methimazole administration, (ii). Hashimoto's thyroiditis (with subclinical hypothyroidism) both before and after l-T4 therapy, (iii). Hashimoto's thyroiditis with fibrosis and (iv). overt hypothyroidism before l-T4 administration and in individuals during long-term l-T4 treatment (after subtotal thyroidectomy).. Serum sIL-2Ralpha concentration in autoimmune thyroid diseases depends on thyroid function. In both autoimmune and non-autoimmune thyroid diseases, thyroxine stimulates the release of sIL-2Ralpha.

Topics: Adult; Antithyroid Agents; Case-Control Studies; Female; Graves Disease; Humans; Hypothyroidism; Interleukin-2 Receptor alpha Subunit; Male; Methimazole; Middle Aged; Receptors, Interleukin; Thyroid Diseases; Thyroidectomy; Thyroiditis, Autoimmune; Thyroxine

Thyroid hormones exert a crucial role on trophic events of the central nervous system during development, adulthood, and ageing. The deficiency of thyroid hormones could also produce a deficiency in neurotransmission in the hippocampal region. Kainic acid (KA) has become an important tool for studying functions related to excitatory amino acid transmission in mammals. Its neurotoxic effects on the pyramidal neurons of the CA3 hippocampal region are well known. We have examined the neurotoxicity of KA on these cells in hypothyroid rats. The hypothyroid state was induced by administration of methimazole. After 4 weeks of treatment, KA was administered once intraperitoneally at doses of 0, 1, 2.5, and 5mg/kg to the hypothyroid group, and 0 and 5mg/kg to the euthyroid group. In the euthyroid group, KA reduced the neuronal density in the CA3 hippocampal region, and in the hypothyroid rats with no administration of KA, the neuronal density of the CA3 hippocampal region is reduced also. Administering KA in hypothyroid rats did not reduce the number of CA3 pyramidal cells.

Topics: Animals; Female; Hippocampus; Hypothyroidism; Kainic Acid; Methimazole; Pyramidal Cells; Rats; Rats, Wistar

The activity of liver mitochondrial flavoprotein-dependent glycerol-3-phosphate dehydrogenase (GPDH) is considered a reliable marker of thyroid status in acute and short-lasting experiments. The aim of this study was to ascertain whether GPDH activity could also be used as an index of thyroid status during chronic experiments over several months. We therefore analyzed GPDH activity in liver mitochondria of female inbred Lewis rats with thyroid status altered for 2 to 12 months. Hyperthyroid state was maintained by triiodothyronine (T (3)) or thyroxine (T (4)) administration, while methimazole was employed for inducing hypothyroidism. We found a seven- and three-fold increase of GPDH activity in female rats after T (3) or T (4) administration, respectively, compared to euthyroid females (8.9 +/- 2.3 nmol/min/mg protein), whereas administration of methimazole reduced the enzyme activity almost to one-third of the euthyroid values. These changes were not significantly influenced by the duration of hyperthyroid or hypothyroid treatment. We conclude that the level of the rat liver GPDH activity could serve as a useful marker for evaluation of hyperthyroid and hypothyroid status in chronic long-lasting experiments on female inbred Lewis rats.

Topics: Animals; Female; Glycerolphosphate Dehydrogenase; Hyperthyroidism; Hypothyroidism; Methimazole; Mitochondria, Liver; Rats; Rats, Inbred Lew; Thyroid Gland; Thyroxine; Triiodothyronine

A 28-year-old woman with thyroid hemiagenesis, who had been diagnosed as having Graves' disease, became pregnant during the course of methimazole treatment. The treatment was terminated in the second trimester. She delivered a normal infant at full term. She became thyrotoxic 3 months after the delivery, hypothyroid 6 months after the delivery, and finally euthyroid 11 months after the delivery without undergoing any treatment. This clinical course indicates that she developed silent thyroiditis after the delivery. A diagnosis of thyroid hemiagenesis was made on the basis of ultrasonography of the thyroid and 99mTc-pertechnetate thyroid scintiscan.

Topics: Adult; Antithyroid Agents; Female; Graves Disease; Humans; Hypothyroidism; Methimazole; Pregnancy; Pregnancy Complications; Puerperal Disorders; Thyroid Gland; Thyroiditis

Previous studies have documented a decrease in the ability of neonatal hypothyroid animals to learn and habituate to maze tests, and an increase in spontaneous activity. However, there is little information about the effects of perinatal (i.e., prenatal and postnatal) hypothyroidism on behaviour. The present study was designed to assess whether perinatal hypothyroidism in rats induces alteration on acquisition and/or short- and long-term retention of a learned response in male Wistar rats. Perinatal hypothyroidism was induced by prolonged (E9-P21) exposure of pregnant and lactating dams to methimazole (administered orally in drinking water, 0.2 mg/ml). Cognitive function was tested at 50 days by means of a step-through passive avoidance task. The effects of perinatal hypothyroidism on the retention of the passive avoidance response are long lasting being, however, highly dependent on the retention after the original training. Our results showed that methimazole-treated rats performed more poorly when retention was tested at long-term (24 h and 7 days) retention interval. Instead, methimazole-treated rats showed longer retrieval latencies than the control ones did when retention was tested at short term (1 h).

Topics: Animals; Animals, Newborn; Antithyroid Agents; Association Learning; Avoidance Learning; Female; Hypothyroidism; Male; Methimazole; Pregnancy; Prenatal Exposure Delayed Effects; Rats; Rats, Wistar; Retention, Psychology; Time Factors

Thyroid hormones show fluctuating levels during the post-hatching development of birds. In this paper we report the results of the first mechanical tests to quantify the effect of hypothyroidism, during post-natal development, on the skeletal properties of a precocial bird, the barnacle goose, as determined by microhardness testing. The effect of hypothyroidism is tissue-specific; bone from the femora of birds is not significantly affected by induced hypothyroidism, however, there is a strong positive relationship between the levels of circulating thyroid hormones and the mechanical properties of bone from humeri. In the barnacle goose the development of the wing skeleton and musculature depends on an increase in circulating thyroid hormones and our analysis shows that, in its absence, the mechanical competence of the bone mineral itself is reduced in addition to the decreased bone length and muscle development previously reported in the literature.

Topics: Age Factors; Analysis of Variance; Animals; Bird Diseases; Bone Development; Femur; Geese; Hardness Tests; Humerus; Hypothyroidism; Methimazole; Thyroxine; Triiodothyronine

A previous study using the 2'3'cyclic nucleotide 3'phosphodiesterase (CNPase), an oligodendroglial marker that also stain ensheathed fibers, showed a decrease in the number of immunoreactive fibers and a change in the pattern of CNPase immunoreactivity (CNPase+) in hypothyroid animals. CNPase+ fibers, in mature hypothyroid animals, showed a continuous pattern of staining in contrast with a discontinuous one in controls. As CNPase, in adult animals, can be found only in regions in which oligodendrocyte cytoplasm remains as internal, external and paranodal loops, it was suggested that the reduction of thyroid hormone levels leads to a failure in myelin compaction. Previous data showed a higher frequency of some abnormalities in myelin sheath as multiple cytoplasmic loops and redundant myelin profiles in mutant animals that present a failure in myelin compaction. The increase in the frequency of these abnormalities (multiple internal and external loops and redundant myelin) indicates a failure in the interrelations between the axons and the oligodendroglial processes. To verify if the thyroid hormone deficiency during CNS development disturbs these interrelations, we evaluated the frequency of the morphological abnormalities (multiple internal and external loops and redundant myelin) in myelin sheath of corpus callosum (cc) in experimental hypothyroidism. Randomic fields were kept by electron microscopy and the analysis of the frequency of morphological abnormalities showed a significant difference in hypothyroid animals at 60-day-old (PND60), with no significant differences at 90-day-old (PND90) animals. The frequency of multiple internal loops is higher in hypothyroid animals at PND60 that indicates a disturbance in the wrapping by the oligodendroglial process. These findings showed that thyroid hormone might modulate the axon-oligodendroglial relationships that are important for the adequate temporal sequence of events that occur during myelinogenesis, with possible consequences on myelin compaction.

Topics: Animals; Axons; Brain; Corpus Callosum; Female; Hypothyroidism; Methimazole; Microscopy, Electron; Myelin Sheath; Oligodendroglia; Rats; Rats, Wistar

Alterations of thyroid function during human development are known to produce extensive damage to the central nervous system including severe mental retardation. Using immunohistochemistry to identify the intermediate filament nestin, we have studied the possible influence of fetal and neonatal hypothyroidism on neocortical neuronal migration by arresting the normal development of the radial glial scaffold. By embryonic day 21 (E21), hypothyroid animals had a significant decrease in the number of nestin immunoreactive processes in the presumptive visual cortex. By postnatal day 5 (P5), hypothyroid animals showed a significant increase in the number of glial processes in relation with controls, although only in the upper layers of the visual cortex. Moreover, by P10, there was a marked increase in the number of radial glial processes in hypothyroid animals in superficial and deep zones of the visual cortex with respect to control animals. Our data indicate an important delay in the formation of the radial glial scaffold during the embryonic stage in hypothyroid animals that was interestingly accompanied by the later presence of abundant nestin immunoreactive fibers at P10. This impairment in the evolution of radial glia during development might be affecting the normal neuronal migratory pattern in the neocortex of hypothyroid rats.

Topics: Animals; Animals, Newborn; Antithyroid Agents; Cell Movement; Disease Models, Animal; Female; Fetus; Hypothyroidism; Immunohistochemistry; Intermediate Filament Proteins; Methimazole; Neocortex; Nerve Tissue Proteins; Nestin; Neuroglia; Neurons; Pregnancy; Rats

During 1 year of amiodarone intake development of amiodarone-associated thyroid dysfunction was observed in 25% of patients (hypothyroidism and thyrotoxicosis in 19.2 and 5.8%, respectively). Development of hypothyroidism was not accompanied with loss of antiarrhythmic efficacy of amiodarone and therapy with L-thyroxin was conducted at the background of continued amiodarone intake. In all patients with clinical and in less than one half (47.6%) of patients with subclinical forms of hypothyroidism replacement therapy with L-thyroxin was carried out. Development of amiodarone-associated thyrotoxicosis was accompanied with loss of antiarrhythmic efficacy of amiodarone in all cases. In all patients with thyrotoxicosis which developed during amiodarone intake thyrostatic therapy with mercasolil was carried out and in case of its inefficacy prednisolone was added. In 87.5% of patients with thyrotoxicosis correction of the thyroid status was conducted under conditions of continued amiodarone intake as this drug had been prescribed because of life saving indications. Achievement of euthyroid state was followed by restoration of antiarrhythmic efficacy of amiodarone. Amiodarone was discontinued just in 1 patient with ventricular extrasystole as correction of thyroid status and restoration of euthyroidosis enabled effective use of other antiarrhythmic drugs.

Topics: Amiodarone; Anti-Arrhythmia Agents; Anti-Inflammatory Agents; Antithyroid Agents; Data Interpretation, Statistical; Female; Humans; Hyperthyroidism; Hypothyroidism; Male; Methimazole; Middle Aged; Prednisolone; Prevalence; Thyroid Diseases; Thyroxine; Time Factors

Topics: Adenoma; Adult; Antithyroid Agents; Diagnosis, Differential; Drug Therapy, Combination; Drugs, Chinese Herbal; Female; Humans; Hyperthyroidism; Hypothyroidism; Male; Medicine, Chinese Traditional; Methimazole; Phytotherapy; Thyroid Neoplasms

The purpose of this study was to investigate the role of peripheral chemoreceptor activity on the hypoxic and hypercapnic ventilatory drives in rabbits with induced hypothyroidism. Experiments were carried out in control and hypothyroid rabbits. Hypothyroidism was induced by an administration of an iodide-blocker, methimazole in food (75 mg/100 g food) for ten weeks. At the end of the tenth week, triiodothyronine (T3) and thyroxine (T4) levels significantly decreased (P<0.001) while thyroid stimulating hormone (TSH) increased (P<0.001). Tidal volume (VT), respiratory frequency (f/min), ventilation minute volume (VE) and systemic arterial blood pressure (BP) were recorded during the breathing of the normoxic, hypoxic (8% O2-92% N2) and hypercapnic (6% CO2-Air) gas mixtures, in the anaesthetised rabbits of both groups. At the end of each experimental phase, PaO2, PaCO2, and pHa were measured. The same experimental procedure was repeated after peripheral chemoreceptor denervation in both groups. VT significantly decreased in some of the rabbits with hypothyroidism during the breathing of the hypoxic gas mixture (nonresponsive subgroup) (P<0.05). After chemodenervation, a decrease in VT was observed in this nonresponsive subgroup during normoxia (P<0.05). The percent decrease in VT in nonresponsive subgroup of hypothyroid rabbits after chemodenervation was lower than that of the chemodenervated control animals (P<0.01). When these rabbits with hypothyroidism were allowed to breath the hypercapnic gas mixtures, increases in VT and VE were not significant. In conclusion, although there is a decrease in peripheral chemoreceptor activity in hypothyroidism, it does not seem to be the only cause of decrease in ventilatory drive during hypoxia and hypercapnia.

Topics: Animals; Antithyroid Agents; Chemoreceptor Cells; Denervation; Female; Hypercapnia; Hypothyroidism; Hypoxia; Male; Methimazole; Rabbits; Respiration

The purpose of this experiment was to determine the possible relationship between certain indices of lipid metabolism and specific gene expression in chickens fed methimazole to simulate hypothyroidism. Male broiler chickens (Gallus gallus) growing from 7 to 28 days of age were fed diets containing 18% crude protein and either 0 or 1 g methimazole per kilogram of diet. At 28 days, these two groups were further subdivided into groups receiving 18% crude protein diets containing either 0 or 1 mg triiodothyronine (T3) per kilogram. Birds were sampled at 28, 30, and 33 days. Measurements taken included in vitro lipogenesis (IVL), malic enzyme (ME) activity, isocitrate dehydrogenase, aspartate amino transferase, and the expression of the genes for ME, fatty acid synthase (FAS), and acetyl coenzyme carboxylase (ACC). Hypothyroidism decreased IVL and ME at 28 days of age; however, T3 supplementation for 2 days restored both IVL and ME. Paradoxically, continuing T3 replenishment for an additional 3 days decreased IVL but did not decrease ME activity. In contrast, supplemental T3 decreased IVL in euthyroid birds, regardless of the dosing interval, but had no effect on ME activity. Although methimazole decreased ME gene expression, there was only a transitory relationship between enzyme activity and gene expression when plasma T3 was restored with exogenous T3. These data may help to explain some of the apparent reported dichotomies in lipid metabolism elicited by changes in the thyroid state of animals. In addition, most metabolic changes in response to feeding T3 occurred within 2 to 5 days, suggesting that changes in intermediary metabolism preceded morphological changes. In conclusion, the thyroid state of the animal will determine responses to exogenous T3.

Topics: Animals; Antithyroid Agents; Chickens; Enzymes; Gene Expression Regulation, Enzymologic; Hypothyroidism; Lipids; Liver; Male; Methimazole; RNA, Messenger; Triiodothyronine

Thyroid hormone (TH) deficiency results in delayed proliferation and migration of cerebellar granule cells. Although extensive cell loss during the development of the cerebellum under hypothyroid conditions is known, its nature and its mechanism are poorly understood. Bcl-2 family gene expression is known to determine the fate of cells to undergo apoptosis. We evaluated the effect of hypothyroidism on Bcl-2 family gene expression in the developing rat cerebellum. Electrophoresis and Western blotting were used to analyze DNA fragmentation and expression of DNA fragmentation factor (DFF-45), Bcl-2, Bcl-xL and Bax genes respectively. In the hypothyroid condition, extensive DNA fragmentation and enhanced cleavage of DFF-45 were seen throughout development (postnatal day 0 to day 24) and adulthood whereas they were absent in the euthyroid state. The anti-apoptotic genes Bcl-2 and Bcl-xL were down-regulated and the pro-apoptotic gene Bax was expressed at higher levels compared with the euthyroid state. These results suggest that normal levels of TH prevent cerebellar apoptosis to a large extent, whereas hypothyroidism not only increases the extent but also the duration of apoptosis by down-regulating the anti-apoptotic genes and maintaining a high level of the pro-apoptotic gene Bax.

Topics: Animals; Apoptosis; bcl-2-Associated X Protein; Blotting, Western; Cerebellum; DNA Fragmentation; Electrophoresis; Female; Gene Expression Regulation; Genes, bcl-2; Hypothyroidism; Imidazoles; Proto-Oncogene Proteins; Proto-Oncogene Proteins c-bcl-2; Rats; Rats, Sprague-Dawley; Weight Gain

The effects of a mild hypothyroidism condition on benzodiazepine (BDZ) and mu opioid receptor levels was investigated. Female Wistar rats were randomly divided into two groups: 1) hypothyroid rats (n=7), which received methimazole (60 mg/kg per day) in drinking water for four weeks, and 2) euthyroid rats (n=8), which drank only tap water. Animals were sacrificed and their brains were used for autoradiography experiments. When compared to the euthyroid group, the hypothyroid group presented reduced benzodiazepine receptor binding in medial amygdala (24%) and high mu-receptor levels in frontal (25%), sensorimotor (65%) and temporal (29%) cortices, basolateral amygdala (50%) and ventroposterior thalamic nucleus (49%). The present data suggest that alterations in BDZ and mu-receptor binding could be associated with the higher excitability observed in animals with triiodothyronine (T(3)) deficiency.

Topics: Animals; Antithyroid Agents; Autoradiography; Binding, Competitive; Brain; Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; Female; Flunitrazepam; GABA Agonists; GABA-A Receptor Agonists; Hypothyroidism; Methimazole; Radioligand Assay; Random Allocation; Rats; Rats, Wistar; Receptors, GABA-A; Receptors, Opioid, mu; Thyroxine; Triiodothyronine

Hypothyroidism is associated with significant abnormalities in the renal handling of salt and water. To address the involvement of tubular transport proteins in these abnormalities, rats were rendered pharmacologically hypothyroid and the abundance of major tubular transport proteins was assessed by immunoblot and immunohistochemistry. Hypothyroidism resulted in a marked reduction in kidney size and creatinine clearance along with decreased or unchanged total kidney abundance of the transport proteins. Whereas the proximal tubular type 3 Na/H exchanger (NHE3) and type 2 Na-phosphate cotransporter (NaPi2) stood out by their disproportionately reduced abundance, the bumetanide-sensitive type 2 Na-K-2Cl cotransporter (NKCC2) and aquaporin-2 (AQP2) were unaltered in their total kidney abundance despite a markedly lower kidney mass. The latter proteins in fact showed enhanced immunostaining. Decreased NHE3 and NaPi2 expression was most likely due to a combination of triiodo-l-thyronine (T(3)) deficiency along with a reduced glomerular filtration rate. The increased abundance of NKCC2 and AQP2 may have been caused by an increased action of vasopressin since urinary excretion of this hormone was elevated. On the other hand, the thiazide-sensitive Na-Cl cotransporter; the alpha-, beta-, and gamma-subunits of the amiloride-sensitive epithelial Na channel; and the alpha(1)-subunit of Na-K-ATPase showed a moderate decrease in total kidney abundance that was largely proportional to the smaller kidney mass. Although the observed expression of transporters was associated with a balanced renal sodium handling, altered transporter abundance may become functionally relevant if the hypothyroid kidney is challenged by an additional destabilization of the milieu interieur that has previously been shown to result in an inadequate natriuresis and clinical symptoms.

Topics: Animals; Antithyroid Agents; Aquaporin 2; Aquaporin 6; Aquaporins; Carrier Proteins; Creatinine; Epithelial Sodium Channels; Hypothyroidism; Kidney; Kidney Glomerulus; Kidney Tubules; Male; Methimazole; Rats; Rats, Sprague-Dawley; Sodium; Sodium Channels; Sodium-Hydrogen Exchanger 3; Sodium-Hydrogen Exchangers; Sodium-Phosphate Cotransporter Proteins; Sodium-Phosphate Cotransporter Proteins, Type II; Sodium-Potassium-Chloride Symporters; Sodium-Potassium-Exchanging ATPase; Solute Carrier Family 12, Member 1; Symporters; Triiodothyronine

The aim of the present work was to investigate the role of the serotoninergic system in the control of sodium appetite of hypothyroid rats (HTR) by administering drugs that affect the serotoninergic activity, and to compare the same homeostatic behaviour in euthyroid rats (ETR) also given these drugs. Fenfluramine (FEN; 5.0 mg x kg(-1), I.P.), which releases serotonin in the brain, significantly reduced the intake of 1.8 % NaCl in HTR subjected to water and sodium depletion (depleted) or water, sodium and food deprivation (deprived) by 31 and 45 %, respectively, 120 min after FEN injection, compared to HTR that received vehicle alone. Similarly, administration of FEN to ETR reduced 1.8 % NaCl intake in depleted and deprived rats by 64 and 46 %, respectively. The presynaptic serotonin reuptake inhibitor fluoxetine (20.0 mg x kg(-1), I.P.) led to the inhibition of sodium appetite in HTR during the initial 30 min in depleted rats and for up to 60 min post-injection in deprived rats, while sodium appetite inhibition persisted for longer periods in ETR. The 5HT2C receptor agonist mCPP (5.0 mg x kg(-1), I.P.) caused a drastic reduction in sodium appetite in HTR and ETR in depleted and deprived rats, respectively, after 120 min. Prior administration of the 5HT2C receptor antagonist LY53857 (5.0 mg x kg(-1), I.P.) completely blocked the inhibitory action of mCPP on sodium appetite in both HTR and ETR. In summary, our results suggest that the recruitment of serotoninergic neurons involved in the modulation of sodium appetite seems to be decreased in hypothyroidism due to a probable deficiency in the cerebral signalling pathway.

Topics: Animals; Appetite Regulation; Brain; Drinking; Ergolines; Fenfluramine; Fluoxetine; Hypothyroidism; Male; Methimazole; Rats; Rats, Wistar; Selective Serotonin Reuptake Inhibitors; Serotonin; Serotonin Antagonists; Sodium Chloride, Dietary

Thyroid hormone (TH) deficiency leads to extensive apoptosis during cerebellar development, but the mechanism still remains unclear. Different signals also converge on mitochondria during apoptosis to induce the release of apoptogenic proteins that activate proteolytic cascade through specific enzymes called caspases. Here we studied the effect of hypothyroidism on alterations in mitochondrial structure and translocation of apoptogenic molecules during rat cerebellar development. Structural analysis of mitochondria was studied by electron microscopy. The translocation of apoptogenic molecules was analyzed by Western blotting. TH deficiency led to vacuolization, enlargement and decrease in the number of cristae. The majority of the proapoptotic molecule, Bax, was localized in mitochondria under hypothyroid conditions whereas a limited presence of Bax was detected in the euthyroid state. Translocation of cytochrome c, apoptosis-inducing factor (AIF) and second mitochondrial-derived activator of caspases (SMAC) from mitochondria to cytosol was detected primarily in early developmental stages in the hypothyroid condition. These experimental results demonstrate that TH maintains mitochondrial architecture and inhibits the release of apoptogenic molecules to prevent excess apoptosis during cerebellar development.

Topics: Animals; Apoptosis; Apoptosis Inducing Factor; Apoptosis Regulatory Proteins; bcl-2-Associated X Protein; Blotting, Western; Carrier Proteins; Cerebellum; Cytochrome c Group; Flavoproteins; Hypothyroidism; Imidazoles; Membrane Proteins; Microscopy, Electron; Mitochondria; Mitochondrial Proteins; Models, Animal; Proto-Oncogene Proteins; Proto-Oncogene Proteins c-bcl-2; Rats; Translocation, Genetic

Seven-day-old chickens were fed diets containing 18% crude protein + 0 or 1g methimazole/kg to produce either euthyroid or hypothyroid groups of birds at 28 days of age. These two groups were then offered diets containing either 0 or 1mg triiodothyronine (T(3))/kg diet. Birds were sampled at 0, 2, 5, and 8 days following the onset of the T(3) treatment. Measurements taken at these intervals included in vitro hepatic lipogenesis (IVL), growth and feed consumption, hepatic enzyme activities (malic enzyme, ME; isocitrate dehydrogenase, ICD; and aspartate amino transferase, AAT), plasma hormones (T(3); thyroxine, T(4); insulin like growth factors I, IGF-I; and insulin like growth factors II, IGF-II) and metabolites (glucose; fatty acids, NEFA; triglyerides; uric acid). Hypothyroidism decreased IVL and ME at 28 days of age; however, T(3) supplementation for 2 days restored both IVL and ME. Paradoxically, continuing T(3) replenishment for an additional 3-6 days decreased IVL without affecting ME activity. In contrast, supplemental T(3) decreased IVL in euthyroid birds, regardless of the dosing interval, but had no effect on ME activity. Methimazole decreased plasma T(3), T(4), uric acid, and IGF-I, but did not affect IGF-II at 28 days. Giving T(3) to birds previously on methimazole increased plasma IGF-I as did feeding a control diet. Supplemental T(3) increased NEFA in both euthyroid and hypothyroid birds, but only for a short period following the initiation of supplementation (2 days post-supplementation). These data may help to explain some of the apparent reported dichotomies in lipid metabolism elicited by changes in the thyroid state of animals. In addition, most metabolic changes in response to feeding T(3) occurred within 2-5 days, suggesting that changes in intermediary metabolism preceded morphological changes. In conclusion, the thyroid state of the animal will determine responses to exogenous T(3).

Topics: Animals; Aspartate Aminotransferases; Chickens; Dietary Proteins; Hypothyroidism; Insulin-Like Growth Factor I; Insulin-Like Growth Factor II; Isocitrate Dehydrogenase; Lipids; Liver; Malate Dehydrogenase; Male; Methimazole; Thyroxine; Triiodothyronine; Uric Acid; Weight Gain

This experimental study was designed to examine whether hyperuricemia in hypothyroidism is associated with insulin resistance. For induction of hypothyroidism, rabbits (n = 12) were administered methimazole orally (75 mg/100 g food) for 30 days. T3, T4 and TSH values measured in plasma prior to and at the end of the experimentation period revealed the establishment of hypothyroidism. In the euthyroid and hypothyroid states of rabbits, crystalline porcine insulin was administered (0.1 unit/kg body weight) intraperitoneally and plasma glucose was measured at 0, 15, 30, 45 and 60 minutes. Sum of post insulin infusion glucose values was considered to reflect insulin resistance. Creatinine clearance (GFR) and uric acid clearance (CuA) were determined. Additionally, triglycerides were measured in plasma and Mg2+ both in erythrocytes and in plasma. Due to hypothyroidism: i) The glycemic response to insulin was not altered. ii) GFR and CuA were both decreased but CuA/GFR unchanged. iii) Triglycerides in plasma decreased. iv) Mg2+ concentration increased in plasma whereas decreased in erythrocytes. Several associations were observed between the variables on correlation analysis. On the basis of our data, it could be suggested that insulin resistance does not exist in hypothyroidism. Hyperuricemia observed in hypothyroidism should be considered to be secondary to decreased renal excretion but not as an indicator of insulin resistance.

Topics: Animals; Antithyroid Agents; Creatinine; Erythrocytes; Humans; Hyperuricemia; Hypothyroidism; Insulin; Insulin Resistance; Kidney; Magnesium; Methimazole; Rabbits; Thyrotropin; Thyroxine; Time Factors; Triglycerides; Triiodothyronine; Uric Acid

Hindlimb ischemia for 4 h, followed by reperfusion, resulted in necrosis of most soleus muscle in euthyroid rats, whereas only slight damage occurred in hypothyroid rats. Muscle repair after transection of the tibialis anterior muscle of hypothyroid rats showed delayed debris removal, initial retardation of myotube formation, and a higher incidence of aberrant sarcomeres in newly formed muscle fibers by electron microscopy. The protective mechanism against ischemia in hypothyroid muscles can probably be attributed to decreased degradation of high-energy phosphates, reduced formation of substrates for xanthine oxidase during ischemia, and attenuated generation of harmful oxygen free radicals during reperfusion. Initial delay of myotube formation seems to reflect retarded proliferation of muscle precursor cells. Prolonged occurrence of aberrant sarcomeres in hypothyroidism is perhaps due to a delay or imbalance in the synthesis of proteins that assemble sarcomeres. These findings demonstrate the significant roles of thyroid hormones in ischemic injury and muscle repair.

Topics: Animals; Antithyroid Agents; Body Weight; Hindlimb; Hypothyroidism; Ischemia; Male; Methimazole; Microscopy, Electron; Muscle Fibers, Skeletal; Muscle, Skeletal; Rats; Rats, Wistar; Regeneration; Thyroid Gland; Wound Healing

Depression of metabolism by hypothyroidism decreases oxidant production and thus protects tIssues against oxidant damage. Moreover, it is well-known that abnormal gut motility is a common manifestation in hypo/hyperthyroidism. In this study, we aimed to investigate the putative beneficial effects of methimazole on oxidative injury and dysmotility in a rat colitis model. Methimazole (0.04%) was administered in drinking water starting 15 days prior to induction of colitis. Colitis was induced by intracolonic administration of trinitrobenzene sulfonic acid (30 mg/ml; 0.8 ml) in ethanol. Six days after the induction of colitis, the fecal output was measured and used as an index for colonic motility. All rats were decapitated on the seventh day. The distal colon was weighed and the mucosal lesions were scored. Colonic lipid peroxidation (LP) and glutathione (GSH) measurements were performed. The macroscopic score, the colonic wet weight and LP values of the euthyroid colitis group were found to be higher than those of the control group (P<0.05-0.001). All these parameters were reduced in the methimazole-treated colitis group (P<0.01-0.001). The decrease in colonic GSH levels in the colitis group was completely abolished in the methimazole-treated colitis rats (P<0.01). Induction of colitis increased the average fecal output compared with the control group (P<0.05) and methimazole in the colitis group exaggerated the fecal output (P<0.001). In conclusion, methimazole reduces colonic oxidative injury probably due to hypometabolism, which is associated with a decrease in the production of reactive oxygen intermediates and an increase in the response of antioxidant systems.

Topics: Analysis of Variance; Animals; Antithyroid Agents; Colitis; Colon; Defecation; Feces; Female; Gastrointestinal Motility; Glutathione; Hypothyroidism; Lipid Peroxidation; Male; Methimazole; Models, Animal; Oxidative Stress; Rats; Rats, Wistar

Topics: Antithyroid Agents; Female; Graves Disease; Humans; Hypothyroidism; Methimazole; Middle Aged; Psychotic Disorders; Recurrence; Thyroid Diseases; Thyroxine; Treatment Outcome

Thyroid hormone is essential for proper development of the mammalian CNS. Previous studies have documented a decrease in the ability of neonatal hypothyroid animals to learn and to habituate to maze tests and an increase in spontaneous activity. However, there is little information about the effects of perinatal (i.e. perinatal and postnatal) hypothyroidism on behaviour. The aim of the present work was to investigate the longitudinal effects of perinatal hypothyroidism on certain aspects of the behaviour in rats. Neuromotor competence was tested at 21, 40 and 60 days, novelty-directed exploratory behaviour and anxiety-related behaviour were evaluated at 40 and 60 days by means of the Boissier tests and associative learning ability was tested at 80 days by means of a step-through passive avoidance task. The persistence of the effects of perinatal hypothyroidism on psychomotor performance was highly dependent on the task examined. Perinatal hypothyroidism caused an increase of locomotor activity as revealed by the total distance travelled in the Boissier test and this increase also comprised a component of decreased anxiety-related behaviour. Methimazole-treated subjects also had higher head-dip scores than controls at 40 days while no differences were observed at 60 days. Finally, our results showed that methimazole-treated rats performed poorly in a passive avoidance learning task.

Topics: Animals; Antithyroid Agents; Anxiety; Association Learning; Avoidance Learning; Exploratory Behavior; Female; Hypothyroidism; Male; Methimazole; Pregnancy; Prenatal Exposure Delayed Effects; Psychomotor Performance; Rats; Rats, Wistar

The effects of the thyroid state on oxidative damage, antioxidant capacity, susceptibility to in vitro oxidative stress and Ca(2+)-induced permeabilization of mitochondria from rat tissues (liver, heart, and gastrocnemious muscle) were examined. Hypothyroidism was induced by administering methimazole in drinking water for 15 d. Hyperthyroidism was elicited by a 10 d treatment of hypothyroid rats with triiodothyronine (10 micro g/100 g body weight). Mitochondrial levels of hydroperoxides and protein-bound carbonyls significantly decreased in hypothyroid tissues and were reported above euthroid values in hypothyroid rats after T(3) treatment. Mitochondrial vitamin E levels were not affected by changes of animal thyroid state. Mitochondrial Coenzyme Q9 levels decreased in liver and heart from hypothyroid rats and increased in all hyperthyroid tissues, while Coenzyme Q10 levels decreased in hypothyroid liver and increased in all hyperthyroid tissues. The antioxidant capacity of mitochondria was not significantly different in hypothyroid and euthyroid tissues, whereas it decreased in the hyperthyroid ones. Susceptibility to in vitro oxidative challenge decreased in mitochondria from hypothyroid tissues and increased in mitochondria from hyperthyroid tissues, while susceptibility to Ca(2+)-induced swelling decreased only in hypothyroid liver mitochondria and increased in mitochondria from all hyperthyroid tissues. The tissue-dependence of the mitochondrial susceptibility to stressful conditions in altered thyroid states can be explained by different thyroid hormone-induced changes in mitochondrial ROS production and relative amounts of mitochondrial hemoproteins and antioxidants. We suggest that susceptibilities to oxidants and Ca(2+)-induced swelling may have important implications for the thyroid hormone regulation of the turnover of proteins and whole mitochondria, respectively.

Topics: Animals; Antioxidants; Calcium; Hyperthyroidism; Hypothyroidism; In Vitro Techniques; Lipid Peroxidation; Male; Methimazole; Mitochondria, Heart; Mitochondria, Liver; Mitochondria, Muscle; Mitochondrial Swelling; Oxidative Stress; Rats; Rats, Wistar; Triiodothyronine; Ubiquinone; Vitamin E

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

Hormone secretion by thyrocytes occurs by fluid phase uptake and lysosomal degradation of the prohormone thyroglobulin (Tg). However, some Tg internalized by megalin bypasses lysosomes and is transcytosed across cells and released into the bloodstream. Because the hormone content of Tg is variable, we investigated whether this affects transcytosis. We found that rat Tg with a low hormone content [low-hormonogenic rat Tg (low-horm-rTg)] is transcytosed by megalin across thyroid FRTL-5 cells to a greater extent than rat Tg with a high hormone content [hormonogenic rat Tg (horm-rTg)]. In immunoprecipitation experiments, the Tg sequence Arg-2489-Lys-2503 (required for binding to megalin and heparan sulfate proteoglycans) was found to be more exposed in low-horm-rTg, which accounted for its preferential transcytosis. Thus, removal of surface heparan sulfate proteoglycans from FRTL-5 cells or blocking of 2489-2503 reduced transcytosis of low-horm-rTg to a greater extent than that of horm-rTg. Preferential transcytosis of low-horm-rTg affected hormone release. Thus, the increase in hormone release from horm-rTg in FRTL-5 cells determined by megalin blocking (due to reduced transcytosis and enhanced Tg degradation) was rescued by low-horm-rTg, suggesting that megalin is required for effective hormone release. This finding was confirmed in a small number of megalin-deficient mice, which had serological features resembling mild hypothyroidism. Reduced hormone formation within Tg in vivo, due to treatment of rats with aminotriazole or of patients with Graves' disease with methimazole, resulted in increased Tg transcytosis via megalin, in confirmation of results with FRTL-5 cells. Our study points to a major role of megalin in thyroid homeostasis with possible implications in thyroid diseases.

Topics: Adult; Amitrole; Animals; Dose-Response Relationship, Drug; Endocytosis; Enzyme-Linked Immunosorbent Assay; Female; Graves Disease; Heparitin Sulfate; Homozygote; Hormones; Humans; Hypothyroidism; Low Density Lipoprotein Receptor-Related Protein-2; Male; Methimazole; Mice; Mice, Transgenic; Middle Aged; Models, Biological; Precipitin Tests; Rats; Rats, Inbred Lew; Thyroglobulin; Thyroid Gland; Thyroid Hormones

The effects of long-term cold exposure on brown adipose tissue (BAT) thermogenesis in hypothyroid rats have been examined. Thyroid ablation was performed in normal rats after 2 mo of exposure to 4 degrees C, when BAT hypertrophy and thermogenic activity were maximal. After ablation, hypothyroid and normal controls remained in the cold for 2 additional months. At the end of the 4-mo cold exposure, all untreated hypothyroid rats were alive, had normal body temperature, and had gained an average 12.8% more weight than normal controls. Long-term cold exposure of hypothyroid rats markedly increased BAT weight, mitochondrial proteins, uncoupling protein (UCP)-1, mRNA for UCP-1, and oxygen consumption to levels similar to those seen in cold-exposed normal rats. The results indicate that thyroid hormones are required for increased thermogenic capacity to occur as an adaptation to long-term cold exposure. However, cold adaptation can be maintained in the absence of thyroid hormone.

Topics: Acclimatization; Adipose Tissue, Brown; Animals; Antithyroid Agents; Body Weight; Carrier Proteins; Cold Temperature; Female; Glyceraldehyde-3-Phosphate Dehydrogenases; Hypothyroidism; Ion Channels; Isoenzymes; Male; Membrane Proteins; Methimazole; Mitochondria; Mitochondrial Proteins; Oxygen Consumption; Rats; Rats, Wistar; RNA, Messenger; Thermogenesis; Thyroid Gland; Time Factors; Uncoupling Protein 1

Thyroid hormones are well known modulators of signal transduction. The effect of hyper- and hypo-thyroidism on diacylglycerol/protein kinase C (DAG/PKC) signaling in cardiomiocytes has been determined. Triiodothyronine (T3) has been shown to prevent the alpha1-adrenoreceptor-mediated activation of PKC but does not alter the stimulation of enzyme and hepatic metabolism by phorbol ethers. It has been suggested that the elevation of endogenous DAG in senescent or hypothyroid cells changes the PKC-dependent response of cells to phorbol esters and hormones. In the present study, was examined the formation of DAG and activation of PKC in liver cells from rats of different thyroid status.. The results obtained provide the first demonstration of DAG accumulation in liver and cell plasma membranes at age- and drug-dependent thyroid gland malfunction. The experiments were performed in either the [14C]CH3COOH-labeled rat liver, liver slices or hepatocytes labeled by [14C] oleic acid and [3H]arachidonic acid or [14C]palmitic acid as well as in the isolated liver cell plasma membranes of 90- and 720-day-old rats of different thyroid status. The decrease of T4 and T3 levels in blood serum of 720-day-old rats and mercazolil-treated animals was associated with increases of both the DAG mass in liver and liver cell plasma membranes and newly synthesized [14C]DAG level in liver and isolated hepatocytes. Hypothyroidism decreased PKC activity in both membrane and cytosol as well as phospholipid and triacylglycerol synthesis in liver. These hypothyroidism effects were restored in liver by injection of T4. T4 administration to the intact animals of different ages decreased the DAG level in liver and isolated plasma membranes and the content of newly synthesized DAG in liver. The reduction of DAG level in liver was not associated with increasing free fatty acid level. DAG labeling ratio 14C/3H in liver slices of rats of different thyroid state sharply differed from PL. DAG was relatively enriched in [14C]oleic acid whereas PL were enriched in [3H]arachidonic acid.. The above data have indicated that thyroid hormones are important physiological modulators of DAG level in rat liver and cell plasma membranes. Age- and drug-induced malfunction of thyroid gland resulted in a prominent decrease of glycerolipid synthesis which may promote DAG accumulation in liver.

Topics: Aging; Animals; Carbon Radioisotopes; Diglycerides; Hepatocytes; Hypothyroidism; Injections, Intraperitoneal; Liver; Male; Membrane Lipids; Methimazole; Phospholipids; Protein Kinase C; Rats; Rats, Wistar; Triglycerides

We investigated the time dependency of hypothyroid-induced changes in beta-adrenoceptor-mediated relaxation of vascular smooth muscle. Methimazole (0.03%) was administered to male Wistar-Imamichi rats for 3 days, 1, 2 or 6 weeks. This treatment led to significant increases in thyroid weight while inhibiting growth rate. Tension in isolated rings of thoracic aortae from control and hypothyroid rats was measured isometrically. Responses of aortic rings to cumulative doses of acetylcholine (ACh) and sodium nitroprusside (SNP) were not significantly different between control and hypothyroid groups. After 3 days and 1 week of treatment, isoprenaline (ISO)-induced relaxation was unchanged, but after 2 and 6 weeks, a marked increase was observed as compared to controls. Removal of the endothelium and pretreatment with NG-nitro-L-arginine (L-NOARG) inhibited the ISO-induced relaxation in both groups; but whereas this degree of inhibition was the same for both groups after 3 days and 1 week, it was significantly less pronounced in hypothyroid rats after 2 and 6 weeks as compared to their controls. These results suggest that hypothyroidism has a time-dependent influence on beta-adrenoceptor-mediated relaxation in the rat thoracic aortae and that the enhancement after 2 and 6 weeks of methimazole treatment may be due to a hypothyroid-induced alteration in arterial smooth muscle function.

Topics: Acetylcholine; Adrenergic beta-Agonists; Animals; Antithyroid Agents; Aorta, Thoracic; Endothelium, Vascular; Hypothyroidism; In Vitro Techniques; Isoproterenol; Male; Methimazole; Muscle Relaxation; Muscle, Smooth, Vascular; Nitroprusside; Rats; Rats, Wistar; Receptors, Adrenergic, beta; Time Factors

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

Many interrelationships exist between the thyroid gland and the gastrointestinal tract. Several past and recent studies have shown that the thyroid gland profoundly influences the structure and function of the exocrine pancreas in the rat. In the present study we investigated the effect of methimazole (METZ), an antithyroid drug, on cerulein induced acute pancreatitis (AP) in rats.. Rats were divided into 3 groups (10-12 weeks age, 200-250 g weight, n: 10). Group B was made hypothyroid with methimazole 5 mg/kg daily for 10 days and the others were untreated euthyroid groups. After 10 days, acute pancreatitis was induced with four doses of 20 microg/kg body weight of cerulein administered s.c at hourly intervals in group A and B while the control group C was given 4 doses of I ml saline. Pancreas wet weight (mg), plasma amylase activity (IU/l) and pancreatic histology were used as endpoints to quantify the severity of the AP.. Plasma tri-iodothyronine (T3) (ng/dl) and thyroxine (T4) (microg/dl) levels were significantly reduced after METZ treatment for 10 days (p < 0.01). METZ pretreatment reduced significantly the cerulein induced increase in pancreatic weight (1,205 +/- 12 mg in METZ treated AP group versus 1,617 +/- 14 mg in AP group, p < 0.05) and the rise in amylase activity (7,078 +/- 816 IU/l in METZ treated AP group versus 8,611 +/- 830 IU/l in AP group p < 0.05).. METZ reduces the severity of cerulein induced AP in rats. This effect might be through its antithyroid property.

Topics: Acute Disease; Amylases; Animals; Ceruletide; Disease Models, Animal; Hypothyroidism; Male; Methimazole; Pancreatitis; Rats; Rats, Wistar; Thyroid Hormones

Seven day old male broiler chickens were fed diets containing 12, 18 or 24% crude protein + 0 or 1 g methimazole/kg diet for 21 days to examine the interaction of the birds' thyroid status and crude protein levels on metabolism. Methimazole (1-methyl-2-mercaptimidazole) inhibits thyroidal production of thyroid hormones and results in hypothyroidism. Birds were fed a diet containing 18% crude protein for an additional 21 days to determine the carry over effects of treatments. Birds were killed at 28 and 49 d. In vitro lipogenesis was inversely related (P < 0.05) to dietary protein levels in control birds at 28 d. Dietary methimazole attenuated (P < 0.05) this effect, resulting in a common rate similar to that attained in the birds fed the highest level of protein without methimazole. Birds fed methimazole for an initial 21-day period (7 to 28 d of age) had greater lipogenic rates (P < 0.05) at 49 d than did their control counterparts. In contrast, methimazole increased (P < 0.05) abdominal fat pad (AFP) lipoprotein lipase (LPL) at both age periods, indicating increased ability by the AFP to remove triglycerides from systemic circulation. Observations at 49 d suggest that perturbations in the thyroid of the young bird may substantially change metabolism in later life. Results also show that obesity in hypothyroid birds cannot be explained by increases in de novo lipogenesis, but probably relates to changes in LPL activity.

Topics: Adipose Tissue; Animals; Antithyroid Agents; Aspartate Aminotransferases; Chickens; Dietary Proteins; Hypothyroidism; In Vitro Techniques; Isocitrate Dehydrogenase; Lipids; Lipoprotein Lipase; Liver; Malate Dehydrogenase; Male; Methimazole

The study was to investigate the protective effect of antioxidants against methimazole (MMI) induced hypothyroidism in rats. Male Wistar rats were fed MMI, MMI plus vitamin C, MMI plus vitamin E and MMI plus turmeric extract (TE) supplemented diet. At the end of the experiments, thyroid weights, thyroxine (T4), triiodothyronine (T3) and cholesterol levels were determined. It was observed that MMI treated rats showed increase in thyroid weights, very low levels of circulating T4, T3 and increased levels of total cholesterol as compared to controls (P< 0.001). However, rats which received Vit. C, Vit. E or TE along with MMI showed reduced weights (38-55% less) in thyroid glands (P < 0.01), less suppressed T4 and T3 levels (2-6% and 7-35% respectively) and less increase in total cholesterol levels (19-52%) which are statistically significant. The data suggest the positive effect of antioxidants on thyroid gland which could be due to direct involvement of antioxidants on thyroid gland.

Topics: Animals; Antioxidants; Antithyroid Agents; Ascorbic Acid; Cholesterol; Condiments; Curcuma; Dietary Supplements; Hypothyroidism; Lipid Peroxidation; Male; Methimazole; Plant Extracts; Rats; Rats, Wistar; Thyroid Gland; Thyroxine; Triiodothyronine; Vitamin E

We examined the contribution of hypothyroidism to streptozotocin diabetes-induced alterations in the arrhythmia susceptibility of ex vivo hearts to regional zero-flow ischaemia. Diabetic rats received either protamine zinc insulin (10 IU/kg/day, s.c.) or triiodothyronine (10 microg/kg/day, s.c.) for 8 weeks commencing 72 h after injection of streptozotocin (60 mg/kg, i.p.). Arrhythmias were determined in ex vivo Langendorff-perfused hearts, subjected to a 30-min main left coronary artery occlusion, followed by 30-min reperfusion. Serum free thyroxine concentrations, rectal temperature and ex vivo heart rate were significantly decreased in the 8-week diabetic group (P<0.001). These changes were prevented by administration of triiodothyronine or insulin. Ventricular fibrillation during reperfusion was abolished in hearts from diabetic rats. This protection was prevented by treatment with either triiodothyronine or insulin. Hearts from methimazole-hypothyroid rats also showed no ventricular fibrillation during reperfusion. The protection against ischaemia-reperfusion-arrhythmias observed in hearts from streptozotocin-diabetic rats may be due to diabetes-induced hypothyroidism.

Topics: Animals; Arrhythmias, Cardiac; Blood Glucose; Body Temperature; Body Weight; Diabetes Mellitus, Experimental; Disease Models, Animal; Heart; Heart Rate; Hypothyroidism; Insulin; Long QT Syndrome; Male; Methimazole; Myocardial Ischemia; Myocardial Reperfusion Injury; Organ Size; Protein Kinase C; Rats; Rats, Sprague-Dawley; Streptozocin; Thyroid Hormones; Triiodothyronine; Ventricular Fibrillation

The aim of this work was to study the influence of the endocrine balance between thyroid hormones, insulin and growth hormone (GH) on the regulation of insulin-like growth factor binding proteins (IGFBPs), complementing a study previously reported for insulin-like growth factors (IGFs) in similar populations. Serum concentrations of IGFBPs-1 to -3 were assayed by Western ligand blot and their mRNA expression in the liver assayed by RNase protection assay in the hypothyroid populations: thyroidectomized and mercapto-1-methylimidazole (MMI)-treated neonates, and thyroidectomized adult rats at different periods after thyroidectomy. Serum concentrations of insulin, GH and IGF-I were increased in thyroidectomized neonates and decreased in the other populations. IGFBPs-1 and -2 increased 79% and 50% respectively in thyroidectomized neonatal rats compared with control at 15 days after thyroidectomy, whereas only IGFBP-2 increased (87%) in MMI-treated neonates, which had low serum insulin and GH compared with control on the same days. In thyroidectomized adult rats, IGFBPs-1 and -2 decreased 60% compared with controls on all days studied. Furthermore, when streptozotocin was administered to thyroidectomized neonates and insulin was given to thyroidectomized adult rats to restore insulin to control values in both groups, a differential regulation was found for IGFBPs-1 and -2. The transcriptionally induced decrease in IGFBP-3 (20-25% compared with control in neonates and 50% in adult rats), however, seemed to be regulated by GH and IGF-I. The similarity of changes in IGFBPs found in hypothyroid, undernourished and streptozotocin-induced diabetic neonatal rats suggests that the regulatory effect of insulin or GH on the IGFBPs requires the reduced biologically active thyroid hormone that is found in these three populations.

Topics: Animals; Animals, Newborn; Diabetes Mellitus, Experimental; Female; Growth Hormone; Hypothyroidism; Imidazoles; Insulin; Insulin-Like Growth Factor Binding Protein 1; Insulin-Like Growth Factor Binding Protein 2; Insulin-Like Growth Factor Binding Protein 3; Insulin-Like Growth Factor Binding Proteins; Insulin-Like Growth Factor I; Liver; Male; Models, Animal; Rats; Rats, Wistar; RNA, Messenger; Thyroidectomy

The effects of neonatal hypothyroidism on the number of Leydig cells were studied in neonatal Wistar rats. Moderate or severe hypothyroidism were induced during neonatal life by giving different amounts of methimazole (MMI; 0.05% or 0.1%) in the drinking water of pregnant and lactating dams. Rats were sacrificed on day 21 of postnatal life. Severely hypothyroid rats had approximately 45-fold higher serum thyrotropin (TSH) values and demonstrated approximately a 65% decrease in testes weight (p < 0.05) and the number of Leydig cells. However, in moderately hypothyroid rats, in which serum TSH was only approximately 16-fold higher, testicular weight was normal and the number of Leydig cells almost doubled (p < 0.01). There were no significant differences between the serum-free testosterone levels of the moderately and severely hypothyroid rats versus controls. Serum levels of 3alpha-androstanediol glucuronide, although decreased to less than 10% in severely hypothyroid rats (p < 0.01), were not changed by mild hypothyroidism. The number of Sertoli cells was increased in moderately hypothyroid rats versus controls (p < 0.05) and even further increased in severely hypothyroid rats (p < 0.05). We conclude that (1) severe neonatal hypothyroidism impairs the development and function of the testes and (2) moderate neonatal hypothyroidism stimulates the proliferation of Leydig cells.

Topics: Androstane-3,17-diol; Animals; Animals, Newborn; Cell Count; Hypothyroidism; Leydig Cells; Male; Methimazole; Rats; Rats, Wistar; Sertoli Cells; Testis; Thyrotropin; Thyroxine

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 objective of this study was to determine side-effects associated with iodized oil injection in patients with simple goiter. In an iodine-deficient population, 3420 patients with simple goiter, who were not taking supplemental iodine, were chosen for this study. They received a single intramuscular injection of 1 ml iodized oil, containing 480 mg iodide. Clinical and laboratory evaluations were performed every 3 months for one year and every 6 months for the next 4 years. The incidence of hypo- and hyperthyroidism was 0.6% each, with equal prevalence in both sexes. Most cases of hypo- and hyperthyroidism were observed during the first 5 months after the injection. Eight cases of hyperthyroidism were asymptomatic. A further 8 patients had overt thyrotoxicosis and required treatment with methimazole for 18 months. Recurrence of hyperthyroidism was observed in one patient. Five hypothyroid patients were diagnosed only by abnormal thyroid function tests, and 4 cases needed no treatment. Others received T4 treatment for a mean of 14.5 months. Among 14 T4-treated patients, recurrence of hypothyroidism occurred in 7 patients after treatment was discontinued. Twenty-nine patients (0.8%) were afflicted with dermatologic complications. The most common dermatologic side-effect was urticarial reaction. In 15 subjects, skin lesions appeared 8 to 14 days after injection. It is concluded that side-effects of iodized oil injection are rare, and in most cases the complications are transient and self-limited. The occurrence of iodine induced hyperthyroidism following iodized oil administration is close to the ratio observed in spontaneous thyrotoxicosis.

Topics: Adolescent; Adult; Child; Child, Preschool; Female; Goiter; Humans; Hyperthyroidism; Hypothyroidism; Injections, Intramuscular; Iodized Oil; Male; Methimazole; Prospective Studies; Recurrence; Skin Diseases; Thyrotropin; Thyroxine; Triiodothyronine

Thyroid hormone (TH) is essential for proper brain development, acting through nuclear receptors that modulate the expression of specific genes in response to hormone binding. In a screen for genes regulated by TH in the rat cerebellum, we recently identified a novel gene, synaptotagmin-related gene 1 (Srg1). The Srg1 protein is structurally similar to synaptotagmins, a family of proteins involved in regulating neurotransmission. To elucidate a potential role of Srg1 in brain development, we have investigated the developmental and TH-regulated expression of Srg1 in the neonatal rat brain. We show that expression of both Srg1 RNA and protein is detected only in the brain and specifically in neurons. Srg1 mRNA and protein levels increase postnatally, nearing adult levels after the third postnatal week. Neonatal TH deficiency results in a significant reduction and delay in expression of both Srg1 RNA and protein. Using immunohistochemistry, we were able to detect Srg1 protein in numerous brain regions. In the cerebellum, Srg1 protein is localized to the molecular layer, indicating that it is highly expressed in granule cell axons. To further examine Srg1 expression in cerebellar granule cells (CGCs), we used an in vitro cell culture model. In primary cultures of CGCs, Srg1 expression is significantly reduced in the absence of TH. Srg1 mRNA is rapidly upregulated in cultured CGCs, suggesting a direct response to TH. Neuronal and TH-regulated expression of Srg1, together with its localization to neurites, implicates Srg1 as an important component of the program of gene expression induced by TH in the developing brain.

Topics: Aging; Animals; Animals, Newborn; Axons; Brain; Cells, Cultured; Cerebellum; Female; Gene Expression Regulation, Developmental; Hypothyroidism; Immunohistochemistry; In Situ Hybridization; Male; Membrane Proteins; Methimazole; Neurons; Organ Specificity; Pregnancy; Prenatal Exposure Delayed Effects; Rats; Rats, Sprague-Dawley; RNA, Messenger; Synaptotagmins; Thyroid Hormones; Vesicular Transport Proteins

Most research done on hypothyroidism has focused on physiological and biochemical aspects of the tissues, whilst there has been little work on tissue morphology especially on salivary glands. The present study has used hypothyroid Wistar rats as a model for investigating the effects of hypothyroidism on submandibular gland structure. Two groups of Wistar rats were studied. One was made hypothyroid with methimazole and the second was an untreated euthyroid group (control). They were euthanised after 10 weeks. Submandibular glands were removed and studied. Systematic random transverse sections were obtained from submandibular glands and subjected to morphometric analysis. Volume density and absolute volume of granular, striated and excretory ducts and interlobular connective tissue were estimated by point counting. Volume-weighted mean particle volume of serous and mucous acini was also determined by unbiased stereology. Absolute volume of granular ducts in the submandibular gland of hypothyroid rats was reduced by approximately 50% (p<0.009) whilst that of the striated and excretory ducts and interlobular connective tissue was unaffected. Volume of serous acini was also significantly (p<0.03) lower in hypothyroid rats. These changes suggest that hypothyroidism has an effect on submandibular gland structure, and that this effect occurs mostly in two major exocrine compartments (granular duct and serous acinus) of the gland.

Topics: Animals; Antithyroid Agents; Hypothyroidism; Male; Methimazole; Rats; Rats, Wistar; Submandibular Gland

Experimental evidence suggests an involvement of thyroid hormones in myocardial nonmyocyte component growth. We evaluated the possible role of thyroid hormones in myocardial remodeling by ultrasonic tissue characterization (videodensitometry) in 8 hyperthyroid patients, in 10 hypothyroid patients, and in 2 patients with thyroid hormone resistance syndrome (RTH), before, 60, and 120 days after treatment (T0, T60, T120), and in 10 age-matched euthyroids. According to a previously described procedure, the derived collagen volume fraction (dCVF%, an echocardiographic index estimating the collagen content) was predicted from the pixel-level frequency distribution width (broadband, Bb) of the selected echocardiographic images. Thyrotropin (TSH), free thyroxine (FT4), and free triiodothyronine (FT3) were assessed by immunometric method. QT interval dispersion (QTd) on basal electrocardiogram was measured as a marker of dyshomogeneous ventricular repolarization. At T0, Bb and dCVF% were normal in hyperthyroid and euthyroid patients, and slightly increased in RTH patients, whereas significantly higher values were found in hypothyroids. At T60, a significant reduction in Bb was observed in hypothyroids, with nearly normal dCVF% values. This trend was confirmed at T120 with complete normalization of echoreflectivity. No echoreflectivity changes were observed in hyperthyroid and RTH patients during treatment. QTd was significantly increased in hypothyroids at T0, while no significant differences were found among groups at T60 and T120. Because the different videodeonsitometric myocardial properties observed in hypothyroid versus hyperthyroid patients correspond to an increase of dCVF%, this study suggests that thyroid hormones exert an inhibitory effect on myocardial collagen synthesis in humans.

Topics: Adult; Antithyroid Agents; Collagen; Echocardiography; Electrocardiography; Female; Humans; Hyperthyroidism; Hypothyroidism; Male; Methimazole; Middle Aged; Thyroid Diseases; Thyroid Hormone Resistance Syndrome; Thyroid Hormones; Thyroxine; Triiodothyronine; Ventricular Remodeling

The influence of methimazole-induced hypothyroidism on spontaneous rhythmic contractions and Ca2+ channel function of rat uterus was examined. Hypothyroidism significantly reduced the amplitude and frequency of spontaneous rhythmic contractions. Nifedipine (10(-12)-10(-6) M) and diltiazem (10(-9)-10(-4) M) caused concentration-related inhibition of the myogenic responses of the oestrogenised rat uterus obtained from both eu- and hypothyroid rats. However, nifedipine was less potent (IC(50); 5.4 x 10(-9) M; n=6) in hypothyroid rat uterus as compared to euthyroid controls (IC(50): 8.13 x 10(-12) M; n=9) to inhibit the rhythmic contractions. Similarly, diltiazem was less potent (IC(50): 4.57 x 10(-6) M; n=9) to inhibit the uterine spontaneous contractions in hypothyroid than in euthyroid rat uterus (IC(50): 6.4 x 10(-8) M; n=6). A similar decrease in the sensitivity to nifedipine and diltiazem for reversal of K+ (100 mM)-induced tonic contraction was observed in uterus obtained from hypothyroid rats compared to the controls. Both nifedipine and diltiazem were less potent for causing concentration-related inhibition of K+-stimulated 45Ca2+ influx in uterine strips taken from the hypothyroid rats. Thus, the IC(50) values of nifedipine (1.83 x 10(-8) M; n=12) and diltiazem (1.8 x 10(-6) M; n=9) were significantly greater in tissues obtained from hypothyroid rats compared to the controls (IC(50) of nifedipine, 1.15 x 10(-11) M; n=12, diltiazem, 8.1 x 10(-8) M; n=8). Nifedipine-sensitive influx of 45Ca2+ - stimulated either by K+ (100 mM) or Bay k8644 (1,4-dihydro-2,6-dimethyl-5-nitro-4-[2'-(trifluromethyl)phenyl]-3-pyridine carboxylic acid methyl ester) (10(-8) M) was significantly less in uterine strips from hypothyroid rats compared to the controls. The results of the present study suggest that the inhibition of uterine rhythmic contractions may be attributable to a reduction in rat myometrial Ca2+ channel function in the hypothyroid state.

Topics: Animals; Calcium; Calcium Channel Blockers; Calcium Radioisotopes; Diltiazem; Dose-Response Relationship, Drug; Female; Hypothyroidism; In Vitro Techniques; Methimazole; Muscle Contraction; Nifedipine; Rats; Rats, Sprague-Dawley; Sensitivity and Specificity; Thyroxine; Triiodothyronine; Uterus

The activity of antioxidant enzymes, copper-zinc superoxide dismutase (CuZnSOD), manganese superoxide dismutase (MnSOD) and catalase (CAT), as well as that of the mitochondrial FAD-dependent alpha-glycerophosphate dehydrogenase (alpha-GPD) in the rat interscapular brown adipose tissue (IBAT) were studied after the treatment with methimazole (MMI) for three weeks or with iopanoic acid (IOP) for five days. Besides, the mitochondrial concentration of uncoupling protein-1 (UCP-1) and the activity of catecholamine degrading enzyme monoamine oxidase (MAO) in the IBAT as well as the activity of the catecholamine synthesizing enzyme, dopamine beta-hydroxylase (DBH) in rat serum were examined. Judging by the significantly enhanced level of serum DBH, which is an index of sympathetic activity, and that of IBAT MAO, the increase in MnSOD and CAT activities in the IBAT of hypothyroid (MMI-treated) rats seems to be due to elevated activity of sympathetic nervous system (SNS). However, CuZnSOD activity is not affected by SNS. On the contrary, IOP, which is a potent inhibitor of T4 deiodination into T3 producing "local" hypothyroidism, did not change either SNS activity or activities of IBAT antioxidant enzyme. However, both treatments significantly decreased IBAT UCP-1 content and alpha-GPD activity suggesting that the optimal T3 concentration in the IBAT is necessary for maintaining basal levels of these key mitochondrial parameters.

Topics: Adipose Tissue, Brown; Animals; Antithyroid Agents; Carrier Proteins; Catalase; Contrast Media; Dopamine beta-Hydroxylase; Glycerolphosphate Dehydrogenase; Hypothyroidism; Ion Channels; Iopanoic Acid; Male; Membrane Proteins; Methimazole; Mitochondrial Proteins; Monoamine Oxidase; Oxidation-Reduction; Rats; Rats, Wistar; Superoxide Dismutase; Uncoupling Protein 1

We have previously shown that thyroid hormone (T(3)) regulates mitochondrial gene expression, morphology and transmembrane potential in the developing brain. Here, we have analysed the effect of thyroid hormone on mitochondrial function in different brain regions. For this purpose we have determined, in control, hypothyroid and T(3)-treated hypothyroid neonatal rats, the rate of oxidative phosphorylation in isolated mitochondria and the activity of the respiratory complexes in tissue homogenates. Our results showed a decrease in oxidative phosphorylation rate (only in the presence of NADH-generating substrates) and mitochondrial complexes I and III activity in the cerebral cortex and striatum of hypothyroid neonates, but not in the other areas analysed (hippocampus, cerebellum, thalamus, mid brain and brain stem). In parallel with mitochondrial activity, the levels of mitochondrially encoded transcripts were decreased only in the cerebral cortex and striatum of hypothyroid rats. The administration of T(3) corrected all these parameters. In summary, this study showed a down-regulation of mitochondrial gene expression accompanied by a decrease in mitochondrial activity in the cerebral cortex and striatum of developing hypothyroid neonatal rats.

Topics: Adenosine Triphosphatases; Animals; Animals, Newborn; Antithyroid Agents; Carrier Proteins; Cerebral Cortex; Corpus Striatum; Electron Transport Complex I; Electron Transport Complex II; Electron Transport Complex III; Electron Transport Complex IV; Enzyme Activation; Female; Hypothyroidism; Membrane Proteins; Methimazole; Mitochondria; Mitochondrial Proton-Translocating ATPases; Multienzyme Complexes; NADH, NADPH Oxidoreductases; Oxidative Phosphorylation; Oxidoreductases; Pregnancy; Prenatal Exposure Delayed Effects; Rats; Rats, Wistar; RNA; RNA, Mitochondrial; Succinate Dehydrogenase; Triiodothyronine

The involvement of angiotensin AT1 receptors in sodium appetite was studied in hypothyroid rats treated with the angiotensin II antagonist losartan. Losartan was administered chronically by the oral route or acutely by the subcutaneous route after water and sodium depletion or water, sodium and food deprivation. Three days after addition of losartan to the food at the dose of 1.0 mg x g(-1), the rats significantly reduced (P < 0.02) their spontaneous intake of 1.8% NaCl. Increasing the dose of losartan to 2.0 and 4.0 mg x g(-1) did not reduce NaCl intake; in contrast, the intensity of the sodium appetite gradually returned to previous levels. The simultaneous administration of captopril, an angiotensin converting enzyme inhibitor, and losartan significantly increased (P < 0.05) NaCl intake and after captopril removal NaCl intake returned to the levels observed with losartan treatment alone. The administration of losartan 4 days after the beginning of captopril treatment significantly reduced (P < 0.0001) NaCl intake. Following acute administration of losartan, water- and sodium-depleted rats significantly reduced their NaCl and water intake (P < 0.001). The administration of losartan also induced a significant reduction in NaCl and water intake in water, NaCl and food-deprived rats (P < 0.0001 and P < 0.001, respectively). The present results show that chronic treatment with oral losartan inhibited spontaneous sodium appetite in hypothyroid rats. Continuation of treatment rendered rats resistant to the blockade of AT1 receptors. Water and sodium depletion and water, NaCl and food deprivation induced sodium appetite, which in the short term depends on cerebral angiotensinergic activity mediated by the activation of AT1 receptors.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Antihypertensive Agents; Antithyroid Agents; Appetite; Diuretics; Drinking; Eating; Food Deprivation; Furosemide; Hypothyroidism; Losartan; Male; Methimazole; Rats; Rats, Wistar; Receptor, Angiotensin, Type 1; Receptors, Angiotensin; Sodium Chloride; Water Deprivation

Thyroid hormones are critical for maturation of the central nervous system. In a previous study, we showed a change in the pattern of mature myelinated nerve fibers by 2'3'-cyclic nucleotide 3'-phosphodiesterase (CNPase) in developing hypothyroid animals, which suggests a possible role for thyroid hormones in myelin compaction. The classical myelin markers myelin basic protein (MBP) and proteolipidic protein (PLP) are expressed later in oligodendroglial development, when myelin sheath formation is in progress. A myelin constituent designated myelin-associated/oligodendrocytic basic protein (MOBP) has been identified and related to myelin compaction. We assessed the developmental sequence of appearance of CNPase, MBP, MOPB, and PLP proteins in cerebellum (Cb) and corpus callosum (cc) in an experimental hypothyroidism model. The appearance of both MOBP isoforms occurred at postnatal day (P)25 and P30 in cc and Cb, respectively, followed by an increase with age in the control group. However, all the MOBP isoforms were weakly detectable in both regions at P30 from the hypothyroid (H) group, and the higher molecular weight isoform remains decreased in cc, even at P90. The developmental pattern of expression of CNPase, MBP, and PLP proteins was also delayed in the H group. CNPase and MBP expression was recovered in cc and Cb, whereas PLP remained below control levels at P90 in cc. Our data show that the experimental hypothyroidism affects the developmental pattern of the oligodendrocytic/myelin markers. Furthermore, thyroid hormone may modulate specific genes, as demonstrated by permanent down-regulation of MOBP and PLP expression in adulthood.

Topics: 2',3'-Cyclic-Nucleotide Phosphodiesterases; Animals; Cerebellum; Congenital Hypothyroidism; Corpus Callosum; Female; Fetal Diseases; Fetal Proteins; Gene Expression Regulation, Developmental; Hypothyroidism; Methimazole; Myelin Basic Protein; Myelin Proteins; Myelin Proteolipid Protein; Myelin-Associated Glycoprotein; Myelin-Oligodendrocyte Glycoprotein; Pregnancy; Pregnancy Complications; Protein Isoforms; Rats; Rats, Wistar

Two groups of hypothyroid rats were used; one group was given 2-mercapto-1-methylimidazole (MMI) treatment in the drinking water of the mothers and was killed at 2 and 4 days of life, and the other group was given similar MMI treatment and then was thyroidectomized at 5 days of life and killed at 8 or 20 days. Serum insulin, growth hormone (GH), and insulin-like growth factor I (IGF-I) were decreased in MMI-treated rats but increased in MMI-treated plus thyroidectomized rats. No significant reduction of thyroid hormones was observed in 2-day-old MMI rats. Protein and mRNA expression of GLUT-1 increased, and those of GLUT-4 decreased, in the heart in all populations independent of changes in insulin, GH, and IGF-I levels. However, GLUT-4 protein and mRNA expression in quadriceps and gastrocnemius skeletal muscles decreased at 4 days and increased at 8 and 20 days of life in parallel with insulin, GH, and IGF-I levels. GLUT-1 in the skeletal muscles seemed regulated posttranscriptionally and presented a decrease of mRNA expression in all stages studied. A differential sensitivity to insulin regulation of GLUT-1 and GLUT-4 glucose transporters seems to be one of the causes for the tissue-specific regulation of these glucose transporters in heart and skeletal muscles during the perinatal period.

Topics: Animals; Animals, Newborn; Female; Gene Expression; Gestational Age; Glucose Transporter Type 1; Glucose Transporter Type 4; Growth Hormone; Hypothyroidism; Insulin; Insulin-Like Growth Factor I; Liver; Maternal-Fetal Exchange; Methimazole; Monosaccharide Transport Proteins; Muscle Proteins; Muscle, Skeletal; Myocardium; Pregnancy; Rats; Rats, Wistar; RNA, Messenger; Thyroidectomy

The influence of thyroid hormones on cortical development was analysed in rat somatosensory cortex. Maternal and foetal hypothyroidism was induced and maintained by methimazole treatment from embryonic day 13 onwards. 5-Bromo-2'-deoxyuridine (BrdU) labelling in hypothyroid rats showed that cell positioning during corticogenesis followed an inside-out pattern. The radial neurogenetic gradients were more diffuse at all ages with respect to normal rats due to the inappropriate location of many cells, including those of the subcortical white matter. Most (62%) of the cells in the subcortical white matter of hypothyroid rats were labelled at embryonic day 15. Nissl staining of the primary somatosensory cortex showed blurred cortical layer boundaries and an abnormal barrel cytoarchitecture. Cytochrome oxidase and peanut agglutinin staining showed that the tangential organisation of the posteromedial barrel subfield and its layer IV specificity was not lost in hypothyroid rats. However the temporal pattern of peanut agglutinin labelling was delayed 3-4 days with respect to normal rats. In hypothyroid rats, the total barrelfield tangential area was reduced by 27% with respect to normal. The total tangential barrel area, corresponding to peanut agglutinin-negative labelling, occupied 77% of the barrelfield area and only 66% in hypothyroid rats. This reduction was larger with cytochrome oxidase staining where the total barrel area occupied 69% of the barrelfield area in normal and 46% in hypothyroid rats. Our data stress the importance of maternal and foetal thyroid hormones during development, and demonstrate the irreversible effects that maternal and foetal hypothyroidism may have on the intrinsic organisation and maturation of the neocortex.

Topics: Animals; Antithyroid Agents; Brain Mapping; Hypothyroidism; Methimazole; Rats; Somatosensory Cortex; Thyroid Hormones; Vibrissae

In the current study, the authors examined the effects of experimentally induced hypothyroidism on peripheral thyroid hormone metabolism and growth in two closely related tilapia species: the Nile tilapia (Oreochromis niloticus) and the slower growing black tilapia (Sarotherodon melanotheron). Hypothyroidism, induced by administration of 0.2% methimazole through the food, significantly decreased plasma T(3) and T(4) in both species. This decrease in circulating thyroid hormones was accompanied by an increase in hepatic type II deiodinase (D2) and a decrease in hepatic type III deiodinase (D3). Hepatic type I deiodinase (D1), which is barely expressed in euthyroid tilapia, was significantly upregulated during hypothyroidism. The changes in hepatic D1 and D2 enzyme activity were paralleled by changes in D1 and D2 mRNA levels, indicating pretranslational regulation. Hypothyroidism also resulted in severe growth retardation that was accompanied by an increase in condition factor. Because hyperthyroidism has been shown to decrease the condition factor, these results suggest that thyroid hormones play an essential role in the control of proportional body growth in fish. The authors conclude that (1) hepatic D1 expression is induced by hypothyroidism in tilapia, (2) the changes in hepatic iodothyronine deiodinases during hypothyroidism in tilapia are predominantly regulated at a pretranslational level, and (3) thyroid hormones are involved in the control of proportional body growth in fish.

Topics: Amino Acid Sequence; Animals; Base Sequence; DNA, Complementary; Gene Expression; Hypothyroidism; Iodide Peroxidase; Liver; Methimazole; Molecular Sequence Data; Species Specificity; Thyroxine; Tilapia; Triiodothyronine

Free radicals, hydroxyperoxides and H(2)O(2) are all known to damage cell components. This study was designed to compare the concentrations of hydroxyperoxide and free radical scavengers in the cardiac muscles of old rats in the hyper- or hypothyroid condition, to determine whether rates of peroxidation would differ with age, thyroid status, or both. Rats were rendered hyper- or hypothyroid by administration of l-thyroxine or methimazole for 4 weeks. Among the old rats, the lipid peroxide (LPO) concentrations, measured as thiobarbituric acid (TBA) reactants, were significantly greater in the hyperthyroid than in the euthyroid state and the LPO concentrations measured as TBA+Fe(3+) reactants, which may be precursors of LPO, were significantly greater in the hyperthyroid state, whereas in young rats, the LPO concentrations measured by TBA or TBA+Fe(3+) methods did not differ significantly in the hyperthyroid state. In the euthyroid state, the concentration of LPO measured as TBA+Fe(3+) reactants was significantly reduced with age. Xanthine oxidase (XOD) activity also was markedly increased with age, being more pronounced in the hyperthyroid than in the euthyroid state. The Mn and Cu/Zn superoxide dismutase activities were greater in the hyperthyroid than in the euthyroid state. Glutathione peroxidase activity decreased with age in the euthyroid and, particularly, in the hyperthyroid state. Catalase activity was not affected in the old rats. Concentrations of alpha-tocopherol in the old rats were high in the hyperthyroid state and low in the hypothyroid state, whereas the levels of beta- and gamma-tocopherols in these rats were unchanged in both conditions as compared with the euthyroid state findings. Data suggest that the site of free radical generation differs in older rats, with additional shifts in the location of intracellular lipid peroxidation being noted during hyperthyroidism. Thus, as rats age, the reduction of the free radical scavenger system and the increase in LPO and XOD activities might induce myocardial dysfunction.

Topics: Aging; Analysis of Variance; Animals; Antithyroid Agents; Glutathione Peroxidase; Hyperthyroidism; Hypothyroidism; Lipid Peroxidation; Male; Malondialdehyde; Methimazole; Myocardium; Rats; Rats, Wistar; Superoxide Dismutase; Thyroid Diseases; Thyroid Gland; Thyroxine; Vitamin E; Xanthine Oxidase

The behavior of five groups of rats (seven rats per group) made hypothyroid for varying lengths of time and one group of seven normal control rats was assessed under forced alternation fixed-ratio (FR1, FR3, FR5 and FR10), alternating lever cyclic-ratio (ALCR) and progressive-ratio (PR3) schedules of reinforcement. Hypothyroidism was produced by adding methimazole (MMI) to the drinking water of pregnant dams from embryonic day E16 to postnatal day P25. Four groups were given replacement thyroxine (T4) injections beginning at specific time points (P1, P7, P13, and P19). There were no differences in behavioral performance between control and experimental groups under the FR schedule, which indicates that the animals' sensorimotor abilities were intact. Under the forced ALCR schedule, all groups reached criteria similarly. However, under the choice lever ALCR schedule, control animals and those which received T4 replacement from early on (P1, P7, P13 groups) performed well and all had reached criteria by 11 sessions. In contrast, animals which did not receive any T4 replacement or received it late (P19 group) took longer to reach criteria and 5/14 animals had not reached criteria at all by 20 sessions. This deterioration in performance was paralleled by an increase in perseverative behavior as evidenced by an increased frequency of pressing the wrong lever when alternation of lever was required. This suggests that congenital hypothyroidism results in increased perseveration leading to a decrease in learning when a discrimination between correct and incorrect operanda is made available.

Topics: Animals; Antithyroid Agents; Behavior, Animal; Congenital Hypothyroidism; Discrimination Learning; Dose-Response Relationship, Drug; Female; Hypothyroidism; Male; Methimazole; Pregnancy; Rats; Rats, Wistar; Task Performance and Analysis; Thyroxine; Time Factors

Calcium-dependent uncoupling of liver mitochondrial oxidative phosphorylation by a non-metabolizable long chain fatty acyl analogue was compared with uncoupling induced by in vivo thyroid hormone treatment. beta,beta'-Methyl-substituted hexadecane alpha, omega-dioic acid (Medica 16) is reported here to induce a saturable 20-30% decrease in liver mitochondrial DeltaPsi, DeltapH and protonmotive force which proceeds in the presence of added Ca(2+) to cyclosporin A-sensitive mitochondrial permeabilization. Ca(2+)-dependent uncoupling by Medica 16 was accompanied by atractylate-enhanced, bongkrekic-inhibited activation of mitochondrial Ca(2+) efflux. The direct mitochondrial effect exerted in vitro by Medica 16 is similar to that induced by in vivo thyroid hormone treatment. Hence, the thyromimetic protonophoric activity of Medica 16 and the uncoupling activity of TH converge onto components of the mitochondrial permeabilization transition pore.

Topics: Animals; Hyperthyroidism; Hypolipidemic Agents; Hypothyroidism; Ion Channels; Male; Membrane Proteins; Methimazole; Mitochondria, Liver; Mitochondrial Membrane Transport Proteins; Mitochondrial Permeability Transition Pore; Palmitic Acids; Proton-Motive Force; Rats; Triiodothyronine; Uncoupling Agents

Both a genetic or acquired neonatal thyroid hormone (TH) deficiency may result in a profound mental disability that is often accompanied by deafness. The existence of various TH-sensitive periods during inner ear development and general success of delayed, corrective TH treatment was investigated by treating pregnant and lactating rats with the goitrogen methimazole (MMI). We observed that for the establishment of normal hearing ability, maternal TH, before fetal thyroid gland function on estrus days 17-18, is obviously not required. Within a crucial time between the onset of fetal thyroid gland function and the onset of hearing at postnatal day 12 (P12), any postponement in the rise of TH-plasma levels, as can be brought about by treating lactating mothers with MMI, leads to permanent hearing defects of the adult offspring. The severity of hearing defects that were measured in 3- to 9-mo-old offspring could be increased with each additional day of TH deficiency during this critical period. Unexpectedly, the active cochlear process, assayed by distortion product otoacoustic emissions (DPOAE) measurements, and speed of auditory brain stem responses, which both until now were not thought to be controlled by TH, proved to be TH-dependent processes that were damaged by a delay of TH supply within this critical time. In contrast, no significant differences in the gross morphology and innervation of the organ of Corti or myelin gene expression in the auditory system, detected as myelin basic protein (MBP) and proteolipid protein (PLP) mRNA using Northern blot approach, were observed when TH supply was delayed for few days. These classical TH-dependent processes, however, were damaged when TH supply was delayed for several weeks. These surprising results may suggest the existence of different TH-dependent processes in the auditory system: those that respond to corrective TH supply (e.g., innervation and morphogenesis of the organ of Corti) and those that do not, but require T3 activity during a very tight time window (e.g. , active cochlear process, central processes).

Topics: Animals; Auditory Threshold; Cochlea; Deafness; Drug Administration Schedule; Evoked Potentials, Auditory, Brain Stem; Female; Fetus; Gene Expression; Hypothyroidism; Immunohistochemistry; Maternal-Fetal Exchange; Methimazole; Myelin Basic Protein; Myelin Proteolipid Protein; Organ of Corti; Otoacoustic Emissions, Spontaneous; Pregnancy; Rats; Rats, Wistar; Reaction Time; RNA, Messenger; 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

Hypothyroid pups were obtained by adding methimazole in the mother's drinking water from day 15 of gestation and sacrificed at 4, 8 or 15 days. Circulating corticosterone decreased at all ages, while CBG concentrations diminished at day 4, increased at day 8 and did not change at day 15 in hypothyroid rats. As opposed to controls, plasma ACTH concentrations decreased steadily with age while there was an accumulation of ACTH in the anterior pituitary of hypothyroid 15-day-old rats. Anterior pituitary POMC contents were unaffected by the treatment. In the hypothalamic PVN, CRF mRNA levels in the total population of CRF-synthesizing cells and in the CRF+/AVP+ subpopulation were below those of controls whatever the age considered while AVP mRNA in the CRF+/AVP+ subpopulation did not change at day 4 and decreased at day 8 and 15 in hypothyroid animals. Both the number of cell bodies expressing detectable levels of CRF mRNA and the percentage of CRF and AVP colocalization decreased at day 4 and were unchanged thereafter. CRF and AVP immunoreactivity in the zona externa of the median eminence increased with age but was not affected by methimazole treatment. The concentration of AVP mRNA in the magnocellular cell bodies of the PVN and the SON as well as AVP immunoreactivity in the zona interna of the median eminence were not changed by the treatment at days 4 and 8. In hypothyroid 15-day-old rats, SON AVP mRNA increased, AVP immunoreactivity decreased while plasma osmolality was enhanced. In conclusion, our data demonstrate that experimental hypothyroidism impairs specifically the maturation of hypothalamic parvocellular CRF and AVP gene expression during the stress hyporesponsive period. These observations suggest that the physiological peak in plasma thyroxine concentrations that occur between day 8-12 may participate in the maturation of hypothalamic CRF- and AVP-synthesizing cells.

Topics: Administration, Oral; Adrenocorticotropic Hormone; Aging; Animals; Arginine Vasopressin; Corticosterone; Corticotropin-Releasing Hormone; Disease Models, Animal; Female; Gene Expression Regulation, Developmental; Hypothalamo-Hypophyseal System; Hypothyroidism; Methimazole; Paraventricular Hypothalamic Nucleus; Pituitary Gland, Anterior; Pituitary-Adrenal System; Pregnancy; Prenatal Exposure Delayed Effects; Pro-Opiomelanocortin; Rats; Rats, Sprague-Dawley; Supraoptic Nucleus; Thyrotropin; Transcortin

The effects of hypothyroidism on oligodendroglial differentiation and myelination are for the first time studied by immunohistochemical localization of an early oligodendroglial marker, the 2'3'cyclic nucleotide 3'phosphodiesterase (E.C. 3.1.4.37-CNPase), in developing rats. Two groups received methimazol; one during gestation (H) and another postnatally (PN). One H sub-group received thyroxine after birth (T). We observed a delay in CNPase expression followed by a decrease in the number of CNPase immunoreactive fibers in both H and PN groups. The T sub-group was not different from controls. Furthermore, the immunoreactive fibers, in mature hypothyroid animals, showed a continuous pattern of staining in contrast with a discontinuous one in controls. Myelinogenesis is a highly regulated timed event. CNPase links myelin related proteins to the cytoskeleton also interacting with membrane lipids during extension and wrapping of the oligodendroglial process around the axon (ensheathment phase). In mature myelinated fiber the CNPase is absent from compact myelin sheath, being located only in the inner and outer loops and in paranodal loops. Thus, our data suggest a disorder in myelin compaction and point once more to the post-natal period as critical for the mechanisms that are thyroid hormone regulated in myelinogenesis.

Topics: 2',3'-Cyclic-Nucleotide Phosphodiesterases; Animals; Antithyroid Agents; Brain; Congenital Hypothyroidism; Female; Hypothyroidism; Immunohistochemistry; Methimazole; Myelin Sheath; Oligodendroglia; Pregnancy; Prenatal Exposure Delayed Effects; Rats; Rats, Wistar; Thyroxine

Spontaneous remission of Graves' disease with a decrease of thyroid stimulating antibody (TSAb) activity is commonly observed in pregnancy. In this article, however, a Graves' patient who developed primary hypothyroidism with an appearance of thyroid stimulation-blocking antibody (TSBAb) activity in late pregnancy is reported. A 25-year-old woman presented with clinical and biochemical hyperthyroidism with an elevation of 99mTcO4- thyroid uptake (4.7%; normal range, 0.7%-3.0%) and mildly elevated activity of thyrotropin-binding inhibitory immunoglobulin (TBII; 30.4%). She was euthyroid with normal TBII (8.0%) and TSAb (126%) before pregnancy, when the patient was taking a 5-mg daily dose of methimazole (MMI). MMI was stopped by the patient when she became pregnant. Subsequently, the patient progressed into primary hypothyroidism with a marked elevation of TBII activity (78.4%) in the third trimester of the pregnancy (at that time, TSAb activity was not detected). TSBAb measured 2 weeks later was detected at the activity of 85.0%. Replacement therapy was initiated with levothyroxine (LT4) (0.05-0.1 mg/day), which was discontinued on the 55th day postpartum because of the onset of mild thyrotoxicosis followed by short-term euthyroid state despite high TSBAb activity. Subsequently, because the patient developed primary hypothyroidism 5 months after delivery, replacement therapy with LT4 (0.1-0.125 mg/day) was readministered. Thus, it is suggested that the development of hypothyroidism with the appearance of TSBAb in Graves' patients can occur even in late pregnancy.

Topics: Adult; Antithyroid Agents; Autoantibodies; Female; Graves Disease; Humans; Hypothyroidism; Immunoglobulins, Thyroid-Stimulating; Male; Methimazole; Pregnancy; Pregnancy Complications; Pregnancy Trimester, Third; Receptors, Thyrotropin; Thyroxine

In this study, the risk of iodine-induced thyrotoxicosis in unselected patients from an iodine-deficient area was investigated. The patients were consecutively enrolled. Thyroid hormone values and urinary iodine excretion were determined before, as well as 1, 4 and 12 weeks after iodine contamination by coronary angiography. Two of 788 unselected patients developed hyperthyroidism within 12 weeks. The two patients did not belong to a risk group for iodine-induced thyrotoxicosis (i.e. old people, patients with goiter or possible thyroid autonomy, low TSH). Both patients had normal TSH levels at baseline and ultrasound of the thyroid was without evidence of nodules. The study shows that in euthyroid unselected patients from an iodine-deficient area short-term iodine contamination by contrast media rarely leads to hyperthyroidism. On account of these facts, prophylactic therapy, e.g. by perchlorate or thiamazole, is not generally recommended, because the risk of side-effects is perhaps even greater than the risk of iodine-induced thyrotoxicosis.

Topics: Adult; Aged; Aged, 80 and over; Antithyroid Agents; Contrast Media; Coronary Angiography; Female; Humans; Hypothyroidism; Iodide Peroxidase; Iodine; Male; Methimazole; Middle Aged; Thyroid Gland; Thyrotoxicosis; Thyrotropin; Thyroxine

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

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

IGF-I, IGF-I receptor and IGF-binding proteins (IGFBPs) are expressed in thyroid tissue and are associated with the function and growth of the thyroid. This study investigated the in vivo and in vitro effects of increased IGFBP-1 levels on the function and growth of the thyroid gland.. Transgenic mice which constitutively overexpress IGFBP-1 were used. These mice have a phenotype consistent with partial inhibition of IGF-I action.. Thyroid growth, morphology and hormonogenesis were determined in transgenic mice treated with goitrogens, sodium perchlorate and methimazole. In vitro cell proliferation in thyroid follicles was assessed in response to IGF-I and TSH.. Thyroid weight was increased in transgenic mice, relative to their body mass, whereas serum tri-iodothyronine (T(3)), thyroxine and T(3)-binding capacity were reduced, compared with wild-type. While an inverse relationship between T(3) and TSH was observed in both groups of goitrogen-treated mice, the slope of the line of best fit was less steep in transgenic mice compared with wild-type mice. Thyroid growth was less marked in transgenic than wild-type mice in response to goitrogens, although TSH levels were higher in goitrogen-treated transgenics. In vitro proliferative response of isolated thyroid follicles to IGF-I, but not to TSH, was reduced in transgenic, compared with wild-type mice.. The results of this study suggest that, while overexpression of IGFBP-1 attenuates IGF-I action in vitro, it enhances thyroid growth in vivo, presumably as a result of perturbations in thyroid function at multiple levels.

Topics: Aging; Animals; Antithyroid Agents; Cell Division; Disease Models, Animal; Hypothyroidism; In Vitro Techniques; Insulin-Like Growth Factor Binding Protein 1; Insulin-Like Growth Factor I; Male; Methimazole; Mice; Mice, Transgenic; Organ Size; Perchlorates; Sodium Compounds; Thyroid Gland; Thyroid Hormones; Up-Regulation

A 69-year-old man had hypothyroid dementia as a result of I-131 therapy and an overdose of methimazole. Tc-99m HMPAO SPECT revealed diffuse cerebral hypoperfusion. The findings of brain SPECT normalized with the disappearance of symptoms and a return to the euthyroid state. There was a 25% or 26% reduction of the mean cerebral blood flow during dementia. This may be the first report in which SPECT brain imaging revealed reversible hypoperfusion associated with reversible hypothyroid dementia.

Topics: Aged; Antithyroid Agents; Brain; Cerebrovascular Circulation; Dementia; Graves Disease; Humans; Hypothyroidism; Iodine Radioisotopes; Male; Methimazole; Radiopharmaceuticals; Technetium Tc 99m Exametazime; Tomography, Emission-Computed, Single-Photon

In this study, plasma leptin concentrations were measured in rats artificially rendered hyper- or hypothyroid by administration of thyroxine or TRH, by administration of methimazole, or by thyroidectomy. Compared with those in untreated controls, leptin immunoreactivity was not affected in the hyperthyroid state, but was significantly increased in hypothyroid animals. Methimazole administration for longer time periods caused a stepwise increase in plasma leptin immunoreactivity. Greatest leptin concentrations were seen after 28 days of methimazole. Seven days after withdrawal of the methimazole, leptin concentrations no longer differed from those observed in control animals. In hypothyroid animals, expression of leptin mRNA was increased in both retroperitoneal and epididymal adipose tissue, whereas no difference was seen for subcutaneous or mesenteric fat. Incubation of rat leptin with plasma of eu- or hypothyroid rats and subsequent HPLC analysis of leptin plasma peaks gave no indication of an altered hormone stability. We conclude that, in hypothyroid rats, leptin concentrations may be increased as a result of stimulated leptin synthesis in retroperitoneal and epididymal adipose tissue.

Topics: Adipose Tissue; Analysis of Variance; Animals; Antithyroid Agents; Chromatography, Gel; Chromatography, High Pressure Liquid; Hyperthyroidism; Hypothyroidism; Leptin; Male; Methimazole; Radioimmunoassay; Rats; Rats, Wistar; RNA, Messenger; Thyroidectomy; Thyrotropin-Releasing Hormone; Thyroxine

Inhibition of thyroid gland function in rats with mercasolil sharply decreased thyroxine and triiodothyronine levels in blood serum and increased acid sphingomyelinase activity and sphingomyelin content in liver. Thyroxine injected into hypothyroid rats normalized the sphingomyelin content, reduced the free ceramide content, and further increased the acid sphingomyelinase activity in liver. Thyroxine stimulated de novo sphingomyelin synthesis. Changing the thyroid status of the rats did not influence the free sphingosine content. Thyroxine blocks the accumulation of free sphingosine in the liver during activation of sphingomyelinases.

Topics: Animals; Ceramides; Hypothyroidism; Liver; Male; Methimazole; Rats; Rats, Wistar; Sphingomyelin Phosphodiesterase; Sphingomyelins; Sphingosine; Staphylococcus aureus; Thyroid Gland; Thyroxine; Triiodothyronine

To determine the age-related changes in thyroid hormone (TH) effects on cardiac glucose transporter one (GLUT-1) and four (GLUT-4) isoforms, male Fischer 344 rats at 4, 12, and 25 months of age were studied at euthyroid, hyperthyroid and hypothyroid conditions. Hyperthyroidism was induced with daily intraperitoneal injections of triiodothyronine (15 microg/100 gm) for 10 days. Hypothyroidism was achieved with 0.025% methimazole in the drinking water for 4 weeks. Immunoblot analysis indicated that at euthyroid basal conditions GLUT-1 protein was not significantly altered with age while GLUT-4 protein was significantly reduced in 25 month old rats (82.0 +/- 28.8% of a 4 month old rat p <0.01). In 4 months old rats, GLUT-1 was increased in both hypothyroidism (432.5 +/- 208.7% of age-matched euthyroid control) and to a lesser extent in hyperthyroidism (242.0 +/- 93.3% of control) p<0.01. In 25 month old rats, hyperthyroidism was also associated with increased GLUT-1 mass (190.8 +/- 117.6% of age-matched euthyroid control) p<0.01. Hypothyroidism in this age group was not associated with significant change in GLUT-1 protein. The cardiac GLUT-4 protein was increased during both hypothyroidism and hyperthyroidism. The changes of GLUT-4 in aged rats were similar to those found in young rats. It is concluded that TH effect on GLUT-1 expression in the heart is altered with age while TH effects on GLUT-4 are age independent.

Topics: Aging; Animals; Blotting, Western; Creatinine; Glucose Transporter Type 1; Glucose Transporter Type 4; Heart; Hyperthyroidism; Hypothyroidism; Male; Methimazole; Monosaccharide Transport Proteins; Muscle Proteins; Myocardium; Organ Size; Rats; Rats, Inbred F344; Thyroxine; Triiodothyronine

Since amiodarone was introduced in Japan in 1992, the incidence of the drug-induced thyroid dysfunction has been increasing. We studied the thyroid function of 13 patients with amiodarone-induced thyrotoxicosis (AIT) and 11 patients with amiodarone-associated hypothyroidism (AAH) who had been referred to our Institute in the last 6 years. AIT and AAH developed after 39+/-21 and 20+/-16 months of amiodarone treatment, respectively. One patient developed AAH followed by AIT. The AIT ranged from subclinical to overt thyrotoxicosis. Four patients with moderate to marked AIT were treated with methimazole. Their thyrotoxicosis persisted for 3 to 9 months, despite administration of antithyroid agents. One patient with mild thyrotoxicosis was treated with prednisolone, resulting in a euthyroid state in a few months. Eight patients with asymptomatic to moderate thyrotoxicosis resolved spontaneously without any treatment. In four asymptomatic patients with AIT, serum levels of T3 and T4 were in the upper normal range or slightly high (< 12 microg/dl), accompanied by suppressed TSH (<0.1 microU/ml) and high thyroglobulin levels, suggesting destruction-induced thyrotoxicosis. Such a subclinical thyrotoxicosis developed repeatedly in one patient. Ultrasonographic studies revealed no nodular lesion in the thyroid, and color flow Doppler sonography demonstrated no hypervascularity in the thyroid gland in any AIT patient. Although it is postulated in Europe that there are two types of AIT, namely type I, which develops in patients with latent Graves' disease or toxic multinodular goiter, and type II, which develops in an apparently normal thyroid as destructive thyroiditis, all AIT patients we have seen so far had developed destructive type AIT. Sufficient intake of iodide and a very low incidence of toxic multinodular goiter may account for the rare incidence of type I AIT in our country. Mild to moderate AIT resolved spontaneously without discontinuing amiodarone, but it was discontinued in two of 13 AIT patients because of extrathyroidal adverse reactions.

Topics: Adult; Aged; Amiodarone; Anti-Arrhythmia Agents; Antithyroid Agents; Female; Humans; Hypothyroidism; Japan; Male; Methimazole; Middle Aged; Prednisolone; Thyrotoxicosis; Thyrotropin; Thyroxine; Time Factors; Triiodothyronine

The behavior of six congenitally hypothyroid and six normal control rats was assessed under forced alternation fixed-ratio, alternating lever cyclic-ratio (ALCR) and progressive-ratio schedules of reinforcement. Hypothyroidism was produced by adding methimazole (MMI) to the drinking water of pregnant dams from embryonic day 16 to postnatal day 25. There were no differences in behavioral performance between MMI-treated and control animals under the fixed-ratio and progressive ratio schedules. There were also no differences in circulating triiodothyronine levels between groups at the end of the study. Under the ALCR schedule, when alternation of responding was forced during the first three cycles but both levers (choice) were presented during the last three cycles (correct lever active), the entire control group reached a competency criteria in nine sessions. In contrast, only two MMI-treated animals reached criteria after 17 sessions, and the remaining four MMI-treated animals did not reach criteria by 30 sessions of training. These results suggest that congenital hypothyroidism impairs learning when a discrimination between correct and incorrect operanda is made available.

Topics: Animals; Antithyroid Agents; Conditioning, Operant; Congenital Hypothyroidism; Discrimination Learning; Female; Hypothyroidism; Male; Methimazole; Pregnancy; Rats; Rats, Wistar; Triiodothyronine

Using a rat fracture model, we investigated the effects of a decrease in serum levels of thyroid hormone on the fracture-repair process. Rats were divided into the following groups: (a) controls, (b) those treated with methimazole for the duration of the experiment, and (c) those treated with methimazole and L-thyroxine, receiving both for the same duration. Three weeks after the initiation of pharmacologic treatment, closed femoral fractures were produced. The formation of cartilage tissue in the fracture callus in all rats was not obviously different on day 7 after fracture. In the rats treated with methimazole, differentiation from proliferating to hypertrophic chondrocytes in the fracture callus was less advanced and vascular invasion was clearly inhibited on day 12. Gene expression of alkaline phosphatase and osteocalcin in the callus was significantly lower in these rats than in the controls on days 10, 12, and 14. The mechanical properties of the fracture callus were also significantly weaker in these animals than in the controls on day 21, resulting in impaired fracture repair. These results demonstrate that hypothyroidism inhibits endochondral ossification, resulting in an impaired fracture-repair process. L-thyroxine replacement in the rats treated with methimazole caused the impaired repair process to revert to normal. These results indicate that thyroid hormone is one of the critical systemic factors for fracture repair.

Topics: Alkaline Phosphatase; Animals; Biomechanical Phenomena; Cartilage; Fracture Healing; Gene Expression; Hypothyroidism; Male; Methimazole; Osteogenesis; Procollagen; Rats; Rats, Long-Evans; Thyroxine

We investigated the interrelationship and the influence of thyroid-stimulating antibodies (TSAb), TSH-blocking antibodies (TSHBAb), and of radioiodine (131I)-induced thyroid damage in the early (within 1 yr) outcome of thyroid function in hyperthyroid patients with Graves' disease (GD) treated with 131I. TSAb, TSHBAb, and ultrasound thyroid volume (as an index of thyroid damage) were simultaneously measured before and at 1, 3, 6, and 12 months after 131I in 31 GD patients. One year after radioiodine, 9.7% of patients were hyperthyroid (Hyper-group), requiring methimazole; 12.9% were euthyroid (Eu-group); and 77.4% were hypothyroid (Hypo-group). Pretreatment thyroid volume in the Eu-group and Hyper-group was significantly greater (P = 0.009) than in the Hypo-group. Pre-131I TSAb levels were higher in the Hyper-group vs. the Hypo-group (P = 0.01) or the Eu-group (P = 0.03). A significant post-131I increase in TSAb levels occurred in 66% of patients developing hypothyroidism but not in those remaining hyperthyroid. After 131I, TSHBAb appeared in 7 patients, in all but one associated with high levels of TSAb. One year after radioiodine: 1) the mean percent reduction in thyroid volume was greater in the Hypo-group (80.7%) or the Eu-group (83.5%) than in the Hyper-group (35.7%) (P = 0.007 and 0.0033 respectively); 2) hypothyroid patients had smaller (P = 0.0058) post-131I thyroids than hyperthyroid patients; and 3) TSAb were still elevated in 75% hypothyroid patients, but all of them had a thyroid volume < or = 8 mL, indicating major postradioiodine gland damage.. 1) the early outcome of thyroid function after 131I for GD is mainly related to pretreatment thyroid volume and to the degree of its reduction after therapy; 2) high TSAb levels before 131I are associated with a relative resistance to therapy; 3) a postradioiodine increase in TSAb levels is related to the development of hypothyroidism; and 4) the concomitant appearance of TSHBAb and disappearance of TSAb are not frequent after 131I and play a role in the development of early postradioiodine hypothyroidism only in a minority of patients.

Topics: Adult; Aged; Antithyroid Agents; Autoantibodies; Female; Follow-Up Studies; Graves Disease; Humans; Hyperthyroidism; Hypothyroidism; Immunoglobulins, Thyroid-Stimulating; Iodine Radioisotopes; Male; Methimazole; Middle Aged; Thyroid Gland; Thyrotropin; Time Factors; Ultrasonography

The case presented is a 12 year-old girl with hyperthyroidism due to juvenile Grave's disease, who during the course of treatment developed hypothyroidism due to TSH-receptor blocking antibodies, measured by bioassay. The bioassay used was performed on CHO-R cells measuring c-AMP. The role of radioreceptor assays and bioassays in measuring TSH receptor antibodies in hyper- and hypothyroid Graves' disease in discussed.

Topics: Age Factors; Antibodies, Blocking; Antithyroid Agents; Child; Female; Graves Disease; Humans; Hypothyroidism; Methimazole; Receptors, Thyrotropin; Thyroxine

We describe a 75-year-old man who had had a lump in his neck for about 15 years. At his first visit to our hospital, poorly differentiated papillary carcinoma of the thyroid was diagnosed by means of aspiration cytology; x-rays revealed the presence of lung metastases. He was thyrotoxic with positive thyroid stimulating antibody (TSAb). He was reluctant to undergo surgery. In an early stage of the treatment for Graves' disease, he became hypothyroid with decreased TSAb activity and strongly positive thyroid stimulation blocking antibody (TSBAb), and rapid growth of the thyroid carcinoma with anaplastic transformation was observed. The increase in the size of the transformed thyroid carcinoma was shown to be exponential by ultrasonography. This is a rare case in which anaplastic transformation of the thyroid papillary carcinoma became apparent during treatment of Graves' disease with varied activity of thyrotropin receptor antibodies.

Topics: Aged; Antibodies; Antithyroid Agents; Carcinoma; Carcinoma, Papillary; Graves Disease; Humans; Hypothyroidism; Immunoglobulins, Thyroid-Stimulating; Male; Methimazole; Receptors, Thyrotropin; Thyroid Neoplasms; Ultrasonography

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

The mechanism underlying transient reduction of cell number in the developing cerebellum have been studied for several decades. In this study we analyzed cell death by apoptosis in the developing cerebellum of euthyroid and hypothyroid rats. Results showed that in both groups the apoptotic activity is limited to the internal granular layer from postnatal (p) day 2 to day 12 in euthyroid animals, with the peak at 8 days. No apoptotic cells were detected in the cerebellum of 22 days old euthyroid rats. The level of apoptosis in the cerebellum of hypothyroid rats also reached a peak at 8 days but was four times higher than in control animals. Apoptosis in hypothyroid animals was also observed at p22 and corresponds to the value found in the time of the apoptotic peak in euthyroid cerebellum. At the age of 42 days, no apoptotic cells were found in the cerebellum of either group. Furthermore, it appears that the hormone also plays a role in the disappearance of the external germinal layer, since its presence is still apparent in 42 day old hypothyroid cerebellum. Hence, our results suggest that the deficiency of thyroid hormone (TH) not only increases, but also extends apoptosis during rat cerebellum development and affects the disappearance of the external germinal layer.

Topics: Aging; Animals; Animals, Newborn; Antithyroid Agents; Apoptosis; Cerebellum; DNA Fragmentation; Hypothyroidism; Methimazole; Rats; Thyroid Gland; Thyroid Hormones

Populations living in goitre endemic areas consume foods rich in a variety of goitrogens of different potencies and some are severely hypothyroid. Recently we observed in Wistar/NIN rats that chronic feeding of KSCN to dams produced only a moderate hypothyroidism and decreased the transport of 2-deoxy-D-glucose (2-DG) across the blood-brain barrier (BBB) in the offspring. The present studies were conducted to assess whether severe hypothyroidism would have greater effect on BBB nutrient transport. It has now been observed that weaning the pups of KSCN fed dams on to KSCN diet for four weeks had no further effect either on their thyroid status or the BBB 2-DG transport. However, feeding KSCN to rats through two generations produced somewhat severe hypothyroidism in F2 pups than that in F1 pups. Interestingly, unlike in F1 pups, the BBB transport of all the three nutrients tested (2-DG, Leu and Tyr) was significantly decreased in F2 pups, albeit to a small extent (10-15%). On the other hand the potent goitrogen: methyl mercaptoimidazole (MMI) even on short term feeding to pregnant dams produced very severe hypothyroidism in the offspring [Serum T4:0.55+/-0.09 microg/dl vs 4.96+/-0.85 in controls]. Surprisingly, the BBB transport of 2-DG, Leu, Tyr and also sucrose, the background marker, was significantly increased in these pups (20-30%). The diverse effects of goitrogen-induced moderate and severe hypothyroidism observed here on the BBB nutrient transport probably suggest different mechanisms for iodine deficiency disorders of different aetiologies and hence the need for discrete approaches for their management.

Topics: Animals; Antithyroid Agents; Blood-Brain Barrier; Deoxyglucose; Female; Hypothyroidism; Leucine; Methimazole; Pregnancy; Rats; Rats, Wistar; Sucrose; Thiocyanates; Tyrosine

It has been known that type II iodothyronine deiodinase activity is present in rat Harderian gland and the activity is significantly increased by isoproterenol administration. We have performed Northern analyses to study whether the transcript for type II iodothyronine deiodinase is expressed in rat Harderian gland and whether the isoproterenol stimulation of type II iodothyronine deiodinase activity in rat Harderian gland is due to the change in its mRNA level. Northern analyses have demonstrated that type II iodothyronine deiodinase mRNA, approximately 7.5 kb in size, is expressed in rat Harderian gland, and the mRNA levels as well as the deiodinase activities are greater in hypothyroid rats than those in euthyroid rats. Type II iodothyronine deiodinase mRNA levels and the deiodinase activities in Harderian gland were increased by isoproterenol administration, and the increase in the mRNA levels preceded that in the deiodinase activities. These results indicate that 7.5 kb transcript for type II iodothyronine deiodinase is expressed in rat Harderian gland and beta-adrenergic stimulation of type II iodothyronine deiodinase activity is due at least in part to the increase in its mRNA level.

Topics: Actins; Adrenergic beta-Agonists; Animals; Antithyroid Agents; Blotting, Northern; Harderian Gland; Hypothyroidism; Iodide Peroxidase; Iodothyronine Deiodinase Type II; Isoproterenol; Male; Methimazole; Rats; Rats, Wistar; RNA, Messenger

The effects of hyperthyroidism and hypothyroidism on brown adipose tissue (BAT) thermogenesis and phospholipid fatty acid composition were investigated in rats. Chronic triiodothyronine (T3) treatment (hyperthyroidism) increased the interscapular BAT pad weight, its triacylglycerol content, and its DNA content. It did not affect basal and noradrenaline-stimulated in vitro oxygen consumption of BAT expressed per microg DNA, although it significantly increased the oxygen consumption of the whole BAT pad. T3 treatment had little effect on phospholipid content and phospholipid fatty acid composition. In contrast, chronic methimazole treatment (hypothyroidism) decreased the BAT pad weight and the triacylglycerol content, but did not significantly change the DNA content in comparison with the control. It significantly decreased the noradrenaline-stimulated BAT oxygen consumption expressed per microg DNA and per BAT pad, but did not change the basal oxygen consumption. Methimazole treatment significantly affected phospholipid content and phospholipid fatty acid composition. Among the major fatty acids of BAT, it decreased docosahexaenoic acid (DHA), arachidonic acid, palmitic acid, palmitoleic acid, and oleic acid, and it increased linoleic acid, stearic acid, and eicosapentaenoic acid. A regression analysis revealed a positive relationship between in vitro respiration and DHA levels in phospholipids (r = 0.404, p<0.05). These results suggest that thyroid hormones have trophic action on BAT and are necessary for BAT thermogenic activity. This study also suggests that DHA is involved in the regulation of BAT thermogenic activity, as we previously indicated.

Topics: Adipose Tissue, Brown; Animals; Antithyroid Agents; Body Temperature Regulation; Docosahexaenoic Acids; Fatty Acids; Hyperthyroidism; Hypothyroidism; Male; Methimazole; Organ Size; Oxygen Consumption; Phospholipids; Rats; Rats, Wistar; Thyroid Hormones; Triiodothyronine

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

A three-part study explored the basis for an interaction between changes in thyroid status and bulbospinal serotonin (5HT) metabolism. In experiment 1, three well-characterized models of primary hypothyroidism were all accompanied by significant increases in 5HT metabolism. In experiment 2, circulating thyroid hormone levels were experimentally varied from very low methimazole (Meth) treatment to very high (T3 implants: 2.5, 5.0, or 7.5 mg triiodothyronine). As in experiment 1, Meth led to elevated 5HT. Hyperthyroidism was accompanied by significant reductions in 5HT, while urinary norepinephrine excretion paralleled 5HT. In experiment 3, rats were subjected to Meth either 2 weeks before or after induction of diabetes with streptozotocin (Stz). Meth prevented Stz-associated reductions in 5HT and attenuated development of hyperphagia. Meth could not reverse established Stz-associated reduction in 5HT or hyperphagia, although both were slightly attenuated. Thus, although the first two experiments argue for a simple inverse relationship between circulating thyroid hormone levels and 5HT in the brain, experiment 3 demonstrated that Stz-associated decrements in 5HT could not be reversed by subsequent lowering of circulating thyroid hormone. Nor did accompanying measurements indicate that glycemic status or circulating levels of leptin were important predictors of 5HT. Thus the interaction between thyroid hormones and 5HT is both more subtle and more complex than previously thought.

Topics: Animals; Blood Glucose; Body Weight; Brain Stem; Diabetes Mellitus, Experimental; Hydroxyindoleacetic Acid; Hyperphagia; Hyperthyroidism; Hypothyroidism; Male; Methimazole; Norepinephrine; Rats; Rats, Sprague-Dawley; Serotonin; Spinal Cord; Thyroid Hormones; Tryptophan

Experimental models of hypothyroidism and hyperthyroidism in Sprague-Dawley rats were established in this study. Diazepam was given to rats at a single oral dose of 30-40 mg.kg-1 and the plasma concentration of diazepam was detected by HPLC. The results showed that the plasma concentration of diazepam was significantly higher in hypothyroid rats than that in controls (P < 0.05). The Cmax, AUC and T1/2 (Ka) were increased. The Vd was decreased and the elimination was slowed. Mild hyperthyroidism showed nearly no effect on the plasma concentration, Cmax and AUC of diazepam in the rats. But when the rats became more heavily hyperthyroid, the plasma concentration, Cmax and AUC of diazepam were increased gradually. The absorption of diazepam was changed slightly in mild and moderate hyperthyroid rats, the Vd was decreased and the elimination was accelerated. In heavily hyperthyroid rats, however, the absorption of diazepam was obviously accelerated. The Vd was decreased and the elimination was slowed. Therefore, we conclude that different thyroid status may have different effects on the pharmacokinetics of diazepam.

Topics: Animals; Anti-Anxiety Agents; Area Under Curve; Diazepam; Hyperthyroidism; Hypothyroidism; Male; Methimazole; Random Allocation; Rats; Rats, Sprague-Dawley

Leptin, the product of the ob gene, is a recently discovered hormone secreted by adipocytes. Serum leptin concentrations increase in correlation with the percentage of body fat, but besides that, little is known about the physiological actions of leptin in humans. The aim of this study was to assess the influence of hypo- and hyperthyroidism on serum leptin levels. Thirty-two patients (16 with hypothyroidism and 16 with hyperthyroidism) were studied before and after treatment with replacement doses of T4 (hypothyroid patients) or methimazole (hyperthyroid), when thyroid function was normal. Control serum for each group was obtained from healthy age-, sex-, and body mass index-matched subjects. Plasma leptin levels were measured by specific RIA. The mean leptin level in the hypothyroid patients was lower before treatment (4.7 +/- 0.7 microg/L) than that in the controls (8.6 +/- 1.4 microg/L; P < 0.02) and was lower than that during treatment with T4 and normalization of thyroid function in the same group of patients (6.3 +/- 0.8 microg/L; P < 0.05). Leptin levels in the hyperthyroid patients were similar before (7.2 +.0 1.1 microg/L) and after normalization of thyroid function following treatment with methimazole (6.2 +/- 1.1 microg/L) and were similar to the control value (8.8 +/- 1.4 microg/L). In conclusion, leptin levels are decreased in the hypothyroid patients and unchanged in hyperthyroidism. Whether decreased leptin levels may contribute to the decreased energy expenditure in patients with hypothyroidism merits further investigation.

Topics: Female; Humans; Hyperthyroidism; Hypothyroidism; Leptin; Male; Methimazole; Proteins; Thyroxine

Hepatocytes are hypothesized to continually stream from the portal tract to the terminal hepatic vein. By this model, when a cell divides, one of its progeny replaces the dividing ancestor and the other is displaced into a more remote location. The present experiment aims to demonstrate that hypothyroidism affects liver cell turnover. Thirty male adult rats were divided into two groups. One received methimazole for two weeks and the other served as control. Each rat was injected intraperitoneally with 18.5 KBq [3H]thymidine/g body weight. Rats were killed after 1 hr and two and four weeks. Autoradiography was done. The distance of the labeled cells from the portal tract was measured. The mean TSH levels of the methimazole-treated group and controls were 1.45 and 0.25 mM/liter, respectively (P < 0.01). Hepatocyte streaming was lower in hypothyroid (1.8 microns/day) than in untreated rats (2.5 microns/day) (P < 0.01). The respective labeling indices 1 hr after labeling were 0.9% and 1.24% (P < 0.05). We conclude that hypothyroidism diminishes hepatocyte and littoral cell turnover and slows down their streaming.

Topics: Animals; Antithyroid Agents; Cell Division; Hypothyroidism; Liver; Male; Methimazole; Rats; Thyrotropin; Time Factors

The effects of thyroid and glucocorticoid hormones on the expression of the Kv1.5 potassium channel gene were studied in the rat left ventricle. Rats were rendered hypothyroid by oral administration of methimazole (MMI). Hyperthyroidism was induced in the MMI-treated rats by administration of L-thyroxine (T4). Kv1.5 mRNA levels decreased markedly in the hypothyroid rats, whereas they increased in the hyperthyroid rats. Propranolol, a beta-adrenergic blocker, did not inhibit the T4-dependent increase in Kv1.5 mRNA, indicating that the increase is not due to the increased beta-adrenergic stimuli under hyperthyroidism. Accordingly, treatment of the MMI-treated hypothyroid rats with isoproterenol, a beta-adrenergic receptor agonist, did not increase the mRNA. The Kv1.5 mRNA levels positively correlated with the thyroid hormone levels in sera. When rats were adrenalectomized and rendered hypothyroid, Kv1.5 mRNA become undetectable. Administration of 3,3',5-triiodothyronine (T3) at a dose to induce hyperthyroidism did not restore the mRNA level. However, T3 significantly increased the mRNA level when dexamethasone was co-administered at a physiological dose. These results for the first time demonstrate that thyroid hormone up-regulates Kv1.5 mRNA levels in the rat left ventricle and they demonstrate that glucocorticoid is required for this induction.

Topics: Animals; Dexamethasone; Heart Ventricles; Hyperthyroidism; Hypothyroidism; Kv1.5 Potassium Channel; Male; Methimazole; Myocardium; Potassium Channels; Potassium Channels, Voltage-Gated; Propranolol; Rats; Rats, Wistar; RNA, Messenger; Thyroid Gland; Thyroxine; Transcription, Genetic; 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

The effects of altered thyroid states on lipid peroxidation, antioxidant capacity, and susceptibility to oxidative stress of rat tissues were examined. Hypothyroidism was induced by administering methimazole in drinking water for 15 days. Hyperthyroidism was elicited by a 10-day treatment of hypothyroid rats with tri-iodothyronine (10 micrograms/100 g body weight). In tissues of hypothyroid rats the lipid peroxidation was not modified, whereas in hyperthyroid rats lipid peroxidation increased in liver and heart but not in skeletal muscle. The glutathione peroxidase activity increased significantly in heart and muscle of hypothyroid rats and in muscle of hyperthyroid rats. The glutathione reductase activity was not modified in tissues of hypothyroid and hyperthyroid rats. In both rat groups the whole antioxidant capacity of tissues decreased, but significantly only in liver and heart. The results obtained studying the response to oxidative stress in vitro indicated that the susceptibility to oxidative challenge was increased in all tissues of hyperthyroid rats and in heart and muscle of hypothyroid animals. These results are explainable in terms of tissue variations in haemoprotein content and/or of antioxidant capacity. Since it has been reported that hypothyroidism offers in vivo protection against free radical damage, we suggest that such an effect could be due to greater effectiveness of cellular defence systems different from antioxidant ones.

Topics: Analysis of Variance; Animals; Antioxidants; Antithyroid Agents; Glutathione Peroxidase; Glutathione Reductase; Hyperthyroidism; Hypothyroidism; Lipid Peroxidation; Liver; Male; Methimazole; Muscle, Skeletal; Myocardium; Oxidative Stress; Rats; Rats, Wistar; Thyroid Diseases; Thyroid Gland; Triiodothyronine

Hypo- or hyperthyroid states were induced in adult male mallards (Anas platyrhynchos) by subchronic exposure to daily injections of methimazole or a 9:1 ratio of thyroxine (T4): triiodothyronine (T3). The levels of T4 given were 0, 125, 250, or 500 micrograms/kg/day and for methimazole; 10 mg/kg/day for 22 or 21 days. Plasma T3 showed a lasting decrease with T4:T3 treatment, despite the attempt to maintain the normal T4:T3 ratio. Antibody formation to sheep red blood cells was decreased only at the 125 micrograms/kg/day dose of T4, and was unaffected by methimazole treatment. Natural killer cell activity to RP-9 tumor cells and macrophage phagocytosis of killed, opsonized Saccaromyces cereviseae were unaffected by treatment throughout the study. However, lectin-dependent cellular cytotoxic activity to RP-9 tumor cells was significantly decreased after 21 days of methimazole treatment, indicating that hypothyroidism may have an influence on cell-mediated immunity. Hypo- and hyperthyroid conditions had opposing effects on plasma cholesterol levels.

Topics: Animals; Antithyroid Agents; Biomarkers; Blood Chemical Analysis; Cholesterol; Cytotoxicity Tests, Immunologic; Dose-Response Relationship, Drug; Ducks; Hyperthyroidism; Hypothyroidism; Killer Cells, Natural; Lectins; Leukocyte Count; Male; Methimazole; Phagocytosis; Thyroid Hormones; Tumor Cells, Cultured

In this study, experimental hypothyroidism was established and used to investigate possible alterations in the calcium, magnesium, and zinc homeostasis by assessing their concentration in plasma and erythrocytes. Hypothyroidism was induced by administration of methimazole an iodine blocker at a dose of 75 mg/100 g food for 3 wk. In the methimazole-induced hypothyroid state, the experimental animals showed a significant decrease in plasma zinc concentration, whereas a significant increase in plasma magnesium concentration occurred. No change was observed in plasma calcium concentration. The erythrocyte zinc and calcium concentrations were found to be increased, whereas magnesium concentration decreased. Erythrocyte magnesium concentration showed a significant positive correlation with T4 values. The study provides evidence for marked alterations in homeostatis of zinc, magnesium, and calcium.

Topics: Animals; Antithyroid Agents; Calcium; Disease Models, Animal; Erythrocytes; Female; Homeostasis; Hypothyroidism; Magnesium; Methimazole; Rats; Rats, Wistar; Spectrophotometry, Atomic; Zinc

A possible role of tri-iodothyronine (T3) on the interplay between testicular steroids and Sertoli cells has been investigated on the basis of previous findings demonstrating a direct inhibitory influence of T3 on aromatase activity and oestradiol production in peripuberal Sertoli cells. In this context, the present study was focused on the effects of T3 on oestrogen receptor (ER) and androgen receptor (AR) contents in the cytosol and nucleus of Sertoli cells isolated from 2-, 3- and 4-week-old euthyroid, hypothyroid and hypothyroid treated rats. Hypothyroidism was induced by the oral administration of 0.025% methimazole (MMI) from birth until the rats were killed at 2, 3 and 4 weeks of age. Half of the MMI-treated animals were injected i.p. with L-tri-iodothyronine (T3; 3 micrograms/100 g body weight) during the last week before death. Sertoli cells from all groups were initially cultured under basal conditions for the first 24 h and subsequently in the presence of testosterone with or without T3 for an additional 24 h. Hypothyroidism was associated with severe impairment of body as well as testicular growth. Euthyroid ERs showed an elevated Kd (0.76 nM) which was similar in the different age groups investigated. The in vitro addition of T3 or testosterone induced a decrease in ER content and this decrease was greater after exposure to both hormones. In 2- and 3-week-old hypothyroid rats, ER content was markedly increased and was reversed in euthyroid rats when T3 was given in vivo. When ERs were assayed in the Sertoli cell nucleus and cytoplasm of 2- and 3-week-old animals, a strong relationship in ER content in the two cellular compartments was observed. Neither of the hormones tested seemed to affect the AR content in the nucleus significantly, while the in vitro addition of testosterone or T3 or both hormones together augmented the ARs in the cytosol to a greater extent, resulting in an increase in their total (cytosolic and nuclear) content in the cells. The present data suggest that T3 down-regulates ERs and up-regulates ARs in peripuberal Sertoli cells. The additive effect of testosterone and T3 in up-regulating ARs could possibly involve a role for T3 in influencing the androgen responsiveness of the Sertoli cells during spermatogenesis.

Topics: Animals; Cell Nucleus; Cells, Cultured; Cytosol; Estradiol; Hypothyroidism; Male; Methimazole; Metribolone; Protein Binding; Rats; Rats, Wistar; Receptors, Androgen; Receptors, Estrogen; Sertoli Cells; Testosterone; Triiodothyronine

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

Hypothyroidism leads to a decreased activity of the low-density lipoprotein (LDL) receptor, which contributes to the hypercholesterolemia frequently seen during hypothyroidism. It is not known whether the decreased activity of the LDL receptor is directly due to the absence of thyroid hormone, or secondary to a deficiency of growth hormone (GH). Therefore, the effect of GH administration on LDL receptor activity was studied in hypothyroid rats. Following induction of hypothyroidism, the level of LDL receptor mRNA was significantly decreased in liver homogenates to 31 % +/- 6% of the control value. LDL binding to liver cell membranes and plasma membranes decreased during hypothyroidism to approximately 65% of the control value. The effect of hypothyroidism on the hepatic LDL receptor was reflected in a significantly increased half-life of (125)I-LDL of 29 hours in controls versus 48 hours in hypothyroid rats. Treatment of hypothyroid rats with human GH (hGH) resulted in normalization of both the amount of hepatic LDL receptor mRNA and LDL binding on liver cell membranes. The plasma half-life of human (125)I-labeled LDL decreased during GH substitution but did not normalize. GH treatment significantly reduced plasma LDL cholesterol levels by 36% (P < .05, n = 8), to levels that were still higher than in control animals. These data indicate that at least part of the decreased LDL receptor activity during hypothyroidism is secondary to GH deficiency.

Topics: Animals; Gene Expression Regulation; Growth Hormone; Humans; Hypothyroidism; Liver; Male; Methimazole; Rats; Rats, Wistar; Receptors, LDL; RNA, Messenger

Two recent studies have claimed that thyroid hormone administration accelerates malic enzyme gene expression in the neonatal brain in contrast to the well-documented lack of effect of triiodothyronine on malic enzyme gene expression in the adult brain. Since these observations conflict with earlier observations in our laboratory, we reinvestigated the effect of thyroid hormone status on the ontogeny of malic enzyme gene expression in the neonatal rat. Neither hypothyroidism nor hyperthyroidism influenced the ontogenesis of malic enzyme activity in neonatal brain whereas the patterns of gene expression and enzyme activity in liver were markedly affected. Our results suggest that tissue-specific factors in brain block thyroid hormone-induced gene expression by thyroid hormone.

Topics: Aging; Animals; Animals, Newborn; Brain; Female; Gene Expression Regulation, Enzymologic; Hyperthyroidism; Hypothyroidism; Liver; Malate Dehydrogenase; Methimazole; Organ Specificity; Pregnancy; Rats; Rats, Sprague-Dawley; RNA, Messenger; Thyroid Gland; Transcription, Genetic; Triiodothyronine

The kidney androgen-regulated protein (KAP) gene exhibits a cell-specific hormonal regulation of its expression in the epithelial cells of proximal tubules of mouse kidney, where T3 is required for constitutive expression in the straight segments and androgens for expression in the convoluted ones. By using different models of hypothyroidism, we demonstrate that maximal androgen-mediated induction of the gene depends on thyroid hormone as well. This constitutes a specific event, since vitamin D3 cannot mimic the effects of T3, albeit their remarkable functional relationship. It is also shown that while congenital hypothyroid hyt/hyt male mice, exposed to maternal T3 in the gestational period, exhibit diminished but existent androgen-dependent cortical responses, mice exposed to goitrogens during gestation and postnatally are unable to express the gene even at postnatal day ninety. Impairment of KAP cortical expression in hypothyroid animals does not correlate with lower levels of androgens or androgen receptor expression.

Topics: Animals; Antithyroid Agents; Dihydrotestosterone; Epithelium; Female; Gene Expression Regulation, Developmental; Hypothyroidism; Kidney; Male; Methimazole; Mice; Mice, Inbred C57BL; Mice, Mutant Strains; Orchiectomy; Perchlorates; Potassium Compounds; Pregnancy; Proteins; Receptors, Androgen; RNA, Messenger; Testosterone; Thyroid Hormones; Thyroxine

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

The thyroid hormone plays a critical role in normal development of the mammalian central nervous system. This study was designed to examine the effect of perinatal hypothyroidism on ontogenic change in cytochrome c oxidase subunit I (COX I) gene expression in the rat cerebellum by using quantitative in situ hybridization histochemistry (ISH). Newborn rats were rendered hypothyroid by continuous administration of methimazole in the mothers' drinking water. The pups were then killed by decapitation on 1, 5, 10, 15, 20, and 30 days after birth (P1, P5, P10, P15, P20, and P30). Their cerebella were removed, and frozen sections were cut and processed for ISH with 35S-labeled RNA probe for COX I messenger RNA. After hybridization, emulsion autoradiography was performed. The numbers of grains within the external granule cell layer, molecular layer, and internal granule cell layer were then counted. A significant decrease in grain density was detected in the hypothyroid animal in all these areas on P5, P10, and P15. On P15, in the molecular layer, a greater hybridization signal was detected in the inner portion than in the outer portion in the euthyroid animal. No such difference was seen in the hypothyroid animal. Daily T4 treatment for 15 days restored the effect of methimazole treatment. The significant effect of perinatal hypothyroidism on COX I gene expression was not detected after P20. These results indicate that altered thyroid states affect the COX I gene expression in the cerebellar cortex during development, suggesting that the COX I gene is one of the key genes regulated by the thyroid hormone and plays an important role in the morphogenetic changes observed in the perinatal hypothyroid cerebellum.

Topics: Aging; Animals; Animals, Newborn; Cerebellar Cortex; Electron Transport Complex IV; Gene Expression Regulation, Developmental; Gene Expression Regulation, Enzymologic; Hypothyroidism; In Situ Hybridization; Methimazole; Rats; Rats, Sprague-Dawley; Reference Values; RNA, Messenger; Thyroxine; Transcription, Genetic

The aim of this study was to assess the impact on neonatal neurobehavioral development of methimazole (MMI)-induced in-utero hypothyroxinemia and of correction by maternal-fetal thyroxine (T4) transfer in the rat. Two groups of pregnant Sprague-Dawley rats received MMI as drinking water from gestation day 10 until birth. From day 16 until parturition, one of these groups received daily intraperitoneal injections of L-T4 and the other received saline injections. A third (control) group drank tap water and received saline injections. From day of birth, offspring from all groups were raised by untreated foster dams. Their neurobehavioral development was monitored, on postnatal days 5-14 (N = 3/litter, from 30 litters) by experimenters blind to treatment group. Prenatal T4 treatment resulted in correction of MMI-induced delayed appearance of three different reflexes. Body-weight gain of treated pups was similar to that of controls and more rapid than development of rats treated with MMI-alone. T4 treatment did not prevent, however, MMI-induced delay in maturation of physiological landmarks (e.g. ear opening). At least a portion of the developmental delay resulting from prenatal (maternal) MMI administration may be reversed by maternal-fetal transfer of T4 administered to the gravid dam.

Topics: Administration, Oral; Animals; Animals, Newborn; Antithyroid Agents; Behavior, Animal; Body Weight; Embryonic and Fetal Development; Female; Hypothyroidism; Male; Methimazole; Pregnancy; Prenatal Exposure Delayed Effects; Rats; Rats, Sprague-Dawley; Thyroxine

This paper describes the effects of goitrogen-induced hypothyroidism on GH, prolactin and the testis size of rats. Hypothyroidism was caused by lifetime-rearing on goitrogen methimazole (MMI). This condition was brought on by adding 0.025% (Weight/ Volume) MMI to the mother's drinking water immediately after birth. Offspring, after weaning, were given the same food and drinking water as that of the mother until sacrified. Four experimental groups were designed: group 1, CMF (normal rat chow) and tap water; group 2, CMF with 0.025% thyroid powder and tap water; group 3, CMF and tap water containing 0.025% MMI and group 4, CMF with the thyroid powder and tap water containing 0.025% MMI. The rats were killed at 73 days of age after rearing under the 4 conditions described. Pituitary GH and PRL and serum PRL were significantly less in group 3 than in the others. Testis weight was the same for groups 3 (2.51 +/- 0.14 g; Mean +/- SD), 1 (2.76 +/- 0.07 g) and 2 (2.60 +/- 0.06 g). Increased testis weight was noted only in group 4 (3.25 +/- 0.1 g). The ratio of testis to body weight was significantly higher in group 3 than in the other groups. The authors concluded that hypothyroidism causes pituitary dysfunction with GH and PRL deficiency and also causes testis enlargement with age.

Topics: Animals; Antithyroid Agents; Body Weight; Female; Growth Hormone; Hypertrophy; Hypothyroidism; Male; Methimazole; Organ Size; Pituitary Gland; Pregnancy; Prolactin; Rats; Rats, Wistar; Testis; Thyrotropin; Thyroxine

Glucuronidation is a major pathway of thyroid hormone metabolism in rats, involving at least three different hepatic UDP-glucuronyltransferases (UGTs): bilirubin UGT, phenol UGT and androsterone UGT. We have studied the effects of short-term (3 days) fasting and long-term (3 weeks) food restriction to one-third of normal intake (FR33) on hepatic UGT activities for thyroxine (T4), triiodothyronine (T3), bilirubin and androsterone in male and female Wistar rats with either a functional (high activity, HA) or a defective (low activity, LA) androsterone UGT gene. Because food deprivation is known to induce centrally mediated hypothyroidism in rats, results were compared with those obtained in methimazole (MMI)-induced hypothyroid rats. Both fasting and FR33 produced largely parallel increases in T4 and bilirubin UGT activities. These effects were greater in males than in females, and were reproduced in MMI-treated rats. In male and female HA rats, fasting induced insignificant increases in T3 UGT activity and had no effect on androsterone UGT activity. In male HA rats, FR33 was associated with an increase in T3 UGT activity, while androsterone UGT activity showed little change. However, in female HA rats both T3 and androsterone UGT activities were markedly decreased by FR33. Triiodothyronine UGT activity in LA rats was strongly decreased compared with HA rats, but was not further decreased by FR33 in female LA rats, supporting the importance of androsterone UGT for T3 glucuronidation. These results demonstrate different sex-dependent effects of food deprivation on hepatic T4 and T3 glucuronidation that are associated with changes in the expression of bilirubin UGT and androsterone UGT, respectively. For the increased T4 and bilirubin UGT activities at least, these effects appear to be mediated by the hypothyroid state of the (semi)starved animals.

Topics: Androsterone; Animals; Bilirubin; Fasting; Female; Food Deprivation; Glucuronosyltransferase; Hypothyroidism; Iodide Peroxidase; Liver; Male; Methimazole; Phenotype; Rats; Rats, Wistar; Sex Characteristics; Thyroid Hormones; Thyroxine; Time Factors; Triiodothyronine

Neuromedin B (NB), a bombesin-like peptide, has been recently characterized as a physiological paracrine/autocrine inhibitor of thyrotropin (TSH) secretion. We hypothesized on the basis of our prior experiments that thyroid hormones stimulate pituitary NB secretion which mediates, at least in part, the TSH-suppressive effect of thyroid hormone. Here, we evaluated the time-course of the effect of thyroid hormones administration to eu- and hypothyroid rats on the anterior pituitary content of NB and on serum TSH. As previously reported, the pituitary content of NB increased in hyperthyroidism and decreased in hypothyroidism. Chronic treatment of hypothyroid rats with a physiological dose of thyroxine (0.8 microgram/100 g b.w. s.c, for 3 or 5 days) normalized pituitary NB content, while 5 days of treatment with a pharmacological dose of thriiodothyronine (0.4 microgram/100 g b.w.) induced an increase above that of normal pituitaries. Thyroxine and triiodothyronine injected once, s.c., into hypothyroid rats required 30 min to normalize NB content, which reached higher than normal values in 3-6 h. At these times, the increment in NB preceded or was simultaneous with the suppression of serum TSH. This rapid and marked effect on pituitary neuromedin B content, associated in time with TSH suppression, is in agreement with the hypothesis that neuromedin B may mediate at least in part, the acute suppression of TSH release by thyroid hormone, a hypothesis that still needs further verification.

Topics: Animals; Antithyroid Agents; Hyperthyroidism; Hypothyroidism; Male; Methimazole; Neurokinin B; Pituitary Gland; Rats; Thyroid Hormones; Thyrotropin; Thyroxine; Triiodothyronine

Topics: Carbimazole; Consensus Development Conferences as Topic; Humans; Hyperthyroidism; Hypothyroidism; Long-Term Care; Methimazole

To determine the age-related changes in the effect of thyroid hormone on apolipoprotein A1 (ApoA1) gene expression, male Fischer 344 rats at 4 (young) and 26 (aged) mo of age were studied. Hyperthyroidism was induced with daily intraperitoneal injections of 3,5,3'-triiodothyronine (15 micrograms/100 g body wt) for 10 days. Hypothyroidism was induced with 0.025% methimazole in drinking water for 4 wk. Hyperthyroidism was associated with increased serum ApoA1 levels in young rats [7.52 +/- 0.41 vs. 3.67 +/- 0.30 optical density (OD); P < 0.01]. The increase in aged rats (6.5 +/- 0.87 vs. 5.14 +/- 0.09 OD) did not reach statistical significance. Hypothyroidism was not associated with significant changes in serum ApoA1 levels in either young or aged rats. Hyperthyroidism was associated with a 2.5-fold increase in ApoA1 mRNA in young rats and a 1.7-fold increase in aged rats. Hypothyroidism was associated with a 3.6-fold reduction in ApoA1 mRNA in young rats, but there was no significant change in aged hypothyroid rats. Mobility shift assays indicated that the binding of transacting factors to ApoA1 promoter increased in hyperthyroid young rats but not in hyperthyroid aged rats. It is concluded that aging in rats is associated with reduced ApoA1 responsiveness to thyroid hormones. This altered responsiveness could partly be the result of changes in the binding activity of nuclear factors to the ApoA1 promoter.

Topics: Aging; Animals; Antithyroid Agents; Apolipoprotein A-I; Autoradiography; Blotting, Northern; Hyperthyroidism; Hypothyroidism; Liver; Male; Methimazole; Rats; Rats, Inbred F344; Reference Values; RNA, Messenger; Triiodothyronine

To determine how lipid peroxides and free radical scavengers are changed in the brain of hyper- or hypothyroid rats, we examined the behavior of lipid peroxide and free radical scavengers in the cerebral cortex of aged (1.5 years old) rats that had been made hyper- or hypothyroid by the administration of thyroxine or methimazol for 4 weeks. Concentrations of catalase, Mn-superoxide dismutase (SOD) and glutathione peroxidase (GSH-PX) were increased in hyperthyroid rats compared with euthyroid rats. Concentrations of total SOD, Cu,Zn-SOD and GSH-PX were increased but that of Mn-SOD was decreased in hypothyroid animals. There were no differences among hyperthyroid, hypothyroid and euthyroid rats in the levels of coenzymes 9 or 10. The concentration of lipid peroxides, determined indirectly by the measurement of thiobarbituric acid reactants, was decreased in hyperthyroid rats but not in hypothyroid rats when compared with euthyroid animals. These findings suggest that free radicals and lipid peroxides are scavenged to compensate for the changes induced by hyper- or hypothyroidism.

Topics: Animals; Antithyroid Agents; Brain; Catalase; Free Radical Scavengers; Glutathione Peroxidase; Hyperthyroidism; Hypothyroidism; Lipid Peroxidation; Magnesium; Male; Methimazole; Rats; Rats, Wistar; Superoxide Dismutase; Thyroxine

The inhibitory effect of an antithyroid drug on mouse T lymphocytes was investigated. Inbred C57BL/6 mice were provided with an antithyroid drug, methimazole, for 2, 4 and 6 weeks and the in vitro responses of the lymphocytes were studied. The proliferative responses of T lymphocytes from the spleen of methimazole (MMI)-treated mice significantly (p < 0.05) decreased following concanavalin A stimulation, and the inhibitory effect became prominent with the increased duration of MMI treatment. A concomitant increase in the frequency of induced sister-chromatid exchanges was also observed in these T lymphocytes. When the splenocytes were stimulated with concanavalin A for 24 h, their ability to produce interleukin-2 (IL-2) was significantly decreased (p < 0.05). The results indicated that methimazole interfered with the normal proliferation of T lymphocytes by suppressing the production of IL-2, a cytokine also known as T cell growth factor, as well as inducing a higher incidence of sister-chromatid exchange during cell division.

Topics: Animals; Cell Division; Concanavalin A; Hypothyroidism; Immunosuppressive Agents; Interleukin-2; Male; Methimazole; Mice; Mice, Inbred C57BL; Sister Chromatid Exchange; T-Lymphocytes

The effect of thyroid hormone on the expression of mitochondrial proteins was evaluated during development by measuring cytochrome c oxidase (CYTOX) activity and cytochrome c protein and mRNA levels in heart and skeletal muscle of control and hypothyroid rats. Animals were killed at the late fetal, early, and late postnatal stages up to 56 days of age. In heart, CYTOX activity increased 2.3-fold above the fetal level throughout development, most of which occurred prior to 2 days of age. No increase was observed in muscle. CYTOX activity was reduced in hypothyroid animals throughout development in heart compared to controls (by 50% at 56 days), but in muscle no effect of hypothyroidism was observed. In muscle and heart 4- and 1.5-fold increases in cytochrome c above the fetal level were evident by 1 day of age, with further increases to 8.5- and 2.7-fold by 56 days, respectively. The increase in cytochrome c differed from the increase in CYTOX, indicating changes in mitochondrial composition. Hypothyroidism reduced cytochrome c in muscle by 30-35% at 56 days, but had no effect in heart, indicating a muscle type-specific effect of thyroid hormone on cytochrome c protein expression. Cytochrome c mRNA increased rapidly to 4-5 fold above the fetal level in both heart and muscle by 6 h post-partum. Between 7 and 56 days of age, further increases to 6- and 25-fold were observed in muscle and heart, respectively. In muscle, the 6-fold developmental increase in mRNA paralleled that of the protein, suggesting transcriptional regulation.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Cytochrome c Group; Disease Models, Animal; Electron Transport Complex IV; Female; Fetus; Gene Expression Regulation, Developmental; Hypothyroidism; Male; Methimazole; Mitochondria, Heart; Mitochondria, Muscle; Pregnancy; Proteins; Rats; RNA; RNA, Messenger

We have recently reported that hypothyroidism increases immunoreactive (IR)-vasoactive intestinal polypeptide (VIP) and VIP mRNA content in both parvocellular and magnocellular neurons of the rat, hypothalamic paraventricular nucleus (PVN). As VIP can stimulate vasopressin (AVP) secretion, we conducted an anatomical investigation to determine whether VIP-containing neurons in other regions of the brain that are involved with homeostatic mechanisms of water and salt conservation are also affected by hypothyroidism. The distribution and intensity of VIP immunostaining in neurons and fibers of the magnocellular-neurohypophysial system, including the hypothalamic PVN, supraoptic nucleus (SON) and accessory magnocellular cell groups, circumventricular subfornical organ (SFO), preoptic and anterior hypothalamus, midline thalamus, subthalamic zona incerta and posterior septal nuclei were studied using a highly sensitive immunocytochemical technique and unbiased neuronal counting methods, based on the optical dissector principle. Hypothyroidism increased the intensity of VIP immunostaining and/or the number/section, percentage and numerical density of IR-VIP neurons in the PVN, SON, nucleus circularis, periventricular preoptic nucleus of the hypothalamus and SFO. In addition, IR-VIP perikarya and/or fibers in the hypothalamic medial preoptic area and anterior periventricular nucleus, nucleus reuniens of the thalamus and dorsal fornix-triangular septal nucleus complex were also apparent in the hypothyroid animals while no immunostaining was seen in these areas in control animals. No quantitative and/or qualitative modifications in IR-VIP neurons and fibers were noted in the anterior hypothalamic area, suprachiasmatic nucleus, thalamic paraventricular nucles an subthalamic zona incerta between hypothyroid and control animals. These findings suggest an inverse relationship between thyroid hormone and VIP content and/or distribution of IR-VIP neurons in specific forebrain regions involved in the control of AVP release, extracellular fluid volume, thirst, blood pressure and anterior pituitary secretion. This raises the possibility that changes in fluid homeostasis and cardiovascular function occurring in hypothyroidism may be mediated, at least in part, by VIP-producing neurons in diverse regions of the brain.

Topics: Animals; Antithyroid Agents; Body Weight; Hypothyroidism; Immunohistochemistry; Male; Methimazole; Nerve Fibers; Neurons; Pituitary Gland, Posterior; Prosencephalon; Rats; Rats, Sprague-Dawley; Thyroid Hormones; Vasoactive Intestinal Peptide

Portal hypertension is accompanied by a hyperdynamic circulatory state that shares some similarities with thyrotoxicosis. This study was conducted in order to investigate the hemodynamic effects of hypothyroidism in a rat model with portal hypertension induced by partial portal vein ligation (PVL). Four groups of 10 rats each were studied: normal control and hypothyroid rats, and PVL control and hypothyroid rats. Hypothyroidism was induced by methimazole 0.04% in drinking water. Hemodynamic measurements were performed using the radioactive microsphere technique. Induction of hypothyroidism was confirmed by elevated TSH levels. In the PVL groups, hypothyroidism ameliorated the hyperdynamic circulation. Portal venous inflow and portal pressure dropped significantly: 7.1 +/- 0.2 vs 4.8 +/- 0.3 ml/min/100 g body wt (P < 0.01) and 13.4 +/- 0.9 vs 10.9 +/- 0.8 mm Hg; (P < 0.01), respectively. In normal rats, hypothyroidism was manifested by a hypodynamic circulatory state. These results demonstrate that hypothyroidism induced by methimazole is followed by amelioration of the hyperdynamic circulation, normalization of portal venous inflow, and reduction of portal pressure.

Topics: Animals; Hemodynamics; Hypertension, Portal; Hypothyroidism; Male; Methimazole; Microspheres; Portal Pressure; Portal System; Rats; Rats, Sprague-Dawley; Ruthenium Radioisotopes

The effect of triiodothyronine (T3) on regulation of fatty acid synthase in chicken liver was investigated. In hypothyroid animals, enzyme activity was about one half of that in euthyroid animals. T3 treatment increased the enzyme activity in hypothyroid animals. There is little difference in both the mRNA concentration and the transcription rate between euthyroid and hypothyroid animals. T3 treatment markedly decreased both the mRNA concentration and the transcription rate in euthyroid and hypothyroid animals. These results suggested that T3 maintained the normal level of enzyme expression primarily by stimulating the post-transcriptional step, while the transcription of the gene was inhibited by hyperthyroidism.

Topics: Animals; Cell Nucleus; Chickens; Coenzyme A Ligases; Gene Expression Regulation, Enzymologic; Hypothyroidism; Liver; Methimazole; Repressor Proteins; RNA, Messenger; Saccharomyces cerevisiae Proteins; Time Factors; Transcription, Genetic; Triiodothyronine

The aim of this study was to evaluate through the auditory brainstem responses (ABRs) the electrical events generated along the auditory pathway in 56 adult patients affected with hyper- and hypothyroidism. Twenty-four normal-hearing hyperthyroid patients affected with Graves' disease and 32 normal-hearing hypothyroid patients (9 with subclinical and 23 with overt hypothyroidism) were subjected to standard (clicks at 21 pps) and sensitized ABR with masking wide-band (masking noise). In addition, thyroid scintiscan and ultrasonography, free T3 and T4, total T3 and T4, TSH, antimicrosomal and antithyroglobulin antibodies, audiogram and impedance tests were performed in all the patients. This study was repeated after 6-12 months of treatment in conditions of euthyroidism. The results showed changes of ABRs both in the standard procedure as well as in the sensitized test in 6 hyperthyroid (25%) and 8 hypothyroid patients (25%). All the patients with abnormal ABRs had overt hypothyroidism (8/23; 34.7%). The ABRs became normal in 5 out of 6 Graves' patients after 6-12 months of methimazole treatment. ABRs remained abnormal in all the hypothyroid patients despite their having been on L-thyroxine treatment for 6-12 months and were euthyroid for at least 5 months before the study was repeated. These findings suggest that ABR abnormalities are indicative only of a nonspecific injury in the bulbo-ponto-mesencephalic centers. Alterations of ABRs in thyroid diseases are not specific in relation to hyper- or hypothyroidism. Lastly, there is a relationship between ABR abnormalities and the degree of hypothyroidism, even if ABR alterations are not always reversible after long-term therapy.

Topics: Adult; Evoked Potentials, Auditory, Brain Stem; Female; Graves Disease; Humans; Hyperthyroidism; Hypothyroidism; Male; Methimazole; Middle Aged; Thyroid Diseases; Thyroxine

The effects of hyperthyroidism on uric acid metabolism were investigated. First, the serum uric acid level was measured in 92 patients with hyperthyroidism due to Graves' disease, eight patients with subacute thyroiditis, six patients with hypothyroidism, and 70 sex- and age-matched controls. Second, the correlation between serum thyroxine (T4) and serum uric acid was obtained in hyperthyroid Graves' disease patients before and during antithyroid drug therapy. Finally, uric acid clearance (CUA) was determined in untreated patients with hyperthyroidism due to Graves' disease. Serum uric acid was significantly elevated in patients with hyperthyroidism, and the elevation correlated well with serum T4 before treatment as a group and during treatment in each patient. A significant elevation of serum uric acid was not present in patients with a transient mild thyrotoxicosis due to subacute thyroiditis. Serum uric acid was significantly decreased in patients with hypothyroidism. Renal excretion of uric acid clearly increased in hyperthyroid patients, and CUA also increased. The increase in CUA corresponded to the increase in renal plasma flow (RPF), which was measured by p-aminohippuric acid clearance. The fractional excretion of uric acid as determined by CUA/glomerular filtration rate (GFR) was similar and within the normal range in hyperthyroid patients and normal controls. A significant inverse correlation between CUA and serum uric acid concentration was present in hyperthyroid patients as in normal controls, indicating that the renal handling of uric acid in the tubule affected uric acid excretion.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adolescent; Adult; Aged; Child; Female; Graves Disease; Humans; Hyperthyroidism; Hypothyroidism; Kidney; Male; Methimazole; Middle Aged; Regional Blood Flow; Thyroxine; Uric Acid

The effects of hyper- and hypothyroidism on the vasorelaxing responses to acetylcholine (ACh), sodium nitroprusside (NP), and CaCl2 were investigated in aortic strips and isolated perfused kidneys. The renal vascular reactivity to ACh and NP was increased in hyperthyroid rats, whereas the concentration-response curve to ACh in hypothyroid rats was flattened. In the renal vasculature from hypothyroid rats, NP produced a dual response: vasoconstriction at low doses and vasodilation at medium to high doses. Aortic strips from hyperthyroid rats showed an increased response to ACh without significant differences between hypothyroid and control groups. Aortic strips from all three experimental groups showed a similar relaxing response to CaCl2. These results indicate that: (1) the raised arterial pressure of hyperthyroid rats is not associated with a reduced endothelium-dependent and calcium-induced vasodilation, and (2) the changes in responsiveness to vasodilators in resistance vessels from hyper- and hypothyroid rats may play a role in the increased and decreased peripheral vascular resistances, respectively, previously reported in such animals.

Topics: Animals; Aorta, Thoracic; Endothelium, Vascular; Hemodynamics; Hyperthyroidism; Hypothyroidism; Male; Methimazole; Muscle, Smooth, Vascular; Rats; Rats, Wistar; Renal Circulation; Thyroxine; Triiodothyronine; Vasodilation; Vasodilator Agents

Combined immobilisation and cold for 3 and 6 hrs induced depression of cardiac contractile function and functional reserve, death rate of 30 and 80 per cent resp., hypothermia, alterations in adrenal glands and spleen, gastric mucosa ulceration in euthyroid rats. The changes were more obvious in hypothyroid rats. The cold adaptation significantly reduced the changes in the euthyroid rats whereas this effect was absent in hypothyroid animals. The data obtained corroborate the significance of intact thyroid status for the cold adaptation.

Topics: Adaptation, Physiological; Animals; Cold Temperature; Gastric Mucosa; Hypothyroidism; Male; Methimazole; Myocardial Contraction; Rats; Restraint, Physical; Stress, Physiological; Thyroid Gland; Thyroid Hormones; Time Factors; Ventricular Function, Left

Topics: Adult; Age Factors; Aged; Aged, 80 and over; Drug Monitoring; Humans; Hydrocortisone; Hyperthyroidism; Hypothyroidism; Iodine; Iodine Radioisotopes; Methimazole; Middle Aged; Propylthiouracil; Thyrotropin; Thyroxine

1. The physiological relevance of cardiac and vascular alpha-adrenoceptors may increase in disease states in which beta-adrenoceptors are altered. To test this, positive inotropic and vasoconstrictor responses to phenylephrine were measured in isolated tissues from rats with experimentally-induced hyperthyroidism, hypothyroidism and diabetes as well as in genetically spontaneous hypertensive rats (SHR). 2. In left atria, positive inotropic responses to phenylephrine were increased in hypothyroid and diabetic rats and abolished in hyperthyroid and SHR. 3. In contrast, phenylephrine produced increased positive inotropy in left ventricular papillary muscles from hyperthyroid rats, increased potency in diabetic rats and negative inotropic responses in hypothyroid rats. 4. The potency of phenylephrine as a vasoconstrictor in thoracic aortic rings was increased in hyperthyroid and SHR and decreased in hypothyroid rats. 5. Thus, disease states which alter beta-adrenoceptor responsiveness can independently regulate atrial, ventricular and vascular responses to the alpha 1-adrenoceptor agonist, phenylephrine. Therefore, these disease states may alter the physiological control of the cardiovascular system by noradrenaline and adrenaline as well as the responsiveness in disease states to therapeutic agents acting via alpha-adrenoceptors.

Topics: Animals; Cardiovascular System; Diabetes Mellitus, Experimental; Disease Models, Animal; Hemodynamics; Hypertension; Hyperthyroidism; Hypothyroidism; In Vitro Techniques; Male; Methimazole; Phenylephrine; Rats; Rats, Inbred SHR; Rats, Wistar; Receptors, Adrenergic, alpha-1; Triiodothyronine

Vascular reactivity to vasoconstrictors in relation to altered thyroid function was studied in two preparations: aortic strips and the isolated perfused kidney. To assess whether the possible alterations in vascular reactivity were restricted to a specific agonist or whether they involved the contractile system, receptor-mediated and nonspecific smooth muscle stimulants were used. Male Wistar rats were divided into three groups: control, hyperthyroid and hypothyroid rats. Aortic strips from hypothyroid rats were less sensitive to phenylephrine and KCl when the data were expressed in absolute values or as percentages of the maximum responses. Sensitivity and reactivity in strips from hyperthyroid rats were similar to those observed in control strips. Renal vasculature obtained from hypothyroid rats also showed a markedly reduced sensitivity to phenylephrine, with normal maximal responses. The response to vasopressin at 3-10(-11) mol/l was also decreased, as was the reactivity to barium chloride. In contrast, renal vasculature of hyperthyroid rats showed markedly enhanced reactivity to all agonists: the concentration-response curves were characterized by a similar threshold and a greater maximal response. These results demonstrate that hypothyroidism is accompanied by a marked decrease in sensitivity to vasoconstrictors in large arteries as well as in resistance vessels. This decrease may be secondary to a generalized alteration in the contractile system of vascular smooth muscle cells and may play a role in the decreased blood pressure in these animals. In contrast, isolated perfused kidneys of hyperthyroid rats showed increased vascular reactivity to vasoconstrictors, which may play a role in the maintenance of elevated blood pressure in these animals.

Topics: Animals; Aorta, Thoracic; Barium Compounds; Blood Pressure; Chlorides; Disease Models, Animal; Dose-Response Relationship, Drug; Hyperthyroidism; Hypothyroidism; In Vitro Techniques; Kidney; Male; Methimazole; Muscle Contraction; Muscle, Smooth, Vascular; Perfusion; Phenylephrine; Potassium Chloride; Rats; Rats, Wistar; Thyroxine; Vascular Resistance; Vasoconstrictor Agents; Vasopressins

Gammaglutamyltranspeptidase (GGT) activity is considered as a marker of liver phenotype, being maximally expressed in fetal liver and virtually absent in adult mature tissue. Since thyroid hormone has been identified to influence growth and development of almost all tissues, we have investigated the possible involvement of such factors in regulating rat hepatic GGT. Our results indicate that the activity of GGT in liver of perinatal hypothyroid rats is low as well as in control animals; instead, it is greatly increased in adult hypothyroid rats compared to controls of the same age (+260% in 2-month-old hypothyroid rats). Replacement therapy with T3 to hypothyroid rats normalizes the enzyme activity to the levels of control animals. Thyroid hormone appears to modulate the gene expression of the enzyme, since in the different thyroid status GGT mRNA level closely parallels the variations of the enzyme activity. These results further suggest that thyroid hormone plays a crucial role in maintaining the phenotype of adult liver tissue.

Topics: Animals; gamma-Glutamyltransferase; Gene Expression Regulation; Hypothyroidism; Liver; Male; Methimazole; Rats; Rats, Wistar; RNA, Messenger; Thyroid Hormones; Thyroxine; Triiodothyronine

Changes in serum amino-terminal type III procollagen propeptide (PIIIPN) and hydroxyproline were compared with indices of thyroid function in 33 patients with hyperthyroidism and 16 patients with hypothyroidism before and after treatment. Control values were obtained from 26 healthy individuals. Hyperthyroidism was shown to be associated with an increased level of PIIIPN and hypothyroidism with a decreased PIIIPN level. An increase in PIIIPN was found in 100% of hyperthyroid patients and a decrease in 31% of those with hypothyroidism, while hydroxyproline increased in only 54% of patients with hyperthyroidism and its level was decreased in only 6% of patients with hypothyroidism. Correlation between PIIIPN and thyroxine and triiodothyronine levels was shown. The results obtained suggest that PIIIPN is a valuable index of tissue response to thyroid hormones.

Topics: Adolescent; Adult; Female; Humans; Hydroxyproline; Hyperthyroidism; Hypothyroidism; Male; Methimazole; Middle Aged; Peptide Fragments; Procollagen; Radioimmunoassay; Thyroxine; Triiodothyronine

It has been postulated recently that cytokines, and in particular interleukin 1 (IL-1) and tumor necrosis factor-alpha (TNF-alpha), may have a role in the pathogenesis of the changes of serum thyroid hormone concentrations that are encountered in patients with non-thyroidal illness (NTI). Many of the IL-1 and TNF-alpha effects are believed to be mediated by the induction of IL-6 synthesis, which might, therefore, represent an important mediator of thyroid hormone changes in NTI. To address this problem, male Wistar rats were injected subcutaneously with 2.5 micrograms of recombinant human IL-6 (rhIL-6, in 500 microliters of saline solution), with 2.5 micrograms of rhIL-6 preincubated with 100 microliters of anti-IL-6 neutralizing antibody or with saline solution alone (control group). Administration of rhIL-6 resulted in a significant decrease of thyroxine (T4) from 82 +/- 4 nmol/l (mean +/- SEM) to a nadir of 33 +/- 3 nmol/l (p < 0.0001) after 48 h, and of triiodothyronine (T3) from 1.6 +/- 0.1 to 0.8 +/- 0.1 nmol/l after 48 h (p < 0.0001). A slight decrease in serum T4 and T3 concentrations also was observed in the control group, but the lowest values (T4, 66 +/- 3 nmol/l; T3, 1.2 +/- 0.1 nmol/l) were significantly higher (p < 0.0001) than in IL-6-treated rats. The IL-6-induced changes could be prevented by preincubation of rhIL-6 with its neutralizing antibody.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Hypothyroidism; Injections, Subcutaneous; Interleukin-6; Male; Methimazole; Pituitary Gland; Rats; Rats, Wistar; Recombinant Proteins; Thyroid Gland; Thyrotropin; Thyroxine; Triiodothyronine; Triiodothyronine, Reverse

Hypothyroidism was induced in young female Sprague-Dawley rats by the addition of methimazole (50 mg/kg BW.day) to drinking water for a period of 7 weeks (7-14 weeks of age). Replacement therapies of 0.7 U/kg BW human GH (hGH), 15 micrograms/kg BW L-T4 (T4), and a combination of hGH and T4 at the same doses were introduced during the last 2 weeks of the experiment. The responses of the cartilage and subchondral spongiosa of mandibular condyles were assessed by morphological and morphometric parameters. In addition, immunohistochemical localization of the GH receptor and insulin-like growth factor-I was determined by the streptavidin-biotin-peroxidase technique. In the hypothyroid rats, the trabecular bone volume of the subchondral spongiosa increased by 49%, indicating osteopetrosis. Along the ossification front, bone trabeculae occupied 18% and vascular elements 82% in mandibular condyles of control rats, whereas in hypothyroid rats, the percentage occupied by bone trabeculae increased to 89%. The cellularity of the cartilage in hypothyroid condyles was markedly reduced and was fully restored by T4, but not by GH replacement. Immunohistochemistry revealed the presence of GH receptors throughout the condyle regardless of the thyroid state of the animal. On the other hand, insulin-like growth factor-I immunohistochemical localization revealed the peptide to be present at all maturational stages of the cells in condyles from control and T4-treated rats, but to be lacking in young chondrocytes of hypothyroid and hGH-treated rats. This result demonstrates that the hypothyroid cartilage is compromised in its response to hGH.

Topics: Animals; Bone and Bones; Cartilage; Female; Growth Hormone; Growth Plate; Hypothyroidism; Immunohistochemistry; Insulin-Like Growth Factor I; Mandibular Condyle; Methimazole; Osteogenesis; Rats; Rats, Sprague-Dawley; Receptors, Somatotropin; Thyroxine

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

The thymus, as part of the immune-neuroendocrine axis, is greatly influenced by factors from most endocrine glands, especially the thyroid. Antithyroid drugs (carbimazole and methimazole) were used to induce hypothyroidism in rats. Histological and ultrastructural examination of the thymus showed progressive thymic involution after 4 weeks of drug treatment to the end of observations (7 weeks). The involution was characterised by increased thymocyte apoptosis and thymocyte phagocytosis by macrophages. This resulted in thymocyte depopulation, increases in numbers of interdigitating cells, alterations to mainly subcapsular and medullary epithelial cells, an apparent increase of mast cells and collagen in the capsule and septa, and increased numbers of B cells and plasma cells. Lymphoid cells immuno-reactive with MRC OX12 (which detects B cells) were observed within blood vessel walls, suggesting that they may have been moving in and out of the thymus. The administration of drugs causing hypothyroidism, therefore, also caused marked involution of the thymus.

Topics: Animals; Apoptosis; Body Weight; Carbimazole; Epithelium; Hypothyroidism; Immunohistochemistry; Macrophages; Male; Methimazole; Organ Size; Rats; Rats, Wistar; Thymus Gland; Triiodothyronine

Earlier studies have shown that plasma concentrations of endothelin 1 (ET-1) and the receptors for ET are altered during hyperthyroidism, while they are not affected during hypothyroidism. The present study was undertaken to determine the changes in concentration of endogenous ET-1 in various tissues of hyper- and hypothyroid rats. Hyperthyroidism was induced by daily administration of thyroxine (T4, 0.1 mg/kg, i.p.) for 8 weeks, while hypothyroidism was induced by daily administration of methimazole (10 mg/kg, i.p.) for 8 weeks. The concentration of endogenous ET-1 was determined in the brain regions (hypothalamus, corpus striatum, pituitary, hippocampus and spinal cord), heart, adrenals, kidneys and thoracic aorta using a radioimmunoassay procedure. Blood pressure and heart rate were significantly increased in hyperthyroid rats, while they were not affected in hypothyroid rats when compared with control (euthyroid) rats. Serum T4 and T3 levels were significantly increased in hyperthyroid rats, while they were significantly decreased in hypothyroid rats when compared with euthyroid rats. The concentrations of ET-1 in the hypothalamus, corpus striatum, hippocampus and spinal cord were not altered in hyper- or hypothyroid rats when compared with euthyroid rats. However, the pituitary showed a significant (p < 0.001) increase (104%) in ET-1 concentration in hyperthyroid rats when compared with euthyroid ones, while hypothyroid rats did not show any significant change in ET-1 concentration in the pituitary. In peripheral tissues ET-1 concentrations were not altered in the heart and adrenals of hyper- and hypothyroid rats when compared with euthyroid rats.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adrenal Glands; Animals; Aorta, Thoracic; Blood Pressure; Brain; Endothelins; Heart Rate; Hyperthyroidism; Hypothyroidism; Injections, Intraperitoneal; Kidney; Male; Methimazole; Myocardium; Radioimmunoassay; Rats; Rats, Sprague-Dawley; Thyroxine

Thyroid hormone deficiency following treatment with methimazole for 7 days does not reduce PAH secretion in renal tubular cells as expected from data in thyroid hormone treated rats. This treatment with methimazole causes an increase in renal excretion of PAH in rats of various age groups, statistically significant in 5-, 10- and 20-day-old rats. In 20-day-old, methimazole treated rats the increase in renal excretion of PAH is obviously caused by a higher transport rate in renal tubular cells, proved also in 33-day-old rats. An increased filtered fraction of PAH in 5- and 10-day-old rats could be the reason for the rise in renal excretion of PAH after repeated treatment with methimazole. The mechanism of renal effects of methimazole treatment remains unclear.

Topics: Animals; Biological Transport; Female; Hypothyroidism; Kidney; Kidney Tubules; Methimazole; p-Aminohippuric Acid; Rats; Rats, Wistar; Thyroid Hormones; Thyroxine; Triiodothyronine

The presence of human blood-group antigens in developing and adult hypothyroid rat cochleas was analyzed using antibodies directed against antigens H and B. During postnatal development, hypothyroid rat cochleas exhibited a highly selective expression of both B and H antigens, mainly at the hair cell level. Labeling for antigen B was found throughout the hair cells, whereas the antibody directed against antigen H selectively labeled the apical part of these cells. These immunostaining patterns were similar to those found in normal (euthyroid) rat cochleas, but antigenic expression periods were clearly prolonged. Thus, whereas in normal rat cochleas, the B and H antigenic expression disappears from postnatal day (PD) 9 on, in cochleas of hypothyroid rats the reactivity was intense until PD15; it decreased from this developmental stage, and was negative or only faintly positive at PD30. Therefore, in congenital hypothyroidism, hair cell immunoreactivity is present at developmental stages that are negative in normal rat cochleas. These results suggest that human blood-group antigen expression on the developing cochlear hair cells of rats is modulated by thyroxine and that thyroxine is necessary for the temporal expression pattern and secretion of normal glycoproteins.

Topics: ABO Blood-Group System; Age Factors; Animals; Antibodies, Monoclonal; Cell Differentiation; Cochlea; Cochlear Diseases; Congenital Hypothyroidism; Female; Fluorescent Antibody Technique; Gene Expression Regulation; Hair Cells, Auditory; Hypothyroidism; Methimazole; Pregnancy; Prenatal Exposure Delayed Effects; Rats; Rats, Sprague-Dawley; Thyroxine

We have examined the effects of perinatal hypothyroidism on the levels of several G protein subunits in developing rat cerebral cortex. Thyroid deficiency significantly reduced the levels of the short form of G alpha s (G alpha s-s) by 70% and 83%, on P17 and P22, respectively, but had no effect on the long form of G alpha s (G alpha s-1), except that the G alpha s-1 levels were moderately increased on P22. Compared with age-matched controls, no significant differences were observed for G alpha i-1, G alpha i-2, G alpha o, G alpha q/11, G beta 1 and G beta 2 immunoreactivity in the cerebral cortex of the 22-day-old hypothyroid pups. These findings suggest that thyroid hormones may play an important role in controlling the pattern of expression of G alpha s isoforms during neonatal brain development and the reduced levels of G alpha s-s may contribute to some of the developmental abnormalities seen with perinatal hypothyroidism by altering signal transduction and intercellular communication.

Topics: Aging; Animals; Cerebral Cortex; Electrophoresis, Polyacrylamide Gel; Female; GTP-Binding Proteins; Hypothyroidism; Immunoblotting; Isomerism; Methimazole; Pregnancy; Rats; Rats, Wistar

Our previous studies indicate the Sertoli cell as a target for thyroid hormone action at testis level. In the present study we evaluated the effect of thyroid hormone on Sertoli cell oxidative capacity measured by specific cytochrome oxidase (COX) activity and intracellular adenosine triphosphate (ATP) content. Sertoli cells were isolated from 21-day-old rats. Hypothyroidism, induced from the day of birth by administration of 0.025% methimazole, was characterized by a severe delay of body and testis growth and resulted in a lower COX activity (-40%, p < or = 0.01) and a lower ATP content (-35%, p < or = 0.01) by isolated Sertoli cells. Administration of triiodothyronine (10 micrograms/100 g body wt on alternate days) to hypothyroid rats improved body and testis growth and restored both COX activity and ATP content. The presence of high-affinity, low-capacity binding sites for triiodothyronine in Sertoli cell mitochondria also was demonstrated. This study, unlike that carried out on the whole testis from adult rats, demonstrates that thyroid hormone affects the energy metabolism of Sertoli cells from midpubertal rat testes.

Topics: Adenosine Triphosphate; Aging; Animals; Cell Separation; Cells, Cultured; Electron Transport Complex IV; Energy Metabolism; Hypothyroidism; Male; Methimazole; Mitochondria; Oxidation-Reduction; Rats; Rats, Wistar; Sertoli Cells; Testis; Thyroid Gland; Triiodothyronine

The aim of the present study was to investigate the influence of thyroid hormones on androgen metabolism in Sertoli cells isolated from 3- and 4- week-old rats. Hypothyroidism was induced by the oral administration of 0.025% methimazole (MMI) from birth until the rats were killed at 3 and 4 weeks of age. Half of the MMI-treated animals were injected i.p. with L-triiodothyronine (T3 3 micrograms/100 g body weight) during the last week before death. Sertoli cells from all groups were initially cultured under basal conditions for the first 24 h and subsequently in the presence of testosterone with or without T3 for an additional 24 h. Hypothyroidism was associated with severe impairment of body as well as testicular growth. Indeed, body and testicular weights were similar in 4-week-old hypothyroid animals to those in 3-week-old control rats. Testosterone metabolism in Sertoli cells isolated from 3- and 4-week-old hypothyroid rats was mainly expressed by the lowering of 5 alpha-dihydrotestosterone + androstane 3 alpha, 17 beta-diol and an enhanced formation of 5 alpha-reduced steroids with poor androgenic properties (e.g. 5 alpha-androstane, 3, 17 alpha-dione (androstanedione), 5 alpha-androstane, 3-ol-17-one (androsterone)). Treatment of the same group of animals with T3 in vivo and in vitro did not influence the pattern of 5 alpha-reductase steroids substantially. The most striking finding in the Sertoli cells of 3-week-old hypothyroid rats was the dramatic enhancement of oestradiol formation which persisted to a lesser extent 1 week later.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Androgens; Androstane-3,17-diol; Androstenedione; Androsterone; Animals; Body Weight; Cells, Cultured; Dihydrotestosterone; Estradiol; Hypothyroidism; Male; Methimazole; Organ Size; Rats; Rats, Wistar; Sertoli Cells; Sexual Maturation; Testis; Testosterone; Triiodothyronine

Endothelin (ET) mechanisms were studied in hyper- and hypo-thyroid states in rats. Hyperthyroidism was induced by daily administration of thyroxine (0.1 mg/kg, i.p.) for 8 weeks, while hypothyroidism was induced by daily administration of methimazole (10 mg/kg, i.p.) for 8 weeks. The concentration of endogenous ET-1 was determined in the kidneys using radioimmunoassay. Systemic hemodynamics and renal blood circulation was measured using a radioactive microsphere technique. A significant increase in systolic and diastolic blood pressure, heart rate and cardiac output was observed in hyperthyroid rats as compared to eu- and hypo-thyroid rats. Total peripheral resistance was found to be similar in eu-, hyper- and hypo-thyroid rats. The endogenous concentration of ET-1 in the kidneys was significantly lower in hyper- as compared to eu- and hypo-thyroid rats. The blood flow to the kidneys was significantly increased in hyper- as compared to eu- and hypo-thyroid rats. Infusion of ET-1 (100 ng/kg/min i.v. for 45 min) produced a significant decrease in blood flow to the kidneys of eu-, hyper- and hypo-thyroid rats. The decrease in blood flow was similar in eu-, hyper- and hypo-thyroid rats, indicating that the response of renal blood vessels to exogenous ET-1 is not altered during thyroid dysfunction. Since endogenous ET-1 is involved in the regulation of vascular tone, it may be concluded that in hyper-thyroid rats decrease in concentration of the renal ET-1 could be contributing to an increase in blood flow to the kidney.

Topics: Animals; Endothelins; Hemodynamics; Hyperthyroidism; Hypothyroidism; Kidney; Male; Methimazole; Rats; Rats, Sprague-Dawley; Renal Circulation; Thyroxine

This study has investigated adrenoceptor-mediated responses and beta-adrenoceptors in neonatal-onset hypothyroidism in rats. Four groups of adult rats were studied: controls, neonatal-onset uncorrected hypothyroidism (continuous oral methimazole treatment) and after chronic triiodothyronine (T3) replacement of these rats at either 25 or 100 micrograms/kg/day for 8 weeks beginning at 12 weeks of age. Hypothyroid rats were 61% smaller with an 18% decrease in heart rate; food and water intake were reduced to 43% and 52%, respectively; O2 consumption was reduced to 20% and rectal temperature was 2.9 degrees lower. T3 administration increased body weight to 60-62% of controls; metabolic changes were reversed; but tachycardia and cardiac hypertrophy (60-120% increases) resulted. The positive inotropic responses to the selective alpha 1-adrenoceptor agonist, phenylephrine, in left ventricular papillary muscles were abolished; the beta 1-adrenoceptor agonist, noradrenaline, was significantly less potent as an inotropic compound in isolated cardiac tissues from hypothyroid rats. The potency of phenylephrine to contract thoracic aortic rings was reduced in hypothyroid rats. These changes in alpha- and beta-adrenoceptor mediated responses were reversed by T3 administration. Both beta 1- and beta 2-adrenoceptor densities were increased in the hypothyroid left ventricle; T3 administration further increased beta 1-adrenoceptor density. We conclude that neonatal hypothyroidism produces pronounced physiological responses, changes in adrenoceptor-mediated responses and an increased ventricular beta 1-adrenoceptor density. T3 replacement reversed the changes in cardiac responses and metabolic parameters, except body weight, but produced cardiac symptoms of hyperthyroidism (tachycardia, hypertrophy as well as an increased beta 1-adrenoceptor density).

Topics: Animals; Aorta, Thoracic; Calcium Chloride; Dose-Response Relationship, Drug; Hypothyroidism; In Vitro Techniques; Methimazole; Myocardial Contraction; Norepinephrine; Papillary Muscles; Phenylephrine; Rats; Rats, Wistar; Receptors, Adrenergic, beta; Triiodothyronine

Callosal connections were studied with tracers (horseradish peroxidase (HRP) and wheat germ agglutinin-horseradish peroxidase (WGA-HRP)) in normal rats and rats deprived of thyroid hormones with methimazole (Sigma) since embryonic day 14 and thyroidectomized at postnatal day 6. In hypothyroid rats, the auditory areas, in particular the primary auditory area, showed cytoarchitectonic changes including blurred lamination and decrease in the size of layer V pyramidal neurons. In control rats, callosally-projecting neurons were found between layers II and VI with a peak in layer III and upper layer IV. In hypothyroid rats, labelled neurons were found between layers IV and VI with two peaks corresponding to layer IV and upper layer V, and in upper layer VI. Quantitative analysis of radial distribution of callosally-projecting neurons confirmed their shift to infragranular layers in hypothyroid rats. Three-dimensional reconstructions showed a more continuous tangential distribution of callosally-projecting neurons in hypothyroid rats which may be due to the maintenance of a juvenile 'exuberant' pattern of projections. These changes in cortical connectivity may be relevant for understanding epilepsy and mental retardation associated with early hypothyroidism in humans and to clarify basic mechanisms of cortical development.

Topics: Animals; Auditory Pathways; Axonal Transport; Corpus Callosum; Female; Horseradish Peroxidase; Hypothyroidism; Methimazole; Neurons; Rats; Rats, Wistar; Thyroidectomy; Wheat Germ Agglutinin-Horseradish Peroxidase Conjugate; Wheat Germ Agglutinins

Normal somatic growth requires that both the thyroid hormone axis and GH axis be intact. Thyroid hormone stimulates GH secretion, and many thyroid hormone actions on the insulin-like growth factor (IGF) system can be explained by this mechanism. We have previously described distinct changes in IGF binding protein (IGFBP) expression in experimental hypothyroidism in the rat; these changes could be completely corrected by thyroid hormone replacement. To see if the effects of thyroid hormone on IGFBP expression are, in fact, indirect GH effects, we rendered both newborn and adult rats hypothyroid with methimazole treatment, and investigated whether we could correct the resulting IGF and IGFBP changes with GH replacement. The prolonged high expression of serum IGFBP-2 and liver IGFBP-2 messenger RNA (mRNA) during the perinatal period in hypothyroid rat pups could not be normalized by GH therapy, although serum IGF-I values (reduced to 54% of control levels in the hypothyroid animals) were brought up to control level. In adult hypothyroid rats, serum IGF-I concentrations (51% of control levels), were increased up to 79% of control levels, but not totally corrected, by GH therapy. Reduced IGFBP-3 expression (80% of control serum and 50% of control liver mRNA levels) in adult hypothyroid animals was normalized by GH, but there was no correction of the reduced IGFBP-4 serum levels (50% of control levels). Hepatic mRNA levels for the type 1 and 2 IGF receptors were not altered by hypothyroidism, or by thyroid or GH replacement. Somatic growth in hypothyroid pups and adults was only partially corrected by GH therapy. We conclude that GH treatment of hypothyroid animals normalized serum IGF-I levels in the hypothyroid rat pup, but did not correct their prolonged IGFBP-2 expression. In the mature animal, serum IGF-I levels were partially corrected and IGFBP-3 levels were normalized by GH, but no change could be induced in the reduced serum IGFBP-4 levels. All the above changes were normalized by thyroid hormone replacement. Thus, the effects of thyroid hormone on serum IGF levels and IGFBP-3 expression seem to be mediated indirectly via GH. The effects on IGFBP-2 ontogeny, and IGFBP-4 expression in the mature animal, however, are either direct thyroid hormone effects, or mediated by some other route, independent of GH, IGFs, or IGF receptors.

Topics: Aging; Animals; Animals, Newborn; Carrier Proteins; Cell Membrane; Female; Growth Hormone; Hypothyroidism; Insulin-Like Growth Factor Binding Protein 1; Insulin-Like Growth Factor Binding Protein 2; Insulin-Like Growth Factor Binding Protein 4; Insulin-Like Growth Factor Binding Proteins; Insulin-Like Growth Factor I; Liver; Male; Methimazole; Pregnancy; Rats; Rats, Wistar; Reference Values; RNA, Messenger; Thyroxine; Weight Gain

Congenital hypothyroidism strongly affects myelination. To assess the role of thyroid hormone on myelin gene expression, we have studied the effect of hypothyroidism on the steady state levels of myelin-associated glycoprotein (MAG) and its mRNA in rat brain during the first postnatal month. As studied by immunoblot analysis of several brain regions, MAG increased from days 10-15 onwards, reaching constant levels by days 20-25. Hypothyroid samples showed a delay in the accumulation of MAG that was more severe in rostral regions, such as cortex and hippocampus. The effect of hypothyroidism on the accumulation of the protein correlated with mRNA levels. MAG mRNA started to accumulate in the cerebrum of normal animals by postnatal day 7, reaching maximal levels by day 20. Hypothyroid rats showed a delay of several days in the onset of mRNA expression, increasing thereafter at the same rate as in normal animals, and eventually reaching similar values. When individual brain regions were analyzed, we found strong regional differences in the effect of hypothyroidism. The cerebral cortex was most affected, with messenger levels lower than in normal animals at all ages. In more caudal regions differences between control and hypothyroid rats were evident only at the earlier stages of myelination, with spontaneous recovery at later ages. By run on analysis, we found no differences in transcriptional activities of the MAG gene in normal, hypothyroid, or T4-treated rats. Therefore, the effects of hypothyroidism on MAG mRNA and protein levels were most likely caused by decreased mRNA stability. We propose that thyroid hormone contributes to enhanced myelin gene expression by affecting the stability of newly transcribed mRNA in the early phases of myelination.

Topics: Aging; Animals; Animals, Newborn; Blotting, Northern; Brain; Cerebellum; Cerebral Cortex; Corpus Striatum; Hippocampus; Hypothalamus; Hypothyroidism; Mesencephalon; Methimazole; Myelin Proteins; Myelin-Associated Glycoprotein; Organ Specificity; Rats; Rats, Wistar; RNA, Messenger; Thyroxine; Triiodothyronine

In this study, we determined gene expression of both insulin-like growth factor (IGF)-I and bone Gla protein (BGP; osteocalcin) in calvaria in comparison with their serum levels in methimazole (MMI)-induced congenital hypothyroid (CHT) rats during the first 4 weeks of life. Pups from the MMI-treated dams revealed congenital hypothyroidism with cretinoid physical appearance and showed significant growth retardation compared to the controls. The expression of mRNA for IGF-I in the CHT pups lacked the age-associated increase with a little spurt in their somatic growth rate, although the expression in the controls increased steeply (from 1.86-fold on postnatal day 21 to 3.52-fold on day 28 compared to the day 7 value; P < 0.01) according to the spurt in their growth. Moreover, serum IGF-I levels in the CHT rats were significantly lower than those in the controls on postnatal day 28 (63.0 +/- 8.0 ng/ml vs. 285.0 +/- 33.2 ng/ml, respectively; P < 0.01). Both BGP gene expression in calvaria and serum intact molecular BGP levels determined by a newly developed ELISA (164.4 +/- 15.5 ng/ml in the CHT rat vs. 238.6 +/- 17.8 ng/ml in the control on postnatal day 28; P < 0.01) correlated well with the somatic growth in the two groups and clearly demonstrated impaired osteogenesis in the CHT rats. Further studies are needed to clarify how hypothyroidism affects somatic growth and bone metabolism; it is particularly important to understand the autocrine/paracrine mechanisms of action of IGFs in the bone matrix turnover, in vivo.

Topics: Animals; Blotting, Northern; Densitometry; Enzyme-Linked Immunosorbent Assay; Female; Gene Expression; Hypothyroidism; Insulin-Like Growth Factor I; Methimazole; Osteocalcin; Pregnancy; Radioimmunoassay; Rats; Rats, Sprague-Dawley; RNA, Messenger; Skull; Thyronines

To investigate the role of thyroid hormone in the expression of the gene encoding the growth hormone receptor (GHR) and growth hormone binding protein (GHBP), fetal rats were made hypothyroid through the administration of the goitrogen methimazole to the mother. Euthyroidism was maintained in the mother by concurrent administration of L-thyroxine, which crosses the placenta poorly. Methimazole and L-thyroxine were continued in the mothers until weaning. After birth, groups of methimazole-treated or control pups were sacrificed immediately and at one, two, three, four, five, or six weeks after birth. In each group, weight was recorded, blood was obtained for measurement of T4, thyroid stimulating hormone (TSH), and growth hormone (GH), and liver tissue was obtained for quantitation of GHR and GHBP mRNA. The methimazole-treated pups were demonstrated to be hypothyroid, with markedly higher TSH and lower T4 concentrations, until weaning occurred between weeks three and four, after which they transiently became hyperthyroid at week five (T4 = 17 +/- 5 micrograms/dL vs. 6 +/- 0.5 micrograms/dL for controls) but returned to an euthyroid state at week six. In control pups the relative abundance of GHR and GHBP mRNA increased abruptly in week one, and increased three to four fold over the ensuing six weeks. Immediately after birth, the hypothyroid pups expressed significantly more GHR and GHBP mRNA than did the controls (P < 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Animals, Newborn; Blotting, Northern; Carrier Proteins; Female; Gene Expression Regulation; Growth Hormone; Hypothyroidism; Methimazole; Pregnancy; Rats; Receptors, Somatotropin; RNA, Messenger; Thyrotropin; Thyroxine

In this study we compared the functions of normal peritoneal macrophages with those from methimazole-induced hypothyroid C57BL/6 mice. Methimazole (MMI) suppressed the expression of the tumor necrosis factor (TNF) gene in peritoneal macrophages (MAM) at both transcriptional and translational levels. The kinetics of TNF synthesis by MAM following in vivo and in vitro lipopolysaccharide (LPS) challenge were different, but both treatments resulted in significant decreases (P < 0.05) in TNF mRNA and protein after 60 min. Similarly, the production of reactive nitrogen and oxygen intermediates by MAM were significantly (P < 0.05) lower compared with control macrophages (CAM). In addition, the serum TNF protein was significantly lower (P < 0.05) in MMI-treated mice following intravenous LPS challenge for 90 min. These data suggested that peritoneal macrophages were inactivated in MMI-induced hypothyroid mice.

Topics: Animals; Blotting, Northern; Cells, Cultured; Gene Expression; Hypothyroidism; Lipopolysaccharides; Macrophages; Male; Methimazole; Mice; Mice, Inbred BALB C; Nitrites; Peritoneal Cavity; RNA, Messenger; Superoxides; Tumor Necrosis Factor-alpha

The authors used a new protocol, based upon a supersensitive TSH assay, to examine the thyroid status of 1720 patients. Based upon the serum hormone levels, the patients were divided into different clinical groups. The biochemical relationship between the different hormone levels, and the rate of occurrence of various thyroid diseases were studied. 76.1% of the new patients hadn't received any previous treatment. 15.5% of those patients who had received treatment had hyperthyroidism, while 8.4% of those had hypothyroidism. 76% of the new patients, 38.3% of those who had hyperthyroidism, and only 29.7% of those who had hypothyroidism, were euthyroid. Undetectable TSH levels (< 0.03 mU/L) where observed in 51.8% of the new hyperthyroid patients, and in 33.8% of those who had subclinical hyperthyroidism. Similar results were obtained with those who had been previously treated for hyperthyroidism. The new protocol has the following advantages: it's more convenient to the patients, it's quick, it's economical. With this method it is possible to reduce the assays per patient by 31%. The algorithm was supplemented with results of free hormone levels. By doing this the authors were able to measure free-T4 and T3 hormone levels of 150 more patients. According to the authors, the free-T4 test is more informative than the free-T4-index, especially in the border-line cases and in treated hyperthyroidism. Primarily the free-T3 test is most necessary when examining patients treated with methimasol.

Topics: Adrenergic beta-Antagonists; Algorithms; Female; Humans; Hyperthyroidism; Hypothyroidism; Male; Mass Screening; Methimazole; Monitoring, Physiologic; Thyroid Function Tests; Thyrotropin; Thyroxine; Triiodothyronine

The purpose of this work was to study if TSH has a role in TPO antigen expression in vivo. Using the cytotoxicity assay we measured TPO expression and correlated it with TSH serum levels in 3 groups of rats: control, hypothyroid and hypothyroid supplemented with thyroxine. For comparative purposes, in the cytotoxicity assay we used rat monoclonal antiTPO or human sera with high titles for antiTPO antibodies. Hypothyroid rats showed marked elevations of TSH serum levels and TPO antigen expression in their thyrocytes when compared to the control and supplemented group. A positive correlation between TPO antigen and TSH levels was observed (r = 0.69, p < 0.001). There was an excellent correlation between TPO results using rat monoclonal or human sera antibodies (r = 0.94 p < 0.0001). It is concluded that TSH modulates TPO antigen expression. These data are of clinical relevance considering that TSH modulates the expression of other antigens that can maintain the immune response and perpetuate the immune disease in patients with Graves disease treated with antithyroid drugs. Thus, the avoidance of TSH hypersecretion with administration of thyroxine could be useful to treat these patients.

Topics: Analysis of Variance; Animals; Body Weight; Humans; Hypothyroidism; Iodide Peroxidase; Male; Methimazole; Rats; Rats, Sprague-Dawley; Thyrotropin; Thyroxine; Time Factors

Topics: Animals; Erythrocytes; Female; Ferritins; Hypothyroidism; Iron; Methimazole; Rats; Rats, Wistar; Reference Values; Thyrotropin; Thyroxine

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

Topics: Animals; Dermatologic Surgical Procedures; Fibroblasts; Hypothyroidism; Male; Methimazole; Rats; Rats, Wistar; Thyroid Gland; Wound Healing

Male Sprague Dawley rats were rendered hyperthyroid and hypothyroid by the intraperitoneal injections of 1-thyroxine or methimazole and sacrificed 21 days after the start of the treatment. The pituitaries were studied by immunoelectron microscopy by the immunogold labeling technique. In both hyperthyroidism and hypothyroidism, the numbers of growth hormone (GH) cells, GH-secreting granules and immunogolds in the secretory granules all were significantly decreased as compared with those in controls. The results indicate that low or high levels of thyroid hormones may cause decrease of GH production of the pituitary.

Topics: Animals; Growth Hormone; Hyperthyroidism; Hypothyroidism; Male; Methimazole; Microscopy, Immunoelectron; Pituitary Gland; Rats; Rats, Sprague-Dawley; Thyroxine

Endothelin (ET) and its receptor characteristics were studied in hyper- and hypo-thyroid states in the rats. Hyperthyroidism was induced by daily administration of thyroxine (0.1 mg/kg i.p.) for 8 weeks, while hypothyrodism was induced by daily administration of methimazole (10 mg/kg i.p.) for 8 weeks. The chronic administration of thyroxine to rats decreased their rate of gain of body weight, increased serum T3 and T4 concentration, blood pressure and heart rate. The chronic administration of methimazole decreased the rate of gain of body weight, serum T3 and T4 concentration, blood pressure and heart rate as compared to vehicle-treated control. Plasma ET-1 levels were found to be similar in control and methimazole-treated rats, while the levels were found to be significantly (P < 0.002) increased in thyroxine-treated rats as compared to control rats. Binding studies showed that [125I]ET-1 bound to a single, high affinity binding site in the cerebral cortex, hypothalamus and pituitary. The density (Bmax) and the affinity (Kd) of [125I]ET-1 binding in the cerebral cortex and hypothalamus were found to be similar in control, methimazole- and thyroxine-treated rats. The pituitary of thyroxine-treated rats showed a decrease in the binding (34.3% decrease in the density) of [125I]ET-1 as compared to control rats. No difference was observed in the binding of [125I]ET-1 to pituitary membranes from control and methimazole-treated rats. Competition studies showed that the IC50 and Ki values of ET-3 for [125]ET-1 binding were about 8 to 11 times higher than ET-1 in cerebral cortex, hypothalamus and pituitary.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Binding, Competitive; Blood Pressure; Body Weight; Cerebral Cortex; Endothelins; Heart Rate; Hyperthyroidism; Hypothalamus; Hypothyroidism; Iodine Radioisotopes; Kinetics; Male; Methimazole; Pituitary Gland; Radioimmunoassay; Rats; Rats, Sprague-Dawley; Receptors, Endothelin; Thyroxine; Triiodothyronine

To assess the effects of hypothyroidism (HT) on small-intestinal function, HT was induced in rats (120-150 g) by methimazole in drinking water. After 6 wk of methimazole, intestinal absorption studies were performed in HT and in control (C) rats by in situ luminal perfusion of a 20-cm proximal jejunal loop with a bicarbonate buffer containing sodium, glucose or fructose, glycine or lysine, and phenol red as a nonabsorbable marker for determination of water fluxes. Mucosa from the perfused segment was taken for assay of disaccharidases and ATPases and for light and electron microscopy. Compared with C rats, HT rats had significantly lower jejunal transport rates of water (2.54 +/- 0.36 versus 5.02 +/- 0.7 microL/min/microgram mucosal protein, p < 0.03), sodium (37.1 +/- 10.3 versus 102.7 +/- 18.6 mumol/min/microgram protein, p < 0.05), and glucose (1.49 +/- 0.28 versus 5.17 +/- 0.82 mumol/min/microgram protein, p < 0.02). A reduction in glycine transport was also observed but did not attain statistical significance (p = 0.058). Fructose and lysine transport was unchanged. Mucosal sucrase and lactase activities were similar in both groups, but Na,K-ATPase was significantly lower in HT rats (1.17 +/- 0.3 versus 4.03 +/- 1.5 mumol inorganic phosphate/h/mg protein; p < 0.05), with a diminution of ouabain binding sites by 41.5%. Light microscopy of jejunal mucosa from HT rats did not differ from that from C rats; electron microscopy showed mild mitochondrial swelling in HT enterocytes. A group of HT rats were treated with L-thyroxine during 4 wk; these rats had absorption rates, mucosal enzyme activities, ouabain binding, and mucosal morphology not different from C rats.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Biological Transport, Active; Body Water; Glucose; Hypothyroidism; Intestinal Absorption; Intestinal Mucosa; Jejunum; Male; Methimazole; Perfusion; Rats; Rats, Sprague-Dawley; Sodium; Sodium-Potassium-Exchanging ATPase

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

Although characterized as hypothyroid, streptozotocin-diabetic rats have reduced serotonin turnover (5-hydroxyindoleacetic acid/serotonin, 5-HIAA/5-HT) in brain stem, while hypothyroid rats have increased 5-HIAA/5-HT. In the present study the two treatments were combined to determine if they affected 5-HIAA/5-HT through the same mechanism. In addition, an alternative method was used to assess 5-HT activity in thyroidectomized (TX) rats, i.e. measurement of 5-HT disappearance after inhibition of tryptophan hydroxylase with p-chlorophenylalanine (PCPA). Adult male rats were first TX (experiment 1) or given methimazole (METH; experiment 3). Two weeks later, diabetes (DB) was induced with streptozotocin in hypothyroid rats and euthyroid controls. Two weeks later, functional measurements were taken. Rats were then killed, and spinal cord and brain stem serotonin turnover (5-HIAA/5-HT), as well as plasma T3, T4 and corticosterone (CORT) concentrations were measured. TX attenuated diabetic hyperphagia and weight loss. DB alone led to moderate reductions in T3 and T4, but the hormones were barely detectable in plasma of TX and METH rats. CORT was elevated in DB but was not affected by TX. Open field activity was not affected by DB or TX. TX and METH significantly increased 5-HIAA/5-HT in both spinal cord and brain stem. TX also led to enhanced disappearance of 5-HT after PCPA. DB significantly reduced 5-HIAA/5-HT, suggesting independent effects of the treatments. However, DB-TX rats still had significantly higher 5-HIAA/5-HT than control-sham surgery rats, while DB-METH rats had 5-HIAA/5-HT indistinguishable from controls. In both cases, prior induction of primary hypothyroidism interfered with the expected diabetes-induced reduction in 5-HT turnover.

Topics: Animals; Corticosterone; Diabetes Mellitus, Experimental; Exploratory Behavior; Fenclonine; Hydroxyindoleacetic Acid; Hypothyroidism; Male; Methimazole; Rats; Rats, Sprague-Dawley; Serotonin; Streptozocin; Thyroid Gland; Thyroidectomy; Thyroxine; Triiodothyronine

In a patient chronically treated with amiodarone, subclinical iodine-induced hypothyroidism occurred as a result of excess iodine released from the amiodarone molecule. The patient was maintained on amiodarone and developed thyrotoxicosis as a result of a destructive process into the thyroid follicles. Amiodarone was withdrawn and methylprednisolone and methimazole treatment was started with resolution of the thyrotoxic phase. Months later, off therapy, the patient developed subclinical hypothyroidism. This is the first description of hypo- and hyperthyroidism in the same patient caused by amiodarone therapy. This unusual observation suggests that patients treated with amiodarone are at risk to develop hyperthyroidism even if they show laboratory findings consistent with hypothyroidism.

Topics: Amiodarone; Antibodies; Humans; Hypothyroidism; Male; Methimazole; Methylprednisolone; Middle Aged; Tachycardia, Supraventricular; Thyroglobulin; Thyrotoxicosis; Thyrotropin; Thyroxine; Triiodothyronine

The aim of the study was answering the question whether determination of psychical reaction time may be useful for the monitoring of treatment of hypothyreosis and hyperthyreosis. The correlation of disease symptoms (diagnostic index for hypothyroidism after Murray and for hypothyroidism according to Crooks), concentration of triiodothyronine, thyroxine, index of free thyroxine in blood serum and Achilles tendon reflex--with the simple reaction time (srt) as well as with the choice reaction time (chrt) before and during treatment was investigated in 18 patients with primary hypothyroidism and in 24 with hyperthyroidism caused by Graves-Basedow's disease. Two control groups comprised 84 healthy persons. Either in hypothyroidism or in hyperthyroidism the srt and chrt was significantly prolonged. The substitution therapy in hypothyroidism resulted in a normalization of both parameters. On the other hand, administration of thiamazole, especially in the early period of treatment of hyperthyroidism, further prolonged the srt and chrt. A shortening of the time of each of the two reactions occurred, however, when the restoration of euthyroidism was achieved, which was accompanied by reduction of thiamazole dosage. The obtained data point to the usefulness of srt and chrt determination for the diagnosis and therapy monitoring of functional disturbances of the thyroid gland.

Topics: Adult; Female; Humans; Hyperthyroidism; Hypothyroidism; Male; Methimazole; Middle Aged; Reaction Time

The purpose of this study was to evaluate the contribution of endogenous GH-releasing hormone (GHRH) to exogenous GH-releasing hexapeptide (GHRP-6) activity, and to determine whether TRH or GnRH are endogenous analogs of GHRP-6. The activity of GHRP-6, a synthetic GH secretagogue, was significantly attenuated in rats administered GHRH antiserum or alpha-methyl-rho-tyrosine to reduce endogenous GHRH concentrations, and also in rats administered 5-50 micrograms/kg of [N-Ac-Tyr1,D-Arg2]-GRF 1-29 amide to block pituitary GHRH receptors. However, GHRP-6 activity was potentiated in rats administered 150 micrograms/kg [N-Ac-Tyr1,D-Arg2]-GRF 1-29 amide, presumably due to partial agonist activity of the GHRH receptor antagonist at the higher dose. These data show that endogenous GHRH contributes to full expression of exogenous GHRP-6 activity in vivo. Like TRH, a subthreshold dose of GHRP-6 was significantly more effective in hypothyroid rats than in euthyroid rats. However, suprathreshold doses of GHRP-6 were less effective in hypothyroid rats. Unlike TRH, GHRP-6 had no effect on GH and prolactin release from GH3 cells, and TRH and GnRH were poor competitors for 3H-GHRP-6 binding sites on pituitary membranes. A GnRH receptor antagonist did not block GHRP-6 activity in vivo, and GnRH administered alone or in combination with GHRP-6, did not stimulate GH release. The results of this study suggest that synergy between GHRH and GHRP-6 seen in pharmacological studies is physiologically relevant, and that TRH and GnRH are not endogenous analogs of GHRP-6.

Topics: alpha-Methyltyrosine; Animals; Cell Line; Dose-Response Relationship, Drug; Female; Growth Hormone; Growth Hormone-Releasing Hormone; Hormones; Hypothyroidism; Immune Sera; Methimazole; Methyltyrosines; Oligopeptides; Pituitary Neoplasms; Rats; Rats, Inbred Strains; Receptors, Neuropeptide; Receptors, Neurotransmitter; Receptors, Pituitary Hormone-Regulating Hormone; Thyroid Gland; Thyroxine; Triiodothyronine

The effects of hypothyroidism on whole body thermogenesis, brown adipose tissue recruitment state, and alpha 1-adrenergic receptor density were investigated. Treatment of rats with methimazole for 4-5 wk led, as expected, to reduction of growth and resting metabolic rate. The thermogenic response to norepinephrine injection was practically abolished. Generally, only small effects of hypothyroidism on brown adipose tissue were observed: total protein content, mitochondrial GDP binding capacity, and total content of the uncoupling protein thermogenin were not altered. The density of beta-adrenergic receptors (estimated with [3H]CGP-12177 as a ligand) was also unchanged. However, the density of alpha 1-adrenergic receptors (estimated with [3H]prazosin) was markedly increased; in other physiological conditions, such an increase has been associated with an increased degree of recruitment of the tissue. These data indicate that brown adipose tissue in the subthermoneutral hypothyroid animal, probably due to homeostatic mechanisms, is exposed to an increased sympathetic stimulation, leading to an increased alpha 1-adrenoceptor density. However, other features of recruitment are only poorly induced, probably due to attenuation of the beta-adrenergic signaling mechanism. The increased alpha 1-adrenergic receptor density may be responsible for certain altered features of brown adipose tissue in hypothyroid animals, such as peroxisomal recruitment and perhaps also for maintenance of the thermogenin content. The results also indicate that the increased alpha 1-adrenergic density generally seen in recruitment would not result from chronic beta-adrenergic stimulation of the tissue but may be controlled via another regulatory pathway, e.g., via the alpha 1-adrenergic pathway itself.

Topics: Adipose Tissue, Brown; Animals; Body Temperature Regulation; Cold Temperature; Female; Hypothyroidism; Methimazole; Norepinephrine; Rats; Rats, Sprague-Dawley; Receptors, Adrenergic; Receptors, Adrenergic, alpha; Rest

Thyroid hormone is essential for normal growth and development. For certain T4 effects, there is a critical period during ontogeny when normal T4 levels are required, and thyroid replacement after that period cannot correct the changes in hypothyroid animals. We have previously described a prolonged high expression of serum insulin-like growth factor binding protein (IGFBP)-2 during the perinatal period in congenitally hypothyroid rats. To see if this effect was confined only to a certain period during rat ontogeny, we made rats hypothyroid with methimazole treatment either prenatally, or at different postnatal ages from 1 to 14 days of life, and at adult age. Serum IGF-I levels were reduced by approximately 30% in all the 18-day-old hypothyroid animals, and did not correlate with the duration of the hypothyroid state. Serum IGF-I levels in the adult animals were 50% of control levels. At the age of 18 days, control animals had only very low levels of IGFBP-2 demonstrable by western ligand blotting, whereas the congenitally hypothyroid animals had elevated levels. Pups placed on methimazole treatment since the first day of life showed higher IGFBP-2 levels at the age of 18 days, although the change was not as prominent as in the congenitally hypothyroid animals (200% vs. 500% of control levels, respectively). Binding protein changes were approximately 2-fold at the mRNA level. Rats started on methimazole after the first 5 days of life showed normal low levels of IGFBP-2 at the age of 18 days. Abnormal IGBFP-2 expression in congenitally or neonatally hypothyroid animals could be corrected by thyroid hormone replacement, if started during the first week of the life, but not later. In adult hypothyroid animals, there was no induction of IGFBP-2 expression, but the levels of IGFBP-3 and -4 were decreased to 80% and to 30% of control levels, respectively. IGFBP-3 messenger RNA (mRNA) levels were decreased to 50% of control levels but IGFBP-4 mRNA levels were paradoxically increased in the hypothyroid animals. All these changes could be corrected by T4 replacement. In conclusion, there exists a critical period during the perinatal development of the rat, when thyroid hormone is essential for a subsequent normal IGFBP-2 ontogenic pattern. Adult animals show a completely different IGFBP response to hypothyroidism, with a decrease of IGFBP-3 and -4 levels. Thus, the effects of thyroid hormone on IGF-IGFBP axis regulation depend on the developmental stage of the an

Topics: Aging; Animals; Animals, Newborn; Body Weight; Carrier Proteins; Female; Gene Expression; Hypothyroidism; Insulin-Like Growth Factor Binding Protein 2; Male; Maternal-Fetal Exchange; Methimazole; Milk; Pregnancy; Rats; Rats, Inbred Strains; Reference Values; RNA, Messenger; Somatomedins; Thyrotropin; Thyroxine

Plasma atrial natriuretic hormone (ANH) values were evaluated in 28 hyperthyroid patients and in 11 hypothyroid patients and compared with 20 healthy subjects. In hyperthyroid patients plasma ANH basal levels were significantly (p less than 0.01) higher (14.2 +/- 1.6 pmol/l) than in controls (7.8 +/- 0.4 pmol/l) and in hypothyroid patients (6.4 +/- 0.3 pmol/l). No significant differences were found between controls and hypothyroid patients. The propranolol-induced decrease in heart rate in hyperthyroid patients did not significantly affect the plasma ANH values. Conversely, after the methimazole-induced euthyroidism a return within the normal range of ANH values was observed. The thyroxine replacement in hypothyroid patients determined a small but significant (p less than 0.05) increase in plasma ANH values. Observed data suggest that in humans thyroid hormones may influence plasma ANH concentrations independently of their effect on heart rate.

Topics: Adolescent; Adult; Aged; Atrial Natriuretic Factor; Female; Heart Rate; Humans; Hyperthyroidism; Hypothyroidism; Male; Methimazole; Middle Aged; Propranolol; Thyroxine

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

To understand the regulation by thyroid hormone, 3,3',5-triiodo-L-thyronine (T3), of the synthesis of a cytosolic thyroid hormone binding protein (p58-M2) during liver regeneration, the synthesis of p58-M2 was evaluated. The synthesis of p58-M2 was measured by metabolic labeling of primary cultures derived from the regenerating liver of euthyroid, hypo- or hyperthyroid rats. During regeneration, the increase in the liver/body weight ratio is approximately 25% higher in hyper- than in hypothyroid rats. However, T3 has no effect on the rate of overall liver regeneration observed in four days. In mature liver, T3 increased the synthesis of p58-M2 by approximately 2.5-fold. During regeneration, however, the change in the synthesis of p58-M2 varied with the thyroid status. In euthyroid rats, the synthesis of p58-M2 continued to increase up to 2-fold during liver regeneration. In hyperthyroid rats, after an initial increase by 1.5-fold on day 1, the synthesis of p58-M2 subsequently declined during regeneration. In hypothyroid rats, the synthesis of p58-M2 remained virtually unchanged during regeneration. These results indicate that T3 regulates the synthesis of p58-M2 in mature and regenerating liver.

Topics: Animals; Autoradiography; Cells, Cultured; Cytosol; Hepatectomy; Hyperthyroidism; Hypothyroidism; Isoenzymes; Liver; Liver Regeneration; Male; Methimazole; Methionine; Pyruvate Kinase; Rats; Rats, Sprague-Dawley; Reference Values; Sulfur Radioisotopes; Triiodothyronine

The biosynthesis of TRH in hypophysiotropic neurons of the paraventricular nucleus (PVN) is inversely regulated by feedback effects of circulating levels of thyroid hormones. As the PVN contains little or no deiodinase activity, the enzyme necessary to convert T4 to biologically active T3, we determined whether feedback inhibition of pro-TRH mRNA in thyroid hormone-sensitive neurons of the PVN is mediated exclusively by circulating levels of T3. The concentration of pro-TRH mRNA in the PVN of hypothyroid male rats receiving constant infusions of T3 over 7 days from ip implanted osmotic minipumps was studied by in situ hybridization histochemistry using computerized image analysis. Pro-TRH mRNA could not be suppressed to euthyroid levels by an infusion of T3 that returned plasma T3 levels to normal and required the infusion of higher concentrations of T3 that elevated plasma T3 into the supranormal range. By regression analysis, the mean concentration of plasma T3 required to suppress pro-TRH mRNA to euthyroid levels was estimated to be 110.3 ng/dl, similar to the amount of T3 estimated to be necessary to suppress TSH secretion from the anterior pituitary (108.7 ng/dl). We conclude that both T3 and T4 contribute to feedback inhibition of TRH biosynthesis in hypophysiotropic neurons of the PVN and propose that the effects of T4 on the PVN could be mediated after its monodeiodination at a different locus within the brain.

Topics: Animals; Feedback; Gene Expression Regulation; Hypothyroidism; Infusions, Parenteral; Male; Methimazole; Paraventricular Hypothalamic Nucleus; Protein Precursors; Pyrrolidonecarboxylic Acid; Rats; Rats, Inbred Strains; Regression Analysis; RNA, Messenger; Thyrotropin-Releasing Hormone; 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

1. Urinary excretion of digoxin-like immunoreactive factor and arginine-vasopressin and other parameters related to salt and water metabolism were studied in hyper- and hypo-thyroid rats after different tests. 2. Urinary excretion of arginine-vasopressin was increased in hyperthyroid and reduced in hypothyroid rats with respect to controls, in response to water deprivation or a hypertonic saline load. 3. Control and hypothyroid rats showed the highest urinary excretion of digoxin-like immunoreactive factor after a hypertonic saline load. However, hyperthyroid rats had the highest urinary levels of digoxin-like immunoreactive factor under normal conditions. 4. From these results it is suggested that: (a) hyper- and hypo-thyroid rats exhibit hyper- and hypo-responsiveness of arginine-vasopressin secretion to osmotic stimuli, respectively; (b) an unidentified digoxin-like immunoreactive factor measured in unextracted rat urine may be related to diuresis and natriuresis in control and hypothyroid rats; however, dissociation between this factor and natriuresis is observed in hyperthyroid rats.

Topics: Animals; Arginine Vasopressin; Blood Proteins; Cardenolides; Digoxin; Hyperthyroidism; Hypothyroidism; Kidney; Male; Methimazole; Rats; Rats, Inbred Strains; Saline Solution, Hypertonic; Saponins; Sodium-Potassium-Exchanging ATPase; Thyroxine; Water Deprivation

Chemically induced hypothyroidism changes the functions of rat alveolar macrophages. Treatment of female rats with an anti-thyroid drug, methimazole (1% aqueous solution in drinking water for 6 weeks) significantly (p less than 0.05) reduced the ability of alveolar macrophages (MAM) to phagocytose and kill the yeast, Saccharomyces cerevisiae. Undigested yeasts were observed in phagolysosomes within MAM using transmission electron microscopy. The activities of the lysosomal enzymes, acid phosphatase and beta-glucuronidase, and the Fc receptor binding ability for immunoglobulin G, were lowered in MAM when compared with control macrophages (CAM). MAM also produced less tumor necrosis factor under the stimulation of lipopolysaccharide.

Topics: Acid Phosphatase; Animals; Female; Glucuronidase; Hypothyroidism; Immunoglobulin G; Lysosomes; Macrophages; Methimazole; Microscopy, Electron; Phagocytosis; Pulmonary Alveoli; Rats; Rats, Inbred Lew; Receptors, Fc; Tumor Necrosis Factor-alpha

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

Resting oxygen consumption (VO2) and mitochondrial GDP binding were measured in hypothyroid and euthyroid rats after administration of selective and nonselective beta-adrenoceptor agonists (BRL 35135A and Isoprenaline--BRL, ISO). Resting VO2, VO2 increment and mitochondrial GDP binding after beta-agonists were lower in hypothyroid rats than in the euthyroid group. The reduced response was more marked for ISO than for BRL. These results suggest that BRL is acting on a beta-adrenoceptor which differs from beta-1 and beta-2 adrenoceptors, responsible for the effect of ISO. Activation of thermogenesis via this beta-3 adrenoceptor seems to be less dependent on permissive levels of thyroid hormones than on activation via beta-1 and/or beta-2 adrenoceptors.

Topics: Adipose Tissue; Adrenergic beta-Agonists; Animals; Body Weight; Disease Models, Animal; Guanosine Diphosphate; Hypothyroidism; Isoproterenol; Male; Methimazole; Oxygen Consumption; Phenethylamines; Rats; Rats, Sprague-Dawley; Thermoreceptors; Thyroidectomy

In the rat a developmental switch in the serum insulin-like growth factor (IGF) and IGF-binding protein (IGFBP) profile takes place during the first 3 postnatal weeks. The fetal expression pattern of high IGF-II and IGFBP-2 is replaced by the adult pattern of low levels of IGF-II and IGFBP-2 and high levels of IGF-I and IGFBP-3. The regulatory mechanisms mediating these changes are unknown, but may include perinatal changes in endocrine function. To study the effects of thyroid function and the perinatal thyroid secretory burst on IGF and IGFBP expression, we established a rat model of congenital hypothyroidism, leading to marked postnatal growth retardation during the perinatal period. The hypothyroid animals lacked the steep rise in serum IGF-I levels normally occurring during the third week of life, showing only a modest rise to approximately 50% of control levels. The pattern of serum IGF-II decline in hypothyroid animals was slightly different from that in controls, with lower IGF-II levels during the second week of life and a slower decline down to the very low final levels. The hypothyroid pups continued to express high levels of IGFBP-2 up to the age of 19 days, while the control animals, after a slow initial decline, showed an abrupt fall of IGFBP-2 serum levels during the third week of life. Liver IGFBP-2 mRNA levels reflected the serum changes, with elevated IGFBP-2 mRNA in hypothyroid animals. The expression of other IGFBPs did not differ from that in the control group. At the age of 18 days, serum GH levels in the hypothyroid animals were approximately one third of control GH levels, which suggests a role for GH as a possible mediator of thyroid hormone actions on the IGF system. The changes in growth parameters and in the IGF and IGFBP profile of hypothyroid pups could be abolished by thyroid hormone replacement from birth. We conclude that thyroid hormone is, directly or indirectly, essential for some of the neonatal changes in IGF and IGFBP profiles.

Topics: Animals; Animals, Newborn; Carrier Proteins; Congenital Hypothyroidism; Growth Hormone; Hypothyroidism; Insulin-Like Growth Factor Binding Protein 2; Insulin-Like Growth Factor Binding Proteins; Methimazole; Rats; Rats, Inbred Strains; Somatomedins; Thyroid Hormones; Thyroxine; Time Factors

The effects of thyroid status on the binding capacity, association constant (Ka) and receptor occupancy during postnatal rat testis development were evaluated. Hypothyroidism (induced by oral administration of 0.05% methimazole from the day of birth) increased the total T3 binding capacity in the testis, retarding the normal developmental decrease in T3 receptor number (mean maximal binding capacities estimated by Scatchard analysis for 21-day-old eu- and hypothyroid rats were 117 and 173 fmol/mg DNA, respectively). The rat thyroid status also affected the percentage of T3 receptor occupancy but not the affinity of binding (as measured by Ka). The postnatal developmental changes in T3 binding capacity induced by hypothyroidism were completely reversed by T3 replacement. These results suggest that T3 nuclear receptors in the developing rat testis are modulated by thyroid hormones.

Topics: Animals; Body Weight; Cell Nucleus; Hypothyroidism; Male; Methimazole; Rats; Rats, Inbred Strains; Receptors, Thyroid Hormone; Sertoli Cells; Testis; Thyroid Hormones; Triiodothyronine; Up-Regulation

Serum bone gamma-carboxyglutamic acid-containing (Gla) protein (BGP) was measured before and with initially 2 weeks, later 4-8 weeks intervals for 20-58 weeks during treatment of patients with hyperthyroidism (n = 10) and hypothyroidism (n = 4). Biochemical euthyroidism was obtained in the hyperthyroid patients after a median of 3 weeks (range 1-8 weeks), and in the hypothyroid patients after a median of 17 weeks (range 10-27 weeks). Serum BGP levels closely followed the thyroid state, being high respectively low in the hyperthyroid and hypothyroid state and reaching a stable plateau just at the time biochemical euthyroidism was obtained. These data suggest that osteoblastic activity is enhanced in hyperthyroidism and reduced in hypothyroidism, and that normalization occurs in close conjunction with the normalization of the thyroid state, without any delay, indicating a direct effect on the function of the excisting osteoblasts by the thyroid hormones.

Topics: Aged; Female; Follow-Up Studies; Humans; Hyperthyroidism; Hypothyroidism; Longitudinal Studies; Male; Methimazole; Osteocalcin; Radioimmunoassay; Thyrotropin; Thyroxine; Triiodothyronine

The relationship between thyroid function and testicular development in the rat was investigated. Hypothyroidism was induced during fetal or post-natal life by adding methimazole (MMI) to the drinking water of pregnant or lactating mothers. A group of newborn rats was treated with MMI and i.p. injections of L-tri-iodothyronine (L-T3). Hypothyroidism was shown by the reduced serum levels of total T3 and of total thyroxine (T4) in pregnant mothers and in pubertal rats. Testes were studied using light microscopy at 18 and 21 days post coitum or during puberty (21, 35 and 50 days after birth); serum levels of gonadotrophins were also evaluated in pubertal rats. Hypothyroidism had no effect on testicular development during fetal life and when induced in newborn rats it was associated at puberty with reduced serum levels of FSH and LH and with delayed maturation of the testis compared with control rats. The delay in maturation consisted of a reduction in the diameter of seminiferous tubules, and a reduction in the number of germ cells per tubule; this was associated with increased degeneration and arrested maturation of germ cells. In addition, Sertoli cells demonstrated retarded development, as indicated by a delay in the appearance of cytoplasmic lipids and in the development of a tubule lumen. Hormonal and morphological abnormalities were absent in rats treated with MMI plus L-T3. In conclusion, hypothyroidism occurring soon after birth caused reduced levels of gonadotrophins in the serum and a delay in pubertal spermatogenesis, possibly due to retarded differentiation of the Sertoli cells.

Topics: Animals; Follicle Stimulating Hormone; Hypothyroidism; Luteinizing Hormone; Male; Methimazole; Rats; Rats, Inbred Strains; Seminiferous Tubules; Sertoli Cells; Sexual Maturation; Spermatozoa; Testis; Thyroid Hormones; Thyroxine; Triiodothyronine

Methimazole-treated hypothyroid rats were injected intravenously with triacylglycerol/cholesteryl oleate/cholesterol/phospholipid emulsions designed to model the composition of chylomicrons. Compared with controls, hypothyroidism decreased the clearance rates of emulsion cholesteryl oleate. Clearance of emulsion triolein was affected much less and could be accounted for by residual triolein in remnants, suggesting that triacylglycerol lipolysis by lipoprotein lipase was unaffected by hypothyroidism but that clearance of remnants from plasma was decreased. Assays in vitro showed increased activities of lipoprotein lipase and hepatic lipase in hypothyroid rats. Emulsions were incubated with post-heparin plasma lipoprotein lipase to prepare remnants in vitro. The clearance from plasma of pre-formed remnants was slower after injection into hypothyroid rats than in control rats. Uptake of remnant cholesteryl oleate by the liver was significantly decreased in the hypothyroid rats. Treatment of hypothyroid rats for 7 days with 3,3',5'-tri-iodo-L-thyronine (T3) reversed the inhibition of hepatic remnant uptake and normalized plasma cholesterol. A thyroid hormone analogue with decreased hypermetabolic side-effects, L-94901, attenuated plasma cholesterol and improved but did not normalize remnant clearance. Emulsions incubated with plasma from hypothyroid rats had a decreased ratio of apolipoprotein E/apolipoprotein C compared with control rats or hypothyroid rats treated with T3. The change in the apolipoprotein E/apolipoprotein C ratio probably accounts for the defect in remnant clearance in hypothyroidism.

Topics: Animals; Apolipoproteins C; Apolipoproteins E; Cholesterol; Cholesterol Esters; Diet, Atherogenic; Emulsions; Hypothyroidism; Lipoprotein Lipase; Liver; Male; Metabolic Clearance Rate; Methimazole; Phospholipids; Rats; Rats, Inbred Strains; Triglycerides; Triiodothyronine, Reverse

Studies carried out in hypophysectomized adult rats have demonstrated that both thyroid hormone and GH can suppress hepatic expression of the steroid 6 beta-hydroxylase P450 2a (IIIA2). The present study further characterizes the influence of thyroid hormone on the expression of P450 2a and two other male-specific hepatic P450s, a steroid 2 alpha/16 alpha-hydroxylase, designated P450 2c (IIC11), and a steroid 15 alpha-hydroxylase, designated P450 RLM2 (IIA2). These studies were carried out in rats rendered hypothyroid by treatment with methimazole, which allows for the nonsurgical depletion of circulating T4, and in hypophysectomized rats. Hypothyroidism led to an increase in hepatic P450 2a (IIIA2) protein and mRNA in both male and female rats that was fully reversed by T4 replacement. In contrast, hypothyroidism decreased by 70-80% the expression of P450 2c (IIC11) activity and mRNA, but did not significantly alter the expression of P450 RLM2 (IIA2). The decrease in P450 2c (IIC11) was not reversed by T4 replacement, suggesting that it is a consequence of the loss of plasma GH pulses that occurs secondary to hypothyroidism. In agreement with these findings, T4 given to hypophysectomized rats partially suppressed the expression of P450 2a (IIIA2) mRNA, but not P450 2c (IIC11) or P450 RLM2 (IIA2) mRNA. A more complete suppression of P450 2a (IIIA2) mRNA as well as P450 2c (IIC11) mRNA was achieved when the hypophysectomized rats were treated with T3 at a supraphysiological, receptor-saturating dose. Although GH administered to intact male rats by continuous infusion fully suppressed all three male-specific P450 proteins and their mRNAs, the same treatment given to hypothyroid rats was only partially suppressive in the case of P450 2a (IIIA2) and P450 RLM2 (IIA2), unless combined with T4. In the case of P450 2c (IIC11), substantial suppression of the residual P450 present in hypothyroid rats was achieved by treatment with GH alone, despite persistent thyroid hormone deficiency. These studies demonstrate that while thyroid hormone is a negative regulator of P450 2a (IIIA2) expression and is required for the full suppression of that P450 and P450 RLM2 (IIA2) by the continuous plasma GH profiles associated with adult female rats, the suppression of P450 2c (IIC11) by continuous plasma GH is largely independent of the presence of thyroid hormone.

Topics: Animals; Aryl Hydrocarbon Hydroxylases; Base Sequence; Blotting, Western; Cytochrome P-450 Enzyme System; Female; Gene Expression; Growth Hormone; Hypophysectomy; Hypothyroidism; Male; Methimazole; Microsomes, Liver; Molecular Sequence Data; Nucleic Acid Hybridization; Rats; Rats, Inbred F344; RNA, Messenger; Steroid 16-alpha-Hydroxylase; Steroid Hydroxylases; Suppression, Genetic; Thyroxine; 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

We have examined the oligosaccharide structure of secreted thyrotropin (TSH) in perinatal and mature rats with congenital primary hypothyroidism. Rat pituitaries from euthyroid control animals and those rendered hypothyroid by methimazole treatment were incubated with [3H]glucosamine in vitro. Secreted TSH was purified, and oligosaccharides were enzymatically released and characterized by anion-exchange HPLC. In perinatal hypothyroid animals compared with control animals, oligosaccharides from TSH alpha and beta subunits contained more species with three or more negative charges. Moreover, perinatal hypothyroid animals demonstrated a dramatic increase in the ratio of sialylated to sulfated species within oligosaccharides of the same negative charge (2.9- to 7.4-fold increase for TSH-alpha; 15.1- to 25.5-fold increase for TSH-beta). In mature hypothyroid 9-week-old animals compared with control animals, changes were less pronounced, suggesting that endocrine regulation of oligosaccharide structure is dependent upon the maturational state of the animal. These changes were specific for TSH because glycosylation of free alpha subunit (synthesized by the thyrotroph and gonadotroph) and of total glycoproteins was minimally altered by hypothyroidism. Together, these data provide direct evidence and characterization of specific changes in the structure of a secreted pituitary glycoprotein hormone occurring as a result of in vivo endocrine alterations during early development. Moreover, they provide a potential structural basis to explain the delayed clearance of both TSH and the gonadotropins with end-organ deficiency, which may have important implications for the in vivo biological activities of these hormones. Specifically, such posttranslational changes may be an important adaptive response to prevent the consequences of endocrine deficiency during early development.

Topics: Animals; Chromatography, High Pressure Liquid; Congenital Hypothyroidism; Female; Fetus; Glucosamine; Glycoprotein Hormones, alpha Subunit; Hypothyroidism; Methimazole; Oligosaccharides; Pituitary Gland; Pregnancy; Rats; Rats, Inbred Strains; Reference Values; Sialic Acids; Thyrotropin

Topics: Adolescent; Adult; Atrioventricular Node; Female; Humans; Hyperthyroidism; Hypothyroidism; Male; Methimazole; Middle Aged; Sinoatrial Node

To examine the potential role of epidermal growth factor (EGF) in mediating the effects of thyroid hormone on linear growth, we measured serum EGF levels by RIA in cynomolgus monkeys before and during methimazole-induced hypothyroidism, and after 9 weeks of T4 replacement at different doses. Ten castrated prepubertal monkeys were rendered hypothyroid by methimazole (0.0125% in drinking water for 12 weeks). Methimazole was continued, and T4 was then administered for 9-week intervals. Six weeks elapsed between successive T4 doses. The sequence of different T4 doses for each animal was random. Serum EGF level was measured at baseline and at the end of each treatment period with a newly developed RIA using a polyclonal antiserum against human recombinant EGF. Serum EGF level correlated significantly with the level of serum thyroxine but not with serum triiodothyronine, over the thyroxine dosage range of 1-4 micrograms/kg/day (r = 0.41, p less than 0.005). Lower-leg growth rate correlated significantly with serum EGF level over this same thyroxine dosage range (r = 0.41, p less than 0.005). These data are consistent with the hypothesis that EGF may mediate some of the effects of thyroid hormone on skeletal growth.

Topics: Animals; Dose-Response Relationship, Drug; Epidermal Growth Factor; Growth; Hypothyroidism; Macaca fascicularis; Male; Methimazole; Radioimmunoassay; Thyroid Hormones

This study tested the hypothesis that activity of the enzyme N-acetyltransferase (NAT) in the Harderian gland of the Syrian hamster is regulated both by androgens and by hormones of the pituitary-thyroid axis. To test the effects of castration and hypothyroidism, intact or castrated male hamsters were given either tap water or methimazole in their drinking water for 3 weeks. Methimazole suppresses iodination of thyroglobulin, thereby decreasing circulating levels of thyroid hormones and increasing TSH levels. Hypothyroidism or castration caused elevated or depressed Harderian gland NAT activities respectively, compared with euthyroid controls. When castration and hypothyroidism were combined, the animals exhibited high NAT activity compared with castrated euthyroid males. To test the effects of castration and hyperthyroidism, male hamsters were given daily injections of thyroxine (T4) or diluent and were either castrated or left intact for 4 weeks. Intact animals given T4 had depressed Harderian NAT activity; serum thyroid hormone levels were elevated and TSH levels were depressed compared with those of intact controls. Castrated animals had depressed NAT activity below that of intact controls; serum thyroid hormone levels were normal but TSH levels were depressed. Castrated animals given T4 injections had NAT activity similar to that of euthyroid castrated hamsters; thyroid hormone levels were elevated but TSH levels were similar to those seen in euthyroid castrated hamsters. In another experiment, both T4 and tri-iodothyronine (T3) were equally effective in decreasing NAT activity in intact males. To determine the effects of the removal of pituitary influences, male hamsters were hypophysectomized. NAT activity in the Harderian glands of these animals was reduced compared with intact controls.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Androgens; Animals; Arylamine N-Acetyltransferase; Castration; Cricetinae; Female; Harderian Gland; Hormones; Hypophysectomy; Hypothyroidism; Iodide Peroxidase; Kinetics; Male; Mesocricetus; Methimazole; Pituitary Gland; Thyroid Gland; Thyroxine

The changing roles of the hypothalamus and pituitary in regulating thyroid hormone levels in the rat during ontogeny has not been fully elucidated. It has been reported that endogenous TRH begins to stimulate TSH secretion at 5-8 days after birth but that the pituitary responds to hypothyroidism during late gestation. To determine the onset and extent of TRH response to low thyroid hormone levels during ontogeny, normal and hypothyroid rats treated with methimazole for 7 days were sacrificed at 16 days gestation (E16), 20 days gestation (E20), 7, 21 and 56 days after birth (n = 5/study group). Plasma hormones were assayed from pregnant mothers, pups (pooled) and adults. Levels of TRH mRNA were measured in the paraventricular nuclei (PVN) by in situ hybridization histochemistry. A labeled 48-base cDNA oligonucleotide for TRH was hybridized with brain slices (n = 6/animal) in the region of the medial parvocellular division of the PVN of the hypothalamus and the signal was quantitated by digitized computer analysis. Plasma-free T4 levels decreased and plasma TSH levels increased in the animals treated with methimazole as compared to the euthyroid controls. TRH mRNA was detected in the PVN at E16 after brain slices were dipped in emulsion and granules observed by dark-field microscopy. In the euthyroid animals, TRH mRNA increased from E20 (150 +/- 9 OD units) to 7 days (222 +/- 5 OD units) and remained unchanged at 21 days (252 +/- 27 OD units) and 56 days (244 +/- 6 OD units).(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; DNA Probes; Hypothyroidism; Methimazole; Nucleic Acid Hybridization; Paraventricular Hypothalamic Nucleus; Rats; Rats, Inbred Strains; RNA, Messenger; Thyroid Hormones; Thyrotropin; Thyrotropin-Releasing Hormone; 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

Oxygen consumption (VO2) and mitochondrial guanosine diphosphate (GDP) binding of interscapular brown adipose tissue (BAT) were measured in hypothyroid, hyperthyroid and euthyroid rats after stimulations with selective and nonselective beta-adrenoceptor agonists: BRL 35135A (BRL) and Isoprenaline (ISO). Resting VO2, VO2 increment and mitochondrial GDP binding after beta-adrenergic stimulations were lower in hypothyroid rats than in the euthyroid group. The reduced responses were more marked for ISO than for BRL. Restion VO2 and VO2 increment after beta-adrenergic stimulations were higher in hyperthyroid rats than in the eurthyroid group; the increment was more marked for BRL than for ISO. In hyperthyroidism, mitochondrial GDP binding after BRL and after ISO was in the same magnitude; it was higher in the hyperthyroid than in the euthyroid group after BRL but not after ISO. The different thermogenic responses after ISO and BRL stimulations suggest that BRL is acting on a beta-adrenoceptor differing from the beta-1 and beta-2 adrenoceptors responsible for the effects of ISO. Activation of thermogenesis via the beta-3 adrenoceptor seems to be less dependent on the permissive levels of thyroid hormones than activation via beta-1 and/or beta-2 adrenoceptors. The beta-3 adrenoceptor may be more sensitive to increased levels of thyroid hormones.

Topics: Adipose Tissue, Brown; Animals; Body Weight; Guanosine Diphosphate; Hyperthyroidism; Hypothyroidism; Male; Methimazole; Mitochondria; Organ Size; Oxygen Consumption; Rats; Rats, Inbred Strains; Reference Values; Thyroid Gland

Postnatal development of rat liver mitochondrial functions, i.e. differentiation of pre-existing mitochondria, is a key regulatory process that is accomplished during the first postnatal hour (Valcarce, C., Navarrete, R. M., Encabo, P., Loeches, E., Satrústegui, J., and Cuezva, J. M. (1988) J. Biol. Chem. 263, 7767-7775). The general mechanism that appears to control this process is the rapid (2-fold) increase in inner mitochondrial membrane proteins, as a result of a rapid increase in the rates of protein synthesis for mitochondrial proteins. Fetal hypothyroidism induced by administration of methimazole to pregnant rats resulted in half the ATPase activity and amount of beta-F1-ATPase protein in liver homogenates compared with normal fetuses. Furthermore, hypothyroid neonates showed no postnatal increase in the amount of mitochondrial beta subunit of the F1-ATPase complex. Administration of thyroid hormones to hypothyroid neonates at birth promoted a 2-fold increase in liver ATPase activity and in the amount of beta-F1-ATPase protein both in liver homogenates and in isolated mitochondria. The rapid increase in beta-F1-ATPase protein observed in thyroid hormone-treated hypothyroid neonates was paralleled by a 2-fold increase in the relative rates of beta-F1-ATPase synthesis and by a 2-fold increase in the relative amount of hepatic beta-F1-ATPase mRNA. The results show that the basal expression of the beta-F1-ATPase gene is regulated by thyroid hormones at either a transcriptional and/or post-transcriptional level. Thus, these results show the requirement of thyroid hormones for proliferation and differentiation of mitochondria in the fetal and neonatal liver, respectively. On the other hand, the fact that liver mRNA level of beta-F1-ATPase protein does not change between 0 and 1 postnatal h in the normal neonatal liver indicates that postnatal mitochondrial differentiation is regulated at a translational level.

Topics: Animals; Animals, Newborn; Female; Gene Expression Regulation; Hypothyroidism; Immunosorbent Techniques; Liver; Maternal-Fetal Exchange; Methimazole; Mitochondria, Liver; Molecular Weight; Pregnancy; Protein Biosynthesis; Protein Precursors; Proton-Translocating ATPases; Rats; Rats, Inbred Strains; RNA, Messenger; Thyroid Hormones; Thyroxine; Triiodothyronine

Carbonic anhydrase (CA) and Mg2(+)-dependent ATPase and Mg2(+)-dependent, HCO3(-)-stimulated ATPase (Mg2(+)-HCO3(-)-ATPase) activities in rat duodenal mucosa and kidney cortex were examined with respect to thyroidal status. Administration of 50 and 150 micrograms thyroxine (T4)/kg per day s.c. for 7 days decreased duodenal cytosol CA activity to 66% of control with the former and 43% with the latter dose, while Mg2(+)-HCO3(-)-ATPase activity in brush borders of duodenal mucosa was increased to 116% of control by 150 micrograms T4/kg. CA and Mg2(+)-HCO3(-)-ATPase activities in the cytosol and brush border of kidney cortex did not change after administration of T4. Hypothyroidism induced by thyroidectomy for 2 and 4 weeks or administration of methimazole (2.5-20 mg/kg per day s.c. or peroral) for 2, 3 and 4 weeks all increased duodenal cytosol CA activity, to about 140% at 2 weeks and 153% at 4 weeks after thyroidectomy, and to about 136% after the oral administration of 10 mg methimazole/kg per day for 4 weeks, while brush border Mg2(+)-HCO3(-)-ATPase activity was decreased to 56% of control 4 weeks after thyroidectomy and to 74% after the s.c. administration of 20 mg methimazole/kg day for 3 weeks. The increase in CA activity and the decrease in ATPase activity after thyroidectomy were restored to normal levels by replacement with T4. Neither enzyme activity in the kidney changed in hypothyroidism. Serum concentrations of T4 and cortisol-like material increased after administration of T4, and serum concentrations of T4, aldosterone and cortisol-like material all decreased in hypothyroidism. Correlations were observed between duodenal CA and Mg2(+)-HCO3(-)-ATPase activities and serum concentrations of T4 (P less than 0.01). These results reveal that the decrease in CA activity and the increase in Mg2(+)-HCO3(-)-ATPase activity of duodenal mucosa in hyperthyroidism are reversed in hypothyroidism, while both enzyme activities in the kidney are unrelated to thyroidal status.

Topics: Adenosine Triphosphatases; Animals; Anion Transport Proteins; Ca(2+) Mg(2+)-ATPase; Carbonic Anhydrases; Duodenum; Enzyme Activation; Hyperthyroidism; Hypothyroidism; Intestinal Mucosa; Kidney Cortex; Male; Methimazole; Rats; Rats, Inbred Strains; Thyroidectomy; Thyroxine

The influence of hypothyroidism on testicular steroidogenesis was investigated by evaluating the production of testosterone and its precursors by isolated testes from adult male rats. Animals were made hypothyroid starting from the 4th week of life either by daily oral administration of 0.1% methimazole (MMI) or by surgical thyroidectomy (TZ). Half of the thyroidectomized rats were i.p. injected with 3 gamma T3/100 g body weight on alternate days during the last three weeks before sacrifice. Hypothyroidism is associated with a severe retardation of body growth, which appears more marked in thyroidectomized than in MMI treated rats; no significant variations in testis weight are observed. Administration of T3 does not completely restore body weight. A significant decrease in the "in vitro" production of testosterone and its precursors by testes isolated from hypothyroid rats is observed. This effect is more evident in thyroidectomized rats where a marked drop in the "in vitro" production of some testosterone delta 4 precursors is associated with the increase in DHEA/delta 4 ratio. T3 injection to thyroidectomized rats only partially restores the "in vitro" testosterone production. Results suggest that as the degree of hypothyroidism became more severe, the rate of testosterone production decreases and testicular steroidogenesis changes from the delta 4 to delta 5 metabolic pathway as a consequence of the impairement of 3-beta-ol-dehydrogenase activity.

Topics: Androstenedione; Animals; Body Weight; Dehydroepiandrosterone; Dihydrotestosterone; Glucosephosphate Dehydrogenase; Hypothyroidism; Male; Methimazole; Organ Culture Techniques; Organ Size; Phosphogluconate Dehydrogenase; Progesterone; Rats; Rats, Inbred Strains; Testis; Testosterone; Thyroidectomy; Triiodothyronine

The serum ACE activity was determined in male Fischer 344 rats at 2, 6, 13, and 25 months of age to determine whether serum angiotensin converting enzyme (ACE) activity is a potential biomarker of tissue hypothyroidism in aged rats. Since rodent serum contains an ACE activity inhibitor, the measurements were done in both undiluted and 1:8 diluted sera. The highest serum inhibitor activity was found in the 2-month-old animals. The serum ACE activity measured in the diluted serum of the aged rats (77.6 +/- 2.9 units/ml) was significantly reduced compared to 2-month-old (178.2 +/- 6.4 units/ml), 6-month-old (101.5 +/- 6.1 units/ml) and 13-month-old rats (84.9 +/- 8.6 units/ml); (p less than 0.001). Hyperthyroidism induced by injecting L-triiodothyronine (T3) 15 micrograms/100 gm body weight intraperitoneally for 10 days increased the serum ACE activity in the older rats, but reduced the levels in 2-month-old rats. There was no significant change in 6-month-old rats. The levels of serum ACE activity in hypothyroid 6-month-old rats (95.5 +/- 3.5 units/ml) and in 2-month-old-rats (94.2 +/- 4.0 units/ml) were similar to the level seen in hypothyroid old rats (88.9 +/- 5.8 units/ml). Pair feeding of young rats (8 months old) with old did not alter the baseline ACE level (117.4 +/- 3.7 units/ml) or the T3 stimulated (105.2 +/- 10.2 units/ml) serum ACE activity. It is concluded that the reduced serum ACE activity in aged rats cannot be accounted for by the reduced caloric intake or reduced serum thyroid hormone levels.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Aging; Animals; Eating; Hyperthyroidism; Hypothyroidism; Male; Methimazole; Peptidyl-Dipeptidase A; Rats; Rats, Inbred F344; Triiodothyronine

The number, but not affinity, of binding sites for [3H]3-methyl-histidine2-TRH ([3H]Me-TRH) on chicken adenohypophysial plasma membranes was increased in chickens made hypothyroid by goitrogen (methimazole) treatment (50 mg/kg per day for 7 days), which also increased circulating GH concentrations. Daily i.p. injection of thyroxine (T4; 100 micrograms/kg for 7 days) had no effect on [3H]Me-TRH binding to pituitary membranes, although it suppressed endogenous GH secretion. Binding of [3H]Me-TRH to pituitary caudal lobe membranes was, however, suppressed by tri-iodothyronine (T3) injected chronically (100 micrograms/kg per day, i.p., for 7 days) or acutely (100 micrograms/kg, 2 h before being killed). The suppression of [3H]Me-TRH binding and inhibition of GH secretion following T3 administration was dose related. Binding of [3H]Me-TRH to caudal lobe membranes was also suppressed following the incubation of pituitary glands with T3 in vitro, and the response was both dose and time related. These results suggest that T3 inhibits GH secretion in fowl by a down-regulation of pituitary TRH receptors. However, other mechanisms are involved in thyroidal inhibition of GH release in birds, since T4 had no effects on [3H]Me-TRH binding yet suppressed GH secretion in vivo.

Topics: Animals; Binding Sites; Cell Membrane; Chickens; Down-Regulation; Growth Hormone; Hypothyroidism; Methimazole; Pituitary Gland; Pyrrolidonecarboxylic Acid; Receptors, Neurotransmitter; Receptors, Thyrotropin-Releasing Hormone; Thyrotropin-Releasing Hormone; Thyroxine; Triiodothyronine

The sexually differentiated microsomal enzyme steroid 5 alpha-reductase (NADPH: delta 4-3-oxosteroid 5 alpha-oxido-reductase, EC 1.3.99.5) catalyzes the NADPH-dependent conversion of testosterone to 5 alpha-dihydrotestosterone, a more potent androgen. In rat liver, this enzyme is expressed at a 10-fold higher level in adult females as compared to adult males. The pituitary regulation of this enzyme and its mRNA was studied in untreated and hypophysectomized rats and in rats rendered hypothyroid by treatment with the antithyroid drug methimazole. Hepatic 5 alpha-reductase activity was elevated 8-fold, to 85% of adult female levels, in adult male rats given growth hormone by continuous infusion. This same treatment was only partially effective in restoring 5 alpha-reductase in rats depleted of endogenous growth hormone by hypophysectomy, indicating that other pituitary-dependent factors contribute to the elevation observed in the inact animals. Further analysis revealed that thyroxine, but not adrenocorticotropic hormone (ACTH) or chorionic gonadotropin, could elevate 5 alpha-reductase activity and mRNA when given to the hypophysectomized rats and that this effect was enhanced by the presence of growth hormone. This thyroid hormone dependence was confirmed by the decrease in hepatic 5 alpha-reductase expression in hypothyroid rats and by its substantial restoration following thyroxine replacement. Thyroxine also stimulated expression of another female-predominant hepatic mRNA, encoding the steroid 16 alpha-hydroxylase cytochrome P-450f (IIC7), in a manner that was independent of the stimulatory effect of growth hormone on this transcript. In contrast, thyroid hormone did not significantly affect protein or mRNA levels of the growth hormone-stimulated, female-specific steroid sulfate 15 beta-hydroxylase P-450 2d (IIC12). These findings establish that thyroid hormones act at a pretranslational level to modulate the expression of some, but not all, growth hormone-stimulated hepatic mRNAs and demonstrate that both thyroxine and growth hormone can independently contribute to the sex-dependent expression of hepatic enzymes of steroid metabolism.

Topics: 3-Oxo-5-alpha-Steroid 4-Dehydrogenase; Adrenocorticotropic Hormone; Animals; Cytochrome P-450 Enzyme System; Female; Growth Hormone; Hypophysectomy; Hypothyroidism; Liver; Male; Methimazole; Multigene Family; Rats; Rats, Inbred F344; Reference Values; RNA, Messenger; Sex Factors; Steroid 16-alpha-Hydroxylase; Thyroxine; Transcription, Genetic

Oral administration of the antithyroid drug methimazole (50 mg/kg per day) to rats during the last six days of pregnancy, and subsequent daily s.c. injection of methimazole (20-30 mg/kg) to their pups from birth to postnatal day 30 provoked hormonal and somatic alterations resembling (with all caution to any association between rodent and human data) those of congenital hypothyroidism. The steady-state concentrations of striatal dopamine were similar in hypothyroid and euthyroid, 32-day-old rats, while the levels of the dopamine metabolites 3,4-dihydroxyphenylacetic and homovanillic acids were markedly decreased in hypothyroidism. The results of this and our earlier study [Vaccari A. and Gessa G. L. (1989) Neurochem. Res. 14, 949-955] show that the maximal synaptosomal uptake of [3H]dopamine, an index for the density of nigrostriatal dopaminergic terminals, and the maximum number of membrane [3H]tyramine binding sites, reflecting the concentration of the vesicular transporter for dopamine, were decreased in the hypothyroid striatum. There was also a loss of those D1-type dopaminergic receptors claimed to be located on neurons intrinsic to the striatum, and, consequently, dopamine-stimulated, D1-regulated adenylate cyclase activity was depressed. It is suggested that individual dopaminergic nerve endings in the neonatal hypothyroid striatum must contain more dopamine, owing to some loss of pertinent innervation and, therefore, to the presence of less vesicular transport sites for dopamine. Hypothyroidism-related decreases in the maximum number of striatal D1- and, reportedly, D2-receptors, plus the impairment of D1-coupled second messenger activity, may play a role in the derangement of those neurobehavioural patterns where a dopaminergic regulation is putatively implied.

Topics: 3,4-Dihydroxyphenylacetic Acid; Animals; Animals, Newborn; Benzazepines; Body Weight; Corpus Striatum; Dopamine; Dopamine Antagonists; Female; Homovanillic Acid; Hypothyroidism; Male; Methimazole; Rats; Rats, Inbred Strains; Receptors, Dopamine; Reference Values; Synaptosomes; Thyroxine; Triiodothyronine; Tyramine

Hypothyroidism was induced in adult rats by oral administration of methimazole. Euthyroid and hypothyroid rats were maintained at 23 degrees C or exposed at 6 degrees C for 3 weeks. Both euthyroid and hypothyroid rats maintained at 23 degrees C had similar interscapular brown adipose tissue (BAT) composition and thermogenic activity. Cold-exposed hypothyroid rats showed the same interscapular BAT mass and gross tissue composition as cold-exposed euthyroid animals, but the interscapular BAT of cold-exposed hypothyroid rats did not show the characteristic increase in GDP binding, and the increase in mitochondrial mass was lower than in euthyroid rats. From these results we conclude that thyroid hormones do not influence BAT significantly when thermogenic requirements are moderate, but they participate in the trophic response of the tissue when thermogenic requirements are intense. This thyroid hormone participation in the BAT trophic response occurs at the mitochondrial level, both in quantitative (mitochondrial mass) and qualitative (GDP-binding) aspects.

Topics: Administration, Oral; Animals; Body Temperature Regulation; Cold Temperature; Hypothyroidism; Male; Methimazole; Rats; Rats, Inbred Strains; Thyroid Hormones

L-T4 suppositories containing 50, 100 or 200 micrograms of L-T4 were given to rabbits treated with MMI. The serum T4 gradually increased within 3.5 and 6.5 hours following the use of 100 and 200 micrograms of L-T4 suppositories, respectively, without an acute increase in serum T3. The increase in serum T4 continued up to 48 hours. The area under the curve (AUC) for serum T4 was evidently dose-dependent. It is concluded from these results that the T4 suppository will be useful as a replacement therapy for patients with hypothyroidism.

Topics: Animals; Hypothyroidism; Methimazole; Rabbits; Suppositories; Thyroxine; Triiodothyronine

The outcome of radioiodine therapy of Graves' hyperthyroidism was retrospectively evaluated in 274 consecutive patients treated from 1975 to 1984. At 1-yr follow-up, permanent hypothyroidism occurred in 36.9% of patients and the cumulative incidence of hypothyroidism progressively increased up to 79.3% after 7-10 yr. At the end of the follow-up period, 148 patients (54%) were hypothyroid, 115 (42%) euthyroid and 11 (4%) still hyperthyroid. The prevalence of hypothyroidism was significantly higher in patients with small goiters (less than or equal to 50 g) than in those with large goiters (greater than 90 g). Moreover, hypothyroidism was more frequent in patients with high thyroglobulin antibodies titers (greater than or equal to 1:25,600) than in those with low titers or negative tests, and occurred earlier in the former group than in the latter ones Correction of thyrotoxicosis was obtained after the administration of a single dose of 131I in 187 patients (63.6%); 69 patients required two doses and 11 three or more doses. Seven patients refused further treatment with 131I after the first dose. In an effort to identify possible factors affecting the efficacy of 131I therapy, we evaluated the results obtained after the administration of the first dose of radioiodine. We found that large goiters, rapid iodide turnover and adjunctive therapy with methimazole shortly after radioiodine were associated with a higher rate of persistence of thyrotoxicosis, whereas an increased prevalence of hypothyroidism was observed in patients with small goiters and in those not treated with methimazole up to one week after 131I.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adult; Aged; Aged, 80 and over; Combined Modality Therapy; Female; Graves Disease; Humans; Hyperthyroidism; Hypothyroidism; Iodine Radioisotopes; Male; Methimazole; Middle Aged; Radiotherapy; Thyroid Gland; Thyrotoxicosis

Synthesis of "sex-hormone binding globulin" (SHBG) is influenced by thyroid hormones and its concentration in the serum of female subjects may be a marker of thyroid hormone effect at the peripheral tissue (liver) level. Compared to the levels found in euthyroid females (n = 46), the mean (+/- S.D.) serum SHBG concentration was found elevated in overt hyperthyroidism (Graves' disease: n = 56; 141.6 +/- 37.6 vs. 48.3 +/- 16.2; toxic nodular goiter: n = 16; 119.9 +/- 50.7 vs. 48.3 +/- 16.2 nmol/l; P less than 0.001). In contrast, it was decreased in manifest hypothyroidism (n = 25; 24.9 +/- 14.8 vs. 48.3 +/- 16.2; P less than 0.001). In the group of preclinical hyperthyroidism (n = 43), despite suppressed TSH secretion, the serum value of SHBG was normal (47.4 +/- 16.8), while its serum level approached the lower border of the normal range in subclinical hypothyroidism (n = 10; 33.6 +/- 6.1 vs 48.3 +/- 16.2 nmol/l; P less than 0.01). Data indicate that the pituitary responds more sensitively than the liver to a slight change of the serum thyroid hormone level. During thyroid hormone replacement for hypothyroidism, measurement of serum SHBG may provide help to assess the response of the target organ to the given therapy. In patients with generalized resistance to thyroid hormone, the serum SHBG level is within the normal range (51.3 +/- 9.8 nmol/l), thus, its determination supports the diagnosis of this disease.

Topics: Biomarkers; Goiter, Nodular; Graves Disease; Humans; Hyperthyroidism; Hypothyroidism; Methimazole; Reference Values; Sex Hormone-Binding Globulin; Thyroidectomy; Thyrotropin; Thyroxine; Triiodothyronine

In view of the defective neurotubule assembly observed in congenital hypothyroidism and the striking morphological abnormalities of the cerebellum in this condition, we have investigated the expression of microtubule-associated protein-2 (MAP2) in the cerebellum of rats with congenital hypothyroidism. Analysis included the measurement of immunoreactive MAP2 and its mRNA. In addition, the intracellular distribution of MAP2 was studied by immunostaining of the appropriate histological preparations. The results showed that the developmental increase in MAP2 is delayed in congenital hypothyroidism, but eventually the concentration of this protein reached normal levels in animals with this condition, even if untreated. These abnormalities in the immunoreactive protein are not paralleled by abnormalities in the abundance of MAP2 mRNA, which was not affected by the thyroid status of the animals. In spite of the normalization of the content of the protein, the distribution of MAP2 in the Purkinje cells of hypothyroid rats remained abnormal. Whereas in euthyroid rats the protein rapidly migrated into the dendrites, in the Purkinje cells of hypothyroid pups, MAP2 remained largely confined to the body and the most proximal part of the dendrites. These results suggest that thyroid hormone affects the expression of MAP2 at translation or posttranslational levels. The abnormality in distribution may result from some posttranslational abnormality of the protein itself or some underlying defect in the function of the neurons. These observations are probably relevant to the abnormalities in cerebellar function seen in animals and humans with untreated congenital hypothyroidism.

Topics: Animals; Animals, Newborn; Cerebellum; Congenital Hypothyroidism; Cytosol; Dendrites; Gene Expression; Hypothyroidism; Immunoassay; Methimazole; Microtubule-Associated Proteins; Nucleic Acid Hybridization; Purkinje Cells; Rats; Rats, Inbred Strains; RNA, Messenger; Tissue Distribution

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

Dietary carbohydrate and thyroid hormone (T3) interact to regulate rat liver S14 gene expression. The molecular basis for this interaction was examined by analysis of hepatic mRNAS14 levels, S14 gene transcription, and chromatin structure. While starvation of euthyroid rats inhibited hepatic S14 gene transcription greater than or equal to 90%, sucrose administration induced mRNAS14 and S14 transcription to 82% of euthyroid-fed levels within 4 h. In contrast, administration of sucrose or T3 to starved hypothyroid animals restored S14 gene transcription to only 30% of euthyroid-fed values. Both T3 and sucrose were required to restore S14 run-on activity and mRNAS14 to euthyroid-fed levels within 4 h. Thus, T3 and sucrose interact synergistically and rapidly to induce S14 gene transcription. Analysis of S14 chromatin structure showed that starvation of hypothyroid rats inhibited the formation of three DNase I-hypersensitive sites flanking the 5'-end of the S14 gene (Hss-1 at -65 to -265 base pairs; Hss-2 at -1.2 kilobases and Hss-3 at -2.67 kilobases). The loss of these sites correlated with the repression of S14 gene transcription in starved hypothyroid rats. Whereas administration of sucrose to starved hypothyroid rats consistently induced the Hss-1 and Hss-2 sites, T3 consistently induced all three DNase I-hypersensitive sites. Yet, neither treatment alone induced S14 gene transcription to euthyroid levels. The combination of T3 and sucrose induced no additional change in S14 chromatin structure over that induced by T3 alone. Thus, regulation of S14 chromatin structure alone is not the sole mechanism by which these stimuli regulate S14 gene transcription. We speculate that the synergistic regulation of S14 gene transcription by T3 and dietary carbohydrate involves a complex interaction between factors which regulate the accessibility of putative cis-regulatory elements through changes in chromatin structure and the regulation of "transcription factors" which interact with these elements.

Topics: Animals; Base Sequence; Deoxyribonuclease I; Dietary Carbohydrates; DNA Probes; Gene Expression Regulation; Genes; Hyperthyroidism; Hypothyroidism; Liver; Male; Methimazole; Molecular Sequence Data; Nuclear Proteins; Proteins; Rats; Rats, Inbred Strains; RNA, Messenger; Transcription Factors; Transcription, Genetic; Triiodothyronine

The effect of hypothyroidism in the adult rat on blood-brain barrier and muscle transport of hexoses, neutral amino acids, basic amino acids, monocarboxylic acids, and ketone bodies was examined using single arterial injection-tissue sampling technique. The cerebral blood flow and brain extraction of 3H2O (internal reference substance) was not altered in 3-month-old hypothyroid rats maintained on methimazole, 0.025% in the drinking water, for 7 weeks. The brain uptake index of D-beta-hydroxybutyrate was significantly reduced in hypothyroid rats (2.4 +/- 0.3 vs 4.6 +/- 0.6% p less than 0.001). Hypothyroid rats given thyroid hormone replacement therapy had normal brain uptake of D-beta-hydroxybutyrate (4.4 +/- 0.8%). The brain uptake index of butyrate was also significantly reduced in hypothyroid rats (39.3 +/- 2.1 vs 47.2 +/- 0.74%, p less than 0.001). The brain uptake index of other test substances and muscle uptake of nutrients examined were not altered in hypothyroid rats. These studies indicate that of the four transport systems examined in two tissues, the blood-brain barrier monocarboxylic acid transport system is most susceptible to the hypothyroidism-induced changes.

Topics: 3-Hydroxybutyric Acid; Amino Acids; Animals; Biological Transport; Blood-Brain Barrier; Brain; Carboxylic Acids; Cell Membrane Permeability; Hexoses; Hydroxybutyrates; Hypothyroidism; Ketone Bodies; Male; Methimazole; Muscles; Rats; Rats, Inbred F344; Triiodothyronine

To determine whether age-related differences in body weight loss in hyperthyroidism could be related to caloric intake, the body weight and food consumption of Fischer 344 male rats were monitored every other day for four weeks. Six-month-old (young) rats were compared to 16-month-old rats (intermediate age) and 25-month-old (aged) rats. Hypothyroidism was induced with 0.025% methimazole in the drinking water for four weeks. Hyperthyroidism was induced with triiodothyronine (T3) injections (15 micrograms/100 g body weight i.p.) for the last 10 days of observation. A group of young rats pair fed with aged rats was included as a control group. The body weight changes of aged rats were similar to hypothyroid young rats. An index of T3 catabolic effect was calculated based on the net weight loss and food intake. This index was not different in aged rats compared to young rats. The apparent hypersensitivity of aged rats to T3 as evidenced by excessive weight loss could totally be attributed to decreased caloric intake. It is concluded that aged rats compared to the young are not more sensitive to the overall catabolic effects of thyroid hormones.

Topics: Aging; Animals; Energy Intake; Hyperthyroidism; Hypothyroidism; Male; Methimazole; Rats; Rats, Inbred F344; Thyroid Hormones; Triiodothyronine; Weight Loss

To evaluate the dose-response relationship between thyroxine and tibial growth, 60 male rats age 21 days were rendered hypothyroid by administration of methimazole in the drinking water. Twenty-one days later, the hypothyroid rats were randomly divided into 5 groups which received 0, 2, 8, 32, or 64 micrograms.kg-1.day-1 of T4 im for 21 days. All animals were sacrificed at age 64 days. Rat tibia were removed for measurement of epiphyseal growth plate width and longitudinal growth rate. Serum T4 and IGF-I levels were determined by RIA. Methimazole therapy significantly decreased serum T4, IGF-I, epiphyseal growth plate width, and longitudinal growth rate compared to controls. Epiphyseal growth plate width gradually increased when T4 was administered at doses from 2 to 32 micrograms.kg-1.day-1 (271 +/- 14, 311 +/- 15 and 324 +/- 11 microns), and subsequently decreased when T4 was given at a dose of 64 micrograms.kg-1.day-1 (267 +/- 8 microns). A similar profile was observed for longitudinal growth rate and IGF-I. We conclude that rat tibial growth has a biphasic response to exogenous T4 administration, and that the effects of T4 on tibial growth may be mediated through IGF-I secretion.

Topics: Animals; Body Weight; Bone Development; Eating; Growth Plate; Hypothyroidism; Insulin-Like Growth Factor I; Male; Methimazole; Rats; Rats, Inbred Strains; Thyroxine

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

Amiodarone's class III effects may be due to inhibition of the cardiac effects of thyroid hormone. If so, amiodarone would not be expected to cause QT prolongation in hypothyroid subjects. The electrocardiographic (ECG) changes induced after treatment with amiodarone were compared in euthyroid and hypothyroid guinea pigs. Hypothyroidism was induced with intraperitoneal (i.p.) administration of 1 mCi I131 (eight animals). Three of these animals also received oral methimazole to block any residual thyroid hormone production. Significant increases in body weight (28 +/- 9%), RR (14 +/- 8%), QT (14 +/- 5%), and QTc (7 +/- 2%) intervals occurred after induced hypothyroidism. Pilot studies with amiodarone treatment for 4 weeks in euthyroid guinea pigs demonstrated that maximal effects on ECG intervals were achieved after 1 week of drug therapy. Therefore, both euthyroid and hypothyroid groups were treated with daily i.p. amiodarone (80 mg/kg) for 7 days. Euthyroid guinea pigs treated with amiodarone had significant increases in RR (33 +/- 10%), QT (31 +/- 15%), and corrected QT (13 +/- 11%) intervals. In contrast, when hypothyroid animals were treated with amiodarone, no statistically significant changes occurred in ECG intervals. Plasma concentrations of amiodarone did not differ between the two groups (0.7 +/- 0.6 vs. 0.7 +/- 0.4 mg/L in hypothyroid and euthyroid groups, respectively). We conclude that intact thyroid function is a prerequisite for class III and sinus node effects of amiodarone in the guinea pig. This implies that at least some of amiodarone's effects are mediated through antagonism of thyroid action.

Topics: Amiodarone; Animals; Anti-Arrhythmia Agents; Electrocardiography; Guinea Pigs; Hypothyroidism; Male; Methimazole; Thyroid Hormones

Serum thyroid hormone and TSH concentrations were monitored in a patient with multinodular endemic goiter and severe methimazole (MMI) induced hypothyrodism up to 190 days after drug withdrawal. Serum concentrations of TT3, TT4 and TSH returned to normal values at the 6th., the 140th, and the 120th. day respectively. Within the first 20 days after MMI withdrawal the increase of serum T3 levels was correlated with the observed decrease of serum TSH concentrations. Successively T3 values decreased and T4 levels progressively increased. Six months after MMI withdrawal basal serum TSH concentration was normal while an exaggerated response to TRH was observed. We think that this peculiar hormone pattern is due to iodine depletion. In this case TSH hyperstimulation increases predominantly T3 secretion demonstrating the reduced thyroidal ability to produce T4 when hyperstimulated.

Topics: Female; Goiter, Endemic; Humans; Hypothyroidism; Methimazole; Middle Aged; Regression Analysis; Thyrotropin; Thyrotropin-Releasing Hormone

The effectiveness of therapy involving intravenous administration of methimazole applied in patients with hyperthyroidism resistant to oral thyrostatic drugs has been investigated. Methimazole (Favistan, Asta) was administered intravenously to 3 patients (two women and one man, of ages 21, 24 and 67 years, respectively) in whom there was no remission of the disease after oral methimazole therapy lasting at least two months. Blood serum concentrations of thyroxine (T4), triiodothyronine (T3), reverse++ triiodothyronine (rT3) and triiodothyronine binding index (T3I) have been measured and free thyroxine index (FT4I) calculated before the treatment and on the 4-th, 7-th, 11-th, 14-th and 17-th day of the treatment. The mean value of T4 concentration decreased from 17.0 micrograms/dl before the treatment to 9.7 micrograms/dl after the treatment. T3 from 352 to 177 ng/dl, rT3 from 114 to 103ng/dl the value of T3I from 183 to 161%, and that of FT4I from 30 to 17, respectively. A significant fall of T3 level was observed on the 11-th day of the therapy, that of rT3 on the 14-th day, and that of FT4I on the seventh day. It was concluded that the resistance of some patients with hyperthyroidism to the oral thyreostatic therapy may be caused by the defective absorption of these drugs from the intestinal tract.

Topics: Administration, Oral; Adult; Drug Resistance; Female; Humans; Hypothyroidism; Injections, Intravenous; Male; Methimazole; Middle Aged; Thyroxine; Triiodothyronine

The effect of thyroid hormone on circulating levels of atrial natriuretic peptide (ANP) was studied in experimental hyperthyroid and hypothyroid rats. Plasma ANP was 102 +/- 5 pg/ml in euthyroid rats, 82 +/- 4 pg/ml in hypothyroid rats, and 138 +/- 11 pg/ml in hyperthyroid rats. We have also measured immunoreactive ANP in the atria of euthyroid, hypothyroid, and hyperthyroid rats. ANP content and concentration in the atria were lower (546 +/- 32 pg/mg tissue) in hyperthyroid rats than in hypothyroid rats (802 +/- 74 pg/mg tissue). Right atrium from euthyroid, hypothyroid, and hyperthyroid rats was superfused with a modified Langendorff preparation. Spontaneous release of ANP was significantly higher from the hyperthyroid rats (20 +/- 2 pg.min-1.mg-1) than from the hypothyroid rats (5.6 +/- 0.5 pg.min-1.mg-1). ANP release from the euthyroid rats was 9.3 +/- 1.2 pg.min-1.mg-1. These results indicate hyperthyroidism causes an increase in ANP secretion and a decreased release occurs during hypothyroidism.

Topics: Animals; Atrial Natriuretic Factor; Heart Atria; Hyperthyroidism; Hypothyroidism; In Vitro Techniques; Male; Methimazole; Myocardium; Rats; Rats, Inbred Strains; Thyroxine

The relationship between thyroid activity and Sertoli cell function has been investigated in prepubertal rats. Male 28-day-old Wistar rats were used to prepare Sertoli cells by sequential enzyme digestion of the testes. Hypothyroidism, induced by oral administration of methimazole from the day of birth, was characterized by a severe retardation of body and testis growth and a net inhibition of the increase in Sertoli cell gamma-glutamyl transpeptidase (GGT) activity as well as in androgen-binding protein (ABP) and lactate production, which normally occur during postnatal development of Sertoli cells. The functional parameters of Sertoli cells from hypothyroid 28-day-old rats approximated to those of cells from euthyroid 15-day-old animals. These results are consistent with the impairment of protein synthesis in Sertoli cells from hypothyroid rats compared with controls. Body and testis growth were improved and Sertoli cell functions were restored with 3,3',5-tri-iodothyronine (T3) replacement therapy. An excess of T3 in the serum, induced by daily i.p. injections of T3 (100 micrograms/kg body wt) during the last week before the rats were killed, failed to induce changes in body and testis growth or in the activity of GGT and lactate dehydrogenase of Sertoli cells. Cells from hyperthyroid rats exhibited a specific decrease in ABP production. These results indicate that thyroid hormone is necessary for the postnatal maturation of Sertoli cell function and suggest a regulatory role of the hormone on gametogenic development in the prepubertal rat.

Topics: Aging; Androgen-Binding Protein; Animals; Body Weight; gamma-Glutamyltransferase; Hypothyroidism; L-Lactate Dehydrogenase; Lactates; Male; Methimazole; Organ Size; Rats; Rats, Inbred Strains; Sertoli Cells; Testis; Thyroid Hormones; Thyroxine; Triiodothyronine

1. Indole metabolism and porphyrin content of the Harderian glands of the male Syrian hamster were measured as functions of drug-induced hypothyroidism and exposure to cold conditions. 2. Harderian gland N-acetyltransferase (NAT) activity was reduced from control levels by hypothyroidism induced by methimazole; exposure to cold had no effect on NAT activity. 3. Immunoreactive melatonin in the Harderian glands was unaffected by the state of thyroid secretion. However, immunoreactive melatonin content declined after 180 and 270 min, at 4 degrees C, suggesting that Harderian gland melatonin may be involved in thermoregulation. 4. Porphyrin content of the Harderian glands was not affected by either thyroid secretion or cold.

Topics: Animals; Arylamine N-Acetyltransferase; Cold Temperature; Cricetinae; Harderian Gland; Hypothyroidism; Lacrimal Apparatus; Male; Melatonin; Mesocricetus; Methimazole; Porphyrins; Thyroxine; Triiodothyronine

Hypothyroidism may cause peripheral nerve damage, even if the pathophysiology of these changes is still unclear. It has been suggested by some that an increased vascular permeability is involved in hypothyroidism, while others have suggested a "compressive" mechanism caused by mucinous material deposited in the endoneurium. We have studied histologically the endoneurium and evaluated endoneural-vessel permeability in sciatic nerve by means of the leakage of horseradish peroxidase (HRP) in pharmacologically-induced hypothyroidism in rats. We did not find any substantial differences between the hypothyroid group of animals and the controls with respect to endoneural-vessel permeability. In particular, no macromolecular deposits were present in the extracellular space of the endoneurium in either the treated or the control rats. We therefore believe that a "vascular" hypothesis is unlikely for nerve involvement during hypothyroidism, nor was the "compressive" hypothesis supported by our histological findings.

Topics: Animals; Connective Tissue; Disease Models, Animal; Endothelium, Vascular; Horseradish Peroxidase; Hypothyroidism; Methimazole; Permeability; Rats; Rats, Inbred Strains; Sciatic Nerve

In an effort to define the mechanism by which thyroid hormone increases the synthesis of hepatic cholesterol, we have investigated both in hypophysectomized and methimazole-treated hypothyroid rats the time course of T3 effects on plasma cholesterol concentration, total hepatic cholesterol, the rate of biliary secretion of cholesterol, bile acids, and phospholipids, and the activity and mRNA levels of 3-hydroxy-3-methylglutaryl coenzyme-A (HMG-CoA) reductase, the rate-limiting enzyme in the hepatic synthesis of cholesterol. A single dose of 200 micrograms T3 was estimated to maintain at least 90% nuclear occupancy for the ensuing 54 h of the experiment. In both preparations the relative rise in biliary secretion of cholesterol exceeded that of other biliary constituents and preceded by 12 h an increase in HMG-CoA reductase enzyme activity and its mRNA. The level of total hepatic cholesterol remained constant throughout the experiment. We interpret these findings to suggest that T3-stimulated cholesterol synthesis is mediated by an antecedent T3-induced rise in biliary cholesterol secretion. We postulate that biliary cholesterol secretion is augmented by an intrahepatic shift of cholesterol and depletion of the hepatic sampling center responsible for the feedback regulation of cholesterol synthesis. The level of HMG CoA reductase mRNA appeared to govern enzyme activity in both preparations, but the ratio of mRNA to hepatic enzyme activity was substantially greater in the methimazole-treated compared with the hyphophysectomized animals.

Topics: Animals; Bile; Cholesterol; Hydroxymethylglutaryl CoA Reductases; Hypophysectomy; Hypothyroidism; Lipid Metabolism; Liver; Male; Methimazole; Rats; Rats, Inbred Strains; RNA, Messenger; Triiodothyronine

The rat has been a useful model for studying neuronal and metabolic abnormalities associated with fetal and neonatal hypothyroidism produced by treatment of the mother with antithyroid medication. The neonates are then maintained on this medication via the mother's milk until weaning and subsequently through the drinking water. We have determined the concentrations and contents of immunoreactive cholecystokinin (CCK) and vasoactive intestinal peptide (VIP) in the brain and gut of groups of rats exposed to antithyroid medication from day 16 of gestation. The neonates were sacrificed at 2, 4, 8 and 12 weeks. Compared to controls total body weight was greatly reduced in methimazole (MMI)-treated rats, all of whom were hypothyroid as evidenced by marked reduction of T4 and increase in TSH. Discontinuation of MMI-treatment after 8 weeks resulted in normalization of T4 and TSH and a dramatic weight gain but at 12 weeks the brain weights of the MMI-treated rats were reduced by 17% and the brain contents, of CCK and VIP were similarly reduced. Tissue weights throughout the gut were 1/2 or less than those of control rats. Since VIP but not CCK concentrations in the gut of MMI-treated animals were significantly greater than those of the control animals, it would appear that there was greater loss of mucosal tissue with its endocrine content of CCK than of neuronal tissue with its greater content of VIP.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Aging; Animals; Animals, Newborn; Body Weight; Brain Chemistry; Cholecystokinin; Digestive System; Female; Hypothyroidism; Methimazole; Organ Size; Pregnancy; Radioimmunoassay; Rats; Rats, Inbred Strains; Vasoactive Intestinal Peptide

Lesions in the paraventricular area (PVA) of lactating rats have been found to inhibit PRL release. We have examined whether this reduced PRL release is due to hypothyroidism resulting from destruction of the PVA. Rats were made hypothyroid by thyroidectomy on day 15 of pregnancy or by methimazole treatment from the day of parturition. Electrolytic lesions were placed bilaterally in the PVA on day 15 of pregnancy. The following variables were studied: weight gain of the pups, nursing behavior, thyroid status, and release of PRL. The treatments did not affect the time the mothers spent with the pups but reduced the daily weight gain of the pups. Rats with PVA lesions had reduced PRL and TSH levels during lactation compared with controls. Suckling-induced PRL release after 6 h of separation of mothers and pups was less in PVA-lesioned rats than in controls, but T4-treatment did overcome this blunted response in rats with lesions. Levels of T3 and T4 in PVA-lesioned rats were lower than those in controls. In rats made hypothyroid by thyroidectomy or treatment with methimazole, PRL levels were lower and TSH levels higher than those in euthyroid mothers on days 8, 15, and 22 of lactation. Suckling after 6 h of separation of pups and mothers raised PRL levels both in control and methimazole-treated rats, but in the latter animals the response was blunted. It is suggested that the reduced PRL release in lactating rats with PVA lesions could be due to hypothyroidism resulting from these lesions.

Topics: Animals; Female; Hypothyroidism; Lactation; Litter Size; Methimazole; Paraventricular Hypothalamic Nucleus; Pregnancy; Prolactin; Rats; Thyrotropin; Thyroxine; Triiodothyronine

The effect of hypothyroidism on the thyrotropin-releasing hormone (TRH) receptors in several brain regions and pituitary of rats was determined. TRH receptors were labeled with 3H-(3-MeHis2)TRH (3H-MeTRH). Hypothyroidism was induced in male Sprague-Dawley rats by administering methimazole (0.05% w/v) in drinking water for 32 days. Rats serving as controls were given water without the methimazole. The development of a hypothyroid state was evidenced by significant decreases in colonic temperature, systolic blood pressure, heart rate and serum concentration of triiodothyronine (total T3), thyroxine and T3 uptake (T3U) as compared to control rats. The rate of gain in body weight of methimazole-treated rats was significantly lower than that of control rats. Binding of 3H-MeTRH at 2 nM concentration to membranes prepared from brain regions (striatum, hypothalamus, cortex, midbrain and pons plus medulla) of methimazole-treated and control rats did not differ. However, binding of 3H-MeTRH to pituitary membranes of methimazole-treated rats was significantly lower as compared to the pituitary of control rats. The results indicate that, in the rat, development of hypothyroidism is associated with down-regulation of pituitary TRH receptors but brain receptors remain unaffected.

Topics: Animals; Blood Pressure; Body Temperature; Body Weight; Brain; Brain Chemistry; Heart Rate; Hypothyroidism; Male; Methimazole; Pituitary Gland; Rats; Rats, Inbred Strains; Receptors, Thyrotropin

Hypothyroidism was induced in young female Sprague-Dawley rats by the addition of methimazole (0.67 mg/ml) to drinking water for a period of 7 weeks (7-14 weeks of age). The responses of the articular cartilage, epiphyseal growth plate cartilage, epiphyseal trabecular bone, and metaphyseal trabecular bone in the proximal tibia were assessed by structural parameters. In addition, replacement therapies were introduced for the last 2 weeks of the experimental period. These included 0.7 U/kg BW human GH (hGH), 15 micrograms/kg BW L-T4 (T4), and a combination of hGH and T4 at the same doses. In the hypothyroid rats, the width of epiphyseal growth plate cartilage decreased by 27%, that of articular cartilage by 35%, epiphyseal trabecular bone volume by 30%, and metaphyseal trabecular bone volume by 66% relative to those in age-matched control tissues. T4 treatment led to a full restoration of the epiphyseal trabecular bone and surpassed by 40% the control value. The magnitude of the articular cartilage and the epiphyseal trabecular bone volume returned to control values, while that of metaphyseal trabecular bone was 68% of control values. Treatment with hGH did not improve the epiphyseal growth plate cartilage or articular cartilage. It did restore epiphyseal trabecular bone to almost normal values, but metaphyseal trabecular bone improved to only a small though significant level (45% of control value). The combination of T4 and hGH resulted in an additional enlargement in the width of the epiphyseal growth plate cartilage and an increase in metaphyseal trabecular bone volume compared to those in the T4 group. Qualitative examinations indicated that it was only in the T4 and T4 plus hGH groups that the lowest chondrocytes in the epiphyseal growth plate cartilage resumed their normal hypertrophied size. These results suggest that the change in the hypothyroid state do not rely solely on the lack of pituitary GH synthesis and secretion, as replacement by exogenous GH did not restore normal epiphyseal growth plate cartilage morphology or its remodeling into metaphyseal trabecular bone. Treatment with T4 (which restored endogenous pituitary GH to 30% of control levels) results in full recovery of the epiphyseal growth plate cartilage morphology along with its associated metaphyseal trabecular bone. In addition, it can also be concluded that the decrease in epiphyseal trabecular bone volume observed in the hypothyroid animals was due solely to the GH-deficient state

Topics: Animals; Body Temperature; Body Weight; Bone and Bones; Bone Development; Female; Growth Hormone; Growth Plate; Hypothyroidism; Methimazole; Rats; Rats, Inbred Strains; Reference Values; Thyroxine

Thyroid hormone produces metabolic effects similar to those of stimulation of noradrenergic receptors. It has been reported, however, that norepinephrine turnover is reduced during thyrotoxicosis and that beta-noradrenergic receptor number is increased. Metabolic effects of thyroid hormone may therefore reduce noradrenergic activity. We examined effects of thyroid hormone administration or production of hypothyroidism with methimazole on receptors associated with regulation of noradrenergic function. Treatment with thyroid hormone increased beta-receptor binding, increased alpha-2 receptor binding, and decreased desipramine binding, opposite to effects of hypothyroidism produced by methimazole. Heart was more sensitive than brain to these effects. These data are consistent with reduced noradrenergic activity during hyperthyroidism, possibly mediated by an increase in autoreceptor function.

Topics: Animals; Cerebral Cortex; Desipramine; Dihydroalprenolol; Heart; Hypothyroidism; Male; Methimazole; Myocardium; Norepinephrine; Rats; Rats, Inbred Strains; Receptors, Adrenergic, alpha; Receptors, Adrenergic, beta; Triiodothyronine; Yohimbine

The effect of chronic administration of methimazole (0.05% w/v) in drinking water for 32 days to male Sprague-Dawley rats on the binding of opioid ligands, 3H-Tyr-D-Ala-Gly-MePhe-Gly-ol (DAGO, mu-receptors), 3H-Tyr-D-Ser-Gly-Phe-Leu-Thr (DSTLE, delta-receptors) and 3H-ethylketocyclazocine (EKC, kappa-receptors) to membranes of brain regions was determined. Chronic administration of methimazole to rats decreased their rate of body weight gain, colonic temperature, systolic blood pressure and heart rate in comparison to vehicle-treated rats. Administration of methimazole also decreased the serum concentration of triiodothyronine (total T3) and T4 when compared to vehicle-treated rats. The binding of 3H-DAGO to membranes of amygdala, pons and medulla, striatum, midbrain and cortex of methimazole-treated rats was greater than vehicle-treated rats, however, the binding to membranes of hypothalamus in the two treatment groups did not differ. The binding of 3H-DSTLE in amygdala and hypothalamus of methimazole-treated rats did not differ but it was significantly greater in pons and medulla, midbrain, cortex and striatum of methimazole-treated rats than vehicle-treated rats. The binding of 3H-EKC to membranes of pons and medulla was lower and of striatum and cortex of methimazole-treated rats was significantly greater than vehicle-treated rats, but the binding to membranes of amygdala, hypothalamus, and midbrain of the two treatment groups did not differ. The results indicate that brain, mu-, delta- and kappa-opioid receptors are differentially altered in hypothyroidism.

Topics: Animals; Body Temperature; Body Weight; Brain Chemistry; Cyclazocine; Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; Enkephalin, Leucine; Enkephalins; Ethylketocyclazocine; Heart Rate; Hypothyroidism; Male; Methimazole; Oligopeptides; Rats; Rats, Inbred Strains; Receptors, Opioid; Triiodothyronine

The serum BGP level was assayed in patients with hyperthyroidism (untreated and remittent cases) and hypothyroidism. The mean serum BGP concentration was 9.7 +/- 0.90 ng/ml in 30 patients with untreated hyperthyroidism which was significantly higher than the 2.7 +/- 0.38 ng/ml in 15 remittent patients and 1.3 +/- 0.31 ng/ml in 13 patients with hypothyroidism (p less than 0.001, p less than 0.001). Serum BGP had a significant positive correlation with the concentrations of free triiodothyronine and alkaline phosphatase in the serum, while it had a significant negative correlation with serum PTH. In the patients with hypothyroidism, serum BGP increased significantly in parallel with increases in serum free triiodothyronine with thyroxine therapy. In the patients with hyperthyroidism, serum free triiodothyronine decreased significantly after the first month of methimazole treatment, and fluctuated within the normal range after two months. Serum alkaline phosphatase and BGP did not show significant changes during the first six months of treatment, although they were eventually reduced significantly at the end of one year. These results suggest that thyroid hormone directly stimulates the synthesis and secretion of BGP in existent osteoblasts and also acts on the bone remodeling cycle, therapy accelerating the rate of bone formation; the latter action may occur over a long period.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Alkaline Phosphatase; Bone and Bones; Calcium; Calcium-Binding Proteins; Female; Humans; Hyperthyroidism; Hypothyroidism; Male; Methimazole; Middle Aged; Osteocalcin; Parathyroid Hormone; Thyroid Gland; Thyroxine; Triiodothyronine

In euthyroid rats a 17-day treatment with nafenopin, a hypolipidemic agent and peroxisome proliferator, decreased serum total and free T4 concentrations to 32 +/- 5% and 62 +/- 8% (mean +/- SEM; n = 10), respectively, with no change in serum T3 and TSH concentrations. In methimazole-treated rats infused with 3 nmol T4/day/100 g BW, the nafenopin inhibitory effect was not significantly different from that in euthyroid rats. Nafenopin treatment had the following effects on peripheral T4 and T3 metabolism in euthyroid rats. The plasma clearance rate of T4 (PCR), which was measured by Alzet minipump infusion of tracer, was increased 2-fold (1.58 +/- 0.09 vs. 0.82 +/- 0.06 ml/h.100 g BW; P less than 0.001; n = 5), while the PCR of T3 was decreased (37.5 +/- 1.3 vs. 53.8 +/- 1.8; P less than 0.001; n = 5). The fecal clearance rate of radioactivity derived from T4 was increased 2-fold (1.93 +/- 0.10 vs. 0.77 +/- 0.07 ml/h.100 g BW), whereas the urinary clearance rate was not significantly modified. The 5'-deiodinase (5'D) activity, measured by deiodination of labeled rT3, was strongly inhibited in liver and kidney, not modified in brown fat and anterior pituitary, and increased in cerebral cortex. In methimazole-treated rats substituted with isopropyl-diiodothyronine only hepatic 5'D activity was decreased. It is concluded that the decrease in serum total and free T4, without alteration in serum T3 and TSH concentrations, resulting from nafenopin treatment is mainly due to changes in peripheral T4 and T3 metabolism, since it is also observed in T4-substituted animals. The increased PCR of T4 cannot be explained by an increase in deiodination activity, since the major 5'D pathways are inhibited after nafenopin treatment, and the urinary clearance rate is not modified. It can partly be explained by an increase in the fecal clearance rate of T4, which could be due to an increase in glucoronoconjugation. In addition, nafenopin was found to be a weak competitor of T4 binding to serum proteins, leading to a small increase in the free T4 fraction which might also contribute to the increased T4 PCR. The decrease in T3 PCR remains to be explained.

Topics: Adipose Tissue, Brown; Animals; Cerebral Cortex; Diiodothyronines; Feces; Hormones; Hypothyroidism; Iodide Peroxidase; Iodine Radioisotopes; Kidney; Liver; Male; Metabolic Clearance Rate; Methimazole; Microbodies; Nafenopin; Propionates; Rats; Rats, Inbred Strains; Thyrotropin; Thyroxine; Triiodothyronine

The placenta contains iodothyronine 5-deiodinase activity (P5-Dase) that probably acts on iodothyronines in the fetal circulation to convert T4 to rT3 and T3 to 3,3'-T2. Since thyroid status and fasting have profound effects on iodothyronine deiodinases in other tissues, the present studies were performed to determine if these perturbations affected P5-Dase. Control and treated rats were mated and killed near term on the 20th day of gestation. P5-Dase was determined in placenta homogenates enriched with dithiothreitol by measuring the conversion of T4 to rT3. In four of five studies, P5-Dase was similar in dams that underwent thyroidectomy (Tx) on day 7 of gestation and sham Tx dams. P5-Dase was not altered in dams that were treated with methimazole (MMI) to induce maternal and fetal hypothyroidism. Treatment of dams with supraphysiological doses of T4, beginning on the seventh day of gestation, did not significantly affect P5-Dase. In three of four studies, P5-Dase was similar in fed dams to values in dams fasted for the last 5 days of pregnancy. Placenta iodothyronine 5'-deiodinase activity (P5'-Dase) was also measured in some studies. P5'-Dase was not decreased in Tx rats and was modestly decreased in MMI-treated rats. However, the effect of MMI was not reversed by the administration of supraphysiological doses of T4, Tx, MMI treatment, and fasting all decreased hepatic T4 5'-deiodinase activity in pregnant rats. These results strongly suggest that thyroid status and fasting do not alter P5-Dase activity.

Topics: Animals; Fasting; Female; Hypothyroidism; Iodide Peroxidase; Liver; Male; Methimazole; Placenta; Pregnancy; Rats; Rats, Inbred Strains; Thyroid Diseases; Thyroidectomy; Thyrotoxicosis; Thyroxine

To investigate the dose-response relationship between thyroid hormone and linear growth, we studied 10 castrated prepubertal cynomolgus monkeys. Hypothyroidism was induced by administration of methimazole (0.0125% in drinking water) and was confirmed by high serum TSH levels (greater than 40 mU/L) in all animals. Subsequently, each animal received 1, 2, 4, or 8 micrograms/kg.day T4, im, for 9 weeks. The sequence of T4 doses was random, and 6 weeks elapsed between successive T4 doses. Serum T4, T3, TSH, and insulin-like growth factor I (IGF-I) levels and lower leg length were measured every 3 weeks. Methimazole administration decreased thyroid hormone and IGF-I levels and lower leg growth rate. With increasing doses of exogenous T4, serum T4, T3, and IGF-I as well as lower leg growth rate increased significantly. Animals not given T4 had a 65% decrease in lower leg growth rate (P less than 0.01). Animals given 4 and 8 micrograms/kg.day T4 had 56% and 73% increases, respectively, in lower leg growth rate compared to baseline (P less than 0.05 and P less than 0.01, respectively). Lower leg growth rate correlated better with serum T3 (r = 0.50; P less than 0.001) than with serum T4 (r = 0.29; P less than 0.05). Lower leg growth rate also correlated with serum IGF-I levels (r = 0.53; P less than 0.001). Serum IGF-I correlated with serum T3 (r = 0.47; P less than 0.001), but not with serum T4. We conclude that increased serum T4 and T3 levels cause progressive increases in growth velocity and IGF-I levels over a range from moderate hypothyroidism to moderate hyperthyroidism. Growth velocity and IGF-I levels correlated more strongly with the serum T3 than with the serum T4 level.

Topics: Animals; Castration; Dose-Response Relationship, Drug; Female; Growth; Hyperthyroidism; Hypothyroidism; Macaca fascicularis; Male; Methimazole; Somatomedins; Thyroid Hormones; Thyroxine; Triiodothyronine

The purpose of this study was to explore the relationship between the thyroid status and both ventricular and atrial electrophysiology in the rat. The study was extended to consider the effects of altering the extracellular calcium concentration. The work was performed in two sections. First, hypothyroid animals were compared with euthyroid (untreated animals); second, hypothyroid animals were compared with hyperthyroid animals. Rats were rendered hypothyroid by pretreatment with the goitrogen methimazole and hyperthyroid by additional treatment with triiodothyronine. Action potential recordings were obtained using standard microelectrode techniques. Action potential measurements were made initially in a Krebs solution to which had been added 2.55 mM calcium (higher Ca Krebs solution) and at the end of each experiment after stabilization with Krebs solution to which had been added 1.28 mM calcium (lower Ca Krebs solution). Assessment of the change in action potential duration on transition from higher to lower Ca Krebs solution revealed that the euthyroid preparations demonstrated less prolongation of action potential duration than the hypothyroid group, and the hyperthyroid group showed hardly any response to reduction in calcium concentration.

Topics: Action Potentials; Animals; Calcium; Heart; Hypothyroidism; In Vitro Techniques; Male; Membrane Potentials; Methimazole; Papillary Muscles; Rats; Rats, Inbred Strains; Thyroid Gland

By means of morphological, morphometrical and autoradiographical methods restorative processes in the parathyroid glands in 41 euthyroid and in 41 hypothyroid rats have been studied during 1-24 days after mechanical trauma of the glands or after hemithyroparathyroidectomy. Seven hypothyroid and 7 euthyroid rats serve as a control. Hypothyroidism is produced with daily injection of mercazolil (6 mg/kg) 3 weeks before the operation and during the time of the experiment. In nonoperated hypothyroid rats development of hypertrophy in parathyrocytes is noted. Prolonged injection of mercazolil weakens (posttraumatic regeneration) or completely suppresses (compensatory hypertrophy) mitotic activity of the glandular cells (in comparison with the euthyroid animals). Manifestation of hypertrophy in parathyrocytes of the hypothyroid rats in comparison with the corresponding control is also less, than against the background of euthyreosis.

Topics: Animals; Hyperplasia; Hypertrophy; Hypothyroidism; Male; Methimazole; Mitosis; Parathyroid Glands; Rats; Thyroidectomy

Previous studies have suggested that thyroid hormones influence the number of membrane-bound cardiac adrenoceptors, but their effect on the intracellular distribution of adrenoceptors has not been examined. A plasma cell membrane and a vesicular fraction devoid of membrane markers were prepared from hearts of euthyroid and hyperthyroid rats and were used to compare beta- and alpha-adrenoceptors. During daily injection of l-thyroxine, cardiac hypertrophy developed within 4 days and remained unchanged thereafter. The number of membrane-bound beta-receptors increased progressively and plateaued within 2 weeks of thyroxine administration. Vesicular beta-receptors, on the other hand, increased more gradually and to a lesser extent so that after 2 weeks of l-thyroxine injection, they constituted a smaller proportion of the total beta-receptor population compared to normal rats. In contrast, the number of cardiac alpha 1-adrenoceptors declined rapidly to about 80% of that in euthyroid animals and did not change further for the duration of the study. Membrane-bound and vesicular alpha 1-adrenoceptors were affected to the same extent in hyperthyroidism. During regression of cardiac hypertrophy following cessation of thyroxine administration, alpha 1-adrenoceptors rose rapidly (within 2 days) to normal values while beta-receptors declined more gradually to normal levels within 2 weeks. In hypothyroid rats, there was a significant decline in the density of both alpha 1- and beta-adrenoceptors, with a shift away from the vesicular fraction. These results indicate that both the total numbers of cardiac adrenoceptors and their distribution between the plasma membrane and vesicular fraction are influenced by the thyroid status.

Topics: Animals; Cardiomegaly; Cell Membrane; Dihydroalprenolol; Hyperthyroidism; Hypothyroidism; Kinetics; Male; Methimazole; Myocardium; Rats; Rats, Inbred Strains; Receptors, Adrenergic, alpha; Receptors, Adrenergic, beta; Thyroid Hormones; Thyroxine

We reported recently that chronic thyroid deficiency in rat, beginning in utero and terminating after maturity, suppresses lesion-induced central catecholaminergic axon sprouting in the adult brain [Gottesfeld et al, 1985]. The present work was undertaken to define the critical period of hypothyroidism on subsequent neuronal sprouting. Thyroid hormones deficiency was induced in rats by methimazole during (a) gestational days 8-21 (20 mg/kg/day in the drinking water); (b) postnatal days 1-15 (0.2 or 0.4 mg/pup/day; i.p.), or (c) in the mature animal for 4 weeks (20 mg/kg/day in the drinking water). The olfactory tubercles (OTs) were used as a model to study sprouting of dopaminergic (DA) nerve terminals, elicited by olfactory bulbectomy. Animals in each group received lesions or sham operations as adults, and sacrificed 3 weeks after the operation. Thus, for each of the above treatments four subgroups were formed: (a) euthyroid/sham-operation, (b) euthyroid/lesion, (c) hypothyroid/sham-operation, and (d) hypothyroid/lesion. Sprouting of DA axon terminals in the OTs was identified by biochemical assays and quantitative immunofluorescent microscopy, using tyrosine hydroxylase (TH) as a marker. Serum thyroxine levels served as an index of the thyroid status. The results demonstrate that lesion-induced sprouting of DA axon terminals in OTs of adult rats is suppressed by hypothyroidism induced prenatally or during the early postnatal period, but not after maturity. Thus, there is a perinatal critical period during which altered thyroid function exerts long-term effects on neuronal plasticity.

Topics: Animals; Animals, Newborn; Axons; Dopamine; Female; Hypothyroidism; Male; Methimazole; Nerve Regeneration; Olfactory Bulb; Pregnancy; Rats; Rats, Inbred Strains; Thyroxine; Tyrosine 3-Monooxygenase

Plasma concentrations of atrial natriuretic peptides were measured in 32 normal control subjects, 25 patients with hyperthyroidism, and 18 patients with hypothyroidism. Atrial natriuretic peptide values were measured before and after successful therapy with methimazole or 1-thyroxine. Plasma atrial natriuretic peptide concentration was increased in patients with hyperthyroidism (48.0 +/- 19.5 pg/ml) but was decreased in patients with severe hypothyroidism (16.3 +/- 5.7 pg/ml) compared with values in normal control subjects (31.2 +/- 9.5 pg/ml). There was no significant difference between values in normal control subjects and mildly hypothyroid patients (35.0 +/- 12.2 pg/ml). The plasma atrial natriuretic peptide concentration was correlated with the serum thyroxine level and heart rate. The elevated atrial natriuretic peptide concentration in hyperthyroidism decreased, whereas the reduced atrial natriuretic peptide concentration in severe hypothyroidism increased, compared with the initial value after successful therapy. These results suggest that plasma atrial natriuretic peptide concentration is frequently increased in hyperthyroidism and is frequently decreased in severe hypothyroidism, and that thyroid hormone is one of the regulatory factors for circulating atrial natriuretic peptides.

Topics: Adult; Atrial Natriuretic Factor; Female; Heart Rate; Humans; Hyperthyroidism; Hypothyroidism; Male; Methimazole; Reference Values; Thyroxine

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

Three groups of male Sprague Dawley rats received methimazole without or with Na-thyroxine in drinking water (3 and 0.33 mg T4/l, respectively) to induce characteristic alterations of their thyroid status (hypothyroid, hyperthyroid, euthyroid). A fourth group served as an untreated control without any additive to the drinking water. With respect to the different thyroid status, the following changes in the blood parameters were found: increasing plasma-T3-levels caused a reduction in plasma viscosity, in total plasma protein and in alpha 1-globulin, but an increase in hematocrit, whole blood viscosity, the number of erythrocytes and leukocytes, alpha 2-globulin and beta-globulin. It was concluded that the increase in the plasma viscosity in the hypothyroid status is mainly due to an alteration of the plasma protein pattern, and that the increase in whole blood viscosity in the hyperthyroid rat is a consequence of increased hematocrit.

Topics: Animals; Blood Proteins; Blood Viscosity; Hyperthyroidism; Hypothyroidism; Methimazole; Rats; Rats, Inbred Strains; Thyroxine; Triiodothyronine

The effects of hypothyroidism in utero, and continuing into postnatal life, on the central turnover of catecholamines, noradrenaline and dopamine were studied in rats. Rats were rendered hypothyroid in utero by treating pregnant females with methimazole in the drinking water. In two groups goitrogen treatment continued for 3 or 10 weeks postnatally. Methimazole treatment in utero did not produce significant changes in noradrenaline, dopamine or tyrosine content in either the hypothalamus or striatum. Three weeks' postnatal treatment reduced tyrosine specific radioactivity in the anterior hypothalamus and dopamine specific radioactivity in the striatum. Ten weeks' treatment increased dopamine content and reduced noradrenaline synthesis in the mediobasal hypothalamus and a reduction in tyrosine content in the anterior hypothalamus. These data suggest that hypothyroidism restricted to intrauterine life does not produce permanent changes in adult catecholamine neuronal function. Long term hypothyroidism produced localized changes, suggesting a specific rather than general effect.

Topics: Animals; Brain; Catecholamines; Female; Hypothyroidism; Methimazole; Rats; Rats, Inbred Strains; Tyrosine

The brain topographical distribution of type II 5'-monodeiodinase (5'D-II), which converts thyroxine (T4) to triiodothyronine (T3), was studied in euthyroid and hypothyroid rats. Low levels of 5'D-II activity were detected in the median eminence, but not in any other brain regions of euthyroid rats. The arcuate nucleus and median eminence were also the sites of highest 5'D-II activity in brains of hypothyroid rats. Under these conditions, the paraventricular nucleus contained almost no detectable 5'D-II, while intermediate enzyme activity was present in other medial basal hypothalamic sites.

Topics: Animals; Arcuate Nucleus of Hypothalamus; Brain; Hypothalamus; Hypothyroidism; Iodide Peroxidase; Male; Median Eminence; Methimazole; Rats; Rats, Inbred Strains; Thyroid Gland; Thyroxine; Triiodothyronine

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

Nuclear binding of [125I]T4 in human mononuclear blood cells was examined in six hyperthyroid and six hypothyroid patients before and after treatment. In hypothyroid patients the nuclear T4 binding was initially increased and subsequently normalized as the patients became euthyroid suggesting a homeostatic counter-regulation. The thyroid state did not affect the nuclear T4 binding in hyperthyroid patients. Treatment with methimazol however increased the nuclear T4 binding, suggesting either a direct effect of methimazol on the hormone-receptor interaction or that the patients had become slightly hypothyroid during the treatment. The TSH was shown not to affect nuclear T4 binding. The thyroid state of the patients did not significantly affect the nuclear accumulation of the T3 produced intracellularly by deiodination of T4.

Topics: Adult; Female; Humans; Hyperthyroidism; Hypothyroidism; Male; Methimazole; Middle Aged; Monocytes; Receptors, Cell Surface; Receptors, Thyroid Hormone; Thyrotropin; Thyroxine; Triiodothyronine

A 37-year-old male with total thyroxine-binding globulin (TBG) deficiency associated with Graves' disease is described. Both TBG immunoreactivity and TBG capacity were not detectable in his serum. Serum concentrations of thyroxine-binding prealbumin and albumin were normal. He was initially hyperthyroid. During methimazole-treatment he was maintained in an euthyroid state except for two short hypothyroid periods. His plasma triiodothyronine/thyroxine (T3/T4) ratios during both the untreated hyperthyroid and the methimazole-induced hypothyroid states were higher than those during his methimazole-induced euthyroid state. These findings on changes in his T3/T4 ratio accompanying thyroidal dysfunction were qualitatively comparable with those in patients with Graves' disease with normal TBG levels: that both untreated hyperthyroid and methimazole-induced hypothyroid patients showed higher T3/T4 ratios than methimazole-induced euthyroid patients. These results may provide indirect evidence that changes in hormonal secretion and conversion that raise T3/T4 ratio can occur in thyroidal dysfunctions even in the complete absence of TBG.

Topics: Adult; Graves Disease; Humans; Hyperthyroidism; Hypothyroidism; Male; Methimazole; Thyroid Hormones; Thyroxine; Thyroxine-Binding Proteins; Triiodothyronine

Topics: Female; Graves Disease; Humans; Hypothyroidism; Infant, Newborn; Maternal-Fetal Exchange; Methimazole; Pregnancy; Pregnancy Complications; Propylthiouracil

The induction of hypothyroidism by methimazole produces a delay in CNS development as well as behavioral deficits in rat pups. Methimazole (0.1 mg/ml) was administered via drinking water to dams from gestational day 17 to postnatal day 10. Rat pup body weight was reduced on postnatal day 15 (P15) and 30 (P30) while brain weight was decreased only at P15. Soluble brain protein was decreased at P15 and P30. Total enolase and neuron-specific plus hybrid enolase (NSE+H) specific activity and activity were reduced on P15, while non-neuronal enolase (NNE) activity but not specific activity was depressed. At postnatal day 30, total enolase and NSE+H activity were slightly reduced, but NNE activity and the specific activities of total enolase, NNE and NSE+H were similar to controls. The ratio of NSE+H to NNE was reduced at P15 but not P30. The alterations in enolase activity following methimazole administration suggest a delay in the development and maturation of the CNS at P15. These results provide a biochemical correlate of the developmental delays reported in hypothyroid rat pups.

Topics: Age Factors; Animals; Body Weight; Brain; Female; Fetus; Hypothyroidism; Isoenzymes; Methimazole; Organ Size; Phosphopyruvate Hydratase; Pregnancy; Rats; Rats, Inbred Strains

The effects of thyroid and gonadal status on the content of substance P in the anterior pituitary (AP-SP) were examined in prepubertal rats. A sex difference in AP-SP is evident by age 50 days [males, 287 +/- 35 fmol/mg protein (mean +/- SE); females, 103 +/- 17; P less than 0.05], and this difference becomes greater by 75 days (males, 543 +/- 54; females, 146 +/- 11.5; P less than 0.01). Hypothyroidism was induced in male and female pups by giving lactating dams 0.1% methimazole (wt/vol) in their drinking water after parturition. There was a marked and significant increase in AP-SP in 21-day-old hypothyroid compared to euthyroid control pups. Male pups were made thyrotoxic by daily treatment with T4 (10 micrograms/rat, sc) from age 8 to 15 days. AP-SP was 4 times lower in the thyrotoxic than in the euthyroid pups (P less than 0.001). Rats ovariectomized at age 22 days and killed on day 35 revealed no change in AP-SP, in contrast to the rise in AP-SP in the ovariectomized adult rat. Female pups were treated with dihydrotestosterone (DHT; 50 micrograms/day) or testosterone (50 micrograms/day) from age 8-20 days. Neither androgen induced a change in AP-SP. Female pups which received estradiol (E2; 0.5 micrograms/day) or testosterone (75 micrograms/day) from age 8-20 days also had no change in AP-SP. As opposed to the lack of effect of E2 and DHT on AP-SP in female rats younger than 22 days, E2 (1 microgram/100 g BW daily) caused a decrease and DHT (100 micrograms/100 g BW daily) caused an increase in AP-SP in female rats treated from 22-35 days of age [E2, 91 +/- 6.9; DHT, 226 +/- 31 (P less than 0.05 vs. control for both); control, 154 +/- 13]. We conclude that the responsiveness of AP-SP to alterations in thyroid status is present at the youngest age studied. In contrast, the responsiveness of AP-SP to changes in the levels of gonadal steroids is absent in the infantile period and requires a maturational process that becomes evident during the juvenile state of sexual development.

Topics: Androgens; Animals; Diethylstilbestrol; Dihydrotestosterone; Estradiol; Estrogens; Female; Hyperthyroidism; Hypothyroidism; Male; Methimazole; Orchiectomy; Ovariectomy; Pituitary Gland, Anterior; Rats; Sex Factors; Sexual Maturation; Substance P; Testosterone; Thyroid Hormones; Thyroxine

We have produced two antisera (R-1 & R-2) to human growth hormone-releasing factor (GRF) [1-44] NH2. Both antisera can be used for human GRF radioimmunoassay (RIA) at a final dilution of 1:50000. The antiserum R-2 was specific for the C-terminal amidated sequence of human GRF-44 and selectively recognized GRF [1-44] NH2 but not GRF [1-44] OH or GRF [1-40] OH. The antiserum R-1 also significantly bound 125I-rat GRF [1-43] OH at a final dilution of 1:5000 and enabled us to establish RIA for rat GRF. In both RIA systems, intra- and inter-assay coefficients of variation at 50% inhibition were 8 and 12%, respectively. A median effective dose was 90-120 pg in human GRF RIA and 250-300 pg in rat GRF RIA. Utilizing the RIA, we demonstrated that the hypothalamic GRF content in rats which received monosodium glutamate during the neonatal period was less than 20% of that of controls. However, the hypothalamic GRF content was not altered in rats made hypothyroid by methimazole administration, another condition known to greatly impair GH secretion. An iv administration of the antiserum R-1 significantly suppressed GH release following the injection of antisomatostatin serum. Thus, these antisera can be a useful tool in examining the physiological and/or pathophysiological roles of GRF in human and rat.

Topics: Animals; Epitopes; Female; Growth Hormone-Releasing Hormone; Humans; Hypothalamus; Hypothyroidism; Immune Sera; Immunization, Passive; Male; Methimazole; Peptide Fragments; Radioimmunoassay; Rats; Rats, Inbred Strains; Sodium Glutamate

The action of the antithyroid, sulphydryl reagent methimazole (MMI) on the specific binding of [3H]-imipramine in the cerebral cortex and corpus striatum of immature and mature rats has been examined. Chronic administration of MMI through the first 30 days of life decreased the number of imipramine binding sites in cortical but not striatal membranes, as assessed 48 h after the last injection of goitrogen. A similar treatment did not affect the binding profile of [3H]-imipramine in mature rats. Acute administration of MMI to 30 day-old rats increased the number of imipramine binding sites shortly after the injection, an effect no longer evident 48 h later. MMI in vitro increased the binding of [3H]-imipramine. It is concluded that maturational impairment of the hypothyroid cortex, rather than any alteration of membrane bound thiol groups, was a major cause for the diminished binding of [3H]-imipramine in MMI-treated, immature rats.

Topics: Aging; Animals; Animals, Newborn; Antithyroid Agents; Brain; Carrier Proteins; Cerebral Cortex; Corpus Striatum; Female; Hypothyroidism; Male; Methimazole; Nerve Tissue Proteins; Rats; Receptors, Drug; Receptors, Neurotransmitter; Sulfhydryl Compounds; Time Factors

Hyperthyroidism occurred following primary hypothyroidism in a 46-year-old man with serologically and histologically proved chronic lymphocytic thyroiditis. Repeated thyroid biopsy specimens revealed that histologic features compatible with chronic lymphocytic thyroiditis seen at the initial hypothyroid state subsequently underwent a remarkable resolution, with titers of circulating antithyroid antibodies being reduced in correspondence with the histologic improvement. This case shows that primary hypothyroidism in adults can spontaneously evolve into a hyperthyroid state, as has been suggested previously, and that the histologic abnormalities in chronic lymphocytic thyroiditis may not necessarily be irreversible.

Topics: Antibodies; Follow-Up Studies; Humans; Hyperthyroidism; Hypothyroidism; Immunoglobulins, Thyroid-Stimulating; Male; Methimazole; Middle Aged; Thyroid Gland; Thyroiditis; Thyroxine

The response to methimazole [1-methyl-2-mercaptoimidazole (MMI)] therapy was evaluated in 18 patients with diffuse toxic goiter residing in an area of iodine deficiency (Tehran) and in 18 patients residing in an area of iodine sufficiency (Boston). The mean free T4 index (FT4I) decreased from 22.9 +/- 4.8 (+/- SD) to 4.9 +/- 4.3 in Tehran and from 23.8 +/- 5.2 to 17.0 +/- 4.1 in Boston after 4 weeks of MMI administration (10 mg, three times daily). The mean free T3 index (FT3I) decreased from 489 +/- 124 to 117 +/- 58 in Tehran and from 512 +/- 250 to 368 +/- 152 in Boston. In patients residing in Tehran, the FT4I was normal in 9 (less than 6.3 in 6), above normal in 1, and subnormal in 8 (44%) after 4 weeks of MMI treatment. In 4 of 8 patients with subnormal FT4I, serum TSH was also above normal, and clinical findings of hypothyroidism were evident. MMI (10 mg, twice daily) was then given to 15 additional patients with diffuse toxic goiter in Tehran. Mean FT4I values were 22.7 +/- 6.8, 12.1 +/- 2.5, 10.8 +/- 2.8, and 6.0 +/- 4.3 before and 8, 14, and 28 days after treatment, respectively. Corresponding mean FT3I values were 415 +/- 90, 196 +/- 36, 162 +/- 44, and 117 +/- 46. At 28 days, FT4I was subnormal in 7 (46%) patients, of whom 1 had increased TSH. These results indicate that treatment with recommended doses of MMI rapidly causes hypothyroidism in patients residing in Tehran, an area of iodine deficiency. Furthermore, they support the hypothesis that the dosage of thionamide compounds and the duration of therapy with the initial doses necessary to induce euthyroidism may vary in various parts of the world.

Topics: Adult; Boston; Dose-Response Relationship, Drug; Environment; Female; Graves Disease; Humans; Hypothyroidism; Iodine; Iran; Male; Methimazole; Middle Aged; Thyroxine; Triiodothyronine

Plasma fibronectin concentrations up to 85 mg/100 ml were found in hyperthyroid patients. There was a significant correlation between free thyroxine index and plasma fibronectin values. Hypothyroid patients had low to normal fibronectin concentrations. Parallel decreases of thyroid hormones and plasma fibronectin concentrations were noted during treatment with thiamazole. A direct effect of thyroid hormones on fibronectin synthesis seems probable.

Topics: Adult; Aged; Female; Fibronectins; Humans; Hyperthyroidism; Hypothyroidism; Methimazole; Middle Aged; Prealbumin; Thyroid Diseases; Thyroid Function Tests; Thyroxine

To further understand the regulation of type II iodothyronine 5'-deiodinase (5'D-II) in the central nervous system and pituitary, we examined the response of this enzyme to the acute administration of T4, T3, and rT3 in hypothyroid rats. Enzyme levels were correlated with serum concentrations of T4 and T3 in thyroidectomized rats after acute administration of either iodothyronine and in animals with hypothyroidism of increasing severity induced by methimazole administration. Estimates of the tissue concentrations of the three iodothyronines, nuclear T3, and serum TSH levels were used to assess mechanisms and intrinsic potencies of the three iodothyronines. In four experiments, doses of T4 that reduced 5'D-II activity by 50% (ID50) ranged from 0.18-0.39 micrograms/100 g BW in the cortex and from 0.34-1.05 in the pituitary, whereas the corresponding ID50 values of rT3 were 1.0 and 3.5, and those of T3 were 4.0 and 5.0 micrograms/100 g BW. T3 doses that saturated nuclear receptors and fully suppressed TSH showed only modest suppression of 5'D-II levels in the cortex and pituitary. Based on estimates of the tissue hormone levels resulting in 5'D-II suppression, T4 and rT3 were much more potent than T3 in decreasing 5'D-II. These findings support the concept that the effect of these iodothyronines on 5'D-II is not mediated by the nuclear T3 receptor. The correlation of serum T4 and T3 with enzyme levels after acute injections of T4 or after chronic treatment with methimazole suggested that plasma T4 is probably the main physiological signal regulating 5'D-II. It is conceivable that rT3 produced locally from T4 also plays a role in the regulation of the enzyme.

Topics: Animals; Cell Nucleus; Cerebral Cortex; Dose-Response Relationship, Drug; Hypothyroidism; Iodide Peroxidase; Male; Methimazole; Peroxidases; Pituitary Gland; Pituitary Gland, Anterior; Rats; Rats, Inbred Strains; Thyroidectomy; Thyrotropin; Thyroxine; Time Factors; Triiodothyronine, Reverse

The long-term effects of perinatal hypothyroidism on spontaneous locomotor behaviors were assessed after exposure to the antithyroid drug, methimazole. Perseveration was observed in methimazole-treated rats in a spatial maze. Locomotor activity in residential mazes was examined at 6 weeks, 4 months, and 6 months of age. Treated rats were hypoactive at some intervals compared with controls and were hyperactive at others. These paradoxical differences resulted from changes in exploratory, diurnal, and nocturnal locomotor activity in control rats both with increasing age and on repeated exposures to residential mazes; rats after perinatal hypothyroidism had relatively constant levels of activity on repeated days of exposure to residential mazes and at different ages. These results may be related to perseveration noted in the spatial maze. In an analysis of walking patterns, treated rats tended to have a more pronounced asymmetry in gait than controls.

Topics: Animals; Behavior, Animal; Body Weight; Exploratory Behavior; Female; Hypothyroidism; Methimazole; Motor Activity; Pregnancy; Rats; Rats, Inbred Strains; Sex Factors

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 modification of behavior caused by hypo and hyperthyroidism were studied when the schedule of reinforcement was changed from a fixed ratio to a fixed interval. The conditions of hypo and hyperthyroidism were obtained with a chronic administration of methimazole and of 1-thyroxine. The level of the modifications of thyroid activity was determined by evaluation of the basal metabolic rate and of the plasma levels of T4. Hyperthyroidism caused no modification of the rat behaviour. A difficulty in adapting to the new experimental situation (learning) was found in hypothyroidism. This effect is evident in high hypothyroidism. In low hypothyroidism a depression of the rat behaviour may interfere with the modification of the learning process.

Topics: Animals; Behavior, Animal; Hyperthyroidism; Hypothyroidism; Kinetics; Male; Methimazole; Rats; Rats, Inbred Strains; Reinforcement Schedule; Thyroxine

Topics: Adolescent; Adult; Female; Humans; Hyperthyroidism; Hypothyroidism; Male; Methimazole; Middle Aged

Urine samples from 8 healthy subjects, from 16 patients with primary hypothyroidism and 8 patients with Graves' hyperthyroidism were pre-purified in SP-Sephadex-C-25 cation-exchange-chromatography, subjected to reverse phase high-pressure liquid chromatography (HPLC) with 0.01 M ammonium acetate pH 4 as a polar and propanol as a non-polar solvent with a 1%/min gradient and assayed in our TRH radioimmunoassay. Urine TRH-immunoreactivity levels were measured before and after 3 months of treatment with thyroxine or methimazole. The urine TRH-levels in healthy subjects were 5.5 +/- 1.4 ng/1 (mean +/- SEM, n = 8). In the hypothyroid patients, the urine TRH levels were 50.6 +/- 40 ng/1 before and 71.7 +/- 45.3 ng/1 after 3 months of treatment with thyroxine. These values did not significantly differ from those in healthy subjects. The large variations were due to highly elevated values in 3 patients. In 2 hypothyroid patients with initially high urine TRH values, 67 and 657 ng/1, urine TRH was measured 5 and 18 months later and was found to have decreased to 5 and 11 ng/1. In the hyperthyroid patients, urine TRH levels were 10.3 +/- 3.9 ng/1 before and 8.9 +/- 3.3 ng/1 after the treatment with methimazole and did not differ significantly from the levels in healthy subjects. After 3 months of treatment, the hyper- and the hypothyroid patients were euthyroid. Our results show, that, except in 2 hypothyroid patients, there does not appear to be any relationship between urine TRH levels and serum TSH or thyroid hormone levels in hypothyroid and hyperthyroid patients.

Topics: Chromatography, Gel; Chromatography, High Pressure Liquid; Chromatography, Ion Exchange; Graves Disease; Humans; Hyperthyroidism; Hypothyroidism; Methimazole; Thyrotropin-Releasing Hormone; Thyroxine

Local 5'-deiodination of serum thyroxine (T4) is the main source of triiodothyronine (T3) for the brain. Since we noted in previous studies that the cerebral cortex of neonatal rats tolerated marked reductions in serum T4 without biochemical hypothyroidism, we examined the in vivo T4 and T3 metabolism in that tissue and in the cerebellum of euthyroid and hypothyroid 2-wk-old rats. We also assessed the contribution of enhanced tissue T4 to T3 conversion and decreased T3 removal from the tissues to the T3 homeostasis in hypothyroid brain. Congenital and neonatal hypothyroidism was induced by adding methimazole to the drinking water. Serum, cerebral cortex (Cx), cerebellum (Cm), liver (L) and kidney (R) concentrations of 125I-T4, 125I-T3(T4), and 131I-T3 were measured at various times after injecting 125I-T4 and 131I-T3. The rate of T3 removal from the tissues was measured after injecting an excess of anti-T3-antibody to rats previously injected with tracer T3. In euthyroid rats, fractional turnover rates of T3 per hour were: Cx, 0.26 +/- 0.02 (SE); Cm, 0.20 +/- 0.02; L, 0.98 +/- 0.07; R, 0.97 +/- 0.12; and the calculated unidirectional plasma T3 clearance by these tissues were, in milliliters per gram per hour: Cx = 0.38, Cm = 0.32, L = 5.0, and R = 5.6. In hypothyroidism, the fractional removal rates and clearances were reduced in all tissues, in cortex and cerebellum by 70%, and in liver and kidney ranging from 30 to 50%. While greater than 80% of the 125I-T3(T4) in the brain tissues of euthyroid rats was locally produced, in hypothyroid cerebral cortex and cerebellum the integrated concentrations of 125I-T3(T4) were 2.7- and 1.5-fold greater than in euthyroid rats. In the Cx, this response resulted from an approximately sixfold increase in fractional conversion and an approximately fourfold decrease in T3 removal rate hampered by a decreased uptake of T4 from plasma, whereas in Cm the response resulted only from the reduced T3 removal rate. In euthyroid rats, the calculated production rate of T3 in nanograms per gram per hour by the Cx was 0.96 and 0.89 by the Cm, which on a per organ basis equals 15 and 2%, respectively, of the extrathyroidal production rate as assessed in the body pool exchanging with plasma. Several conclusions can be drawn: Production of T3 by developing brain is a very active process in agreement with the need of thyroid hormones during this period. (b) The brain-plasma exchange of T3 is slow compared with that of L or R. (c) This,

Topics: Animals; Cerebellum; Cerebral Cortex; Hypothyroidism; Iodine Radioisotopes; Kidney; Kinetics; Liver; Mathematics; Methimazole; Models, Biological; Rats; Rats, Inbred Strains; Thyroxine; Triiodothyronine

The effect of hypothyroid state on the transmembrane potential was studied in isolated cardiac ventricular trabeculae of rats. Hypothyroid state was induced by methimazole treatment or thyroidectomy and checked by determining serum thyroxine level. Hypothyroidism decreased the maximum rate of depolarization (Vmax) and the resting potential, increased the overshoot and the duration of action potential at 20, 50 and 90% repolarization. These changes were more pronounced after methimazole treatment than after thyroidectomy. The results strongly suggest that in hypothyroidism the significant alterations in the voltage-time course of the transmembrane action potential influencing Ca2+-movement across the sarcolemma may have an indirect role in the decreased myocardial contractility. On the other hand, methimazole has an aspecific cardiac effect which may modify the cardiac effect of hypothyroidism induced by the drug.

Topics: Action Potentials; Animals; Biomechanical Phenomena; Heart; Heart Ventricles; Hypothyroidism; Male; Methimazole; Myocardial Contraction; Rats; Rats, Inbred Strains; Thyroidectomy

Using a quantitative immunocytochemical technique, antral gastrin cell populations in the rat were studied in various states of thyroid function. Simultaneous determinations of circulating serum gastrin were made by RIA. Rats made hypothyroid by ingestion of methimazole (0.01% solution in drinking water for 30 days) demonstrated a significant 32% decrease in gastrin cell density (306 +/- 9/cm vs. 207 +/- 11/cm for controls) associated with a significant 50% decrease in serum gastrin (143 +/- 12 vs. 307 +/- 20 pg/ml for controls). Induction of hypothyroidism and hypoparathyroidism by surgical thyroparathyroidectomy resulted in similarly significant decreases in gastrin cell numbers (229 +/- 12/cm) and serum gastrin (169 +/- 14 pg/ml). Animals that underwent thyroparathyroidectomy followed by T4 replacement (2.5 micrograms/100 g X day, ip) for 30 days had a mean gastrin cell density that was not significantly different from that of controls; serum gastrin was decreased to 207 +/- 11 pg/ml. The administration of excess T4 (200 micrograms/100 g X day, ip) for either 15 or 30 days was associated with a significant increase in gastrin cell numbers (413 +/- 23/cm at 15 days; 352 +/- 21/cm at 30 days). Mean serum gastrin was increased by 82% after 15 days of T4 administration (558 +/- 51 pg/ml) and by 65% at 30 days (506 +/- 36 pg/ml). We conclude that T4 is trophic for gastrin cells in the rat.

Topics: Animals; Calcium; Female; Gastric Mucosa; Gastrins; Hyperthyroidism; Hypothyroidism; Methimazole; Pyloric Antrum; Rats; Rats, Inbred Strains; Thyroid Gland; Thyroxine

Long-Evans, male and female rats born of mothers kept on an iodide-rich diet prior to delivery and during lactation, were fed this diet after weaning, thus becoming slightly hypothyroid. A more severe hypothyroidism was also provoked with the chronic administration of methimazole to Long-Evans iodide-supplemented, or Charles River iodine-deprived pups through the first month of age. Additional Long-Evans rats were made hyperthyroid with a daily injection of triiodothyronine (T3) through the first 29 days of age. Severe hypothyroidism in both strains of rats markedly increased the density of serotonin type 1 (5-HT1) and type 2 (5-HT2) receptors in the brain (less cerebellum, corpus striatum and olfactory bulbs) at 31-32 days of age. Receptor alterations were not correlated to either the rise in thyrotropin (TSH) levels in hypothyroidism or the direct influence of residual methimazole after the last treatment, or to neonatal malnutrition. This increase in 5-HT receptor density might represent an adaptive (supersensitivity) postsynaptic response to the state of central serotonergic hypofunction occurring in hypothyroidism. Though receptor alterations might be important, their precise functional role in the etiogenesis of hypothyroid-associated mental disturbances is difficult to ascertain.

Topics: Animals; Animals, Newborn; Brain; Female; Hyperthyroidism; Hypothyroidism; Iodides; Male; Methimazole; Rats; Rats, Inbred Strains; Receptors, Serotonin; Spiperone; Triiodothyronine

Hypothyroidism of mild intensity was obtained with prenatal and neonatal submission of Long-Evans rats to an iodide-rich diet. Chronic daily administration of methimazole to iodide-supplemented Long-Evans pups or to iodine-deprived Charles-River rats through the first 29-30 days of age provoked severe hypothyroidism. Monoamine oxidase type A (MAO-A) and not type B (MAO-B) activity was consistently, although slightly (by approximately 20%), increased in the hypothyroid brain. Triiodothyronine (T3)-induced hyperthyroidism did not affect MAO activity. Replacement therapy with T3 did not normalize MAO-A activity in hypothyroidism. Methimazole displayed a competitive and reversible in vitro inhibition of MAO-A but not MAO-B activity. Although this effect was obtained at concentrations far higher than those estimated to reach the brain after a single injection of the goiterogen, the occurrence of accumulation processes in the metabolism-deficient hypothyroid neonate rats cannot be excluded. Thus, MAO-A activity might be either directly depressed during the goiterogenic treatment, or increased as the result of some kind of rebound effect after interruption of methimazole administration.

Topics: Animals; Animals, Newborn; Brain; Female; Hypothyroidism; Isoenzymes; Kinetics; Male; Methimazole; Monoamine Oxidase; Rats; Species Specificity; Succinate Dehydrogenase; Triiodothyronine

Control, radiothyroidectomized, and methimasol-treated short day (6L:18D; beginning of light at 0700) male Japanese quails were studied with regard to their circadian rhythmicity of total, free corticosterone and transcortine plasma level. In the controls, the peak of total and free corticosterone coincided with the maximal corticosterone binding capacity of transcortine; these parameters can be characterized by similar daily rhythm. In hypothyroid birds a synchronous phase shift of these parameters has been observed. In methimasol-treated animals the phase shift of the circadian rhythmicity was 6-8 hr, and in the radiothyroidectomized group 12 hr, respectively. According to the degree of hypothyroidism the metabolic clearance rate (MCR) of corticosterone decreased. This effect leads to the phase shift of total corticosterone rhythm, and the shift includes not only free, but also transcortine concentration.

Topics: Animals; Circadian Rhythm; Corticosterone; Coturnix; Half-Life; Hypothyroidism; Male; Methimazole; Quail; Thyroidectomy; Thyroxine; Transcortin

Topics: Adenosine Triphosphatases; Adenylyl Cyclases; Aging; Animals; Blood Pressure; Hypertension; Hypothyroidism; Methimazole; Myocardium; Rats; Sodium-Potassium-Exchanging ATPase

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

Recent studies have shown that approximately 75% of the nuclear 3,5,3'-triiodothyronine (T(3)) present in adult rat cerebral cortex (Cx) derives from 5'-deiodination of thyroxine (T(4)) within this tissue. The activity of iodothyronine 5'-deiodinase (I 5'D), the enzyme catalyzing T(4) to T(3) conversion, increases rapidly after thyroidectomy, suggesting that this could be a compensatory response to hypothyroxinemia. To evaluate this possibility during the period of central nervous system maturation, we studied several thyroid hormone-responsive enzymes (aspartic transaminase [AT], succinic dehydrogenase [S.D.], and Na/K ATPase) in the Cx of 2-, 3-, and 4-wk-old rats. The rats were made congenitally hypothyroid by placing 1, 2, 5, and 20 mg methimazole (MMI) in 100 ml of the mothers' drinking water from day 16 of gestation throughout the nursing period and to the litters after weaning. In addition, serum thyroid hormones, I 5'D, and, in some experiments, in vivo T(4) to T(3) conversion in Cx were measured in the same pups. Serum T(4) concentrations varied from <1 to 40 ng/ml and were generally inversely related to maternal MMI dose. Serum T(3) was less affected by MMI than was T(4). At 2 wk, decreases in AT, S.D., and ATPase were present in the 20-mg-MMI group but not in the 5-mg-MMI pups despite low serum T(4) (<10 ng/ml) in the latter. At 3 and 4 wk, both 5- and 20-mg-MMI groups had significant reductions in these cortical enzymes despite a normal serum T(3) in the 5-mg-MMI rats. Cortical I 5'D activity was 10-fold the control value in 5- and 20-mg-MMI animals at 2 wk but increased only three- to fivefold at 3 and 4 wk. I 5'D correlated inversely with serum T(4) (r >/= 0.96) at all ages, but the less marked elevation of this enzyme in 3- and 4-wk-old pups was not accompanied by an increase in serum T(4). Serum T(3) increased or remained the same between 2 and 3 wk. These results suggested that the 10-fold increase in I 5'D at 2 wk protected the 5-mg-MMI group from tissue hypothyroidism, but that the three- to fivefold increase at 3 and 4 wk could not. Injection of approximately 250 ng T(4)/100 g body weight to 2-wk-old, 20-mg-MMI pups (one-sixth the normal T(4) production rate) led to both a 1.8-ng/g cortical tissue increment in cortical T(3) and a significant increase in AT at 24 h, compared with a 0.38-ng/g cortical tissue T(3) increment and no change in AT in euthyroid controls. The larger increment in T(3) of the 20-mg-MMI pups was due in great part

Topics: Adenosine Triphosphatases; Animals; Animals, Newborn; Aspartate Aminotransferases; Cerebral Cortex; Female; Hypothyroidism; Iodide Peroxidase; Liver; Methimazole; Peroxidases; Pregnancy; Rats; Rats, Inbred Strains; Succinate Dehydrogenase; Thyrotropin; Thyroxine; Triiodothyronine

Changes in contractility and ATPase activity of SR from hearts of hypothyroid rats were investigated. Rats were made hypothyroid by daily injection of 100 mg/kg methimazole for 14 days. In methimazole-treated rats, the contractile force, the maximum velocity of tension development and relaxation were significantly decreased, however, the time to peak tension remained unchanged. Function of SR was studied by determining of Ca2+-activated ATPase activity, which was significantly decreased after methimazole treatment. This diminution may be partially responsible for a slower reduction of the free Ca2+ in the surroundings of contractile proteins and thus decrease the rate of relaxation.

Topics: Animals; Calcium-Transporting ATPases; Heart; Heart Rate; Hypothyroidism; Male; Methimazole; Myocardial Contraction; Oxygen Consumption; Rats; Rats, Inbred Strains; Sarcoplasmic Reticulum; Succinate Dehydrogenase

Topics: Aging; Animals; Cerebral Cortex; Congenital Hypothyroidism; Female; Hypothyroidism; Iodide Peroxidase; Methimazole; Nutrition Disorders; Pregnancy; Rats; Thyroxine; Triiodothyronine

The aim of the study was to trace subtle changes in the membranous labyrinth after experimental hypothyroidism that, at least in part, could explain how a reversed hearing impairment can occur, as is often clinically encountered in hypothyroid patients after thyroid substitution therapy. Adult Sprague-Dawley rats were made hypothyroid during six weeks by the use of methimazole in their drinking water. Their inner ears were investigated morphologically at the end of this period. The tectorial membrane is the first structure of the inner ear to show morphologic changes in hypothyroidism. Changes in the normal position and structure constantly were found. A thickening of the basilar membrane was indicated in many, but not all, specimens and in some control animals and may be coincidental. The initial morphologic changes are likely to be reversible after substitution therapy.

Topics: Animals; Cochlea; Deafness; Hypothyroidism; Methimazole; Organ of Corti; Rats; Rats, Inbred Strains; Tectorial Membrane; Time Factors

Topics: Animals; Body Weight; Goiter; Hypothyroidism; Iodide Peroxidase; Isoenzymes; Kinetics; Liver; Male; Methimazole; Peroxidases; Rats; Thyroid Gland; Thyroid Hormones; Thyrotropin

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 absence of the thyroid stimulation of hepatic [Na+ + K+]ATPase in obese (ob/ob) mice has been investigated. A wide range of tri-iodothyronine (T3) concentrations failed to enhance the hepatic [Na+ + K+]ATPase of ob/ob mice made hypothyroid by methimazole treatment but glycerophosphate dehydrogenase activity was maximally stimulated at low doses of T3. Adrenalectomy increased the basal activity of [Na+ + K+]ATPase to levels found in lean control mice and restored the response of this enzyme to T3. Body weight gain was unaffected by the induction of hypothyroidism in either lean or ob/ob mice. It is concluded that the adrenal steroids play an important role in the expression of [Na+ + K+]ATPase activity in the ob/ob mouse.

Topics: Adrenalectomy; Animals; Body Weight; Glycerolphosphate Dehydrogenase; Hypothyroidism; Liver; Methimazole; Mice; Mice, Obese; Sodium-Potassium-Exchanging ATPase; Triiodothyronine

Total hexokinase levels (units/g tissue) have been measured during postnatal development of the cerebellum in control, hypothyroid, and hyperthyroid rats. In addition. distribution of hexokinase in the developing cerebellum has been observed with an immunofluorescence method. Hypothyroidism delays the normally observed postnatal increase in total hexokinase activity, whereas hyperthyroidism accelerates the increase. In normal animals, hexokinase levels in maturing Purkinje cells pass through a transient increase, with maximal levels at approximately 8 days postnatally followed by rapid decline to relatively low levels by 12 days; hypothyroidism delays this transient increase and subsequent decline, but hyperthyroidism does not appear to affect markedly the timing of this phenomenon. Cerebellar glomeruli are relatively enriched in hexokinase content, as judged by their intense fluorescence. Hypothyroidism delays the development of intensely stained glomeruli. Hyperthyroidism did not appear to cause precocious increase in numbers of glomeruli but may have increased the rate at which the hexokinase was assimilated by newly formed glomeruli. The effects of hypo- and hyperthyroidism on total cerebellar hexokinase levels are interpreted in terms of the effect of thyroid hormone on the biochemical maturation of synaptic structures rich in hexokinase.

Topics: Animals; Cerebellum; Fluorescent Antibody Technique; Hexokinase; Hyperthyroidism; Hypothyroidism; Methimazole; Purkinje Cells; Rats; Thyroxine

Myelinogenesis was studied in controls and in rats treated since birth with Methimazole (hypothyroid) or thyroxine (hyperthyroid). The amount of myelin in forebrain and its protein composition were determined between 13 and 40 days of age, the period of most rapid myelin accumulation. Hypothyroid rats had reduced on both and brain weights relative to controls and the yield of myelin was reduced on both a per brain and a per milligram brain protein basis. Developmental changes in the protein composition of isolated myelin followed the pattern of control animals (the percentage of total myelin protein present as proteolipid protein, large basic protein, and small basic protein increased, as did the ratio of proteolipid/large basic protein) but were delayed temporally by 1-2 days. Hyperthyroid rats also had reduced body and brain weights. At 13 days myelin accumulation was greater than that of controls, corresponding to an earlier initiation of myelination. At later ages myelin yield was reduced on a per brain basis but not on a per milligram brain protein basis. The developmental pattern of myelin protein composition was accelerated temporally by 1-2 days. Myelination in optic nerve, assayed by proteolipid protein content, also was slightly delayed in hypothyroid animals and somewhat accelerated in hyperthyroid animals. The relative synthesis of myelin proteins (determined as incorporation of intracranially injected [(3)H]glycine into myelin protein relative to incorporation into whole brain protein), as well as distribution of radioactivity among individual myelin proteins, was determined. The results supported the conclusion of the myelin protein accumulation study; hypothyroidism retards the developmental program for myelinogenesis, whereas in the hyperthyroid state myelin synthesis is initiated earlier but is also terminated earlier.

Topics: Animals; Brain; Hyperthyroidism; Hypothyroidism; Methimazole; Myelin Proteins; Myelin Sheath; Optic Nerve; Rats; Thyroxine

Topics: Amitriptyline; Animals; Caffeine; Diazepam; Hyperthyroidism; Hypothyroidism; Male; Memory; Methimazole; Rats; Rats, Inbred Strains; Thyroid Hormones; Thyroxine

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 on chick myogenesis of hypothyroid status induced in ovo by methimazole was histologically (number and types of muscle fibers) and biochemically studied. A single injection of methimazole induced an hypothyroid status during embryogenesis, as shown by the plasma T4 levels which were separately assayed in male and female controls and treated embryos from day 12 of incubation to day 4 after hatching. In both sexes, control plasma T4 reached a peak on day 20 of incubation, but the female values were significantly higher; plasma T4 in the treated embryos remained at a low level independently of sex. Only methimazole-treated males showed a significant increase (P less than 0.01) in the total number of fibers of the two muscles (tibialis posterior and flexor digitorum) studied. Moreover, the histochemical results on succinate dehydrogenase and myofibrillar ATPase evidenced that, of the three fiber types (alpha R, alpha W and beta R) constituting the skeletal muscles, only the alpha fibers increased significantly. Aldolase (glycolytic) and NADP isocitrate dehydrogenase (tricarboxylic acid cycle) activities, measured on the adductor and pectoralis muscles, showed a similar developmental pattern in control and treated animals, but was retarded in the latter due to a 5-day delay in hatching. It is not known whether the tissular differences were related directly to the hypothyroid status, to alterations in nervous system differentiation or, as suggested by intersexual differences, to modifications in hormonal balance.

Topics: Animals; Cell Differentiation; Chick Embryo; Female; Fructose-Bisphosphate Aldolase; Hypothyroidism; Isocitrate Dehydrogenase; Male; Methimazole; Muscle Development; Muscles; Sex Factors; Thyroxine

The effects of tri-iodothyronine on mitochondrial protein synthesis have been studied in in vitro labeled, isolated rat hepatocytes. Hepatocytes were isolated from hypothyroid rats or from hypothyroid rats 24 h after injecting a single, low dose of hormone (20-30 microgram/180-230 g body weight). Tri-iodothyronine increased translation on mitochondrial ribosomes by 2-3-fold, but, under our conditions, appears to have little or not effect on the general synthesis of cytoplasmically-translated mitochondrial proteins. Electrophoretic and fluorographic analysis indicated that tri-iodothyronine stimultes labeling of the four major mitochondrially-translated peptides. The hormone appears to act by inducing a general increase in translation/transcription of mitochondrially-synthesized peptides.

Topics: Animals; DNA, Mitochondrial; Hypothyroidism; Male; Methimazole; Mitochondria, Liver; Protein Biosynthesis; Rats; Triiodothyronine

We have investigated the thyroid uptake of Tl-201 in 37 patients with various types of goiter, and in six with normal thyroids. Significant thallium uptake was found in all cases in which there was thyroid enlargement, including Graves' disease, toxic thyroid nodule, primary hypothyroidism, simple goiter, Hashimoto's disease, thyroid carcinoma, and thyroid adenoma. If goiter was absent, however, there was no demonstrable uptake--e.g., in secondary hypothyroidism, subacute thyroiditis, and the normal controls. Thallium uptake did not correlate with thyroid function tests such as BMR, T3-RU, T3, T4, TSH, antithyroid antibodies, or the 24-hr I-131 uptake. In 23 patients with diffuse goiter, on the other hand, maximum Tl-201 uptake correlated well with thyroid weight: r = 0.836 (p less than 0.001); y = 0.02 x + 0.06.

Topics: Adenoma; Antithyroid Agents; Contrast Media; Goiter; Goiter, Nodular; Graves Disease; Humans; Hypothyroidism; Iodipamide; Methimazole; Radioisotopes; Radionuclide Imaging; Syndrome; Thallium; Thyroid (USP); Thyroid Diseases; Thyroid Function Tests; Thyroid Neoplasms; Thyroiditis; Thyroiditis, Autoimmune; Thyrotropin

Histophysiological pancreatic indices were studied in 1-, 21- and 30-day-old offsprings of white non-lineal female rats that were given antithyreoid drug mercasolil in the dose 3 mg/kg of body weight during pregnancy and lactation. Chemical inhibition of maternal thyreoid function results in decreasing weight index of the offspring's pancreas, in decreasing section area of the terminal secretory parts, in narrowing the homogenous zone of exocrine pancreocytes, in decreasing the portion occupied by the endocrine part on the section area, as well as in decreasing the index of B/A cells ratio of pancreatic islands and of nuclear volume of basophilic insulocytes. It is possible to conclude from the data obtained that maternal hypothyreosis produced by mercasolil unfavourably affects the process of structural and functional setting and the status of the pancreas in the offspring.

Topics: Animals; Female; Hypothyroidism; Islets of Langerhans; Methimazole; Pancreas; Pregnancy; Rats; Time Factors

Topics: Animals; Body Weight; DNA; Dose-Response Relationship, Drug; Heart; Hypothyroidism; Methimazole; Myocardium; Rats; RNA

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

This paper deals with the activity of glucose-6-phosphate dehydrogenase in patients with hyper- and hypothyroidism as well as in hyperthyroxinaemic rats. The activity of glucose-6-phosphate dehydrogenase is enhanced in red blood cells of hyperthyreotic patients and hyperthyroxinaemic animals. The activity will be decreased to normal range in patients by administration of antithyreotic drugs, such as thiamazole. Patients with hypothyroidism exhibit decreased enzymatic activity. It is suggested that thyroid hormones stimulate the HMP-shunt in red blood cells as a defence mechanism against additional oxidative stress.

Topics: Animals; Erythrocytes; Female; Glucosephosphate Dehydrogenase; Humans; Hyperthyroidism; Hypothyroidism; Male; Methimazole; Rats; Thyroid Diseases; Thyroxine

The "grasping reflex" test was performed in adult rats with altered thyroid function. Any modification of the thyroid activity (hyper or hypothyroidism) caused a prolongation of the grasping time. Our data indicate that the condition of hypo or hyperthyroidism induces behavioural modifications in the adult rats.

Topics: Animals; Foot; Forelimb; Hyperthyroidism; Hypothyroidism; Male; Methimazole; Rats; Reflex; Thyroxine

Hypothyroidism is induced in rats treated with thiamazole, an antithyroid drug. If this phase lasts long enough, the follicular cells develop adenomas. Within the same period, the number of parafollicular or C cells increases threefold on an average, but without producing corresponding adenomas, the formation of which is inhibited. When treatment is stopped, a second phase appears during which thyroid function reverts to normal. The previously observed inhibition disappears, and, after a period of latency, the hyperplastic C cells develop parafollicular adenomas. The type of tumors to be found in treated rats (either of them, or both simultaneously) is determined by respective durations of the two phases. The endocrine mechanisms of these phenomena are discussed.

Topics: Adenoma; Animals; Antithyroid Agents; Hypothyroidism; Male; Methimazole; Neoplasms, Experimental; Rats; Thyroid Gland; Thyroid Neoplasms; Time Factors

Isolated terminal colon strips obtained from rats, made hypothyroid by methimazole treatment, were almost completely insensitive to the contractile effects of morphine as compared to strips from control animals. This low morphine sensitivity was accompanied by a significant (40%) reduction in the tissue sulfatide content. Although colon strips from hypothyroid rats showed a reduction of the contractile effects of acetylcholine, the decrease was considerably less than that noted for morphine. The addition of 6.6 X 10(-5) M tri-iodothyronine to colons from hypothyroid rats largely restored the tissue sensitivity to morphine. These results suggest that sulfatides could be linked to the in vitro effects of morphine in the colon.

Topics: Acetylcholine; Animals; Body Weight; Colon; Hypothyroidism; In Vitro Techniques; Male; Methimazole; Morphine; Muscle Contraction; Muscle, Smooth; Rats; Sulfoglycosphingolipids

Total body fat content was determined in growing normal male Wistar rats and hypothyroidized animals 7 weeks after feeding with Methimazol (group MMI-HT), Methyl-thiouracil (group MTU-HT), and performance of radiothyroidectomy by 131-iodine (group R-HT), respectively. At the end of experiments there was an extreme hypothyroid state in all treated groups, verified by external signs, growth kinetics, serum cholesterol estimation and evaluation of the iodothyrosine pattern of the thyroid glands. Changed body composition resulted in all HT-groups from significant increase of total body fat content. The relation of constituents fat : protein : water of 1 : 2 : 6 in the KT-group was changed into 1 : 1 : 3 in the HT-groups. No differences were found between the different HT-groups. Our findings are in good agreement with altered metabolism of plasma lipids described by other authors showing the existence of a highly disturbed lipid metabolism in thyroid hormone deficiency.

Topics: Animals; Body Composition; Cholesterol; Hypothyroidism; Iodine Radioisotopes; Lipid Metabolism; Male; Methimazole; Methylthiouracil; Rats

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

Topics: Animals; Body Weight; Cold Temperature; Heart; Hyperthyroidism; Hypothyroidism; In Vitro Techniques; Kinetics; Male; Methimazole; Muscles; Myocardium; Norepinephrine; Organ Size; Rats; Thyroid Hormones; Thyroidectomy; Thyroxine; Time Factors

Topics: Antibody Specificity; Female; Fetal Blood; Humans; Hyperthyroidism; Hypothyroidism; Isomerism; Methimazole; Myocardial Infarction; Pregnancy; Propylthiouracil; Thyroid Hormones; Thyrotropin; Thyroxine; Triiodothyronine

Topics: Animals; Brain; Dopamine; Hydroxyindoleacetic Acid; Hypothyroidism; Methimazole; Motor Activity; Neurotransmitter Agents; Norepinephrine; Rats; Serotonin; Time Factors; Triiodothyronine; Tryptophan; Tryptophan Hydroxylase; Tyrosine 3-Monooxygenase

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 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

Topics: Acetylcholine; Animals; Brain; Brain Chemistry; Desipramine; Dopamine; Female; Hypothyroidism; Methimazole; Norepinephrine; Pregnancy; Rats; Serotonin; Tryptophan Hydroxylase; Tyrosine 3-Monooxygenase

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

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

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

In rats hypothyroidized with methylthiouracil (MTU), methimazol (MMI), or radiothyroidectomy, the extent of deiodination for L-diiodotyrosine (L-DIT) and L-thyroxine (L-T4) was investigated in homogenate supernatants of liver and kidney. Deiodination in liver and kidney for DIT is twice as high as for T4, but the kidney allows only 25% of the liver deiodination activity both for DIT and T4. In the livers of all hypothyroid animals, iodide splitting both from DIT and T4 is highly significantly reduced by one-half compared with controls. In the kidney of all hypothyroid animals, the DIT deiodination is highly significantly lowered in comparison with controls; the T4 deiodination is significantly reduced only in animals treated with MTU and MMI, and is not significantly enhanced in radiothyroidectomized rats. Thus, there is no difference between MTU and MMI in the extent of deiodination for DIT and T4 in the homogenate supernatants of rat liver or kidney.

Topics: Animals; Binding Sites; Diiodotyrosine; Hypothyroidism; Iodine; Kidney; Liver; Male; Methimazole; Methylthiouracil; Radiation Effects; Rats; Thyroid Gland; Thyroidectomy; Thyroxine

In homogenate supernatants of kidneys of male rats the extent of deiodination of L-diiodotyrosine (L-DJT) and L-thyroxine (L-T4) was investigated in dependence on the thyroid function (hypo- and hyperthyroidized) and also in dependence on age. In rats hypothyroidized by loading with Methylthiouracil (MTU) or Methimazol (MMI) the deiodination for L-DJT and L-T4 was significantly reduced, in rats loaded with 40 mug T4 sc. for 10 days, the deiodination was significantly enhanced compared with untreated control animals. With advancing age (6 weeks, 3 or 12 month) the deiodination activity is highly significantly reduced. The results underline relations between thyroid gland function and deiodination activity in kidney.

Topics: Age Factors; Animals; Diiodotyrosine; Hyperthyroidism; Hypothyroidism; Iodine; Kidney; Male; Methimazole; Methylthiouracil; Monoiodotyrosine; Rats; Thyroid Diseases; Thyroid Hormones; Thyroxine; Triiodothyronine

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: Administration, Oral; Animal Feed; Animals; Antithyroid Agents; Body Weight; Caseins; Dietary Proteins; Female; Glycine max; Hypothyroidism; Iodine; Iodine Radioisotopes; Male; Methimazole; Organ Size; Plant Proteins, Dietary; Protein Binding; Swine; Swine Diseases; Thiocyanates; Thyroid Gland; Time Factors

Topics: Animals; Collagen; Hydroxyproline; Hypophysectomy; Hypothyroidism; Larva; Metamorphosis, Biological; Methimazole; Pituitary Gland; Propylthiouracil; Rana pipiens; Tail; Time Factors

Topics: Animals; Body Weight; Dihydroxyphenylalanine; Humans; Hypothyroidism; Male; Methimazole; Mice; Organ Size; Pituitary Gland; Radioimmunoassay; Rats; Species Specificity; Thyroid Gland; Thyrotropin; Thyrotropin-Releasing Hormone

Topics: Actins; Animals; Body Height; Body Weight; Chick Embryo; DNA; Hypothyroidism; Methimazole; Muscle Development; Muscle Proteins; Muscles; Organ Size; Thyroid Gland; Thyroxine; Time Factors

Topics: Animals; Blood Glucose; Disease Models, Animal; Gluconeogenesis; Glucose Tolerance Test; Hyperthyroidism; Hypothyroidism; Male; Methimazole; Methylthiouracil; Rats; Thyroid Gland; Thyroxine

Topics: Animals; Exophthalmos; Goldfish; Graves Disease; Humans; Hyperthyroidism; Hypothyroidism; Methimazole; Muscles; Orbit; Sulfates; Sulfur Radioisotopes; Thyroid Diseases; Thyrotropin

Topics: Animals; Anura; Disorders of Sex Development; Female; Hypophysectomy; Hypothyroidism; Male; Methimazole; Ovary; Pituitary Gland; Rana catesbeiana; Testis; Thyroid Gland; Thyroidectomy

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; Hypothyroidism; Lactates; Male; Methimazole; Methylthiouracil; Pyruvates; Rats; Thyroid Diseases; Thyroxine

Topics: Alpha-Globulins; Animals; Blood Proteins; Carbon Isotopes; Dose-Response Relationship, Drug; Fibrinogen; Glycoproteins; Haptoglobins; Hydrocortisone; Hyperthyroidism; Hypothyroidism; Insulin; Liver; Male; Methimazole; Perfusion; Rats; Serum Albumin; Thyroid Gland; Thyroidectomy; Thyroxine

Topics: Animals; Cerebellar Cortex; Dendrites; Hypothyroidism; Male; Methimazole; Microscopy, Electron; Purkinje Cells; Rats; Synapses; Time Factors

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; Brain; Brain Chemistry; Carbon Radioisotopes; Cerebrosides; Chromatography, Thin Layer; Fatty Acids; Galactose; Glycolipids; Hypothyroidism; Lipids; Methimazole; Organ Size; Rats; Sphingomyelins; Sulfoglycosphingolipids; Uridine Diphosphate Sugars

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: Animals; Electron Transport Complex IV; Histocytochemistry; Hyperthyroidism; Hypothyroidism; Kidney; Male; Methimazole; Rats; Succinate Dehydrogenase; Thyroid Gland; Thyroidectomy; Triiodothyronine

Topics: Animals; Benz(a)Anthracenes; Benzimidazoles; Female; Hypothyroidism; Mammary Neoplasms, Experimental; Methimazole; Propylthiouracil; Rats; Sulfhydryl Compounds; Thyroid Gland

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: Acclimatization; Adrenal Glands; Animals; Body Temperature Regulation; Body Weight; Catecholamines; Cold Temperature; Epinephrine; Glycols; Hot Temperature; Hyperthyroidism; Hypothyroidism; Male; Methimazole; Myocardium; Norepinephrine; Normetanephrine; Rats; Rats, Inbred Strains; Thyroid Gland; Thyroxine; Time Factors

Topics: Adolescent; Adult; Brain; Female; Humans; Hydroxyindoleacetic Acid; Hyperthyroidism; Hypothyroidism; Male; Methimazole; Middle Aged; Monoamine Oxidase; Serotonin; Thyroidectomy; Triiodothyronine

Topics: Achilles Tendon; Adolescent; Diagnosis, Differential; Female; Humans; Hyperthyroidism; Hypophysectomy; Hypothyroidism; Male; Methimazole; Methods; Middle Aged; Obesity; Reflex, Stretch; Statistics as Topic; Thyroid Diseases; Thyroid Function Tests; Triiodothyronine

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: Adult; Antithyroid Agents; Female; Glucagon; Goiter; Humans; Hypothyroidism; Imidazoles; Iodides; Male; Methimazole; Pituitary Gland; Radioimmunoassay; Stimulation, Chemical; Thyroid Function Tests; Thyrotropin; Time Factors; Vasopressins

Topics: Adolescent; Child; Child, Preschool; Diagnosis, Differential; Germany, East; Humans; Hyperthyroidism; Hypothyroidism; Infant; Infant, Newborn; Methimazole; Methylthiouracil; Thyroid Diseases; Thyroid Hormones; Thyroidectomy

Topics: Adult; Aged; Antibodies; Chronic Disease; Female; Humans; Hyperthyroidism; Hypothyroidism; Iodine Isotopes; Male; Methimazole; Middle Aged; Myxedema; Propranolol; Propylthiouracil; Pulse; Thiocyanates; Thyroid Diseases; Thyroid Function Tests; Thyroiditis; Time Factors; Triiodothyronine

Topics: Animals; Animals, Newborn; Antithyroid Agents; Body Weight; Brain; Centrifugation; Cerebrosides; Cholesterol; Chromatography; Hydrocortisone; Hypothyroidism; In Vitro Techniques; Lipids; Methimazole; Myelin Sheath; Organ Size; Rats; Sulfates; Sulfur Isotopes; Thyroid Gland; Thyroidectomy; Transferases; Triiodothyronine

Topics: Adult; Aged; Blood Pressure; Cholesterol; Female; Humans; Hypertension; Hyperthyroidism; Hypothyroidism; Male; Methimazole; Middle Aged; Myxedema; Norepinephrine; Thyroid Hormones

Topics: Animals; Gluconeogenesis; Glucose-6-Phosphatase; Histocytochemistry; Hyperthyroidism; Hypothyroidism; Islets of Langerhans; Kidney; Liver; Male; Methimazole; Potassium Iodide; Rats; Staining and Labeling; Thyroidectomy; Thyroxine; Triiodothyronine

Topics: Antithyroid Agents; Bronchitis; Drug Therapy; Humans; Hypothyroidism; Leprosy; Methimazole; Pharmacology; Pulmonary Emphysema; Respiratory Insufficiency; Silicosis; Thyroid Function Tests; Thyroid Gland