triiodothyronine--reverse and Hypothyroidism

Thyroid hormone (TH) is a pleiotropic agent that has widespread biological functions, i.e., it controls cellular growth, tissue development and homeostasis and neoplastic transformation. Suitable TH levels are critical for the development of various types of tissues and are essential for the regulation of metabolic processes throughout life. The serum concentrations of TH affect its biological activity. Moreover, at tissue level, TH action is regulated by the expression and activity of deiodinases, i.e., the enzymes that mediate the metabolic pathways by activating and/or inactivating TH. The type I and II deiodinases (D1 and D2) initiate TH action by converting thyroxine (T4) into the active TH form (T3), whereas type III deiodinase (D3) mediates the local attenuation of TH by converting T4 and T3 into the inactive metabolites rT3 and T2, respectively. The deiodinase system is a potent mechanism of pre-receptoral control of TH action; it is often altered in such pathological conditions as cancer. D3 is widely expressed in embryonic tissues and in placenta, where it blocks excessive maternal-to-fetal transfer of TH. In contrast, during late neonatal and adult life, D3 is expressed mainly in the central nervous system and skin. Interestingly, D3 expression is re-activated in various types of human cancers. Here we review recent evidence that D3 expression plays a crucial role in human carcinogenesis, and speculate as to its complex role in the regulation of cell proliferation in several neoplastic contexts. It is conceivable that the local modulation of TH action via deiodinases is a powerful molecular tool to manipulate the intracellular TH status, thus influencing the growth and maintenance of selected hormone-dependent cancers.

Topics: Cell Division; Cell Transformation, Neoplastic; Enzyme Activation; Enzyme Induction; Gene Expression Regulation, Neoplastic; Humans; Hypothyroidism; Iodide Peroxidase; Molecular Targeted Therapy; Neoplasm Proteins; Neoplasms; Neoplasms, Hormone-Dependent; Organ Specificity; Subcellular Fractions; Thyroxine; Triiodothyronine; Triiodothyronine, Reverse

Topics: Biomarkers; Humans; Hyperthyroidism; Hypothyroidism; Immunoassay; Reagent Kits, Diagnostic; Reference Values; Specimen Handling; Thyroid Function Tests; Triiodothyronine; Triiodothyronine, Reverse

Changes in thyroid function and structure during pregnancy, including abnormalities in thyroid ultrasonography. Levels of thyroid stimulating hormone (TSH), free thyroxine (FT4), total thyroxine (TT4), total triiodothyronine (TT3), reverse triiodothyronine (rT3), thyroxin binding globulin (TBG) and thyroglobulin (Tg) as well as the changes in metabolism have been presented. Difficulties in the diagnostics of hyperthyroidism and hypothyroidism in pregnant women have been described. In addition modern ideas about the treatment of thyroid dysfunction in this period of woman life have been presented. Furthermore thyroid physiology and pathology in fetus and newborn have been described.

Topics: Female; Humans; Hyperthyroidism; Hypothyroidism; Infant, Newborn; Pregnancy; Pregnancy Complications; Thyroglobulin; Thyroid Diseases; Thyroid Function Tests; Thyroid Gland; Thyroid Hormones; Thyrotropin; Thyroxine; Thyroxine-Binding Proteins; Triiodothyronine; Triiodothyronine, Reverse

Thyroid hormone action in the brain is strictly regulated, since these hormones play a crucial role in the development and physiological functioning of the central nervous system. Hormone kinetics and molecular events at the nuclear receptor level during the adaptation of the brain of chicken to hypothyroidism were simultaneously investigated. Data obtained by Oldendorff's 'single-pass' technique showed a significantly higher labelled 3,3'5-triiodothyronine (125I-T3) uptake into the brain of surgically thyroidectomized (TX) 2-week-old broilers after 1 week of surgery in comparison to sham-operated (SH) and t3 supplemented (TX + T3) controls in the 10th second after the bolus injection. Telencephalons showed the highest, while cerebellum the lowest uptake intensity in all groups. In a similar arrangement of experiments the expression of the TR alpha- and TR beta nuclear thyroid receptors in the telencephalon of TX and control chickens was investigated by a semiquantitative RT-PCR-based approach for beta-actin, then amplified for thyroid receptors. The level of both the TR alpha and TR beta coding mRNA was elevated in hypothyroidism. In conclusion, the presented hormone kinetics and TR expression data provide further details of the cellular and molecular events occurring during the adaptation to hypothyroidism of the brain of chicken.

Topics: Animals; Brain; Chickens; Disease Models, Animal; Hypothyroidism; Poultry Diseases; Triiodothyronine, Reverse

Topics: Aged; Humans; Hypothyroidism; Syndrome; Thyroid Gland; Thyroid Hormones; Thyrotropin; Thyrotropin-Releasing Hormone; Thyroxine; Thyroxine-Binding Proteins; Triiodothyronine; Triiodothyronine, Reverse

There is extensive deiodinative metabolism of thyroxine (T4) in thyroid hormone target organs, including the pituitary and brain. In both rat and man, most of the 3,3',5-triiodothyronine (T3) in the body is produced outside the thyroid gland by deiodination of T4. T3 is the principal active form of thyroid hormone within cells. In the rat, there are at least three enzymatic iodothyronine-deiodinating pathways which can be distinguished by kinetics and substrate and inhibitor specificities. Two of these (types I and II) can convert T4 to T3. The third pathway (type III) converts T4 to the inactive reverse-T3 and T3 to an inactive diiodothyronine. Both the anterior pituitary and the brain produce most of their intracellular T3 locally, by the type-II pathway. Type-III activity is present throughout the brain, but not in the anterior pituitary. Studies in the rat, using the deiodination inhibitor iopanoic acid, show that the capacities of T4 to inhibit thyrotropin release and stimulate growth hormone synthesis require conversion of T4 to T3 in the pituitary. Studies in man strongly suggest that the same is true in the human adenohypophysis, and a syndrome in man of a deficiency in this process possibly exists. The hypothalamus exhibits some responses to thyroid hormone, including changes in somatostatin and substance P content and changes in activities of type-II and III deiodination. The mechanism(s) of action of thyroid hormone in the hypothalamus, and in the brain in general, are not yet well understood.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Brain; Humans; Hypothalamo-Hypophyseal System; Hypothalamus; Hypothyroidism; Iodide Peroxidase; Median Eminence; Peroxidases; Pituitary Gland, Anterior; Thyroid Hormones; Thyroxine; Triiodothyronine; Triiodothyronine, Reverse

Serum levels of thyroid stimulating hormone, thyroxine, triiodothyronine, free T4, thyroxine-binding globulin, reverse T3, and the TSH secretory areas and peak T3 after intravenous injection of 40 micrograms thyrotropin-releasing hormone were determined weekly from day 5 to 6 to 11 weeks of age in 42 unselected full-term and 61 preterm Belgian infants. The results on day 5 indicated a progressive deficit of thyroid function related to the degree of prematurity. In 92 infants this deficit progressively decreased with age and disappeared at 5 to 7 weeks. However, 11 infants developed biochemical evidence of overt but transient hypothyroidism. Belgian neonates are relatively iodine deficient, and this factor affects the constitution of iodine stores within the thyroid gland: (1) the urinary concentrations of iodine in the 103 infants studied in Belgium were markedly lower than in 30 infants from California; and (2) The iodine concentration of the thyroid gland in preterm infants who died during the 10 first days of life was almost three times lower in Brussels than in Toronto. The results indicate that, in Belgium, the effects of relative iodine deficiency on thyroid function are superimposed on and mask the physiologic state of tertiary hypothyroidism in prematurity.

Topics: Belgium; Female; Humans; Hypothyroidism; Infant, Newborn; Infant, Premature, Diseases; Iodine; Longitudinal Studies; Male; North America; Thyroid Gland; Thyrotropin; Thyrotropin-Releasing Hormone; Thyroxine; Thyroxine-Binding Proteins; Triiodothyronine; Triiodothyronine, Reverse

Modern day evaluation of thyroid disorders requires a combination of accurate clinical judgement and reliable, sensitive, and specific thyroid functions tests. Principle among the latter are thyroxine (T4) 3, 5, 3'-triiodothyronine (T3), and thyroid-stimulating hormone (TSH). Also playing an important role in special situations are free thyroxine, an assessment of bound and unbound thyroid-binding globulin, TRH stimulation, long-acting thyroid stimulator (LATS), antibodies to thyroid hormone and to thyroid receptors. Basic to interpretation of these tests in the clinical setting is a comprehension of the relationship of the hypothalamus, the pituitary, and the thyroid gland as well as a knowledge of the peripheral metabolism of thyroxine and triiodothyronine. The role of each of these laboratory tests in the evaluation of hyper- and hypometabolic states, their alteration in nonthyroid and other endocrine disorders, and the effects of environmental and physiological factors on these tests are reviewed.

Topics: Adult; Aged; Autoantibodies; Calcitonin; Choriocarcinoma; Female; Fetus; Hepatitis; Humans; Hyperthyroidism; Hypothalamo-Hypophyseal System; Hypothyroidism; Infant, Newborn; Kidney Diseases; Male; Mental Disorders; Middle Aged; Pregnancy; Stress, Physiological; Thyroglobulin; Thyroid Diseases; Thyroid Function Tests; Thyroid Gland; Thyrotropin; Thyrotropin-Releasing Hormone; Thyroxine; Triiodothyronine; Triiodothyronine, Reverse

Several alterations in thyroid function are found in diabetes mellitus (see Table I). The most profound changes occur in patients with insulin-dependent diabetes. Plasma T4 is normal whereas plasma T3 is diminished, and the plasma level of rT3 is elevated in diabetic ketoacidosis or in patients with severely uncontrolled diabetes. These changes arise from alterations in the monodeiodination pathways of T4. Both hypo- and hyperthyroidism occur with increased frequency in diabetes. There is an increased prevalence of thyroid autoantibodies in insulin-dependent diabetics. Animals studies suggest a defect in the hypothalamic regulation of the thyroid-pituitary feedback system and an impaired response of the thyroid gland to TSH. Clinical studies are not yet available to confirm the occurrence of these regulatory disturbances in human diabetic patients. It is not clear whether the deiodination and regulatory changes in thyroid hormone economy that are associated with diabetes result in hypothyroidism at the cellular level.

Topics: Animals; Autoantibodies; Diabetes Complications; Diabetes Mellitus; Diabetes Mellitus, Experimental; Humans; Hyperthyroidism; Hypothalamo-Hypophyseal System; Hypothyroidism; Insulin; Receptors, Cell Surface; Receptors, Thyroid Hormone; Thyroid Gland; Thyrotropin; Thyrotropin-Releasing Hormone; Thyroxine; Triiodothyronine; Triiodothyronine, Reverse

Topics: Animals; Feedback; Homeostasis; Humans; Hypothalamo-Hypophyseal System; Hypothyroidism; Infant, Newborn; Infant, Newborn, Diseases; Infant, Premature; Rats; Receptors, Cell Surface; Receptors, Thyroid Hormone; Sheep; Thyroid Diseases; Thyroid Gland; Thyrotropin; Thyroxine; Thyroxine-Binding Proteins; Triiodothyronine; Triiodothyronine, Reverse

Topics: Canada; Congenital Hypothyroidism; Fetal Blood; Humans; Hypothyroidism; Infant, Newborn; Infant, Newborn, Diseases; Mass Screening; Radioimmunoassay; Thyroid Function Tests; Thyrotropin; Thyroxine; Thyroxine-Binding Proteins; Triiodothyronine; Triiodothyronine, Reverse; United States

Topics: Age Factors; Amniotic Fluid; Female; Fetal Blood; Fetus; Humans; Hypothyroidism; Infant, Newborn; Middle Aged; Pregnancy; Prenatal Diagnosis; Thyrotropin; Thyroxine; Triiodothyronine; Triiodothyronine, Reverse

Topics: Animals; Fetus; Humans; Hyperthyroidism; Hypothyroidism; Syndrome; Thyroid Hormones; Thyroxine; Triiodothyronine; Triiodothyronine, Reverse

The diagnosis of central hypothyroidism (CH) is often difficult to establish as serum TSH levels may be low, normal, or slightly increased.. To explore the use of recombinant human TSH (rhTSH) in the diagnosis of CH.. Randomized single-blind clinical trial.. Outpatient clinic of a tertiary care referral center.. A single intramuscular injection of 0.1 and 0.9 mg rhTSH in random order with 1-week interval.. Eighteen adult patients with pituitary insufficiency and six healthy age-, sex-, and body mass index-matched controls. Six patients had untreated CH (newCH), six had treated CH (CH), and six patients were TSH sufficient (nonCH). Five weeks before TSH stimulation, levothyroxine was replaced with tri-iodothyronine (T(3)) for 4 weeks. One week before stimulation, treatment was withdrawn.. Thyroid hormones and thyroglobulin (Tg) before and 2, 3(1/2), 7, 24, 48, and 72 h after each injection.. In the newCH group, basal free thyroxine (FT(4)) levels were lower than in controls (P<0.05). After 0.9 mg rhTSH, the increases in FT(4) and reverse T(3) (rT(3)) were less marked in the newCH group than in controls (FT(4)+/-s.e.m. 9.2+/-0.5 to 19.7+/-1.2 vs 11.3+/-0.5 to 27.8.2+/-2.4 pmol/l, P<0.05). The CH group exhibited reduced basal and stimulated FT(4) compared with the TSH-sufficient groups. Tg increased similarly among all study groups after rhTSH injection.. In this pilot study, patients with untreated CH had lower response to 0.9 mg rhTSH in FT(4) and rT(3) than controls. An rhTSH test may be useful in the diagnosis of CH, but further studies are required.

Topics: Adult; Aged; Dose-Response Relationship, Drug; Female; Humans; Hypothyroidism; Insulin; Insulin-Like Growth Factor I; Male; Middle Aged; Recombinant Proteins; Single-Blind Method; Thyroglobulin; Thyroid Hormones; Thyrotropin; Triiodothyronine, Reverse

Thyroid hormones are essential for brain maturation. Very preterm infants, who are at risk of neurodevelopmental disabilities also have low thyroxine (T4) and free thyroxine (FT4) values in the first weeks after birth. This transient hypothyroxinemia may in part be causal to the neurodevelopmental problems. We have carried out a randomized, double-blind, placebo-controlled trial with T4 in 200 infants less than 30 weeks gestation. T4 (or placebo) was given in fixed dose of 8 microg/kg birth weight per day during the first 6 weeks after birth. It resulted in a significant increase of T4, FT4, and reverse triiodothyronine (rT3). Thyrotropin (TSH) secretion was suppressed, and, probably as a result of TSH suppression, triodothyronine (T3) levels were decreased in the T4 group. Mortality was 14% in the T4 group and 21% in the placebo group (NS). No effect was found on morbidity. Heart rate was significantly higher in T4-treated infants less than 28 weeks gestation, but not in T4-treated infants 28 weeks or more, who had the highest FT4 levels. In the study groups as a whole, no clear effect of T4 administration was found on neurodevelopmental outcome. However, there was a strong trend toward improvement of adverse outcome, defined as death or abnormal developmental outcome at 2 years of age. In addition, mental outcome in a subgroup of T4-treated infants less than 27 weeks' gestation was significantly better than in placebo infants of the same age group. In conclusion, this trial does not clearly have conclusive results. New trials of thyroid hormone treatment should be carried out in preterm infants, in order to investigate whether indeed T4 supplementation is required in preterm infants less than 27 or 28 weeks gestation. Addition of T3 to the treatment schedule needs to be considered.

Topics: Blood Proteins; Double-Blind Method; Drug Administration Schedule; Female; Follow-Up Studies; Heart Rate; Humans; Hypothyroidism; Infant; Infant, Newborn; Infant, Premature; Male; Neuropsychological Tests; Protein Binding; Thyroid Gland; Thyrotropin; Thyroxine; Treatment Outcome; Triiodothyronine; Triiodothyronine, Reverse

Preterm newborns have low serum thyroxine (T4) levels compared with late-gestational fetuses. Low thyroid hormone levels are associated with increased severity of neonatal illness and neurodevelopmental dysfunction. We assessed the endocrine and clinical effects of increasing serum T4 levels in preterm newborns with a gestational age <31 wk. Forty newborns were randomized in a double blind protocol: 20 infants received a daily dose of 20 microg/kg L-T4 for 2 wk, whereas 20 control infants received saline. Serum concentrations of T4, triiodothyronine (T3), reverse T3 (rT3), thyroglobulin (TG), and TSH were measured weekly as well as serum levels of GH, prolactin, and IGF-I. After 2 wk, a TSH-releasing hormone (TRH) test was performed. Neonatal illness and outcome was evaluated by noting heart rate, oxygen requirement, duration of ventilation, development of chronic lung disease, oral fluid intake, and weight gain; a Bayley score was done at the corrected age of 7 mo. L-T4 administration induced a marked increase in serum T4 without apparent change in T3 levels, whereas the postnatal decline in serum rT3 was more gradual. L-T4 treatment was associated with a decrease in serum TG and TSH levels. TRH injection induced a definite rise in serum TSH and T3 in controls, but not in L-T4 treated newborns. Neither L-T4 treatment, nor TRH administration appeared to alter circulating levels of prolactin, GH, or IGF-I. In contrast to the pronounced endocrine effects, no clinical effects of L-T4 administration were detected.

Topics: Dopamine; Double-Blind Method; Female; Human Growth Hormone; Humans; Hypothyroidism; Infant, Newborn; Infant, Premature; Insulin-Like Growth Factor I; Male; Prolactin; Thyroglobulin; Thyrotropin; Thyrotropin-Releasing Hormone; Thyroxine; Triiodothyronine; Triiodothyronine, Reverse

To assess the efficacy of reverse T3 in differentiating between the hypothyroid and euthyroid state in the setting of illness, all reverse T3 determinations obtained over a 4-year period in a University teaching hospital were analyzed in the context of concurrent thyroid function tests, bilirubin, albumin, creatinine, subsequent treatment, and follow-up. Based on T4 (or free T4 index) and TSH, the thyroidal state of the patient and the appropriateness of the reverse T3 determination were assigned. A total of 262 reverse T3 determinations were made in 246 patients. There is an inverse linear relationship between the log TSH and the reverse T3. Patients with hypothyroidism plus illness may have a normal reverse T3 and patients with euthyroidism may have a low reverse T3. Reverse T3 is linearly related to bilirubin up to a bilirubin of approximately 171 microM (10 mg/dL). Sixty percent of the reverse T3 determinations were obtained for seemingly inappropriate indications. In association with a low free T4 index/T4, an unmeasurable reverse T3 did not lead to institution of thyroid hormone treatment in over 52% of cases. Although reverse T3 may be elevated in the setting of nonthyroidal illness, it is not reliable in distinguishing between the hypothyroid sick patient and the euthyroid sick patient. This is probably because of drug and disease effects on thyroid hormone metabolism as well as the presence of sufficient T4 substrate for conversion to reverse T3 in many hypothyroid sick patients.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Bilirubin; Diagnosis, Differential; Euthyroid Sick Syndromes; Female; Humans; Hypothyroidism; Iodine Radioisotopes; Male; Middle Aged; Thyroid Function Tests; Thyroxine; Triiodothyronine, Reverse

Administration of human GH to GH-deficient patients has yielded conflicting results concerning its impact on thyroid function, ranging from increased resting metabolic rate to induction of hypothyroidism. However, most studies have been casuistic or uncontrolled and have used pituitary-derived GH of varying purity, often contaminated with TSH. Therefore, we conducted a double blind, placebo-controlled cross-over study of the effect of 4 months of biosynthetic human GH therapy (Norditropin; 2 IU/m2.day) on thyroid function in GH-deficient adults (8 females and 14 males; mean +/- SE age, 23.8 +/- 1.2 yr). One group (I) was euthyroid without T4 substitution (n = 13), whereas the other (group II) received T4 (n = 9). Serum T4 (nanomoles per L) decreased in both groups after GH treatment [group I, 100 +/- 8 (mean +/- SE) vs. 89 +/- 8 (P less than 0.01); group II, 145 +/- 18 vs. 115 +/- 10 (P less than 0.05)]. Conversely, GH treatment caused an increase in serum T3 (nanomoles per L) in both groups [group I, 1.9 +/- 0.1 vs. 2.0 +/- 0.1 (P less than 0.1); group II, 1.7 +/- 0.1 vs. 1.9 +/- 0.1 (P less than 0.05)]. Similar changes were seen in serum free T4 and T3. The serum T3 level during the placebo period of group I was significantly lower than that in an age-matched reference group (P less than 0.02). Serum rT3 (nanomoles per L) was low in group I and decreased significantly, as in group II, after GH treatment [group I, 0.26 +/- 0.02 (placebo) vs. 0.20 +/- 0.02 (GH; P less than 0.01); group II, 0.38 +/- 0.05 (placebo) vs. 0.29 +/- 0.02 (GH; P less than 0.01)]. Serum TSH decreased in both groups during GH therapy, though not significantly. Serum thyroglobulin was unaltered and did not differ from that in the reference group. In conclusion, our data are consistent with a GH-induced enhancement of peripheral deiodination of T4 to T3. GH thus seems to play an important role, either directly or indirectly, in the regulation of peripheral T4 metabolism.

Topics: Adult; Clinical Trials as Topic; Female; Growth Hormone; Humans; Hypothyroidism; Male; Thyroglobulin; Thyroid Gland; Thyrotropin; Thyroxine; Triiodothyronine; Triiodothyronine, Reverse

In consumptive hypothyroidism associated with infantile hepatic hemangiomas (IHH), elevated reverse triiodothyronine (rT3) is known due to elevated D3. This report shows that rT3 is a new indicator of IHH progression and that three divided doses of LT3 per day were more effective than a single dose.. A 23 day-old boy was diagnosed with diffuse IHH and severe hypothyroidism with high rT3. Propranolol and LT4 were administered. Hemangiomas gradually diminished and rT3 decreased, but the thyroid-stimulating hormone remained elevated, and free triiodothyronine (fT3) did not normalize after 2 weeks of treatment. Liothyronine (LT3) was started as a single dose and then divided into three doses after 1 week, which stabilized thyroid function.. rT3 levels were less variable and decreased in conjunction with tumor shrinkage; thus, rT3 is an indicator of therapeutic outcomes for IHH. LT3 administered in divided doses aided in managing IHH-associated hypothyroidism.

Topics: Hemangioma; Humans; Hypothyroidism; Liver Neoplasms; Male; Thyroxine; Triiodothyronine; Triiodothyronine, Reverse

To fully investigate the thyroid hormonal function in patients with the most common arrhythmia - atrial fibrillation.. 120 patients (aged 55-85 yrs) with symptoms of congestive heart failure exacerbation and no other concomitant disorders (inclusion criteria: normal cardiac troponin T at admission and 12 hours after, normal renal, hepatic and respiratory function; exclusion criteria: inflammatory state, history of myocardial infarction). Depending on the presence of permanent atrial fibrillation (PAF), patients were divided into two groups: PAF (34 females, 26 males) and regular sinus heart rhythm (43 females, 17 males), the groups did not differ in terms of heart rate, blood pressure, presence of overt/subclinical thyroid dysfunction, and medical therapy used. In all subjects thyroid stimulating hormone, free thyroxine, free triiodothyronine, reverse triiodothyronine were measured; echocardiography was performed.. PAF group showed higher FT4 and rT3 (1.41 vs. 1.27 ng/dl, p=0.0007; 0.61 vs. 0.32 ng/ml, p<0.0001, respectively). With ROC curve analysis the biochemical thyroid related factor of the highest prognostic value for PAF occurrence (with the highest sensitivity and specificity: 77% and 72%, respectively) was rT3 with the cut-off of above 0.3 ng/ml. Also, a positive correlation between rT3 levels and left ventricular posterior wall diameter was observed (Spearman's correlation coefficient 0.33, p=0.0093).. PAF is another condition where an increase in rT3 is observed. rT3 concentration above 0.3 ng/ml may be a novel biochemical sign associated with the presence of PAF in patients with chronic heart failure.

Topics: Aged; Aged, 80 and over; Atrial Fibrillation; Case-Control Studies; Cohort Studies; Female; Heart Failure; Humans; Hyperthyroidism; Hypothyroidism; Male; Middle Aged; ROC Curve; Thyroid Function Tests; Thyrotropin; Thyroxine; Triiodothyronine; Triiodothyronine, Reverse

Little is known about the kinetics and metabolism of thyroid hormones in the hypothyroid state. To investigate these factors, we developed a reliable method for measurement of serum thyroxine (T(4)), triiodothyronine (T(3)), reverse-T(3) (rT(3)) and stable isotope-labeled T(4) ([(13)C(9)]T(4)), using online solid-phase extraction liquid chromatography-mass spectrometry/mass spectrometry (online SPE LC-MS/MS). We measured supply and turnover rates of T(4) in thyroidectomized (Tx) rats using [(13)C(9)]T(4) as a tracer. In rats, serum T(4), T(3) and rT(3) were decreased but not completely ablated after surgical Tx. Endogenous T(4) and T(3) levels in Tx rats were maintained at a constant low level throughout the experimental period. [(13)C(9)]T(4) levels declined with a half-life of ∼1.2 days after it was administered to Tx rats intravenously. These findings strongly suggest that serum T(4) levels in Tx rats are maintained by T(4) supplied by extra-thyroidal tissues (e.g. secretion of extra-thyroidal storage, enhancement of enterohepatic recirculation, and production in extra-thyroidal tissues). Moreover, the turnover rate of T(4) in Tx rats was approximately twofold lower than in controls. This finding suggests that degradation of serum T(4) is repressed by Tx. In conclusion, serum T(4) is maintained at a constant low level by T(4) supply from extra-thyroidal tissues and repression of T(4) degradation in Tx rats. The powerful online SPE LC-MS/MS tool can be used to investigate thyroid hormones kinetics and metabolism, and thus has the potential to be used as a diagnostic tool and to investigate the pathogenesis of thyroid disease.

Topics: Animals; Automation, Laboratory; Carbon Isotopes; Chromatography, High Pressure Liquid; Half-Life; Hypothyroidism; Kinetics; Limit of Detection; Male; Rats; Rats, Sprague-Dawley; Reproducibility of Results; Solid Phase Microextraction; Spectrometry, Mass, Electrospray Ionization; Tandem Mass Spectrometry; Thyroid Gland; Thyroidectomy; Thyroxine; Triiodothyronine; Triiodothyronine, Reverse

Type 1 iodothyronine deiodinase (DIO1) catalyses the conversion of prohormone thyroxine to the active thyroid hormone 3,3',5-triiodothyronine (T3), important regulator of cell proliferation and differentiation. DIO1 expression is reduced in the most common type of kidney neoplasia, clear cell Renal Cell Carcinoma (ccRCC). MicroRNAs are small, non-coding RNAs that regulate gene expression at posttranscriptional levels. The aim of this study was to analyze the potential regulation of DIO1 expression by microRNAs in ccRCC. Bioinformatic analysis revealed that 3'UTR of the human DIO1 gene transcript contains miR-224 and miR-383 target sites, which are conserved across mammalian species. Semi-quantitative real-time PCR was used to analyze the expression of miR-224 and miR-383 in 32 samples of ccRCC tumors (T) and in 32 matched control (C) samples. We observed statistically significant (p = 0.0002) more than four fold increase in miR-224 expression and nearly two fold increase in miR-383 expression in samples T compared to samples C. Tumor specific changes in expression of miR-224 negatively correlated with changes in DIO1 expression and intracellular T3 concentration. Transfection of HeLa cell line with miR-224 and miR-383 suppressed the activity of a luciferase reporter containing the 3'UTR of DIO1. This was abolished when constructs mutated at the miR-224 and miR-383 target sites were used instead, indicating that miR-224 and miR-383 directly bind to DIO1 3'UTR. Finally, induced expression of miR-224 in Caki-2 cells resulted in significant (p<0.01) reduction of DIO1 mRNA. This study provides a novel miRNA-mediated regulatory mechanism of DIO1 expression in ccRCC.

Topics: 3' Untranslated Regions; Carcinoma, Renal Cell; Gene Expression Regulation, Neoplastic; HeLa Cells; Humans; Hypothyroidism; Iodide Peroxidase; Kidney Neoplasms; MicroRNAs; Triiodothyronine, Reverse

Hepatic haemiangiomas in infancy are rare. An association with hypothyroidism has been previously reported and is believed to be secondary to the conversion of thyroxine (fT4) to biologically inactive reverse triiodothyronine (rT3) by type 3 iodothyronine deiodinase (D3). We report a case that responded well to the combined use of liothyronine and thyroxine therapy.

Topics: Hemangioma; Humans; Hypothyroidism; Infant; Iodide Peroxidase; Liver Neoplasms; Male; Thyroxine; Triiodothyronine; Triiodothyronine, Reverse

Standard drug information resources recommend that l-thyroxine be taken half an hour before breakfast on an empty stomach, to prevent interference of its intestinal uptake by food or medication. We observed cases in which TSH levels improved markedly after changing the administration time of l-thyroxine to the late evening. We therefore conducted a pilot-study to investigate whether l-thyroxine administration at bedtime improves TSH and thyroid hormones, and whether the circadian rhythm of TSH remains intact. DESIGN Patients were studied on two occasions: on a stable regimen of morning thyroxine administration and two months after switching to night-time thyroxine using the same dose. On each occasion patients were admitted for 24 h and serial blood samples were obtained.. We investigated 12 women treated with l-thyroxine because of primary hypothyroidism, who used no medication known to interfere with l-thyroxine uptake.. Patients were admitted to hospital and blood samples were obtained at hourly intervals for 24 h via an indwelling catheter. Following this first hospital admission, all women were asked to switch the administration time from morning to bedtime or vice versa. After 2 months they were readmitted for a 24-h period of hourly blood sampling. Blood samples were analysed for serum TSH (immunometric assay), FT4 and T3 (competitive immunoassay), T4 and rT3 (radioimmunoassay), serum TBG (immunometric assay) and total protein and albumin (colourimetric methods).. A significant difference in TSH and thyroid hormones was found after switching to bedtime administration of l-thyroxine. Twenty-four-hour average serum values amounted to (mean +/- SD, morning vs bedtime ingestion): TSH, 5.1 +/- 0.9 vs 1.2 +/- 0.3 mU/l (P < 0.01); FT4, 16.7 +/- 1.0 vs 19.3 +/- 0.7 pmol/l (P < 0.01); T3, 1.5 +/- 0.05 vs 1.6 +/- 0.1 nmol/l (P < 0.01). There was no significant change in T4, rT3, albumin and TBG serum levels, nor in the T3/rT3 ratio. The relative amplitude and time of the nocturnal TSH surge remained intact.. l-thyroxine taken at bedtime by patients with primary hypothyroidism is associated with higher thyroid hormone concentrations and lower TSH concentrations compared to the same l-thyroxine dose taken in the morning. At the same time, the circadian TSH rhythm stays intact. Our findings are best explained by a better gastrointestinal uptake of l-thyroxine during the night.

Topics: Adult; Aged; Analysis of Variance; Blood Proteins; Circadian Rhythm; Drug Administration Schedule; Female; Humans; Hypothyroidism; Middle Aged; Pilot Projects; Serum Albumin; Thyrotropin; Thyroxine; Thyroxine-Binding Proteins; Triiodothyronine; Triiodothyronine, Reverse

A study of 350 HIV+ patients in our region showed that 16% suffered from hypothyroidism. Twenty-two HIV+ hypothyroid patients (10 with subclinical hypothyroidism, 12 with low FT4 levels (LT4) (confirmed by a dialysis equilibrium assay) and 22 HIV+ euthyroid controls receiving highly active anti-retroviral therapy were included in an additional study.. No goiter or anti-thyroid antibodies were detected. Use of stavudine was more frequent in the LT4 subgroup (p < 0.01) and subclinical hypothyroidism group (p = 0.04). Use of didanosine (OR, 12.5, p < 0.01) and ritonavir (OR, 33.0, p < 0.01) was more frequent in the LT4 subgroup, with a greater didanosine cumulative dose (616.7 mg [180.0, 1,260.0] vs. 263.7 [63.0, 948.0], p = 0.01). Reverse T3, binding protein levels, the TSH response to thyrotropin-releasing hormone, urinary iodine, plasma selenium and thiocyanate levels did not differ. IFNgamma levels were lower in the subclinical hypothyroidism group (pg/ml) (9.1 [0.0, 22.7] vs. 19.5 [0.0, 40.9], p = 0.03).. None of the investigated mechanisms are able to explain the occurrence of hypothyroidism in HIV patients receiving highly active anti-retroviral therapy except the anti-retroviral treatment. In light of the absence of autoimmunity, the normal adenohypophysis and thyroid responses to thyrotropin-releasing hormone, central hypothyroidism is suspected and could explain LT4 and high TSH levels. Underlying mechanisms need further exploration.

Topics: Adult; Antiretroviral Therapy, Highly Active; Autoantibodies; Autoimmune Diseases; HIV Infections; Humans; Hypogonadism; Hypothyroidism; Interferon-gamma; Iodine; Middle Aged; Prospective Studies; Thyroid Gland; Thyrotropin; Thyrotropin-Releasing Hormone; Thyroxine; Triiodothyronine; Triiodothyronine, Reverse; Ultrasonography

Topics: AMP-Activated Protein Kinases; Animals; Energy Metabolism; Glucose; Hypothyroidism; Insulin Resistance; Leptin; Multienzyme Complexes; Protein Serine-Threonine Kinases; Rats; Thyroid Hormones; Triiodothyronine; Triiodothyronine, Reverse

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

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

We wanted to evaluate changes in the natural course of serum thyroxine (T4), tri-iodothyronine (T3), reverse tri-iodothyronine (rT3), and thyroid stimulating hormone (TSH) concentrations during hospitalization for an acute illness, in subjects rendered euthyroid with Levothyroxine (LT4) replacement therapy.. Six male subjects ranging in age 30 - 65 years with a history of primary hypothyroidism were included. They were euthyroid prior to hospitalization. LT4 continued to be administered orally in the same pre-admission daily dose. Serum, T4, T3, rT3, and TSH concentrations were determined on day of admission to the intensive care unit (ICU) for an acute illness. These were repeated during the first week on alternate days and again during a follow-up visit 1 week after discharge. Student's t-test, analysis of variance, and linear regression were used to analyze the data.. Serum T4, T3 declined to a nadir and serum rT3 rose to its peak by day 3 of hospitalization before returning to pre admission euthyroid levels. Serum TSH declined initially but rose to supernormal levels on day 7 before normalization. Significant correlations were noted between TSH on one hand and T3/T4 (r = 0.76, p < 0.001) and rT3/T4 (r= - 0.64, p < 0.001) ratios.. Alterations ensuing during a short stay in the hospital due to an acute illness in subjects with primary hypothyroidism rendered euthyroid with appropriate replacement therapy with Levothyroxine (LT4) are almost identical to those in normal subjects. These changes are probably secondary to altered thyroid hormone metabolism. The altered levels of thyroid hormones and TSH noted in these subjects are transient and therefore providers should refrain from initiating frequent changes in daily LT4 replacement dose during the acute illness in these subjects.

Topics: Acute Disease; Aged; Critical Care; Hospitalization; Humans; Hypothyroidism; Male; Middle Aged; Thyroid Hormones; Thyrotropin; Thyroxine; Triiodothyronine; Triiodothyronine, Reverse

Thyroid hormones are essential for a variety of developmental and metabolic processes. Congenital hypothyroidism (CHT) results in severe defects in the development of different tissues, in particular brain. As an animal model for CHT, we studied Pax8(-/-) mice, which are born without a thyroid gland. We determined the expression of iodothyronine deiodinase D1 in liver and kidney, D2 in brain and pituitary, and D3 in brain, as well as serum T(4), T(3), and rT(3) levels in Pax8(-/-) vs. control mice during the first 3 wk of life. In control mice, serum T(4) and T(3) were undetectable on the day of birth (d 0) and increased to maximum levels on d 15. In Pax8(-/-) mice, serum T(4) and T(3) remained below detection limits. Serum rT(3) was high on d 0 in both groups and rapidly decreased in Pax8(-/-), but not in control mice. Hepatic and renal D1 activities and mRNA levels were low on d 0 and increased in control mice roughly parallel to serum T(4) and T(3) levels. In Pax8(-/-) mice, tissue D1 activities and mRNA levels remained low. Cerebral D2 activities were low on d 0 and increased to maximum levels on d 15, which were approximately 10-fold higher in Pax8(-/-) than in control mice. D2 mRNA levels were higher in Pax8(-/-) than in control mice only on d 21. Cerebral D3 activities and mRNA levels were high on d 0 and showed a moderate decrease between d 3 and 15, with values slightly lower in Pax8(-/-) than in control mice. One day after the injection of 200 ng T(4) or 20 ng T(3)/g body weight, tissue deiodinase activities and mRNA levels were at least partially restored toward control levels, with the exception of cerebral D3 activity. In conclusion, these findings show dramatic age and thyroid state-dependent changes in the expression of deiodinases in central and peripheral tissues of mice during the first 3 wk of life.

Topics: Aging; Animals; Brain; Congenital Hypothyroidism; Disease Models, Animal; DNA-Binding Proteins; Female; Gene Expression Regulation, Enzymologic; Growth Disorders; Hypothyroidism; Iodide Peroxidase; Kidney; Liver; Male; Mice; Mice, Knockout; Nuclear Proteins; Paired Box Transcription Factors; PAX8 Transcription Factor; Pituitary Gland; RNA, Messenger; Thyroxine; Trans-Activators; Triiodothyronine; Triiodothyronine, Reverse

Liver uptake of thyroxine (T4) is mediated by transporters and is rate limiting for hepatic 3,3',5-triiodothyronine (T3) production. We investigated whether hepatic mRNA for T4 transporters is regulated by thyroid state using Xenopus laevis oocytes as an expression system. Because X. laevis oocytes show high endogenous uptake of T4, T4 sulfamate (T4NS) was used as an alternative ligand for the hepatic T4 transporters. Oocytes were injected with 23 ng liver mRNA from euthyroid, hypothyroid, or hyperthyroid rats, and after 3-4 days uptake was determined by incubation of injected and uninjected oocytes for 1 h at 25 degrees C or for 4 h at 18 degrees C with 10 nM [125I]T4NS. Expression of type I deiodinase (D1), which is regulated by thyroid state, was studied in the oocytes as an internal control. Uptake of T4NS showed similar approximately fourfold increases after injection of liver mRNA from euthyroid, hypothyroid, or hyperthyroid rats. A similar lack of effect of thyroid state was observed using reverse T3 as ligand. In contrast, D1 activity induced by liver mRNA from hyperthyroid and hypothyroid rats in the oocytes was 2.4-fold higher and 2.7-fold lower, respectively, compared with euthyroid rats. Studies have shown that uptake of iodothyronines in rat liver is mediated in part by several organic anion transporters, such as the Na+/taurocholate-cotransporting polypeptide (rNTCP) and the Na-independent organic anion-transporting polypeptide (rOATP1). Therefore, the effects of thyroid state on rNTCP, rOATP1, and D1 mRNA levels in rat liver were also determined. Northern analysis showed no differences in rNTCP or rOATP1 mRNA levels between hyperthyroid and hypothyroid rats, whereas D1 mRNA levels varied widely as expected. These results suggest little effect of thyroid state on the levels of mRNA coding for T4 transporters in rat liver, including rNTCP and rOATP1. However, they do not exclude regulation of hepatic T4 transporters by thyroid hormone at the translational and posttranslational level.

Topics: Animals; Binding, Competitive; Blotting, Northern; Carrier Proteins; Enzyme Activation; Hyperthyroidism; Hypothyroidism; Iodide Peroxidase; Iodine Radioisotopes; Ligands; Liver; Male; Microinjections; Oocytes; Rats; Rats, Wistar; Receptors, Thyroid Hormone; RNA, Messenger; Thyrotropin; Thyroxine; Triiodothyronine; Triiodothyronine, Reverse; Xenopus laevis

Associated autoimmune phenomena might influence metabolic control in children and adolescents with Type 1 diabetes mellitus. A retrospective case control study was performed in order to explore the effect of subclinical hypothyroidism on metabolic control in Type 1 diabetes mellitus.. For this purpose each patient with Type 1 diabetes and subclinical hypothyroidism (cases) was matched for age, duration of disease and, if possible, for sex, with two to three diabetic patients without hypothyroidism (controls). Parameters of metabolic control such as HbA1c, total insulin requirement and frequency of symptomatic hypoglycaemia were retrieved for 12, 6 and 3 months before and after diagnosis of hypothyroidism.. Thirteen patients (two male/11 female) patients were diagnosed with subclinical hypothyroidism and were matched with 31 controls (nine male/22 female). There was no difference (mean and range) in terms of age (11.9 years (4.4-18.1) vs. 11.7 years (3.5-18.1), P = 0.9) and duration of disease (5.1 years (1.2-10.5) vs. 4.38 years (0.9-10.8), P = 0.6) between the two groups. There was no difference in HbA1c and total insulin requirement between the two groups at any time point of assessment (anova P = 0.8 and P = 0.1, respectively). Patients with hypothyroidism had significantly more symptomatic hypoglycaemic episodes during the 12 months before diagnosis (anova P = 0.05), increasing progressively during this time period and reaching a peak at time 0 (5.5+/-0.4 vs. 1.6+/-0.1 episodes/month, P = 0.01). No difference could be detected within 6 months of starting substitution therapy (2.4+/-0.2 vs. 1.6+/-0.1 episodes/week, P = 0.8).. These data suggest that subclinical hypothyroidism is associated with an increased risk of symptomatic hypoglycaemia. The prompt introduction of substitution therapy is recommended as it reduces its frequency.

Topics: Adolescent; Blood Glucose; Child; Diabetes Mellitus, Type 1; Female; Humans; Hypothyroidism; Male; Prevalence; Thyroiditis, Autoimmune; Thyrotropin; Thyroxine; Triiodothyronine; Triiodothyronine, Reverse

Adipocytes are an important target tissue for thyroid hormone action, but little is known of the mechanisms of thyroid hormone entry into the cells. The present results show a strong interaction between transport of iodothyronines [L-thyroxine (T4), L-triiodothyronine (T3), reverse T3 (rT3)], aromatic amino acids, and the System L amino acid transport inhibitor 2-amino[2,2,1]heptane-2-carboxylic acid (BCH) in white adipocytes. System L appears to be a major pathway of iodothyronine and large neutral amino acid entry into these cells in the euthyroid state. We also demonstrate expression of the CD98hc peptide subunit of the System L transporter in adipocyte cell membranes. Experimental hypothyroidism (28-day propylthiouracil treatment) has no significant effect on System L-like transport of the amino acid tryptophan in adipocytes. In contrast, uptake of T3 and especially T4 is substantially reduced in adipocytes from hypothyroid rats, partly due to reduction of the BCH-sensitive transport component. Transport of iodothyronines and amino acids in adipocytes therefore becomes decoupled in the hypothyroid state, as occurs similarly in liver cells. This may be due to downregulation or dissociation of iodothyronine receptors from the System L transporter complex. Regulation of iodothyronine turnover in fat cells by this type of mechanism could contribute significantly to modulation of T4-T3/rT3 metabolism in the hypothyroid state.

Topics: Adipocytes; Amino Acids, Cyclic; Animals; Antigens, CD; Biological Transport; Carrier Proteins; Desipramine; Fusion Regulatory Protein-1; Hypothyroidism; Male; Rats; Rats, Wistar; Reference Values; Thyroxine; Triiodothyronine; Triiodothyronine, Reverse; Tryptophan

Compared with euthyroid controls, patients with congenital hypothyroidism (CH) who are receiving L-T(4) treatment show elevated serum TSH relative to serum T(4) concentrations and increased T(4)/T(3) ratio. These abnormalities could be the consequence of impaired activity of the selenoenzymes deiodinases on which patients with CH rely to convert the ingested L-T(4) into active T(3). Eighteen patients (0.5-15.4 yr), diagnosed with CH in infancy, received selenomethionine (SeM, 20-60 microg selenium/day) for 3 months. The study took place in Belgium, a country where selenium intake is borderline. Compared with the values observed in age- and sex-matched euthyroid controls, patients with CH had decreased selenium, thyroglobulin and T(3) concentrations and increased TSH, reverse T(3), and T(4) concentrations and T(4)/T(3) ratio at baseline. Selenium supplementation caused a 74% increase in plasma selenium values but did not affect the activity of the selenoenzyme glutathione peroxidase used as a marker of selenium status. SeM abolished the TSH difference observed between CH patients and euthyroid controls at baseline and caused a significant decrease in thyroglobulin values. Thyroid hormone concentrations were not affected by SeM. In conclusion, our data suggest that selenium is not a limiting factor for peripheral T(4)-to-T(3) conversion in CH patients. In contrast, we find indirect evidence that SeM improves thyroid hormones feedback at the hypothalamo-pituitary level and decreases stimulation of the residual thyroid tissue, possibly suggesting greater intracellular T(4)-to-T(3) conversion.

Topics: Adolescent; Child; Child, Preschool; Congenital Hypothyroidism; Dietary Supplements; Glutathione Peroxidase; Humans; Hypothyroidism; Infant; Selenium; Selenomethionine; Thyroglobulin; Thyroxine; Triiodothyronine; Triiodothyronine, Reverse

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

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

The effects of GH therapy on thyroid function among previous reports have shown remarkable discrepancies, probably due to differences in hormone assay methods, degree of purification of former pituitary-derived GH preparations, dosage schedules, diagnostic criteria, patient selection, duration of treatment and study design. These considerations motivated us to investigate whether and how GH replacement therapy changes serum thyroid hormone levels, including the much less studied rT3 levels, in a group of unequivocally GH-deficient children receiving long-term recombinant human GH therapy.. Twenty clinically and biochemically euthyroid children were studied in two therapeutic conditions: on GH replacement therapy for at least 6 months and without GH replacement, either before GH was started or after GH was withdrawn for 30-60 days. Eight patients were on thyroxine replacement treatment and thyroxine doses were kept constant during the study. Blood was collected before and after 15, 20 and 60 minutes of TRH administration in both therapeutic conditions (with GH and without GH).. Concentrations of thyroid hormone levels were determined only in sera obtained before TRH administration. FT4, T3 and TSH were measured by immunoflourimetric assays and rT2 was measured by immunoradioassay.. Patients were classified into two groups, according to basal TSH levels: group I (TSH > 0.4 mU/l, n = 12) and group II (on thyroxine and TSH < 0.05 mU/l, n = 8). In both groups, serum FT4 levels decreased (17. 0 +/- 1.1 vs. 14.3 +/- 0.9 mU/l, P < 0.001, and 18.0 +/- 1.7 vs. 14. 2 +/- 1.7 mU/l, P < 0.01, respectively), serum T3 levels increased (1.8 +/- 0.1 vs. 2.4 +/- 0.2 nmol/l, P < 0.001, and 1.9 +/- 0.3 vs. 2.4 +/- 0.2 nmol/l, P < 0.05, respectively), and serum rT3 levels decreased (0.35 +/- 0.03 vs. 0.25 +/- 0.03 nmol/l, P < 0.01, and 0. 48 +/- 0.06 vs. 0.34 +/- 0.06 nmol/l, P < 0.01, respectively). Basal (3.2 +/- 0.50 vs. 2.6 +/- 0.72 mU/l, P = 0.28, paired t-test), TRH-stimulated peak TSH levels (13.9 +/- 5.3 vs. 15.9 +/- 8.0 mU/l, P = 0.35, paired t-test) and TRH-stimulated TSH secretion, expressed as area under the curve (609 +/- 97 vs. 499 +/- 53 mU/l.minutes-1, P = 0.15, paired t-test), remained unchanged during GH replacement in group I patients. Low serum FT4 and high serum T3 levels were observed in only one patient each, but low serum rT3 levels were found in six patients (four in group I and two in group II) during GH replacement.. These results show that long-term GH replacement therapy in children with unequivocal GHD significantly decreases serum FT4 and rT3 levels and increases serum T3 levels; that these changes are independent of TSH and result from increased peripheral conversion of T4 to T3 and that GH replacement therapy in GH deficient children does not induce hypothyroidism, but simply reveals previously unrecognized cases whose serum FT4 values fall in the low range during GH replacement.

Topics: Adolescent; Adult; Child; Female; Follow-Up Studies; Growth Disorders; Growth Hormone; Hormone Replacement Therapy; Humans; Hypothyroidism; Male; Thyroid Hormones; Thyrotropin; Thyroxine; Triiodothyronine; Triiodothyronine, Reverse

Serum thyroxine (T4), triiodothyronine (T3), and reverse triiodothyronine (rT3) were followed for 24 h in dogs resuscitated following 9 min of controlled cardiac arrest (CA). Total T4, free T4, total T3, and free T3 decreased, while reverse T3 was elevated in the 24 h following resuscitation. Similar changes occurred with only 30 sec of CA. Levothyroxine sodium (L-T4) post-CA (7.5 micrograms/kg/h = CA + 7.5 or 15 micrograms/kg/h = CA + 15) increased total T4, free T4, and total T3. Free T3 decreased in the CA + 7.5 group but did not fall in CA + 15 group. Neurologic function improved significantly by 6 through 24 h (p < 0.05). Follow-up studies infusing T3 or rT3 failed to improve neurologic outcome. Systemic oxygen consumption (VO2) and delivery was assessed in a separate group of seven dogs that received a pre-CA L-T4 infusion of 15 micrograms/kg/h for 1.5 h and L-T4 infusion for 6 h afterward while controls (n = 7) received saline. Systemic VO2, VCO2, and RQ were calculated from blood contents and cardiac output and serum levels of circulating TSH, T4, FT4, T3, FT3, and rT3 were measured before L-T4 and periodically over 6 h. L-T4 maintained significantly higher T4, FT4, T3, FT3, rT3, VO2, and cardiac output compared to controls. No change in canine TSH was detected. Rapid and dramatic decreases in thyroid hormones following resuscitation indicate a significant acute serum hypothyroid state that may benefit from L-T4 treatment. L-T4 enhances systemic oxygen consumption and delivery and these changes may contribute to L-T4's neural protective effect.

Topics: Animals; Carbon Dioxide; Cardiac Output; Cardiopulmonary Resuscitation; Dogs; Heart Arrest; Hypothyroidism; Male; Oxygen Consumption; Thyroid Hormones; Thyroxine; Triiodothyronine; Triiodothyronine, Reverse

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

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

To investigate unusual free thyroxine (FT4) responses to T4 replacement doses in a hypothyroid patient with familial dysalbuminemic hyperthyroxinemia (FDH).. In this FDH hypothyroid patient, serum FT4 concentration by equilibrium dialysis and T4, triiodothyronine (T3), and thyroid stimulating hormone (TSH) determinations were supplemented by thyroxine binding globulin (TBG) and thyroxine binding prealbumin (TBPA) measurements.. Initial thyroid function tests were compatible with hypothyroidism and FDH (T4 = 78 nmol/L, T3 = 1.08 nmol/L, FT4 = 11.6 pmol/L, TSH = 45 mU/L). When she was initially treated with T4 (0.112-0.088 mg/day) there was an increase in FT4 concentration to hyperthyroid levels accompanied by TSH inhibition (FT4 = 31-51 pmol/L, TSH = <0.03 mU/L); the patient also complained of intolerance and nervousness, and T4 treatment was discontinued. Concentrations of thyroxine binding globulin (TBG) and thyroxine binding prealbumin (TBPA) were normal. When T4 therapy was later resumed at a dosage of 0.075 mg/day, there was a marked increase in percent dialyzable T4. The elevation in percent dialyzable T4 during T4 replacement in a patient with FDH is unusual in view of the very large T4 binding capacity of FDH albumin. The presence of an inhibitor that reduced T4 binding by both TBG and FDH albumin probably explains the elevation in percent dialyzable T4 during T4 treatment.. This FDH patient represents the first case of a putative inhibitor of T4 binding to both TBG and FDH albumin. The inhibition of T4 binding by these disparate proteins suggests that the inhibitor effect is mediated nonspecifically.

Topics: Aged; Female; Humans; Hyperthyroxinemia; Hypothyroidism; Protein Binding; Serum Albumin; Thyroid Function Tests; Thyrotropin; Thyroxine; Thyroxine-Binding Proteins; Triiodothyronine; Triiodothyronine, Reverse

Iodothyronine binding to plasma lipoproteins (Lp) and gel filtration elution patterns of cholesterol and triglycerides were evaluated in the total lipoprotein fractions (TLF) obtained from 10 healthy blood donors and 7 patients with hypothyroidism of brief duration. TLF (d < 1.210 kg/L) shown to be free of plasma T4 transport proteins (TBG, TTR, HSA) was equilibrated with 0.3 nM 125I-labeled T4, T3 or reverse T3 (rT3) and chromatographed on Sepharose CL-6B. Percent distribution of rT3 among the Lp subtypes was similar in the two groups (in normals: VLDL = 4.2 +/- 2.4, LDL = 15.6 +/- 4.2, HDL = 79.9 +/- 5.2) but HDL in hypothyroid subjects bound significantly more T4 (98.7 +/- 0.4 vs. 91.2 +/- 0.3%) and T3 (95.5 +/- 2.6 vs. 78.3 +/- 11.3%). Correspondingly less T4 and T3 was bound to VLDL and LDL. Whereas rT3 elution coincided with the major HDL cholesterol peak (202 +/- 17 kDa) and was the same in the two groups, both T4 and T3 eluted with smaller HDL particles and differed between hypothyroid and normal subjects. T4 eluted with somewhat larger HDL particles in hypothyroid subjects (176 +/- 24 kDa vs. 111 +/- 34 kDa) and T3 eluted with smaller HDL (94 +/- 30 kDa vs. 148 +/- 31 kDa). The major HDL-cholesterol peak in hypothyroid subjects had a slightly but significantly greater mass than in normals (241 +/- 28 kDa vs. 218 +/- 14 kDa). The HDL elution patterns also differed: in normals there were from 3 to 6 minor peaks on either side of the major peak, whereas in hypothyroid subjects there were only 0 to 2 minor peaks. In conclusion, iodothyronines bind to relatively small size HDL subfractions and these are different for T4, T3, and rT3; hypothyroidism of brief duration induces both quantitative and qualitative changes in iodothyronine distribution among lipoproteins and alters the microheterogeneity of HDL-cholesterol.

Topics: Adult; Female; Humans; Hypothyroidism; Lipoproteins; Lipoproteins, HDL; Lipoproteins, LDL; Lipoproteins, VLDL; Male; Middle Aged; Protein Binding; Thyroxine; Triiodothyronine; Triiodothyronine, Reverse

The effects of L-T3 and several analogues on mitochondrial parameters were determined in hypothyroid rats. These parameters include the 24 hour hormone-induced changes in the bc1 complex and in the inner membrane's proton permeability. L-T3, and all analogues except rT3, increased mitochondrial ubiquinone to euthyroid levels. L-T3, D-T3 and 3'IpT2 but not rT3, Triac, Triprop, or Dimit, altered the bypass respiration in the bc1 complex. L-T3, D-T3, Triac, 3'IpT2, and Triprop, but not rT3 or Dimit, increased the membrane's proton permeability. Actinomycin D did not prevent the increase in mitochondrial ubiquinone or the permeability change. The results show the selective thyromimetic properties of the analogues and that some of the mitochondrial changes do not require protein synthesis.

Topics: Animals; Carbonyl Cyanide p-Trifluoromethoxyphenylhydrazone; Cytochromes c1; Dactinomycin; Electron Transport; Glycerolphosphate Dehydrogenase; Hypothyroidism; Intracellular Membranes; Liver; Male; Mitochondria; Oxygen Consumption; Permeability; Proton Pumps; Rats; Rats, Sprague-Dawley; Triiodothyronine; Triiodothyronine, Reverse; Ubiquinone

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

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

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

Twenty-four-hour thyrotropin (TSH) profiles in eight severely ill patients were compared with those of six healthy subjects. The profiles were assessed using the cosinor method to evaluate circadian variations and using the Pulsar algorithm to analyze episodic secretion. In the normal subjects, the typical periodicity of TSH secretion showed a mean level in the rhythm (mesor) of 2.03 mU/l. The amplitude (half the extent of rhythmic change in the cycle) was 0.58 mU/l; the acrophase (the delay from midnight (0 degrees) of the highest level in the rhythm) was -9.9 degrees. In contrast, severely ill patients showed only slight and anticipated elevations of serum TSH levels (mesor 0.93 mU/l, amplitude 0.22 mU/l, acrophase +82.4 degrees). Moreover, whereas the episodic TSH secretion in healthy individuals consisted of 5-8 pulses/24 h, mainly clustered around midnight, only one pulse of reduced amplitude was detected in two of the eight severely ill patients and no pulses in the other six. Since earlier studies have indicated that the loss of TSH pulsatility is associated with the relative insensitivity of the thyrotrophs to low thyroid hormone levels and our analytical procedures have demonstrated that 24 h pulsatile pattern of TSH closely overlapped with baseline TSH secretion, it seems reasonable to assume that low-thyroid-hormone state, deficient pulsatile TSH secretion and altered nyctohemeral TSH periodicity do not coincide by chance, but that there is a causal relationship between such abnormalities in severely ill patients.

Topics: Adult; Circadian Rhythm; Female; Humans; Hypothyroidism; Liver Cirrhosis; Male; Middle Aged; Neoplasms; Pulsatile Flow; Thyrotropin; Thyroxine; Thyroxine-Binding Proteins; Triiodothyronine; Triiodothyronine, Reverse

Until now, most potent inhibitors of monodeiodination are iodinated, propylthiouracil being an exception. We report here studies on a new non-iodinated substance, triethylene glycol bis-3-(3-tert-butyl-4-hydroxy-5-methyl-phenyl) propionate (TK 12627 or Irganox), which is used as a very efficient antioxidant in the chemistry of plastics. The studies were performed with 23 hypothyroid rats that received Irganox in their daily food (8 mg.day-1 x (100 g body wt)-1) for 3 weeks. Thyroxine (T4) metabolism was studied by implanting minipumps delivering 2.3 nmol T4.day-1 x (100 g body wt)-1 for 1 week. On day 1 before sacrifice, another minipump containing [125I]-3,5,3'-triiodothyronine (T3, 2.6 microCi/day) and [131I]-3,3',5'-triiodothyronine (rT3, 2.1 microCi/day) was implanted. The results showed that with Irganox treatment serum T4 concentrations were higher (p < 0.05). Serum T3 concentrations markedly decreased (1.07 +/- 0.07 vs 0.65 +/- 0.04 nmol/l), accompanied by a decrease of free T3 concentrations (p < 0.001). Serum rT3 concentrations increased by 50% (p < 0.001). Serum thyrotropin levels were mostly unmeasurable. The plasma clearance rate decreased slightly for T4 (19%, p < 0.05) and remarkably for rT3 (46.7%, p < 0.001). The conversion rate of T4 to rT3 did not change. Deiodinase type I (5'D-I) activity decreased in both liver and kidney tissues by 54% and 52%, respectively, and correlated with T3 (r2 = 0.79 and 0.65, respectively). Brain deiodinase type III (5D-III) was unchanged and type II (5'D-II) was unmeasurable.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Actins; Animals; Antioxidants; Blotting, Northern; Hypothyroidism; Iodide Peroxidase; Kidney; Liver; Male; Nuclear Proteins; Polyethylene Glycols; Proteins; Radioimmunoassay; Rats; Rats, Sprague-Dawley; RNA, Messenger; Thyroid Gland; Thyroid Hormones; Thyrotropin; Thyroxine; Tissue Distribution; Transcription Factors; Triiodothyronine; Triiodothyronine, Reverse

We recently showed that thyroxine sulfate (T4S) and 3,3',5-triiodothyronine sulfate (T3S) were major thyroid hormone metabolites in ovine fetuses and neonates. To further characterize the sulfation pathway in ovine fetuses, we measured 3,3',5'-triiodothyronine (rT3S) in serum and other body fluids in samples obtained from fetal (n = 23, 94-145 days of gestational age, term = 150 days), newborn (n = 6), and adult (n = 6) sheep. In addition, T3S, T4S, and rT3S levels were measured in tissue fluids and serum samples obtained from ovine fetuses 13 days after total thyroidectomy (Tx) conducted at gestational age of 110-113 days (n = 5). Sham-operated twin fetuses served as controls (n = 5). The relative order of mean rT3S concentration for various tissue fluids in fetuses were meconium > bile > serum > allantoic fluid > urine or amniotic fluid. Peak mean tissue fluid levels generally occurred at 110-130 days gestation. In hypothyroid fetuses, significant decreases in the mean serum concentrations of T4S and rT3S, but not T3S, were noted. The mean rT3S level also was decreased significantly in allantoic fluid, bile, and meconium, whereas T4S and T3S levels were reduced only in bile of the Tx fetuses. These data demonstrate that sulfation is a major pathway in thyroid hormone metabolism in both euthyroid and hypothyroid ovine fetuses.

Topics: Animals; Body Fluids; Fetal Diseases; Fetus; Hypothyroidism; Sheep; Sulfates; Thyroidectomy; Thyronines; Thyroxine; Triiodothyronine; Triiodothyronine, Reverse

Very preterm infants (less than 30 weeks' gestational age) were treated with thyroxine in three different dosage schemes: 10, 8 and 6 micrograms.kg-1 birthweight.day-1 during the first 6 weeks of life. The aim was to prevent transient hypothyroxinemia of the preterm infant. Plasma levels of thyroxine, free thyroxine, triiodothyronine, reverse triiodothyronine, thyroxine-binding globulin and thyrotropin were measured weekly. Thyroxine administration increased thyroxine and free thyroxine levels most properly in the 8-micrograms supplementation group. It did not result in a change in plasma triiodothyronine levels. Levels of reverse triiodothyronine increased in relation to the thyroxine dosage. Thyrotropin secretion was suppressed in the 6- and 8-micrograms groups during the first 2 weeks, while in the 10-micrograms group suppression lasted 4 weeks. No clinical adverse effects of thyroxine administration were seen. We conclude that 8 micrograms thyroxine.kg-1 birthweight.day-1 for 6 weeks prevents transient hypothyroxinemia. The finding that plasma triiodothyronine concentrations are not influenced by thyroxine administration suggests a specific maturation process in the deiodination of thyroxine.

Topics: Aging; Gestational Age; Humans; Hypothyroidism; Infant, Newborn; Infant, Premature; Kinetics; Thyrotropin; Thyroxine; Triiodothyronine; Triiodothyronine, Reverse

In the present study we report that 3,3',5-tri-iodothyronine (T3) as well as two iodothyronines (3,5-di-iodothyronine (3,5-T2) and 3,3'-di-iodothyronine (3,3'-T2)) significantly influence rat liver mitochondrial activity. Liver oxidative capacity (measured as cytochrome oxidase activity/g wet tissue) in hypothyroid compared with normal rats was significantly reduced (21%, P > 0.01) and the administration of T3 and both iodothyronines restored normal values. At the mitochondrial level, treatment with T3 stimulated respiratory activity (state 4 and state 3) and did not influence cytochrome oxidase activity. On the other hand, both the mitochondrial respiratory rate and specific cytochrome oxidase activity significantly increased in hypothyroid animals after treatment with 3,3'-T2 or 3,5-T2 (about 50 and 40% respectively). The actions of both iodothyronines were rapid and evident by 1 h after the injection. The hepatic mitochondrial protein content which decreased in hypothyroid rats (9.6 mg/g liver compared with 14.1 in normal controls, P < 0.05) was restored by T3 injection, while neither T2 was able to restore it. Our results suggest that T3 and both iodothyronines have different mechanisms of action. T3 acts on both mitochondrial mass and activity; the action on mitochondrial activity was not exerted at the cytochrome oxidase complex level. The action of the iodothyronines, on the other hand, is exerted directly on the cytochrome oxidase complex without any noticeable action on the mitochondrial mass.

Topics: Animals; Diiodothyronines; Electron Transport Complex IV; Hypothyroidism; Male; Mitochondria, Liver; Proteins; Rats; Rats, Wistar; Triiodothyronine, Reverse

3,3'5,5'-Tetraiodothyronine (T4), but not 3,3'5-triiodothyronine (T3), acutely regulates the activity of the plasma membrane-bound enzyme, type II iodothyronine 5'-deiodinase (5'D-II), by inducing internalization of the enzyme through an extranuclear, energy-dependent mechanism that requires an intact actin cytoskeleton. The affinity label, N-bromoacetyl-L-T4, binds to 5'D-II and irreversibly inhibits the enzyme but does not initiate internalization. To determine the structural elements of T4 which are required for enzyme internalization, T4 analogs were modified in the alanine side chain and were then evaluated for their ability to induce enzyme internalization, to inhibit enzyme activity, and to promote actin polymerization in hypothyroid cells. The analogs studied showed marked variability in their ability to inactivate 5'D-II. The rank order of potency for enzyme inactivation was T4 > COOH-blocked analogs > NH3 and COOH blocked analogs >> NH3 blocked analogs (EC50 values range from 1 to > 1000 nM). In contrast, all T4 analogs tested and T4 were excellent competitive inhibitors of 5'D-II with respect to substrate (Ki values ranged from 4 to 27 nM). The differential capability of iodothyronines to inactivate the enzyme was not related to their ability to enter the cell, since Ki values measured in intact glial cells were equivalent to those measured in cell sonicates. The power of the T4 analogs to inactivate 5'D-II was paralleled by their ability to polymerize actin in hypothyroid cells and to induce 5'D-II binding to F-actin. The data show that modification of the alanine side chain markedly alters the ability of T4 analogs to induce 5'D-II inactivation and actin polymerization. A net negative charge on the alanine side chain of T4 is detrimental for the hormone-dependent inactivation of 5'D-II and polymerization of actin, whereas uncharged or positively charged molecules retain significant activity.

Topics: Animals; Animals, Newborn; Brain; Bucladesine; Cells, Cultured; Hypothyroidism; Iodide Peroxidase; Isoenzymes; Kinetics; Molecular Structure; Neuroglia; Protein Binding; Structure-Activity Relationship; Thyroxine; Triiodothyronine; Triiodothyronine, Reverse

A highly sensitive, specific, and reproducible RIA has been developed to measure T4 sulfate (T4S) in ethanol extracts of serum. rT3 sulfate (rT3S) cross-reacted 7.1%, and T3S cross-reacted 0.59% in the RIA; T4, T3, rT3, and 3,3'-diiodothyronine cross-reacted 0.004% or less. The recovery of nonradioactive T4S added to serum averaged 95%. The detection threshold of the RIA was 18 pmol/L. The coefficient of variation averaged 6.9% within an assay and 12% between assays. T4S was bound by T4-binding globulin and albumin in serum. The free fraction of T4S in four normal sera averaged 0.06% compared to a value of 0.03% for T4 (P < 0.001). The serum concentration of T4S was (mean +/- SE) 19 +/- 1.2 pmol/L in normal subjects, 33 +/- 10 in hyperthyroid patients with Graves' disease, 42 +/- 15 in hypothyroid patients, 34 +/- 6.9 in patients with systemic nonthyroidal illnesses, 21 +/- 4.3 in pregnant women at 15-40 weeks gestation, and 245 +/- 26 in cord blood sera of newborns; the value in the newborn was significantly different from normal (P < 0.001). The mean concentration of T4S in amniotic fluid samples at 15-38 weeks gestation was 106 +/- 22 pmol/L (cf. normal adults; P < 0.001). Administration of sodium ipodate (Oragrafin; 3 g, orally) to hyperthyroid patients was associated with a transient increase in serum T4S. The T4S content of the thyroid gland was less than 1/4000th that of T4. We conclude that 1) T4S is a normal component of human serum, and its levels are markedly increased in newborn serum and amniotic fluid; and 2) the sulfation pathway plays an important role in the metabolism of T4 in man.

Topics: Blood Proteins; Cross Reactions; Female; Fetal Blood; Humans; Hyperthyroidism; Hypothyroidism; Immune Sera; Infant, Newborn; Pregnancy; Protein Binding; Radioimmunoassay; Reference Values; Thyroid Gland; Thyrotropin; Thyroxine; Triiodothyronine; Triiodothyronine, Reverse

To clarify the duration and the extent of the antithyroid effect of iodides in hyperthyroidism, and to investigate whether iodides have an additional peripheral effect on the metabolism of thyroid hormones, as has been reported for some organic iodine compounds.. The effect on the peripheral thyroid hormone levels of 150 mg of potassium iodide daily (equivalent to 114 mg of iodide) for 3-7 weeks was compared in 21 hyperthyroid patients and 12 healthy controls. A possible effect of iodide on the peripheral metabolism of thyroid hormones was investigated by assessing the serum levels of thyroid hormone in 12 hypothyroid patients on thyroxine replacement for 2 weeks.. There were 21 thyrotoxic patients, 12 healthy hospital controls, and 12 patients with complete or near-complete hypothyroidism, on thyroxine replacement.. The following were measured before and at weekly intervals after iodide administration: (1) pulse rate, (2) serum T4, (3) serum T3, (4) serum TSH, (5) serum thyroxine-binding capacity (TBC), (6) serum rT3, (7) serum thyroxine-binding globulin (TBG), (8) the free-T4 Index, calculated as T4/TBC.. In the hyperthyroid patients serum T4, T3 and rT3 decreased, whereas serum thyroxine-binding globulin and thyroxine binding capacity increased. Serum T3, however, did not become completely normal in all cases. After 21 days, serum T4 and T3 started increasing again in some cases, but other patients remained euthyroid even after 6 weeks. In the normal controls there was a small but significant and consistent decrease in serum T4, T3 and rT3 and an increase in serum TSH. Finally, in the T4-treated hypothyroid patients there was no consistent change, except for an increase of serum T4 at 1 and 14 days and a decrease of serum TSH the first day.. Iodides in hyperthyroidism have a variable and unpredictable intensity and duration of antithyroid effect. Their antithyroid effect is smaller in normal controls. They have no important effect on the peripheral metabolism of thyroid hormones.

Topics: Adult; Aged; Female; Humans; Hyperthyroidism; Hypothyroidism; Male; Middle Aged; Potassium Iodide; Thyroid Gland; Thyroid Hormones; Thyrotropin; Thyroxine; Triiodothyronine; Triiodothyronine, Reverse

In order to develop a model of thyroid hormone action, we studied the effect of small doses of T3 and T4 on the development of the hypothyroid neonatal cerebellum of rat pubs. Using granulosa cell death at postnatal d15 (picnotic index) as a criterion of hypothyroidism, it was found that a single injection of 50 ng T3/10g bw or 180 ng T4/10 g bw would reduce the picnotic index to levels found in euthyroid rat cerebelli. We further tested if rT3, known to be an excellent blocker of deiodinase type 2 activity, would be able to block the effects of T4. 20 micrograms rT3/10g bw had to be given to be an effective inhibitor in vivo. This dose did not affect the potency of T4 and control experiments with rT3 alone indicated that rT3 was capable of reducing the picnotic index to euthyroid levels. It is speculated that rT3 might act at the nuclear receptor but also at the cell membrane.

Topics: Animals; Cerebellum; Dose-Response Relationship, Drug; Female; Gestational Age; Humans; Hypothyroidism; Infant, Newborn; Iodide Peroxidase; Isoenzymes; Pregnancy; Rats; Thyroxine; Triiodothyronine; Triiodothyronine, Reverse

Some investigators have reported that there is minimal placental transport of thyroid hormones in humans and rats. Consequently, it was thought that thyroid hormones were not present in the fetal brain before fetal thyroid hormone synthesis and, hence, were not important for brain development before fetal thyroid hormonogenesis. Recently, however, thyroid hormones have been detected by 14 days postconception (dpc) in the rat fetus and by 11 dpc in the rat embryotrophoblast. Thyroid hormone receptors have been shown in the fetal rat by 14 dpc. The present experiments were designed to determine if T4, T3, and their metabolites can be detected in rat fetuses at 13 and 16 dpc and if iodothyronines are selectively accumulated in fetal brain and liver. Furthermore, one group of dams was radiothyroidectomized before breeding to ascertain the effect of maternal hypothyroxinemia on fetal tissue iodothyronine concentrations. Tissue iodothyronines were extracted and measured by HPLC. T4, T3, rT3, and 3,5-diiodothyronine were well within the limits of detection by this procedure at both fetal ages. The only possible source of these hormones is the mother. In addition, if maternal serum T4 levels are low, fetal tissue T4 and T3 levels are low. The presence of high intracellular T3 levels, even at 13 dpc, shows that 5'-monodeiodination occurs in the midgestational fetus. Intracellular hormone measurements show that T3, rather than rT3, is the predominant intracellular iodothyronine in the rat fetus. Both brain and liver selectively accumulate T4 and T3, supporting the observations of others that fetal thyroid hormone receptors are present in midgestation. The presence of thyroid hormones in fetal rat brain by 13 dpc coupled with the observation that hormone receptors are present by 14 dpc suggests that thyroid hormones do play a role in midgestational brain development. These data show that normal maternal serum thyroid hormone levels are important during midgestation to provide adequate thyroid hormones to the fetus.

Topics: Animals; Chromatography, High Pressure Liquid; Female; Fetus; Gestational Age; Hypothyroidism; Pregnancy; Pregnancy Complications; Rats; Rats, Inbred Strains; Thyroid Hormones; Thyroxine; Triiodothyronine; Triiodothyronine, Reverse

The photoreactive compound p-nitrophenyl-2-diazo-3,3,3-trifluoropropionate (PAL) was coupled to [125I]rT3, T4, or T3 and incubated with liver and kidney microsomes of hypo-, hyper-, or euthyroid rats to identify the type I iodothyronine deiodinase. Various substrates or inhibitors of the enzyme, including rT3, T4, T3, 6-n-propylthiouracil (PTU), and iopanoic acid, were used as competitors to establish the specificity of protein labeling. The PAL derivatization enhanced the behavior of T4 and T3 as substrates for the type I enzyme. No specific labeling of microsomal proteins was observed with either rT3 or T4-PAL, presumably due to deiodination of the labeled compound. In contrast, T3-PAL labeled a 27-kDa band, the presence of which paralleled thyroid status. The labeling of only this protein was blocked by either substrates or enzyme inhibitors in a dose-dependent fashion, with a rank order of potency predicted by the activity of such compounds in type I enzyme assays. The specific nature of these competitions provides further evidence that this 27-kDa protein, identified in previous studies using N-bromoacetyl [125I]T3 or -T4, contains the active site of the rat type I deiodinase. This is in agreement with the mol wt of the rat type I deiodinase deduced from the recently identified cDNA coding for this protein.

Topics: Affinity Labels; Animals; Binding, Competitive; Diazonium Compounds; Hyperthyroidism; Hypothyroidism; Iodide Peroxidase; Iopanoic Acid; Male; Molecular Weight; Photochemistry; Propionates; Propylthiouracil; Rats; Rats, Inbred Strains; Thyroxine; Triiodothyronine; Triiodothyronine, Reverse

Total and free concentrations of T4 and rT3 in serum and cerebrospinal fluid were estimated by ultrafiltration in 12 patients with unipolar endogenous depression before and after electroconvulsive treatment. Recovery from depression resulted in a decrease in CSF concentrations of free T4 (median) (26.2 to 21.4 pmol/l, p less than 0.02) and free rT3 (14.1 to 12.3 pmol/l, p less than 0.05). Concentrations of free T4 in the cerebrospinal fluid were lower than those in serum (p less than 0.02), the ratio being 0.6. In contrast, levels of free rT3 in the cerebrospinal fluid were considerably higher than those found in serum (p less than 0.01), the ratio being 25. These ratios did not change following recovery from depression. In 9 patients with nonthyroidal somatic illness, concentrations of free T4 and rT3 in the cerebrospinal fluid were similar to those found in patients with endogenous depression, whereas 4 hypothyroid patients and one hyperthyroid patient had considerably lower and higher, respectively, concentrations of both free T4 and rT3. In conclusion, levels of free T4 and free rT3 in the cerebrospinal fluid are increased during depression compared with levels after recovery, probably reflecting an increased supply of T4 from serum and an increased production of rT3 from T4 in the brain. The data also suggest that the transport of iodothyronines between serum and the cerebrospinal fluid is restricted.

Topics: Aged; Depressive Disorder; Electroconvulsive Therapy; Female; Humans; Hyperthyroidism; Hypothyroidism; Male; Middle Aged; Thyrotropin; Thyrotropin-Releasing Hormone; Thyroxine; Triiodothyronine; Triiodothyronine, Reverse

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

The clinical implications of nuclear T3R alterations of circulating lymphocytes in hyperthyroidism, hypothyroidism and nonthyroidal diseases were investigated. Nuclear T3R in lymphocytes was determined by radio-ligand binding analysis. The results showed that in hyper- and hypothyroid patients the nuclear affinity (Ka) for T3 was similar to that of normal subjects. In hyperthyroidism nuclear T3 maximal binding capacity (MBC) was unaltered, whereas in hypothyroidism the MBC was significantly increased. In the patients with diabetes mellitus, chronic renal failure and hepatic cirrhosis, the nuclear T3R MBC of lymphocytes was about 1.5-1.6 times of the normal controls. It was concluded that there existed hormonal regulation of nuclear T3R, and up-regulation was seen in hypothyroidism and low T3 syndrome.

Topics: Diabetes Mellitus; Graves Disease; Humans; Hypothyroidism; Kidney Failure, Chronic; Lymphocytes; Receptors, Thyroid Hormone; Triiodothyronine, Reverse

The plasma levels of thyroxine (T4), triiodothyronine (T3), free T4 (FT4), free T3 (FT3), reverse T3 (rT3) and immunoradiometrically assayed thyrotropin (IRMA TSH) have been measured in 28 L-T4-treated children with congenital hypothyroidism as well as in a control group (group C). The patients were subdivided into 2 groups according to the nonsuppressed (group A) or suppressed (group B) TSH response to TSH-releasing hormone (TRH). Basal IRMA TSH correlated with the TSH increment after TRH and it was significantly lower in group B vs. groups A and C, while no difference was present between groups A and B in regard to T4, FT4 and rT3, all higher than in group C. FT3 levels were similar in the 3 groups. In children, as in adults, basal IRMA TSH seems to be a reliable index in monitoring overtreatment.

Topics: Adolescent; Child; Child, Preschool; Congenital Hypothyroidism; Female; Humans; Hypothyroidism; Male; Radioimmunoassay; Thyroid Function Tests; Thyrotropin; Thyroxine; Triiodothyronine; Triiodothyronine, Reverse

The validity of estimation of the production rates of T3 and rT3 in man based on noncompartmental analysis of blood-derived data has been questioned owing to incomplete exchangeability of T3 and rT3 between plasma and extrathyroidal tissues in which a local production of these iodothyronines takes place. The possible existence of a nonexchangeable or hidden pool of T3 and rT3 would result in an underestimation of the daily production. By contrast, the production rate of T4 can be estimated reliably using noncompartmental analysis. We have studied 16 women with pretreatment severe hypothyroidism on constant levothyroxine therapy. Simultaneous measurements of T4, T3 and rT3 production rates were performed using bolus injection of radiolabelled iodothyronines. The tracers were isolated from plasma using gel separation/antibody extraction, and production rates were calculated by noncompartmental analysis. Mean (+/- SD) production rate of T4, T3 and rT3 were: 119 +/- 43, 40.0 +/- 22.0 and 54.9 +/- 20.0 nmol.day-1.(70 kg)-1, respectively. Thus 79.5 +/- 7.0% of T4 was deiodinated into T3 and rT3. This leaves 20.5% to other metabolic pathways of T4 and to a possible underestimation of T3 and rT3 production rate. Based on conservative estimates from the literature, the other metabolic pathways of T4 amount: oxidative deamination 1.1%; ether link cleavage 0%; urinary excretion 2.5%; and fecal excretion 14%. Thus, the various metabolic pathways seem to explain 97% of daily produced and degradated T4 in man. Therefore the understimation of T3 and rT3 production rates in man using noncompartmental analysis seems of little if any importance, and existence of a hidden pool of these iodothyronines may be questioned.

Topics: Aged; Female; Humans; Hypothyroidism; Iodine; Metabolic Clearance Rate; Middle Aged; Thyroxine; Triiodothyronine; Triiodothyronine, Reverse

A simple and rapid method for the estimation of cellular concentration of thyroxine (T4), 3,5,3'-triiodothyronine (T3), 3,3',5'-triiodothyronine (rT3), 3,3'-diiodothyronine (3,3'-T2), and 3',5'-diiodothyronine (3',5'-T2) as well as their distribution between cytosol and membranes in human red blood cells (RBC) is presented. Concentrations of iodothyronines in RBC (RBC-T) were calculated by multiplying the total serum concentrations by the ratio of radioactivity in equal volumes of packed RBCs and serum, pre-incubated with 125I-labelled iodothyronines of high specific activity. Plasma and RBC were separated by centrifugation in capillary glass tubes. The separation of membranes and cystosol was performed by hypotone lysis and centrifugation. The median RBC-T of T4, T3, rT3, 3,3'-T2, and 3',5'-T2 from 17 euthyroid subjects were 360 pmol/l, 156 pmol/l, 2.77 pmol/l, 6.81 pmol/l, and 2.17 pmol/l, respectively. The cytosol/cytosol + membrane ration were 66%, 40%, 84%, 77%, and 97%, respectively. The differences in RBC-T were not similar to the differences in free serum concentrations. The ratio of RBC-T to free serum concentration differed considerably between T4 (16.6), T3 (24.4), and 3,3'-T2 (15.5) as compared to rT3 (5.8) and 3',5'-T2 (2.6). Data on three patients with thyroid diseases suggested that RBC-T values were increased in hyperthyroidism and decreased in hypothyroidism, whereas the cytosol/cytosol + membrane-ratio was unaltered.

Topics: Adult; Aged; Blood Proteins; Diiodothyronines; Erythrocytes; Female; Humans; Hypothyroidism; Male; Middle Aged; Receptors, Thyroid Hormone; Thyronines; Thyroxine; Triiodothyronine; Triiodothyronine, Reverse; Ultrafiltration

Tri-iodothyronine (T3) and thyroxine (T4) as well as 3,5-di-iodothyronine (T2) stimulated O2 consumption by isolated perfused livers from hypothyroid rats at a concentration as low as 1 pM by about 30% within 90 min. Application of T2 resulted in a faster stimulation than with application of T3 or T4. Inhibition of iodothyronine monodeiodinase by propylthiouracil, thereby blocking the degradation of T4 to T3 and of T3 to T2, demonstrated that only T2 is the active hormone for the rapid stimulation of hepatic O2 consumption: T3 and T4 lost all of their stimulative activity, whereas T2 was as potent as in the absence of propylthiouracil. Perfusion experiments with thyroid-hormone analogues confirmed the specificity of the T2 effect. The nucleus is unlikely to contribute to the rapid T2 effect, as can be deduced from perfusion experiments with cycloheximide and lack of induction of malic enzyme by T2. In conclusion, a new scheme of regulation of mitochondrial activity is proposed: T2 acts rapidly and directly via a mitochondrial pathway, whereas T3 exerts its long-term action indirectly by induction of specific enzymes.

Topics: Animals; Diiodothyronines; Hypothyroidism; Male; Mitochondria, Liver; Oxygen Consumption; Rats; Rats, Inbred Strains; Stimulation, Chemical; Thyronines; Thyroxine; Triiodothyronine, Reverse

Thyroxine (T4) is transferred from the mother to the hypothyroid rat fetus late in gestation, mitigating T4 and T3 deficiency in fetal tissues, the brain included. We have now compared the effects of maternal infusion with T3. Normal and thyroidectomized rats were started on methimazole (MMI) on the 14th day of gestation, given alone, or together with a constant infusion of 0.45 micrograms (0.69 nmol) T3 or of 1.8 microgram (2.3 nmol) T4/100 g per day. Maternal and fetal samples were obtained at the 21st day of gestation. The doses of T3 and T4 were biologically equivalent for the dams, as assessed from maternal plasma and tissue T3, and plasma TSH levels. MMI blocked the fetal thyroid; T4 and T3 levels were low in all fetal tissues, and fetal plasma TSH was high. Maternal infusion with T4 mitigated both T4 and T3 deficiency in all fetal tissues, the brain included, and decreased fetal plasma TSH. In contrast, infusion of T3 normalized fetal plasma T3 and increased the T3 levels in several tissues, but not in the brain. Neither did it decrease the high fetal plasma TSH levels. The results show that when the fetus is hypothyroid, T3 crosses the rat placenta at the end of gestation, but does not affect all tissues to the same degree. In contrast to the effects of maternal T4, maternal T3 does not alleviate the T3 deficiency of the brain or, presumably, of the thyrotrope. Thus, end-points of thyroid hormone action related to TSH release should not be used to measure transfer of maternal T3 to the fetal compartment. Moreover, T4 should be given, and not T3 to protect the hypothyroid fetal brain.

Topics: Animals; Female; Hypothyroidism; Maternal-Fetal Exchange; Pregnancy; Rats; Rats, Inbred Strains; Thyroidectomy; Thyrotropin; Thyroxine; Tissue Distribution; Triiodothyronine, Reverse

A man with diabetes mellitus, chronic hepatitis, chronic pancreatitis, and blind loop syndrome but without any previous thyroid disease developed three episodes of transient primary hypothyroidism associated with protein-calorie malnutrition (PCM). Clinical examinations suggested that this primary hypothyroidism was not caused by chronic thyroiditis, iodine deficiency, or iodine excess. Since the three times association of primary hypothyroidism with PCM suggested the possibility that the primary hypothyroidism was caused by PCM, we have tried to clarify its mechanism. For this purpose we have investigated the change of thyroid functions during protein-calorie repletion and the effect of amino acid deficiency. Total parenteral nutrition with full supplementation of amino acids resulted in a rapid increase in serum thyroxine (T4), triiodothyronine (T3), free T4, and reverse T3, and subsequently, a rapid decrease in TSH in several days after the nutrition was begun. When amino acid solution was changed to that depleted of phenylalanine and tyrosine after the restoration of thyroid functions, serum T4 and T3 showed a gradual decrease, but serum free T4 and TSH remained within normal range. However, resupplementation of phenylalanine and tyrosine after 8 weeks of depletion gave a rapid increase in serum T4, T3, free T4, and reverse T3. These results suggested that the primary hypothyroidism was caused by an impaired T4 production and that the deficiency of amino acids in PCM partly contributed to the impairment of T4 production.

Topics: Aged; Amino Acids; Humans; Hypothyroidism; Male; Parenteral Nutrition, Total; Phenylalanine; Protein-Energy Malnutrition; Thyroid Function Tests; Thyrotropin; Thyroxine; Triiodothyronine; Triiodothyronine, Reverse; Tyrosine

Thyroid function in individuals from a representative population of 79-year-olds was evaluated clinically and from measurements of serum thyrotropin (TSH) and 3,5,3'-triiodothyronine (T3). High TSH concentrations (greater than or equal to 10 mU/l) were found in 16 of 320 women (5%) and 2 of 204 men (1%). Signs and symptoms which traditionally are regarded as related to hypothyroidism were as common in subjects with high TSH concentration as in the remaining population and occurred in 10-50% of the subjects. In the 16 women with high TSH, free thyroxine (free T4) concentrations were low in 10, whereas only one subject had low thyroxine (T4) and T3 concentrations, indicating that free T4 is a more sensitive parameter for thyroid hypofunction in the elderly. Based on the T3 assay, there was no evidence for hyperthyroidism in this population. The results indicate that high TSH concentrations are common in elderly women, less common in men. The results show that classical symptoms of thyroid dysfunction are quite common in 79-year-olds, but do not correlate with biochemical indicators of thyroid dysfunction, indicating that defining "clinically euthyroid" in an elderly may be almost impossible.

Topics: Aged; Female; Humans; Hyperthyroidism; Hypothyroidism; Longitudinal Studies; Male; Mass Screening; Thyrotropin; Thyroxine; Triiodothyronine, Reverse

Thyroid hormones rapidly inhibit type II iodothyronine 5'-deiodinase (5'DII) activity in the rat central nervous system, anterior pituitary gland, and GH3 pituitary tumor cells. To gain insight into the cellular mechanisms responsible for this down-regulation, the effects of substrates, inhibitors, and alterations in the cellular thiol-disulfide balance on 5'DII regulation were investigated. The results demonstrate that in vitro competitive inhibitors, such as iopanoic acid, as well as iodothyronine substrates induce a rapid and irreversible loss of enzyme activity in rat cerebral cortex and anterior pituitary tissue. The potency of these agents in down-regulating this enzymatic process in intact GH3 cells is directly related to their competitive inhibitory effects on 5'DII activity in vitro. Additional studies demonstrated that treatment of intact GH3 cells with the sulfhydryl-oxidizing agent diamide mimicks the effect of substrate and results in the rapid inactivation of 5'DII. In contrast, preincubation of cells with the sulfhydryl-reducing agent dithiothreitol renders the enzyme less susceptible to the down-regulatory effects of substrate. Sulfhydryl-reducing agents thus appear to play a dual role in the 5'DII process by serving as cosubstrates and by modulating the enzymes susceptibility to substrate-induced down-regulation. These findings suggest that the in vivo inhibition of 5'DII by thyroid hormones involves a unique mechanism of enzyme regulation whereby the binding of ligand to the active site induces the rapid and irreversible inactivation and/or degradation of the enzyme. This inactivation of 5'DII initiated by substrate binding may be mediated by alterations in the sulfhydryl state of the enzyme as it progresses through the catalytic cycle.

Topics: Animals; Cell Line; Cerebral Cortex; Cycloheximide; Diamide; Dithiothreitol; Hypothyroidism; Iopanoic Acid; Kinetics; Male; Parathyroid Glands; Pituitary Gland, Anterior; Pituitary Neoplasms; Rats; Rats, Inbred Strains; Thyroidectomy; Thyroxine; Triiodothyronine, Reverse

Recently we reported that hyperglucagonemia induced by glucagon infusion causes a decline in serum T3 and a rise in reverse T3 in euthyroid healthy volunteers. These changes in T3 and rT3 levels were attributed to altered T4 metabolism in peripheral tissues. However, the contribution of altered release of thyroid hormones by the thyroid gland could not be excluded. Since the release of thyroid hormones is inhibited in primary hypothyroidism and is almost totally suppressed following L-thyroxine replacement therapy, we studied thyroid hormone levels for up to 6 hours after intravenous administration of glucagon in subjects with primary hypothyroidism who were rendered euthyroid by appropriate L-thyroxine replacement therapy for several years. A control study was conducted using normal saline infusion. Plasma glucose rose promptly following glucagon administration demonstrating its physiologic effect. Serum T4, Free T4, and T3 resin uptake were not altered during both studies. Glucagon infusion induced a significant decline in serum T3 (P less than 0.05) and a marked rise in rT3 (P less than 0.05) whereas saline administration caused no alterations in T3 or rT3 levels. Thus the changes in T3 and rT3 were significantly different during glucagon study when compared to saline infusion. (P less than 0.01 for both comparisons). Since, the release of thyroid hormones is suppressed by exogenous LT4 administration in these subjects; we conclude that changes in serum T3 and rT3 observed following glucagon administration reflect altered thyroid hormone metabolism in peripheral tissues and not altered release by the thyroid gland.

Topics: Adult; Glucagon; Humans; Hypothyroidism; Middle Aged; Thyroid Hormones; Thyroxine; Triiodothyronine; Triiodothyronine, Reverse

T4 and reverse T3 (rT3) can inhibit 5'-deiodinase type II activity in rat brain cortex, pituitary, and brown adipose tissue, raising the possibility that T4 may act in vivo after conversion to rT3. The aim of this study was to measure in hypothyroid (Tx) rats the content of brain cortex rT3 during a constant 7-day infusion of either [125I]T4 alone, corresponding to 12 pmol T4/day X 100 g body weight (BW), or together with 400 pmol T4/day. [125I]T4, rT3, and T3 were extracted from brain cortex, pituitary, kidney, and liver with a combination of adsorption chromatography on Sephadex G-25, HPLC, and immunoprecipitation. [131I]T4, T3, or rT3 were used as internal standards. [125I]rT3 could be detected in brain cortex, liver, and kidney in Tx rats infused with [125I]T4 (12 pmol T4/day X 100 g BW) and in those infused with 400 pmol T4/day X 100 g BW. The highest rT3 concentrations were found in brain cortex, where it represented 6% to 10.5% of the local T4 concentration. During an infusion of 400 pmol T4/day X 100 g BW, brain cortex T3 concentration was 6 times higher in the brain cortex than in serum, and even exceeded that of T4. In Tx rats receiving [125I]T4 alone the brain cortex to serum T3 ratio was 3:1, but the total serum T3 concentration, measured by RIA, was much higher than that due to conversion [0.50 +/- (SE) 0.1 pmol/ml vs. 0.018 +/- 0.002 pmol T3/ml], indicating thyroidal secretion. The effect of the blood-brain barrier on rT3 was measured by infusing [125I]rT3 over 4 days. After killing, rT3 was isolated as above. Approximately 3% of serum rT3 was retrieved from the brain cortex, whereas during the T4 infusion 40-50% of serum rT3 was found demonstrating that brain cortex rT3 is locally produced.

Topics: Animals; Blood-Brain Barrier; Cerebral Cortex; Hypothyroidism; Kidney; Liver; Male; Pituitary Gland; Rats; Rats, Inbred Strains; Thyroidectomy; Thyroxine; Tissue Distribution; Triiodothyronine; Triiodothyronine, Reverse

The regulation of T4 5'-deiodinase activity was studied in cultured GH4C1 cells. Enzyme activity was measured in cell sonicates as the release of radioiodide from [125I]T4. Enzyme activity was stimulated 2- to 3-fold by hypothyroid serum and activators of protein kinase C, such as TRH and phorbol esters. The hypothyroid serum effect was maximal by 3 h, whereas TRH and phorbol esters required 6 h to achieve a maximal effect. The hypothyroid serum effect was gone within 4 h of returning the cells to control medium. In contrast, the TRH and phorbol ester effects persisted 24-48 h after removal of those agents. Both T4 and rT3 were at least as potent as T3 in blocking the effect of hypothyroid serum. The stimulation of 5'-deiodinase induced by hypothyroid serum was additive with that induced by kinase C activators. Trifluoperazine blocked the effect of TRH and phorbol esters, but not that of hypothyroid serum. It is concluded that stimulation of 5'-deiodinase activity can occur by at least two independent mechanisms: one involving hypothyroidism and another involving activation of protein kinase C. The relative potencies of various iodothyronines for abolishing the hypothyroid effect differ markedly from the relative binding affinities of these agents for the nuclear T3 receptor, suggesting that this thyroid hormone effect may not be mediated by the classical nuclear thyroid hormone receptor.

Topics: 8-Bromo Cyclic Adenosine Monophosphate; Animals; Calcimycin; Cell Line; Colforsin; Cyclic GMP; Dose-Response Relationship, Drug; Enzyme Activation; Hypothyroidism; Iodide Peroxidase; Phorbol Esters; Pituitary Neoplasms; Protein Kinase C; Rats; Tetradecanoylphorbol Acetate; Thyroid Hormones; Thyrotropin-Releasing Hormone; Thyroxine; Trifluoperazine; Triiodothyronine; Triiodothyronine, Reverse

The "euthyroid sick syndrome", representing the changes of thyroid hormone metabolism in disease, embraces the following hormonal changes: 1) A decrease in serum T3 levels which is often accompanied by an increase in rT3 levels. Serum T4 levels remain normal. These changes are extremely frequent in many varied diseases. 2) In very severe disease, serum T4 levels may also decrease. The free T4 index is often decreased and the free T4 may either be normal or decreased. These changes reflect alterations of thyroid hormone metabolism and can be distinguished from primary hypothyroidism by a normal serum TSH level. 3) Occasionally there are transient increases of total and free T4. This disturbance of serum thyroid hormone levels is mostly due to drug interference with thyroid hormone metabolism (amiodarone etc.). Differentiation from hyperthyroidism is difficult. It is important to diagnose the "euthyroid sick syndrome" since this will avoid erroneous diagnosis and treatment or hypo- and hyperthyroidism.

Topics: Diagnosis, Differential; Disease; Humans; Hyperthyroidism; Hypothyroidism; Thyroid Hormones; Thyrotropin; Thyrotropin-Releasing Hormone; Thyroxine; Thyroxine-Binding Proteins; Triiodothyronine; Triiodothyronine, Reverse

In five L-thyroxine-substituted hypothyroid children with partial epilepsy serum total thyroxine (T4) and free T4 (FT4) significantly (P less than 0.01) decreased following 2 months of carbamazepine (CBZ) administration (20 mg/kg per BW per day) from mean (+/- SD) values of 12.7 +/- 1.1 micrograms/dl and 15.5 +/- 1.8 pg/ml to mean values of 7.5 +/- 2.3 and 10.1 +/- 1.7, respectively. In all but one patient important changes in both serum total and free triiodothyronine (T3, FT3) were not observed; consequently T3:T4 and FT3:FT4 ratios significantly (P less than 0.05) increased in the whole series. Three subjects had post-treatment serum TSH that rose to hypothyroid levels parallel to a T4 decrease. The negligible thyroid hormone secretion and the unmodified T3-uptake (T3U) or T4-binding globulin (TBG) exclude direct effects of CBZ on thyroid gland and on carrier serum proteins, respectively. The findings observed, instead, might be due to accelerated T4 metabolic clearance together with augmented T4 to T3 conversion rate, as previously demonstrated for diphenylhydantoin. The sharp reduction in T4 and FT3 concentrations is the peripheral display of this event, which is associated with a decompensation of the metabolic status, as indicated by serum TSH enhancement. In all cases a supplement of L-thyroxine by itself was able to restore euthyroid TSH serum concentrations, suggesting that hypothyroidism in patients with partial epilepsy to whom CBZ had been administered requires a higher L-T4 substitutive regimen.

Topics: Carbamazepine; Child; Child, Preschool; Congenital Hypothyroidism; Epilepsies, Partial; Female; Humans; Hypothyroidism; Male; Thyroid Function Tests; Thyroid Gland; Thyrotropin; Thyroxine; Thyroxine-Binding Proteins; Time Factors; Triiodothyronine; Triiodothyronine, Reverse

We assessed the sensitivity, specificity, predictive value of a positive result, and efficiency of tests for total thyroxin, free thyroxin index, free thyroxin, total triiodothyronine, free triiodothyronine index, and free triiodothyronine in serum from 1619 consecutive new patients with suspected thyroid dysfunction. Multivariate discriminant analysis was also used. Free thyroxin index and free thyroxin were clearly the most sensitive indicators of hypothyroidism. In contrast, all of these tests identified hyperthyroidism with similar efficiencies. By stepwise discriminant analysis, the free thyroxin index was the most efficient test for distinguishing between euthyroidism and hyperthyroidism and between euthyroidism and hypothyroidism. The combination of tests for total thyroxin, free thyroxin index, triiodothyronine, and free triiodothyronine was optimal for separating euthyroidism, hyperthyroidism, and hypothyroidism. We conclude that the free thyroxin index, despite the introduction of newer technologies, is still the best thyroid hormone test for screening for thyroid disease.

Topics: Adult; Diagnosis, Differential; Female; Humans; Hyperthyroidism; Hypothyroidism; Male; Middle Aged; Thyroid Diseases; Thyroid Function Tests; Thyroid Hormones; Thyroxine; Thyroxine-Binding Proteins; Triiodothyronine; Triiodothyronine, Reverse

Further personal observations are made of the case of hypothalamic hypothyroidism with end organ resistance described in an earlier report. The course of the disorder on replacement therapy appears to be a relapsing one, with relapses provoked by seasonal changes and physical stresses. The relapses remit with increased doses of thyroid replacement. There is some evidence of increased levels of reverse T3 prior to T3 replacement and also evidence suggestive of a parallel hypothalamic hypoadrenal deficit.

Topics: Adrenal Glands; Humans; Hypothalamus; Hypothyroidism; Recurrence; Seasons; Thyroid Gland; Triiodothyronine; Triiodothyronine, Reverse

We studied the effect of the state of the thyroid on T4 monodeiodination in the rat placenta, and it was compared with those in the liver and kidney. The tissues, maternal serum, and amniotic fluid were obtained from pregnant rats. The tissues were homogenized in cold 50 mM Tris-HCl buffer, pH 7.5. The homogenate (1 mg protein) was incubated at 37 degrees C for 60 min with 1 microgram T4 in the presence of 5 mM DTT. The T3 and reverse T3 generated in the reaction mixture were extracted into cold ethanol and measured by RIAs. The conversion of T4 to reverse T3 in rat placenta was not significantly changed in MMI-induced hypothyroidism or T4 induced hyperthyroidism. On the other hand, conversion of T4 to T3 in the liver and kidney were changed in parallel with the thyroid state. The concentration of reverse T3 in the amniotic fluid was increased in accordance with the increase in the maternal serum T4 concentration. These results indicate that the placental T4 inner ring deiodination is not affected by the thyroid state, and that the change in the amniotic fluid reverse T3 concentration in this study is mainly dependent upon the change in maternal thyroid function.

Topics: Amnion; Animals; Female; Hyperthyroidism; Hypothyroidism; Kidney; Liver; Organ Specificity; Placenta; Pregnancy; Rats; Rats, Inbred Strains; Thyroid Gland; Thyroxine; Triiodothyronine; Triiodothyronine, Reverse

Brown adipose tissue (BAT) of hypothyroid rats contains a low Km (type II) iodothyronine 5'-deiodinase (I-5'D) that has been characterized as being insensitive to inhibition by propylthiouracil (PTU), based mainly on observations with homogenates prepared in a medium containing 10 mM dithiothreitol (DTT) and enzymatic assays in the presence of 20 mM DTT in vitro. In the studies reported herein, BAT homogenates from hypothyroid rats prepared in a DTT-free medium were found to contain I-5'D activity at 20 mM DTT, comparable to that in homogenates prepared in a DTT-containing medium, and were activated by submillimolar concentrations of DTT with an EC50 of approximately 0.5 mM. Almost all of the homogenate activities could be accounted for in microsomal preparations. The activity was substantially inhibited by 1 mM PTU. The PTU inhibition was progressively alleviated with increasing concentrations of added DTT and was not seen at DTT concentrations higher than 10 mM. At 250 microM DTT, the Km and maximum velocity values for rT3 and T4 were 2.9 and 1 nM and 70 and 200 fmol/mg protein X h, respectively, with a Ki for PTU of approximately 200 microM. On administration of PTU in vivo (2 mg/100 g BW; 1 h before killing) and subsequent assay at 250 microM DTT, the I-5'D in the homogenates was about 50% inhibited, and the microsomes showed a state of persistent inhibition, with activity levels about 70% of the control value. The data show that BAT type II I-5'D can be substantially activated at submillimolar concentrations of DTT, and this activation is sensitive to inhibition by PTU administered both in vitro and in vivo.

Topics: Adipose Tissue, Brown; Animals; Dithiothreitol; Enzyme Activation; Hypothyroidism; Iodide Peroxidase; Kidney; Kinetics; Male; Microsomes; Propylthiouracil; Rats; Thyroxine; Triiodothyronine, Reverse

The local conversion of thyroxine (T4) to 3,5,3'-triiodothyronine (T3) has been recognized as a source of T3 at various sites in euthyroid rats. The present study was designed to evaluate the effect of hypothyroidism on the source and quantity of T3 at several of these sites (liver, cerebral cortex (Cx), thymus, testis, brown adipose tissue). For this purpose intact euthyroid rats and radiothyroidectomized (RTx) rats received a continuous iv infusion of [125I]T4 and [131I]T3 until isotopic equilibrium was attained. In addition to the labelled iodothyronines, RTx rats received a continuous iv infusion of 0.75 microgram T4/day, in order to maintain a defined hypothyroid state. At the end of the infusion period the animals were bled and perfused, and homogenates of the various organs were prepared. The mean plasma T4 and T3 levels in T4-maintained RTx rats, as measured by RIA, were 1.5 micrograms/dl and 15 ng/dl (euthyroid values: 5.2 micrograms/dl and 48 ng/dl, respectively). The plasma and tissue homogenates were processed for thin layer chromatography and the [125I]T4, [125I]T3 and [131I]T3 levels determined. From these data the concentrations of T4, total T3 and T3 derived from local T4 to T3 conversion (LcT3(T4)) in tissue could be calculated. The relative mean contribution of LcT3(T4) to the total T3 in Cx (75%), thymus (31%), testis (43%) and brown adipose tissue (65%) from hypothyroid rats was higher than that determined for euthyroid animals (66%, 19%, 29% and 27%, respectively). The reverse was found for the liver (15% vs 39%).(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Hypothyroidism; Male; Rats; Rats, Inbred Strains; Thyroxine; Tissue Distribution; Triiodothyronine, Reverse

Serum concentrations of total and free T4 (TT4 and FT4), total and free T3 (TT3 and FT3), rT3, T4 binding globulin (TBG), T3 uptake (T3U) and TSH were measured in 12 patients with severe hypothyroidism before and during the introduction of replacement therapy with oral T4. The dose of T4 was increased by increments of 50 micrograms at intervals of 4 weeks to a total of 200 micrograms daily. There was a linear correlation between the concentrations of FT3 and FT4 (FT3 = 1.35 + 0.23FT4, r = 0.916, P less than 0.001). The correlation between TT3 and TT4 was more complex: the data were best fitted by the expression TT3 = 0.195 square root TT4, (r = 0.936, P less than 0.001). The relatively greater rise in TT3 initially may reflect a greater binding of T3 by TBG when the concentration of T4 is low. TBG concentration fell after 50 and 100 micrograms of T4 but did not change at the higher doses. There was a simple linear relation between TT4 and rT3 (rT3 = -0.022 + 0.0027TT4, r = 0.921, P less than 0.001). The expected inverse relation between TSH concentration and the thyroid hormones was seen, the three closest correlations being between the logarithm of the TSH concentration and FT3, the ratio T4/TBG and FT4 (r = 0.927, -0.917 and -0.900 respectively). These correlations were significantly better (P less than 0.05) than the correlations with untransformed TSH values. Suppression of TSH occurred while FT3 tended to remain within normal limits, but FT4 was often raised.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adult; Aged; Female; Humans; Hypothyroidism; Male; Middle Aged; Thyroxine; Triiodothyronine; Triiodothyronine, Reverse

Inner ring (-5) monodeiodination of T4 was studied by incubating T4 (approximately 0.26 mumol/L) with rat cerebral cortical homogenate (approximately 4 mg protein) in the presence of dithiothreitol (up to 400 mmol/L) and quantifying the amount of the product, rT3, by a specific radioimmunoassay. The production of rT3 was dependent on duration of incubation (up to 2 hours), amount of tissue protein (up to 8 mg), temperature (optimal at 37 degrees C) and pH (optimal, 7.0) of the incubation mixture and the concentration of DTT (maximally stimulated at 400 mmol/L). The apparent Km and Vmax of the T4-inner ring monodeiodinating activity were 36 nmol/L and 1.75 pmol/mg protein/h, respectively. The activity was inhibited by T3 and 3,5-T2, but not by 3'5'-T2, PTU, methimazole, sodium salicylate, or 8-anilino-I-naphthalene sulfonic acid. Ipodate weakly inhibited T4-to-rT3 monodeiodination. Hyperthyroidism induced by T4 (100 micrograms/d IP X 3 days), T3 (80 micrograms/d IP X 3 days) or DIMIT (45 micrograms/d IP X 3 days) significantly stimulated T4-to-rT3 conversion; DIMIT was the most potent agent. Hypothyroidism inhibited T4-to-rT3 converting activity in cerebral cortex. Fasting for three days had no appreciable effect on T4-to-rT3 conversion in cerebral cortex. Cerebral cortical T4 5-deiodinase activity in the pregnant rat at term was about 50% of that in the adult nonpregnant rat, whereas that in the fetus was about three-fold higher than that in the nonpregnant adult.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Aging; Animals; Cerebral Cortex; Dithiothreitol; Fasting; Female; Fetus; Hydrogen-Ion Concentration; Hyperthyroidism; Hypothyroidism; In Vitro Techniques; Iodine; Kinetics; Male; Pregnancy; Rats; Rats, Inbred Strains; Thyroxine; Triiodothyronine, Reverse

Topics: Aging; Humans; Hyperthyroidism; Hypothyroidism; Thyroid Hormones; Thyrotropin; Thyroxine; Triiodothyronine; Triiodothyronine, Reverse

Thyroxine (T4) and reverse triiodothyronine are potent inhibitors of brown adipose T4 5'-deiodinase (BAT 5'D). This effect does not require protein synthesis and is due to an acceleration of the rate of disappearance of the enzyme. Growth hormone (GH) also inhibits BAT 5'D but by a mechanism mediated through a long-lived messenger that correlates with growth rate. This explains the failure of BAT 5'D to increase abruptly after thyroidectomy as does the type II 5'-deiodinase in pituitary and central nervous system or the BAT 5'D itself after hypophysectomy. Although virtually inactive when given acutely, triiodothyronine replacement partially reduces BAT 5'D in hypophysectomized and thyroidectomized (Tx) animals probably as a result of improvement of systemic hypothyroidism and an increase in GH levels in the Tx rats. The fine balance between these inhibitory factors and the stimulatory effects of the sympathetic nervous system suggests an important physiologic role for the enzyme in this tissue.

Topics: Adipose Tissue, Brown; Adrenal Cortex; Animals; Cold Temperature; Glucosephosphate Dehydrogenase; Growth Hormone; Hypophysectomy; Hypothyroidism; Iodide Peroxidase; Liver; Male; Norepinephrine; Rats; Rats, Inbred Strains; Sympathetic Nervous System; Thyroidectomy; Thyroxine; Time Factors; Triiodothyronine; Triiodothyronine, Reverse

We measured serum angiotensin-converting enzyme (ACE) activity radiometrically as a possible indicator of reduced thyroid function in 57 euthyroid controls, 27 patients in a noncardiac intensive care unit (13 with medical and 14 with surgical disorders), and 29 patients having coronary artery bypass grafting. In the last group, blood was obtained preoperatively and one day and one month after surgery (group 1; n = 18) or preoperatively and six hours and one day after surgery (group 2; n = 11). Patients in group 1 had significant reductions in levels of serum thyroxine (T4), triiodothyronine (T3), and thyrotropin response to protirelin one day postoperatively. The ACE activity fell significantly. Patients in group 2 had low levels of T4, T3, thyrotropin, and ACE six hours postoperatively. All these levels remained low the next day, and free T4 and free T3 levels were also reduced; the reverse T3 level became elevated. Changes in ACE significantly paralleled changes in T3. The 27 patients without coronary artery bypass grafting also had significant reductions in serum T4, T3, and ACE levels. Dilution studies and dialysis of serum with low ACE activity failed to demonstrate an inhibitor to explain the reduced enzyme function.

Topics: Adult; Aged; Clinical Enzyme Tests; Coronary Artery Bypass; Critical Care; Female; Humans; Hypothyroidism; Male; Middle Aged; Peptidyl-Dipeptidase A; Thyroxine; Time Factors; Triiodothyronine; Triiodothyronine, Reverse

The present studies concern the effects of triiodothyronine (T3) on rat thymic and splenic NaK-ATPase activities. When hypothyroid rats were given a single injection of T3 (250 micrograms/100 g body weight), thymic NaK-ATPase activity increased by 18% at 24 h (p less than 0.005), and remained at this peak at 72 h. Injection of T3 (250 micrograms/100 g body weight, on alternate days X 3) significantly augmented NaK-ATPase activity from the thymus and spleen of hypothyroid rats by 19 and 49%, respectively. Two weeks of daily injections of T3 (1 microgram/100 g body weight) to hypothyroid rats significantly increased NaK-ATPase activity in the thymus and the spleen by 14 and 28%, respectively. Reverse T3 had no significant effect of thymic and splenic NaK-ATPase activities. Mg-ATPase and 5'-nucleotidase activities were not significantly affected by T3 in either tissue under different thyroid states. The lack of response of thymic and splenic NaK-ATPase to reverse T3, and Mg-ATPase and 5'-nucleotidase to T3, substantiates the specificity of the hormone action on NaK-ATPase. To investigate whether the T3-dependent increase in NaK-ATPase activity is a result of an increase in the number of enzyme units, the effect of T3 on the quantity of phosphorylated intermediate of NaK-ATPase was assessed in the partially purified membrane fraction. In the euthyroid state, NaK-ATPase activity and phosphorylated intermediate units were 33 and 43% higher, respectively than in the hypothyroid state, implying that the T3-dependent increase in NaK-ATPase activity is a result of an increase in the number of NaK-ATPase units.

Topics: Animals; Ca(2+) Mg(2+)-ATPase; Cell Membrane; Dose-Response Relationship, Drug; Hypothyroidism; Male; Phosphorylation; Rats; Sodium-Potassium-Exchanging ATPase; Spleen; Thymus Gland; Thyroidectomy; Time Factors; Triiodothyronine; Triiodothyronine, Reverse

We propose a mathematical model of the human hypothalamus-anterior pituitary-thyroid system regulating basal metabolism, and practice computer simulation concerning primary thyropathy such as Graves' disease, hypothyroidism, T4-toxicosis and T3-toxicosis by use of this model. In order to throw light on properties of the system, indicial responses of the hormones, T4, T3, rT3, and TSH, and the function of the thyroid gland are computed. Medical treatments for Graves' disease and for hypothyroidism are simulated with a view to enhancing clinical significance. Performance of the simulation leads to an interesting result that when the convertion rate of blood T4 to blood T3 increases, explicit T3-toxicosis occurs, although the function of the thyroid gland is normal.

Topics: Computers; Graves Disease; Humans; Hyperthyroidism; Hypothalamo-Hypophyseal System; Hypothyroidism; Mathematics; Models, Biological; Thyroid Diseases; Thyroid Gland; Thyroid Hormones; Thyrotropin; Thyroxine; Triiodothyronine; Triiodothyronine, Reverse

Effects of Prednison therapy on serum levels of T4, T3, rT3, TBC, basal TSH and TSH response to TRH in 10 children (7 with nephrotic syndrome, 3 with trombocytopenia) were studied. It has been found out that corticotherapy (Prednison 1--2 mg/kg/24 h; 2--4 weeks) causes a significant decrease of total T3 concentration together with a considerable rise of reverse T3 and lower T3-binding capacity. Basal TSH level was increased about twice; TSH response to TRH between both groups (without and with Prednison therapy) did not differ significantly. The observations suggest the presence of hypothyroidism during chronic corticotherapy in children.

Topics: Child; Child, Preschool; Female; Humans; Hypothyroidism; Male; Nephrotic Syndrome; Prednisone; Thrombocytopenia; Thyrotropin; Thyrotropin-Releasing Hormone; Thyroxine; Triiodothyronine; Triiodothyronine, Reverse

Cord blood and amniotic fluid thyrotropin (TSH), T4, T3, and rT3 concentrations were measured in 49 women who received 400 micrograms thyrotropin releasing hormone (TRH) iv during labor and in 16 control women who received saline. Cord blood serum TSH concentrations were elevated for as long as 4 hours after TRH administration and peak values (38.0 +/- 4.2 microU/ml) were observed from 61-120 minutes after TSH as compared to control values of 5.0 +/- 0.3 microU/ml. The elevations in fetal TSH concentration stimulated the fetal thyroid, resulting in a progressive increase in cord blood T4 and T3 but not rT3 concentrations. These TRH induced elevations in fetal cord blood TSH concentrations were not accompanied by increases in unconcentrated and 4 fold concentrated amniotic fluid TSH concentrations which were almost always below 0.6 microU/ml, the limit of assay sensitivity. Unconcentrated amniotic fluid T4 concentrations were barely detectable and no variation was observed between the TRH treated and saline treated mothers; amniotic fluid T3 was not detectable in any of the groups; and amniotic fluid rT3 concentrations ranged between 46.4 and 55.6 ng/dl and did not differ between groups. These findings suggest that term amniotic fluid TSH values do not reflect transient but marked elevations in fetal serum TSH concentrations and that amniotic fluid TSH determination is probably not useful in the detection of primary fetal hypothyroidism. It is possible, but unlikely, that long-term and even greater elevations in fetal serum TSH concentrations would result in increased amniotic fluid TSH concentrations.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Amniotic Fluid; Delivery, Obstetric; Female; Fetal Blood; Fetal Diseases; Humans; Hypothyroidism; Infant, Newborn; Labor, Obstetric; Pregnancy; Prenatal Diagnosis; Thyrotropin; Thyrotropin-Releasing Hormone; Thyroxine; Triiodothyronine; Triiodothyronine, Reverse

Topics: Adolescent; Adult; Female; Humans; Hyperthyroidism; Hypothyroidism; Male; Middle Aged; Radioimmunoassay; Thyroid Diseases; Thyroiditis; Triiodothyronine, Reverse

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

Studies in vitro have shown that rT3 is a potent and competitive inhibitor of T4 5'-deiodination (5'D). Recent studies in vivo have shown that cerebrocortical (Cx) T4 5'D-type II (5'D-II) activity [propylthiouracil (PTU) insensitive pathway], is reduced by T4 and rT3, the latter being more potent than T3 in Cx 5'D-II suppression. Some other reports had described rT3 production in rat brain as a very active pathway of thyroid hormone metabolism. To examine the possibility that rT3 plays a physiological role in regulating Cx 5'D-II, we have explored rT3 plasma kinetics, plasma to tissue exchange, and uptake by tissues in the rat, as well as the metabolic routes of degradation and the sources of rT3 in cerebral cortex (Cx). Plasma and tissue levels were assessed with tracer [125I]rT3. Two main compartments were defined by plasma disappearance curves in euthyroid rats (K1 = -6.2 h-1 and K2 = -0.75 h-1). In Cx of euthyroid rats, [125I]rT3 peaked 10 min after iv injection, tissue to plasma ratio being 0.016 +/- 0.004 (SE). In thyroidectomized rats, plasma and tissue [125I]rT3 concentrations were higher than in euthyroid rats, except for the Cx that did not change. PTU caused further increases in all the tissues studied, except for the Cx and the pituitaries of thyroidectomized rats. From the effect of blocking 5'D-I with PTU or reducing its activity by making the animals hypothyroid, we concluded that 5'D-I accounts for most of the rT3 clearance from plasma. In contrast, in Cx and pituitary the levels of rT3 seem largely affected by 5'D-II activity. Since the latter results suggest that plasma rT3 does not play a major role in determining rT3 levels in these tissues, we explored the sources of rT3 in Cx using [125I]T4. The [125I]rT3 (T4) to [125I]T4 ratio remained constant at 0.03 from 1 up to 5 h after injection of [125I]T4. From plasma levels of T4 and rT3, Cx concentration was calculated to be 30 pg rT3/g Cx in euthyroid rats, more than 98% locally produced from T4 deiodination. We conclude that rT3 has a very rapid metabolism, mainly attributed to 5'D-I activity, but that 5'D-II could also play a role in certain tissues. Nearly all rT3 present in Cx is locally derived from T4.

Topics: Animals; Cerebral Cortex; Chromatography; Hypothyroidism; Iodine Radioisotopes; Kinetics; Male; Propylthiouracil; Rats; Rats, Inbred Strains; Thyroidectomy; Thyroxine; Tissue Distribution; Triiodothyronine, Reverse

T4 (0.26 microM) was incubated in 0.1 M phosphate buffer (pH 7.4) containing 10 mM EDTA with homogenates (3-5 mg protein) of various rat tissues and up to 400 mM dithiothreitol (DTT) for 1 h at 37 C; the rT3 generated was measured by RIA of ethanol extracts of the incubation mixture. Among the various tissues of the male rat, homogenates of skin and cerebral cortex were very active in the conversion of T4 to rT3; other tissues demonstrated little or no T4 5-monodeiodinating activity (MA). The tissue content of rT3 was also greatest in these two tissues. The MA in skin increased linearly with incubation period (up to 4 h) and with increasing concentration of protein (up to 5 mg), substrate (up to 10 microM) and DTT (up to 400 mM); its optimal pH was 7.4, and optimal temperature was 37 C. Its Km and maximum velocity approximated 0.29 microM and 9.6 pmol/h X mg protein, respectively, in the presence of 400 mM DTT. There was no appreciable difference in T4 to rT3 MA of skin from different parts of the body. The MA was most abundant in microsomes and least in cytosol. The MA was unaffected by propylthiouracil (up to 25 microM), methimazole (up to 100 microM), sodium salicylate (up to 80 microM), or 8-anilino-1-naphthalene sulfonic acid (up to 75 microM). Ipodate (up to 80 microM) weakly inhibited the MA. T3 and 3,5-diiodothyronine inhibited dermal T4 to rT3 MA in a dose-dependent manner; T3 was 3-12 times more potent than 3,5-diiodothyronine on a molar basis in different experiments. Treatment of euthyroid rats with 3,5-dimethyl-3'isopropylthyronine (45 micrograms/day, ip) for 3 or 5 days significantly increased dermal T4 to rT3 MA. Similar treatment of rats with T4 (100 micrograms/day, ip) or T3 (20 or 80 micrograms/day, ip) did not change with MA appreciably. Hypothyroidism markedly inhibited the MA, and fasting inhibited it modestly. Pregnancy was associated with marked reduction in the MA of skin in the mother [0.30 +/- 0.11 (+/- SE) vs. 7.2 +/- 2.2 ng/h X mg protein; P less than 0.02] and fetus (0.67 +/- 0.075; P less than 0.025).(ABSTRACT TRUNCATED AT 400 WORDS)

Topics: Animals; Dithiothreitol; Fasting; Female; Hydrogen-Ion Concentration; Hyperthyroidism; Hypothyroidism; Male; Microsomes; Pregnancy; Propylthiouracil; Rats; Skin; Temperature; Thyroxine; Time Factors; Tissue Distribution; Triiodothyronine, Reverse

The extrathyroidal metabolism of T4, T3, rT3, and 3',5'-diiodothyronine (3',5'-T2) was studied before and after treatment with 350 mg phenytoin (DPH) daily for 14 days in six hypothyroid patients receiving constant L-T4 replacement. The total and free serum concentrations of the four iodothyronines were reduced by approximately 30% during DPH treatment, whereas the free fractions in serum were unaltered. Concomitantly, serum TSH increased 137% (P less than 0.02). The production rate (PR) of T4 decreased 16% (P less than 0.005), indicating decreased intestinal absorption (bioavailability) of oral L-T4 during DPH treatment. The fractional rate of 5'-deiodination of T4 to T3 increased from 27% to 31% (P less than 0.05), whereas the rate of 5-deiodination of T4 to rT3 decreased from 45% to 25% (P less than 0.05). The urinary excretion of free and conjugated T4 was 2.3% of the T4 PR and was unaffected by DPH. Thus, the amount of T4 metabolized through nondeiodinative pathways apart from urinary excretion increased from 25% to 44% (P less than 0.05). The apparent distribution volume (Vd) of T4 increased (P less than 0.05), whereas the pool size was unchanged. The PR of T3 did not change during DPH treatment, nor did the mean transit time or the cellular clearance. The rT3 PR was reduced by 54% (P less than 0.02) during DPH treatment. Concomitantly, the transit time increased 10-fold (P less than 0.05), whereas Vd and pool size increased 5-fold (P less than 0.01 and P less than 0.05, respectively). The turnover of 3',5'-T2, in contrast to that of the other iodothyronines, did not change significantly during DPH treatment. T3 formation from T4 was measured in liver microsomal fractions from rats treated for 8 days with DPH and was almost identical to that in untreated animals. The data demonstrate that DPH in therapeutic concentrations did not affect serum protein binding of the iodothyronines. DPH reduced the intestinal absorption of T4 and increased the nondeiodinative metabolism of T4. The resulting decrease in total and free serum T4 and T3 was associated with an increase in serum TSH, demonstrating reduced negative feedback on the pituitary. Our data do not support the assumption that DPH induces increased hepatic deiodinating enzyme activity.(ABSTRACT TRUNCATED AT 400 WORDS)

Topics: Aged; Animals; Biotransformation; Diiodothyronines; Female; Humans; Hypothyroidism; In Vitro Techniques; Kinetics; Male; Microsomes, Liver; Middle Aged; Phenytoin; Rats; Rats, Inbred Strains; Thyronines; Thyroxine; Triiodothyronine; Triiodothyronine, Reverse

Topics: Aging; Humans; Hypothyroidism; Thyroxine; Triiodothyronine; Triiodothyronine, Reverse

A new method for the estimation of the bioavailability of thyroxine (T4) and 3,5,3'-triiodothyronine (T3) is described based on gel separation followed by antibody extraction of labelled T4 and T3 from serum, and using the area under the curve of disappearance of the tracer (AUC) for the calculations. The peak serum concentrations of radioactive labelled T4 and T3 were reached approximately 90 min after oral administration of both tracers. The relative difference of duplicate estimations was below 10% (n = 3). The bioavailability of T4 in 6 euthyroid controls was in median 65% (range 64-75%), and it was significantly increased both in hyperthyroidism (88% (75-99%), n = 6, P less than 0.01) and hypothyroidism (84% (67-100%), n = 6, P less than 0.02). The bioavailability of T3 in 6 euthyroid controls was in median 78% (69-99%) and significantly greater than that of T4 (P less than 0.02). The bioavailability was unaffected by hyperthyroidism (79% (61-98%), n = 9) and hypothyroidism (77% (66-97%), n = 7). No significant difference between T4 and T3 bioavailabilities was found in hyper- or hypothyroidism. The clinical implication of the present study is that the bioavailability of T4 and T3 is almost identical and approximately 80% in patients with severe hypothyroidism.

Topics: Adult; Aged; Biological Availability; Female; Humans; Hyperthyroidism; Hypothyroidism; Male; Middle Aged; Thyroxine; Triiodothyronine, Reverse

The influence of the medium T3 concentration on iodothyronine 5'-deiodinase activity was studied in cultured anterior pituitary cells derived from chronically hypothyroid rats. Type II (propylthiouracil-insensitive) enzyme activity, measured with T4 as substrate, was reduced by T3 in a dose-dependent manner, with an ED50 of approximately 1.4 X 10(-10) M free T3. Density gradient centrifugation was used to obtain populations of pituitary cells relatively enriched in thyrotrophs, somatotrophs, mammotrophs, or gonadotrophs, and the effect of T3 on type II 5'-deiodinase activity was evaluated in each of these four populations. In the absence of T3, the enzyme activity was 1.5- to 2-fold greater in the somatotroph- and mammotroph-enriched cell pools than in the thyrotroph- and gonadotroph-enriched pools. In contrast, when the cells were cultured in the presence of T3, enzyme activity was reduced to the same low level in all four enriched pools. The results suggest that the increase in whole pituitary type II 5'-deiodinase activity associated with hypothyroidism is due largely or totally to increases occurring within somatotrophs and mammotrophs. The data also suggest that the intrinsic responsiveness of the deiodinase to hypothyroidism is greater in somatotrophs and mammotrophs than in other anterior pituitary cells.

Topics: Adrenocorticotropic Hormone; Animals; Cells, Cultured; Growth Hormone; Hypothyroidism; Iodide Peroxidase; Male; Peroxidases; Pituitary Gland, Anterior; Prolactin; Rats; Rats, Inbred Strains; Thyrotropin; Thyroxine; Triiodothyronine; Triiodothyronine, Reverse

Amiodarone, an iodine-containing drug used frequently in the treatment of cardiac arrhythmias and angina pectoris, has many effects on thyroid hormone metabolism, including decreasing the production of triiodothyronine (T3) and decreasing the clearance of thyroxine and reverse T3. These effects result in elevated serum thyroxine and reverse T3 concentrations and decreased serum T3 concentrations. In addition, iodine-induced hyperthyroidism or hypothyroidism may occur in patients chronically treated with amiodarone. This study is a retrospective analysis of the incidence of thyroid dysfunction in Lucca and Pisa, West Tuscany, Italy, and in Worcester, Massachusetts. Hyperthyroidism was a more frequent (9.6%) complication of amiodarone therapy in West Tuscany, where iodine intake is moderately low; hypothyroidism was more frequent (22%) in Worcester, where iodine intake is sufficient. In patients receiving chronic amiodarone therapy, clinically suspected hyperthyroidism is best confirmed by showing elevations in serum T3 or free T3 concentrations; hypothyroidism is best diagnosed by showing an elevated serum thyrotrophin concentration. Thyroid function should be carefully monitored in patients receiving amiodarone chronically, especially if they have goiter or Hashimoto's thyroiditis.

Topics: Adult; Aged; Amiodarone; Benzofurans; Female; Goiter; Heart Diseases; Humans; Hyperthyroidism; Hypothyroidism; Iodine; Italy; Long-Term Care; Male; Massachusetts; Middle Aged; Retrospective Studies; Thyroglobulin; Thyroid Diseases; Thyroxine; Triiodothyronine; Triiodothyronine, Reverse

Comprehensive evaluation of thyroid hormone indices was performed in 58 children with insulin-dependent diabetes mellitus (IDDM) at the time of diagnosis and prior to insulin therapy. Two patients were found to have primary hypothyroidism, with markedly elevated TSH and very low T4, free T4, T3, and reverse T3 concentrations. The remaining 56 patients had the transient alterations in thyroid hormone indices that are characteristic of "euthyroid sick" or "low T3" syndrome. Mean TSH and reverse T3 values were significantly higher and the mean T3, T4, and free T4 levels were significantly lower than those observed in the control population. Ten of the diabetic patients had elevated TSH concentrations and normal or low free T4 values; eight had normal TSH levels and low T4 and free T4 values. The remainder of the group had thyroid indices compatible with abnormal peripheral metabolism of thyroid hormones. Elevated titers of antimicrosomal antibodies were found in 16% of the children with IDDM. We conclude that abnormal peripheral metabolism and altered hypothalamic-pituitary function are responsible for the transient changes in thyroid hormone indices in patients with untreated IDDM. The most reliable indicators of concomitant primary hypothyroidism in untreated IDDM are markedly elevated TSH and low reverse T3 values.

Topics: Adolescent; Child; Child, Preschool; Diabetes Mellitus, Type 1; Female; Humans; Hypothyroidism; Infant; Male; Thyroid Hormones; Thyrotropin; Thyrotropin-Releasing Hormone; Thyroxine; Triiodothyronine, Reverse

A patient with severe hyperthyroidism (thyroid storm?) and thyroid encephalopathy is described. During her illness only a slightly raised level of total thyroxine and a normal level of total triiodothyronine was found in contrast with very high levels of free thyroid hormones. Very low levels of thyroxine binding globulin, albumin and low levels of thyroxine binding prealbumin in contrast with nearly normal values of T3 resin uptake were observed. All parameters of thyroid function returned to normal after therapy.

Topics: Adult; Coma; Humans; Hyperthyroidism; Hypothyroidism; Prealbumin; Thyroid Crisis; Thyroid Hormones; Thyrotropin; Thyroxine; Thyroxine-Binding Proteins; Triiodothyronine; Triiodothyronine, Reverse

Fifteen patients receiving standard thyroxine replacement therapy (100-200 micrograms daily) for primary hypothyroidism and who had persistently raised free thyroxine concentrations in their serum were investigated to see whether the dose being given was too high. In addition to the usual thyroid hormone assays systolic time intervals (which indicate left ventricular contractility) were calculated as accurate reflectors of tissue thyroid activity. All patients showed the expected increased free and total thyroxine concentrations; but mean total and free concentrations of triiodothyronine were normal, while reverse triiodothyronine values were raised. Mean systolic time intervals were significantly reduced as compared with normal and fell within the thyrotoxic range. Seven patients subsequently had their doses of thyroxine reduced by 50 micrograms daily and were reinvestigated one month later. All showed significant falls in circulating thyroxine and triiodothyronine concentrations and an increase in mean systolic time intervals to the normal range. In patients receiving thyroxine replacement therapy for primary hypothyroidism a raised serum thyroxine concentration may indicate tissue thyrotoxicosis and should prompt a reduction of the thyroxine dose.

Topics: Adult; Aged; Humans; Hypothyroidism; Middle Aged; Systole; Thyroxine; Triiodothyronine; Triiodothyronine, Reverse

In order to clarify the conversion of thyroxine (T4) to triiodothyronine (T3) or to reverse T3 (rT3), serum concentrations of T4, T3, rT3, thyrotropin (TSH), thyroxine-binding globulin (TBG) and values of T3 uptake (T3 U) were measured in 61 hyperthyroid and 31 hypothyroid patients, 8 patients with subacute thyroiditis, and 40 normal subjects. Then, free T4 index (FT4I), T3/T4, rT3/T4, and rT3/T3 ratio were calculated. The rT3/T3 ratio was high in the hyperthyroid patients and low in the hypothyroid patients compared with that in the normal subjects. The ratio was positively related to serum T4, T3, rT3 levels, and FT4I in the patients and normal subjects. The regression equation was represented by rT3/T3 = 0.015[T4] + 0.083. No influences of serum TBG and age on the rT3/T3 ratio were observed. Our results indicated that thyroid hormones themselves could regulate the conversion of T4 to T3 or rT3 by activating 5-monodeiodinase in hyperthyroidism and by activating 5'-monodeiodinase and suppressing 5-monodeiodinase in hypothyroidism. Serum rT3 level was a more sensitive parameter than serum T4 or T3 for evaluating thyroid dysfunction. During the treatment with methimazole (MMI) or L-thyroxine and the natural course of subacute thyroiditis, serum T4 levels and rT3/T3 ratios changed parallel to the regression line. However, once adverse effects of MMI occurred, those changed out of the line. From these results, we concluded that the relationship between serum T4 level and rT3/T3 ratio should be examined for adequate information concerning the peripheral conversion of thyroid hormones under various thyroid diseases.

Topics: Adolescent; Adult; Aged; Female; Humans; Hyperthyroidism; Hypothyroidism; Male; Middle Aged; Radioimmunoassay; Thyroxine; Triiodothyronine; Triiodothyronine, Reverse

Topics: Animals; Extraembryonic Membranes; Female; Gestational Age; Guinea Pigs; Humans; Hypothyroidism; Iodide Peroxidase; Iodine Radioisotopes; Kinetics; Liver; Peroxidases; Placenta; Pregnancy; Rats; Thyroxine; Triiodothyronine; Triiodothyronine, Reverse

This study describes the existence of a peripheral tissue mechanism for maintaining serum T3 concentrations in states of T4 deficiency or excess in man. Serum T3 and T4 levels were determined in 242 primary hypothyroid subjects who had been maintained on varying doses of oral T4 therapy. Subjects treated with sub-maintenance T4 doses were supplemented by additional oral T3 therapy to maintain eumetabolic status as assessed by suppression of serum TSH values. This T3 supplementation was withdrawn 4-5 days prior to study in order to obviate any influence on serum T3 indices. Serum total T3/T4 ratio values in this study population were observed to progressively decline fivefold in a curvilinear manner as serum T4 concentrations rose from less than 0.5 to 20 micrograms/dl (total serum T3/T4 ratio fell from approximately 50 to 10, ng T3/ng T4 X 10(3)). This phenomenon is presumably the result of an altered T4 to T3 conversion by peripheral tissue 5'-deiodinase systems. A similar alteration of T4 to rT3 conversion with changing serum T4 levels does not appear to occur since serum rT3/T4 ratios did not vary in a separate study population over a serum T4 concentration span from 4-16 micrograms/dl. The mechanism by which this autoregulatory control of T4 to T3 conversion occurs is unknown. However, it would appear physiologically to complement the pituitary-thyroid autoregulatory system by acting to defend and maintain serum T3 concentrations in states of T4 deficiency and excess.

Topics: Female; Humans; Hypothyroidism; Middle Aged; Obesity; Radioimmunoassay; Thyrotropin; Thyroxine; Triiodothyronine; Triiodothyronine, Reverse

These studies were performed to evaluate the quantitative role of monodeiodination in the peripheral metabolism of T3 and rT3 in man. As a prerequisite step, the serum concentrations of two diiodothyronines (T2s), 3,5-T2 and 3',5'-T2, were established by specific RIAs. In 20 normal subjects, mean (+/- SEM) serum concentrations of 3,5-T2 and 3',5'-T2 were 0.40 +/- 0.18 and 2.07 +/- 0.13 ng/dl, respectively. The mean concentrations of both T2s were significantly increased in hyperthyroidism. In primary hypothyroidism, the mean 3,5-T2 concentration was not significantly different from normal, but 3',5'-T2 concentrations were undetectable in the majority of subjects. In the first experiments, the MCRs of rT3 and all three T2s were derived by the constant infusion method. Seven normal subjects were infused simultaneously with the three 125I-labeled T2s for 12 h, and in four of the subjects, [131I]rT3 was also administered. The MCRs (liters/day . 70 kg; mean +/- SEM) were: rT3, 130 +/- 17; 3,5-T2, 168 +/- 15; 3,3'-T2, 621 +/- 84; and 3',5'-T2, 305 +/- 45. The daily production rates (PR; micrograms per day/70 kg; mean +/- SEM) were: rT3, 29.1 +/- 1.0; 3,5-T2, 0.6 +/- 0.1; 3,3'-T2, 20.8 +/- 4.1; and 3',5'-T2, 5.7 +/- 2.1. In the four subjects who received [131I]rT3, the serum T2 concentrations and PRs were also derived by turnover rate techniques. At equilibrium, 2.0 +/- 0.7% and 6.0 +/- 1.6% of [131I] rT3 were found as [131I]3,3'-T2 and [131I]3',5'-T2, respectively. The serum T2 concentrations were derived by the product of these percentages and the serum rT3 concentrations and compared with those obtained by T2 RIA. The serum 3',5'-T2 concentration was 1.3 +/- 0.4 ng/dl (tracer), and its PR was 3.4 +/- 1.1 micrograms/day (tracer); these values were closely correlated with those obtained by RIA. Serum 3,3'-T2 concentrations were 0.4 +/- 0.2 ng/dl (tracer) and 2.7 +/- 0.4 ng/dl (RIA), and the PRs were 3.2 +/- 1.6 micrograms/day (tracer) and 20.3 +/- 5.7 micrograms/day (RIA), indicating that rT3 5'-deiodination contributes only a small proportion of serum 3,3'-T2 and its PR. An analysis of the rT3 PR and the 3,3'-T2 and 3',5'-T2 PRs derived from the turnover of rT3 revealed that 28% of the rT3 produced was degraded by monodeiodination. Of this total, 49% of the deiodination occurred at the 5' position and 51% occurred at the 5 position.(ABSTRACT TRUNCATED AT 400 WORDS)

Topics: Chemical Precipitation; Chromatography, Ion Exchange; Chromatography, Paper; Diiodothyronines; Humans; Hypothyroidism; Immunochemistry; Iodine; Metabolic Clearance Rate; Radioimmunoassay; Triiodothyronine; Triiodothyronine, Reverse

Reverse triiodothyronine (rT3), triiodothyronine (T3), thyroxine (T4), and thyroid stimulating hormone (TSH) values were measured by radioimmunoassay in 40 children with congenital hypothyroidism who were being given levothyroxine (0.05-0.35 mg/day) and in 14 normal controls. In 15 of the children with hypothyroidism the treatment, judged by serum T4 and TSH values and thyrotrophin releasing hormone (TRH) test, seemed to be adequate and their mean rT3 value and rT3:T4 ratio were comparable with the controls. The remaining 25 children had a raised serum T4 and a low TSH value. Only 4 (16%) of these children had an abnormally high T3 concentration but the rT3 value was raised in 23 (92%) and their mean rT3 value and rT3:T4 ratio were significantly higher than in the control children. Less than 20% of this 'overtreated' group, however, had clinical hyperthyroidism. We suggest that in patients on T4 replacement treatment the peripheral thyroid homeostatic mechanisms produce larger amounts of rT3, thereby preventing high T3 values where serum T4 values are raised. This may explain why the 'overtreated' children showed no clinical evidence of hyperthyroidism. These findings emphasise the protective and selective role of peripheral monodeiodination.

Topics: Adolescent; Child; Child, Preschool; Humans; Hypothyroidism; Infant; Thyrotropin; Thyroxine; Triiodothyronine; Triiodothyronine, Reverse

Two types of iodothyronine 5'-deiodination have been characterized previously in rat tissues. They can be distinguished by inhibition of type I but not type II by 6-n-propylthiouracil, by the relative suitability of T4 and rT3 as substrates, rT3 much better than T4 for type I and T4 as good as, or better than, rT3 for type II, and by the concentration of T4 required to inhibit deiodination of rT3, 1-10 microM for type I and 1-10 nM for type II. Type I activity (6-n-propylthiouracil sensitive) is most abundant in liver and kidney. Type II activity has, to date, been identified only in the pituitary, central nervous system, and brown adipose tissue. Iodothyronine tyrosyl deiodination has also been identified in homogenates of rat brain, liver, and placenta. It is not clear how many different enzymes carry out this latter reaction. In the present studies, we have extended previous work by determining maturational patterns of the deiodinating pathways in several thyroid hormone-responsive rat tissues, possible modulation of those patterns by glucocorticoids, and the age of onset of responsivity of the deiodinases to hypothyroidism. Iodothyronine 5'-deiodinating activity was found in rat lung and eye, and the reaction was all or nearly all type I in both. Activity in the eye was virtually absent from the lens and vitreous humor. In immature rat cerebrum, pituitary, lung, and eye, between gestational day 17 and postnatal day 21, there was a uniform pattern of an increase in type I 5'-deiodination activity over time, until adult levels were attained. The ages at which adult activity levels were reached varied from tissue to tissue, however. Type II activity was present at the earliest ages tested in the cerebrum (gestational day 17), pituitary, and brown adipose tissue (day of birth). In cerebral cortex, type II activity was highest at day 21 postnatally and equal at birth and in adulthood, and in pituitary and brown adipose tissue it was higher in adulthood than at birth. T3 tyrosyl ring deiodinating activity was several times greater in homogenates of eye and placenta than in cerebral homogenates. In all three tissues, there was similar, dose-dependent inhibition of [125I]T3 tyrosyl deiodination by 5 nM and 20 nM nonradioactive T3. In the eye and brain, T3 tyrosyl deiodination rates decreased progressively with age from gestational day 17 to postnatal day 7.(ABSTRACT TRUNCATED AT 400 WORDS)

Topics: Adipose Tissue, Brown; Age Factors; Animals; Brain; Corticosterone; Eye; Female; Hypothyroidism; Lung; Male; Pituitary Gland; Pregnancy; Rats; Rats, Inbred Strains; Thyronines; Triiodothyronine, Reverse

Thirty-four hypothyroid women on thyroid hormone substitution were followed through 37 pregnancies, and 16 women having previous surgery for thyroid carcinoma and thereafter placed on suppressive thyroxine treatment were followed through 19 pregnancies. The thyroxine treatment needed readjustment in 13 pregnancies (23%) to maintain euthyroidism. At delivery, the maternal free thyroxine index was 126 nmol/L in the group of patients treated for hypothyroidism and 146 nmol/L in the patients with treated thyroid carcinoma. The amniotic fluid thyroxine level in normal pregnancies was 6.7 nmol/L, in hypothyroid patients 6.7 nmol/L, and in patients with thyroid carcinoma 5.6 nmol/L. The amniotic fluid reverse triiodothyronine level in normal pregnancies was 0.51 nmol/L, in hypothyroid patients 0.66 nmol/L, and in patients with thyroid carcinoma 0.70 nmol/L. All infants were euthyroid.

Topics: Adenocarcinoma; Amniotic Fluid; Female; Fetus; Humans; Hypothyroidism; Infant, Newborn; Postoperative Care; Pregnancy; Pregnancy Complications; Thyroid Hormones; Thyroid Neoplasms; Thyroxine; Triiodothyronine; Triiodothyronine, Reverse

In 172 patients over the age of 55, determinations were made of thyrotropin concentrations in plasma. Although they showed such symptoms or signs of hypothyroidism as puffy face, dry skin, general malaise, cold intolerance, or constipation, there were no clinical indications of overt hypothyroidism. All the patients were apparently in a normal nutritional state, without any specific medication that might cause thyroid abnormalities. Seventeen (six men and 11 women, 9.9 percent) of the 172 patients, aged 58 to 83, had elevated plasma thyrotropin levels, ranging from 12.1 microU/ml to 170 microU/nl. To investigate the characteristics of hypothyroidism in the elderly, the perchlorate discharge test was performed in these patients. In 15 of the 17 patients, 123I thyroid uptake diminished markedly immediately after the administration of 1 g perchlorate. Thirteen of these 15 patients showed markedly diminished thyroxine (T4) levels in serum, whereas the magnitude of diminution in serum 3,5,3'-triiodothyronine (T3) values was small. Two patients with the negative discharge results showed normal T4 and T3 levels in serum. Four patients had a very small goiter, and the remaining 13 patients had no detectable goiter. Fifteen of the 17 patients had no detectable circulating thyroid antibodies in repeated determinations, and the histologic features of Hashimoto's thyroiditis were not found in the thyroid specimens obtained from two patients. These findings suggest the existence of hypothyroidism attributable to iodine organification defect without evidence of autoimmune thyroiditis in some cases in elderly patients.

Topics: Aged; Antibodies; Biopsy; Female; Humans; Hypothyroidism; Male; Middle Aged; Perchlorates; Resins, Plant; Sodium Compounds; Thyroid Function Tests; Thyroid Gland; Thyroxine; Triiodothyronine; Triiodothyronine, Reverse

The effect of different thyroid states on glucose homeostasis was investigated during metabolic adaptation to starvation in the conscious unrestrained miniature pig. Moderate hyperthyroidism increased the rate of glucose turnover, whereas hypothyroidism was without effect. Glucose recycling was elevated in hyperthyroid pigs, and reduced after thyroidectomy. Supplementary doses of T4 normalized total glucose recycling. Glucose metabolic clearance rate and pool size were unaffected by thyroid hormones. During starvation serum insulin showed a similar decrease in all thyroid states; glucagon increased in euthyroid and hypothyroid pigs, although it was already elevated in the hyperthyroid fed state. Serum cortisol levels although varying were enhanced in hyperthyroid and hypothyroid-T4-treated pigs. Glucogenic precursor concentration and cumulative urinary N-excretion were increased in hyperthyroid pigs. It is concluded that 1) even a moderate hyperthyroidism produces an increase in glucose turnover and a concomitant acceleration in protein breakdown, and 2) thyroid hormone is essential for the starvation-induced total glucose recycling.

Topics: Animals; Blood Glucose; Glucagon; Hyperthyroidism; Hypothyroidism; Insulin; Kinetics; Lipids; Male; Starvation; Swine; Swine, Miniature; Thyroid Gland; Thyroxine; Triiodothyronine; Triiodothyronine, Reverse

We have previously reported that caloric deprivation inhibits peripheral T4 metabolism and blunts the TSH response to TRH in euthyroid obese subjects. To determine whether these phenomena also occur in hypothyroid subjects, T4, T3, rT3, and the TSH response to TRH were measured initially and after a 60-h fast in seven hypothyroid patients. Short term fasting caused a 29% decrement in the maximum serum TSH increment and a 32% decrement in the integrated TSH response to TRH (P less than 0.01). In two subjects with mild hypothyroidism, basal TSH as well as the TSH response to TRH were reduced to levels within the normal range. Specifically, basal TSH values decreased from 7.6 to 3.5 microU/ml and from 11 to 4.1 microU/ml. In the seven subjects, mean serum T3 decreased significantly from 88 to 60 ng/dl, (P less than 0.05) and rT3, initially undetectable in six of seven subjects, rose to detectable or low normal values in four of seven subjects, serum T4 remained at 2.7 micrograms/dl during both study periods. We conclude that 1) fasting induces changes in both peripheral thyroid hormone metabolism and the hypothalamic-pituitary axis in hypothyroid individuals which are qualitatively similar to those that occur in euthyroid subjects; and 2) in certain hypothyroid subjects, fasting alone can decrease basal TSH values to within the normal range. If these data can be extrapolated to critically ill subjects whose caloric intake may be diminished, they suggest that basal TSH concentrations in moderately and severely hypothyroid critically ill subjects will accurately reflect the biochemically hypothyroid state. However, mild degrees of hypothyroidism in critically ill subjects might be overlooked due to the lowering effect of fasting or poor caloric intake alone on basal TSH concentrations.

Topics: Adult; False Negative Reactions; Fasting; Female; Humans; Hypothyroidism; Male; Middle Aged; Thyroid Function Tests; Thyrotropin; Thyrotropin-Releasing Hormone; Thyroxine; Triiodothyronine; Triiodothyronine, Reverse

Amiodarone, an iodinated benzofuran derivative, has electrophysiologic effects on cardiac muscle akin to those of hypothyroidism. It is possible that the drug exerts its salutary effect, at least in part, by selectively inhibiting the action of triiodothyronine (T3) on the myocardium. The drug produces complex changes in thyroid hormones, with significant elevations in thyroxine (T4) and reverse T3 (rT3), with minor decreases in T3, and with minor and transient increases in thyroid-stimulating hormone, but without effect on thyroid-binding globulin. These changes may interfere with the biochemical evaluation of thyroid function. Rarely, hypothyroidism or hyperthyroidism may develop during the course of amiodarone therapy, a complication caused by the iodine contained in the drug rather than by the direct pharmacologic actions of the compound. The incidence of altered thyroid function induced is likely to vary with populations susceptible to iodine-induced goiter. Under the action of amiodarone, serum rT3 levels increase as a function of dose and duration of therapy and therefore provide a basis for judging the magnitude of in vivo drug cumulation. It was found that therapeutic efficacy was usually predictable on the basis of the attainment of a defined range of serum values, established by a correlation of rT3 levels with therapeutic responses both during loading and maintenance phases as well as after withdrawal of treatment of steady-state drug effects. Serious adverse effects occurred nearly always in association with four- to fivefold increases of rT3 above baseline values, and disappeared when such levels fell as a result of dosage reduction or after temporary drug discontinuation. The data suggest that the determination of serum rT3 levels during amiodarone therapy provides a simple and reliable technique for monitoring the drug's antiarrhythmic efficacy and toxicity, thereby enhancing its clinical utility. The use of rT3 levels may permit the development of a safe but optimal therapeutic regimen for the control of a wide spectrum of refractory atrial and ventricular tachyarrhythmias. The use of this technique, however, presupposes the allowance that must be made for variations in the methods for the serum assay of rT3 and of the systemic conditions in which the rT3 levels fluctuate relative to severity of the illness.

Topics: Amiodarone; Arrhythmias, Cardiac; Benzofurans; Humans; Hyperthyroidism; Hypothyroidism; Iodides; Male; Middle Aged; Thyroid Gland; Thyrotropin; Thyrotropin-Releasing Hormone; Thyroxine; Triiodothyronine; Triiodothyronine, Reverse

The presence of what we believe is a unique variant of thyroxine-binding globulin in a high proportion of Australian Aborigines causes difficulty in the interpretation of thyroid function tests in such subjects. We present reference ranges for the common tests of thyroid function and a suitable combination of tests for the laboratory investigation of thyroid function in Aborigines. We suggest that the thyroid status of Aborigines previously diagnosed as hypothyroid should be reviewed.

Topics: Australia; Female; Humans; Hypothyroidism; Male; Native Hawaiian or Other Pacific Islander; Thyroid Function Tests; Thyroid Hormones; Thyrotropin; Thyroxine; Thyroxine-Binding Proteins; Triiodothyronine; Triiodothyronine, Reverse

Topics: Child; Child, Preschool; Fetal Blood; Humans; Hypothyroidism; Infant; Infant, Newborn; Thyroxine; Triiodothyronine; Triiodothyronine, Reverse

Topics: Adolescent; Adult; Aged; Female; Humans; Hyperthyroidism; Hypothyroidism; Male; Middle Aged; Thyroid Diseases; Thyroxine; Triiodothyronine; Triiodothyronine, Reverse

We previously reported that two sisters with juvenile hypothyroidism due to Hashimoto's thyroiditis (case 1: 13 years old, case 2: 10 years old) had antibodies against T3 and T4, and that the titers of these antibodies decreased but remained above normal levels even in the euthyroid state during L-T4 treatment. In our further investigations we found the binding of 125I-rT3 to serum gamma-globulin in both cases in the pre-treatment period. This binding was completely inhibited by the addition of unlabelled rT3. In addition to these findings, we also found the presence of anti-rT3 antibodies in two rabbits (TG-1, TG-2) immunized with human thyroglobulin. Since it has been suggested that autoantibodies against thyroglobulin cross-react with T3 and T4, we examined the specificities of anti-rT3 antibodies which were found in both cases and in the two rabbits in order to clarify the role of thyroglobulin in rT3 antibody production. The association constants and binding capacities of rT3 antibodies in cases 1 and 2 were 2.9 X 10(8) M -1 and 50 ng/ml serum, and 2.2 X 10(9) M -1 and 1.5 ng/ml serum, respectively. Cross reactivities of these anti-rT3 antibodies with T3 and T4 were 1.8% and 276% in case 1, and 0.24% and 38% in case 2, respectively. These results suggest that anti-rT3 antibodies in case 1 are anti-T4 antibodies interacting with rT3, and those in case 2 are antibodies against rT3 which have a high cross reactivity with T4. In both cases, however, cross reactivities with T3 were very small. Cross reactivities of anti-rT3 antibodies with T3 and T4 in TG-1 and TG-2 were 4.0% and 53%, and 53% and 182%, respectively. These data were compatible with those obtained from both cases. The observation that anti-rT3 antibodies found in two sisters and two rabbits immunized with human thyroglobulin had similar characteristics in terms of cross reactivities with T3 and T4 suggests the role of thyroglobulin as an antigen in rT3 antibody production in both patients.

Topics: Adolescent; Autoantibodies; Child; Cross Reactions; Female; Humans; Hypothyroidism; Thyroiditis, Autoimmune; Thyroxine; Triiodothyronine; Triiodothyronine, Reverse

Two patients, a boy of 8 and a women of 60 years of age, had higher than normal levels of serum total thyroxine (T4), free T4, (FT4), FT4 index, and reverse triiodothyronine, but normal serum triiodothyronine (T3) levels. The pituitary-thyroid axis could be normally stimulated by thyrotropin-releasing hormone, suggesting euthyroidism at the pituitary level. High levels of serum T4-binding globulin decreased during T3 treatment in the boy. Studies show that in these patients a raised serum FT4 is necessary to produce in the peripheral tissues sufficient amounts of T3 for biological action. Two possible mechanisms for a basic defect underlying this newly recognised syndrome are proposed: inhibition of T4 transport into tissue cells and reduced intracellular 5'-deiodinase activity catalysing T4 to T3 conversion.

Topics: Child; Extracellular Space; Female; Humans; Hypothyroidism; Intracellular Membranes; Iodide Peroxidase; Male; Middle Aged; Syndrome; Thyroid Function Tests; Thyrotropin; Thyroxine; Thyroxine-Binding Proteins; Triiodothyronine; Triiodothyronine, Reverse

We studied various tests of thyroid function in sick patients with nonthyroidal illness (NTI) in order to determine the utility of each test for differentiating these patience from a group with hypothyroidism. We evaluated each test in 22 healthy volunteers who served as controls, 20 patients with hypothyroidism, 14 patients admitted to medical intensive care unit whose serum T4 was less than 5 micrograms/dl, 13 patients with chronic liver disease, 32 patients on chronic hemodialysis for renal failure, 13 ambulatory oncology patients receiving chemotherapy, 16 pregnant women, 7 women on estrogens, and 20 hyperthyroid patients. On all samples, we measured serum T4, the free T4 index by several methods, free T4 by equilibrium dialysis, free T4 calculated from thyronine-binding globulin (TBG) RIA, free T4 by three commercial kits (Gammacoat, Immophase, and Liquisol), T3, rT3, and TSH (by 3 different RIAs). Although all of the methods used for measuring free T4 (including free T4 index, free T4 by dialysis, free T4 assessed by TBG, and free T4 assessed by the 3 commercial kits) were excellent for the diagnosis of hypothyroidism, hyperthyroidism, and euthyroidism in the presence of high TBG, none of these methods showed that free T4 was consistently normal in patients with NTI; with each method, a number of NTI patients had subnormal values. In the NTI groups, free T4 measured by dialysis and the free T4 index generally correlated significantly with the commercial free T4 methods. Serum rT3 was elevated or normal in NTI patients and low in hypothyroid subjects. Serum TSH provided the most reliable differentiation between patients with primary hypothyroidism and those with NTI and low serum T4 levels.

Topics: Alpha-Globulins; Chronic Disease; Female; Humans; Hyperthyroidism; Hypothyroidism; Kidney Failure, Chronic; Liver Diseases; Neoplasms; Pregnancy; Radioimmunoassay; Reagent Kits, Diagnostic; Renal Dialysis; Thyroid Function Tests; Thyrotropin; Thyroxine; Thyroxine-Binding Proteins; Triiodothyronine; Triiodothyronine, Reverse

Ten patients with primary hypothyroidism (aged 32--66 yr), replaced on constant daily doses of L-T4 (mean +/- SD, 1.90 +/- 0.22 micrograms/kg BW), were used to examine seasonal variations in serum levels of thyroid-related hormones for a period of 14 months. Basal and peak TSH concentrations after TRH (500 micrograms) were higher in winter than in summer. Summer values for basal TSH were all normal (normal range, less than 4.8 microU/ml), while winter values were supranormal in 5 of 10 patients. Summer values for peak TSH were subnormal or normal (normal range, 5.0--40.0 microU/ml), while winter values were supranormal in 3 patients, with the remaining values being normal [log basal TSH, 0.511 +/- 0.438 vs. 0.084 +/- 0.244 (P less than 0.05); log peak TSH, 1.394 +/- 0.410 vs. 1.017 +/- 0.423 (P less than 0.05)]. Serum resin T3 uptake, T4, free T4 index(FT4I), T3, free T3 index, and rT3 levels did not vary seasonally, although T4 and FT4I tended to fall in the winter. The summer and winter QKd interval (the interval from the onset of a QRS complex in the electrocardiogram to the appearance of the Korotkoff sound at diastolic pressure), basal metabolic rate, and serum cholesterol concentrations were all within the normal range. Basal and peak TSH after TRH were inversely correlated with serum T4 and FT4I levels. The basal TSH concentration was further inversely correlated with the seasonally altering ambient temperature. These results indicate that during the treatment of primary hypothyroidism with constant doses of T4, 1) serum TSH and its response to TRH show seasonal variation, 2) the hypersecretion TSH in the winter is related to small changes in serum T4 and FT4I levels, and 3) the seasonal variation in the serum TSH concentration may need to be taken into consideration when evaluating the adequacy of a T4 replacement dose.

Topics: Adult; Aged; Analysis of Variance; Body Weight; Female; Humans; Hypothyroidism; Male; Middle Aged; Seasons; Thyrotropin; Thyrotropin-Releasing Hormone; Thyroxine; Triiodothyronine; Triiodothyronine, Reverse

Thyroid function tests were obtained from 335 consecutive patients admitted to an intensive care unit. Twenty patients suffering from severe non-endocrine diseases (septicaemia, fulminant hepatic and renal failure, acute pancreatitis, polytrauma, cerebral haemorrhage) were found to have serum thyroxine levels in the hypothyroid range (less than 4 micrograms/dl). Serum concentrations of total thyroxine (2.3 +/- 0.2 micrograms/dl), triiodothyronine (0.23 +/- 0.03 ng/ml), and thyroxine binding globulin (15.1 +/- 1.3 micrograms/ml) were reduced, but were above normal for reverse triiodothyronine (0.43 +/- 0.06 ng/ml). Response of TSH secretion to iv TRH was found to be either normal, lowered or absent. Primary hypothyroidism was excluded, as no enhanced TSH response was observed in any case. Although decreased thyroxine levels may be due to increased thyroid hormone degradation it appears that associated impaired TSH responsiveness to TRH may result from illness-related inhibition of pituitary TSH release. Although the finding of decreased thyroid hormone levels is not rare in care patients, it represents an index of poor prognosis. Differentiation between this "low-T4 syndrome" and true hypothyroidism depends essentially on clinical symptoms and course of disease.

Topics: Acute Disease; Acute Kidney Injury; Adolescent; Adult; Aged; Critical Care; Female; Hepatic Encephalopathy; Humans; Hypothyroidism; Male; Middle Aged; Pancreatitis; Pituitary Gland; Sepsis; Thyroid Function Tests; Thyroid Gland; Thyrotropin; Thyroxine; Thyroxine-Binding Proteins; Triiodothyronine; Triiodothyronine, Reverse; Wounds and Injuries

The effect of D,L-propranolol (80 mg daily) on the peripheral monodeiodination of rT3, 3',5'-diiodothyronine (3',5'-T2), 3,3'-diiodothyronine (3,3'-T2), and 3'-monoiodothyronine (3'-T1) was studied in seven out-patients with severe pretreatment hypothyroidism. The patients were maintained euthyroid on a constant L-T4 replacement therapy. A bolus injection technique was used; MCR, production rate (PR), and conversion rate were determined using a noncompartmental kinetic model. During D,L-propranolol, serum rT3 and 3',5'-T2 increased (P less than 0.02), and 3,3'-T2 seemed to decrease. The MCRs of rT3, 3',5'-T2, and 3,3'-T2 (P less than 0.02) decreased during drug treatment. The MCR and PR of 3'-T1 were reduced, albeit not significantly (P less than 0.10). The PR of 3,3'-T2 was reduced (P less than 0.02), whereas the PRs of rT3 and 3',5'-T2 were unaltered. The conversion rate of rT3 to 3',5'-T2 was unaltered. No changes were seen in the apparent distribution volumes of the iodothyronines studied. The results are compatible with the assumption that D,L-propranolol, or a metabolite thereof, inhibits the 5'-deiodination of all of the iodothyronines.

Topics: Aged; Diiodothyronines; Female; Humans; Hypothyroidism; Isomerism; Kinetics; Male; Metabolic Clearance Rate; Middle Aged; Propranolol; Thyronines; Triiodothyronine; Triiodothyronine, Reverse

Human and rat placentae contain enzymatic activity which converts T4 to rT3 and T3 to 3,3'-diiodothyronine and 3'-monoiodothyronine. This study presents data on the ontogeny of this inner ring iodothyronine deiodinase activity (P-T4ase) in rat placenta. P-T4ase was measured by quantitating the conversion of T4 to rT3 in 700 x g supernatants of placental homogenates. Groups of rats were mated to permit the dams to be killed on the same day, on days 12, 14, 16, 18, and 20 of gestation. Sufficient placental tissue was obtained to measure P-T4ase on all but the 12th day of gestation. The highest level of P-T4ase was observed on day 16. P-T4ase on days 14, 18, and 20 was 52%, 77%, and 41%, respectively, of that observed on day 16 (P less than 0.01, day 16 vs. all other days). Amniotic fluid rT3 concentrations were highest on day 18 and were 61% and 64%, respectively, of that observed on day 18 (P less than 0.01, days 16 and 20 vs, day 18). At 20 days, maternal serum T4 concentrations were significantly lower (P less than 0.01) than on days 14, 16, or 18. A brief period of maternal hypothyroidism (4 or 9 days before the time that the animals were killed on day 20 of gestation) did not significantly alter P-T4ase. These studies indicate that there are age-dependent changes in placental inner ring deiodinase activity in the rat. Amniotic fluid rT3 concentrations may reflect these changes. Brief reductions in maternal serum T4 concentrations do not account for changes in placental inner ring deiodinase activity. These studies emphasize the importance of gestational age in studies of placental inner ring iodothyronine deiodinase.

Topics: Amniotic Fluid; Animals; Female; Fetus; Hypothyroidism; Iodide Peroxidase; Male; Peroxidases; Placenta; Pregnancy; Rats; Rats, Inbred Strains; Thyrotropin; Thyroxine; Triiodothyronine; Triiodothyronine, Reverse

To study the effect of alterations in thyroid status on 5'-monodeiodinase activity, conversions of rT3 to 3,3'-diiodothyronine and 3',5'-diiodothyronine (3',5'-T2) to 3'-monoiodothyronine were examined in vitro. Rats were injected either with T4 (10 micrograms/100 g BW, ip, daily for 12 days) to make them thyrotoxic or thyroidectomized to render them hypothyroid, and liver and kidney homogenates were prepared. Liver homogenates from hyperthyroid animals demonstrated a 2-fold increase in 5'-monodeiodination of both rT3 and 3',5'-T2; both reactions were also significantly increased in the kidneys of hyperthyroid rats. Hypothyroidism produced a significant decrease in 5'-deiodination of both rT3 and 3',5'-T2 in liver and kidney homogenates. These data indicate that the in vitro 5'-deiodination of both rT3 and 3',5'-T2 is increased in hyperthyroidism and decreased in hypothyroidism and suggest that these two iodothyronines are metabolized in a similar fashion in rat liver and kidney homogenates in states of altered thyroid function.

Topics: Animals; Diiodothyronines; Hyperthyroidism; Hypothyroidism; Iodine; Kidney; Liver; Male; Rats; Thyroidectomy; Thyronines; Thyroxine; Triiodothyronine; Triiodothyronine, Reverse

Topics: Female; Fetus; Graves Disease; Humans; Hyperthyroidism; Hypothyroidism; Immunoglobulin G; Immunoglobulins, Thyroid-Stimulating; Infant, Newborn; Infant, Newborn, Diseases; Pregnancy; Pregnancy Complications; Propylthiouracil; Thyrotropin; Triiodothyronine; Triiodothyronine, Reverse

In a survey of 49 children idiopathic growth hormone deficiency, a sex ratio of 3 : 2 was found. Multiple pituitary hormone deficiency (MPHD) was seen in 31 and isolated growth hormone deficiency (IGHD) in 18 cases. The incidence of breech delivery was 32.5%; it occurred more frequently in MPHD than in IGHD. In one family there were two affected brothers whose birth weight was 4800 and 4900 g, respectively, and who were extremely retarded in growth. Screening of 594 children 1 to 9 years of age with cleft lip and palate was carried out; 1 child with growth hormone deficiency was detected. A study of the value of different thyroid hormones in the diagnosis of secondary and tertiary hypothyroidism showed that in spite of low free thyroxin concentrations the thyroxine and triiodothyronine levels are often normal. The discrepancy is probably due to a significantly higher plasma level of thyroxine-binding globulin demonstrated in children with hypopituitarism.

Topics: Adolescent; Birth Weight; Child; Child, Preschool; Cleft Lip; Cleft Palate; Delivery, Obstetric; Female; Growth Hormone; Humans; Hypothyroidism; Infant; Infant, Newborn; Male; Thyroid Function Tests; Thyrotropin; Thyroxine; Thyroxine-Binding Proteins; Triiodothyronine; Triiodothyronine, Reverse

This is a report about three children suffering from pseudo-hypoparathyroidism type I and moderate primary hypothyroidism. The thyroid dysfunction was characterised by slightly low plasma thyroxine and high basal TSH showing an increased response to TRH. T3 and rT3 were within normal limits, the size of the thyroid glands and also bone age were normal. The plasma concentrations of T4 and TSH and the response of TSH to TRH were no different during hypocalcemia from those obtained in normocalcemia during vitamin D treatment. Thyroxine treatment could normalize T4 and TSH. Moderate hypothyroidism is frequently present in pseudohypoparathyroidism. It has to be assumed that the same genetical defect of the second messenger, already proved to exist in the kidneys of patients with pseudohypoparathyroidism may also exist in the thyroid gland.

Topics: Adolescent; Calcium; Child; Female; Follicle Stimulating Hormone; Humans; Hypothyroidism; Luteinizing Hormone; Male; Pseudohypoparathyroidism; Thyrotropin; Thyroxine; Triiodothyronine; Triiodothyronine, Reverse

3,3',5'-triiodothyronine, (rT(3)), is easily measured in human amniotic fluid (AF) during the second and third trimesters. To determine if AF rT(3) levels are maintained by either maternal or fetal thyroid function, or both, models of fetal hypothyroidism (FH), maternal hypothyroidism (MH), and combined maternal and fetal hypothyroidism (MFH) were developed in pregnant rats. Hormone analyses of maternal and fetal serum and AF were performed at term. Thyroxine (T(4)) and 3,3',5-triiodothyronine (T(3)) were not detectable in the sera and AF of term fetuses in all groups. MFH rats were prepared by administration of methimazole to the dams, and in some experiments, by maternal thyroidectomy and a low iodine diet as well. In the MFH groups from the three experiments serum thyrotropin (TSH) was markedly elevated in the dams and in the fetuses. FH rats were prepared by administering T(4) by various routes to dams treated according to the MFH protocols and serum TSH was elevated in fetal serum. Analysis of FH maternal serum T(4), T(3), and TSH concentrations suggested mild maternal hyperthyroidism or hypothyroidism depending upon the schedule of T(4) administration. The MH groups were prepared by maternal thyroidectomy and in all experiments the fetuses had normal serum TSH concentrations. The degree of maternal hypothyroidism in the MH and MFH groups was equivalent. The mean concentration of AF rT(3) in normal rats in three experiments was 28.4+/-2.5 ng/dl (+/-SEM). In the three experiments, AF rT(3) was undetectable or markedly reduced in the MH and MFH rats and was normal in the FH rats. These results in the amniotic fluid could not be explained by transfer of rT(3) from fetal serum to the AF because fetal serum rT(3) concentrations in these various models did not correlate with AF rT(3) concentration. Furthermore, infusion of large doses of rT(3) in MFH dams resulted in a 35-fold elevation in maternal serum rT(3) concentration, a twofold elevation in fetal serum rT(3) concentration, and only a minimal increase in AF rT(3). These studies demonstrated that, in the rat, the maternal thyroid has the dominant role in maintaining AF rT(3), whereas little effect of fetal thyroid status on AF rT(3) could be demonstrated. Transfer of maternal rT(3) or of fetal rT(3) derived from maternal T(4) to the AF do not appear to be the mechanisms whereby the maternal thyroid maintains AF rT(3).

Topics: Amniotic Fluid; Animals; Female; Fetal Diseases; Hypothyroidism; Pregnancy; Pregnancy Complications; Rats; Thyrotropin; Thyroxine; Triiodothyronine; Triiodothyronine, Reverse

A pilot study was performed to establish optimal conditions for nation-wide screening for congenital hypothyroidism in Sweden. The levels of T4 and TSH were determined by automated radioimmunoassay in the dried blood spots, routinely collected for PKU screening on the fifth postnatal day, from all 19 792 infants born in the Stockholm area during a 14-month period. To identify safe minimum recall criteria for routine use, infants were recalled if the TSH level was more than 30 mU/l of plasma or--if they were not preterm--the T4 concentration was less than -2 S.D. of the mean. Altogether 160 infants were recalled. Seven newborns with congenital hypothyroidism were identified, 6 with primary and one with secondary hypothyroidism. Five infants had decreased levels of thyroxine-binding globulin. The results of the follow-up analyses from recalled infants showed that determination of the reverse-T3 level may be of diagnostic value around the 23rd day of life. The results of the clinical investigation of recalled infants are reported in a subsequent paper and a programme for nation-wide screening for congenital hypothyroidism is proposed.

Topics: Congenital Hypothyroidism; Follow-Up Studies; Humans; Hypothyroidism; Infant, Newborn; Mass Screening; Phenylketonurias; Pilot Projects; Radioimmunoassay; Sweden; Thyrotropin; Thyroxine; Triiodothyronine, Reverse

Serum 3'monoiodothyronine (3'-T1) levels were estimated by means of a specific radioimmunoassay (RIA) preceded by an ethanol extraction. The recovery of 3'T1 was in mean (+/-SEM) 110 +/- 9%, and the lower detection limit was 23 pmol/l. Serum levels of 3'T1 in 34 euthyroid healthy subjects were (median (range)) 55 pmol/l (less than 23 - 168 pmol/l), in 13 hyperthyroid patients 133 pmol/l (70 - 265 pmol/l) (P less than 0.01) and in 13 hypothyroid patients less than 23 pmol/l (less than 23 - 68 pmol/l) (P less than 0.01). In 11 patients with chronic renal failure serum 3'-T1 levels were highly increased 285 pmol/l (115 - 1538 pmol/l) (P less than 0.01) and correlated inversely to creatinine clearance (R = -0.68, P less than 0.05). In patients with liver cirrhosis serum 3'-T1 levels were unaffected, whereas in 19 patients with endogenous depression studied before and after recovery from the depression serum levels decreased from 70 pmol/l (less than 23 - 248 pmol/l) to 30 pmol/l (less than 23 - 95 pmol/l) (P less than 0.01). Administration of propranolol 40 mg b.i.d. for 2 weeks did not affect serum 3'-T1 levels. The study shows that 3'-T1 is present in serum from euthyroid man and varies with thyroid function. Further, it is suggested that 3'-T1 in contrast to other iodothyronines primarily is eliminated by the kidneys.

Topics: Adult; Depression; Female; Humans; Hyperthyroidism; Hypothyroidism; Kidney Failure, Chronic; Male; Middle Aged; Propranolol; Thyronines; Thyroxine; Triiodothyronine; Triiodothyronine, Reverse

Topics: Diagnosis, Differential; Humans; Hypothyroidism; Male; Middle Aged; Syndrome; Thyroid Function Tests; Thyroxine; Triiodothyronine; Triiodothyronine, Reverse

Serum thyroxine was consistently unmeasurable by radioimmunoassay in an elderly patient with myxoedema after successful treatment with oral thyroxine. Abnormal binding of thyroxine was suspected and shown to be due to the presence in serum of antibodies of the IgG variety. The characteristics of these antibodies with respect to their binding of thyroxine (T4), triiodothyronine (T3), reverse triiodothyronine (rT3) and human thyroglobulin (Tg) were systematically studied. Three preparations of Tg, and t4, T3 and rT3 were examined for their ability to compete with 125I-Tg, 125I-T4, 125I-T3 and 125I-rT3 for binding to the antibodies. For each tracer used the order of competitive efficiency was Tg greater than T4 greater than T3 greater than rT3. This provides for the first time direct evidence that iodothyronine reacting antibodies occurring in man are generated against Tg. All three iodothyronines were able to inhibit tracer binding of labelled iodothyronines completely, the order of effectiveness being T4 greater than T3 greater than rT3, suggesting antibodies with one type of binding site and that these were probably raised against a Tg sequence incorporating T4, although there was some evidence for the existence of a minor subpopulation of antibodies with higher specificity for T3. Complete displacement of labelled Tg by cold iodothyronines, however, was not possible. The experimental evidence suggests two classes of Tg antibodies, 70% of which were directed towards the T4 containing region, and 30% directed against other part(s) of the Tg molecule. Despite the presence of such Tg antibodies conventional haemagglutination tests of the patient's serum for Tg antibodies were negative.

Topics: Aged; Autoantibodies; Cross Reactions; Female; Humans; Hypothyroidism; Immunoglobulin G; Thyroglobulin; Thyronines; Thyroxine; Triiodothyronine; Triiodothyronine, Reverse

A method for the determination of D- and L-thyroxine in human serum is described. The method involves extraction of thyroxine from serum and the separation of thyroxine enantiomers on a reversed-phase, high-performance liquid chromatographic column by use of a chiral eluent containing L-proline and cupric sulfate. Satisfactory resolution of the enantiomers of thyroxine, triiodothyronine, and reverse triiodothyronine can be achieved in 12 min and, employing amperometric detection to monitor the separation, the detection limit for serum thyroxine is in the range of 1--3 ng per injected sample.

Topics: Chromatography, High Pressure Liquid; Humans; Hyperthyroidism; Hypothyroidism; Isomerism; Microchemistry; Thyroxine; Triiodothyronine; Triiodothyronine, Reverse

The effects of a daily oral dose (1.4 mg) of 3,5,3'-Triiodothyroacetic acid (Triac) on thyroid hormone levels (T4, T3 and rT3) and on the TSH and PRL responses to TRH were studied in 15 normal subjects and 5 hypothyroid patients. There were no significant changes in weight, heart rate, reflex time, or serum concentration of either cholesterol or triglycerides after 6 weeks of Triac administration. However, T4 was significantly reduced to a lower mean level (mean +/- SEM, 7.3 +/- 0.7 to 4.3 +/- 0.6 microgram/dl) in the control group. T3 and rT3 concentrations increased, possibly due to a cross-reaction with Triac in their respective RIAs. The peak TSH response to TRH in the normal subjects was 17.6 +/- 3.4 muU/ml and fell significantly to 2.0 +/- 0.8 muU/ml after Triac administration. In the hypothyroid subjects the mean serum TSH level was significantly reduced from 136 +/- 66 to 12.6, 10.5, and 11.6 muU/ml in the weeks after Triac administration. The mean peak response of both TSH and PRL after TRH (206 muU and 44.8 ng/ml, respectively) declined significantly to 63.4 muU/ml and 24 ng/ml. It was concluded that this dose of Triac partially inhibits the synthesis and secretion of TSH and PRL without any major peripheral metabolic effects.

Topics: Adult; Female; Humans; Hypothyroidism; Male; Prolactin; Reference Values; Thyroidectomy; Thyrotropin; Thyrotropin-Releasing Hormone; Thyroxine; Triiodothyronine; Triiodothyronine, Reverse

Topics: Animals; Diiodothyronines; Dithiothreitol; Edetic Acid; Hyperthyroidism; Hypothyroidism; Iodide Peroxidase; Kinetics; Liver; Male; NADP; Peroxidases; Propylthiouracil; Rats; Starvation; Thyroidectomy; Thyronines; Triiodothyronine; Triiodothyronine, Reverse

Topics: Adult; Contraceptives, Oral; Diiodothyronines; Female; Fetal Blood; Humans; Hyperthyroidism; Hypothyroidism; Infant, Newborn; Kinetics; Male; Thyroid Diseases; Thyroidectomy; Thyronines; Thyroxine; Triiodothyronine; Triiodothyronine, Reverse

Topics: Adult; Age Factors; Female; Fetal Blood; Humans; Hyperthyroidism; Hypothyroidism; Infant, Newborn; Infant, Newborn, Diseases; Male; Pregnancy; Thyroid Hormones; Thyrotropin; Thyroxine; Triiodothyronine; Triiodothyronine, Reverse

Topics: Adult; Diiodothyronines; Disease; Female; Humans; Hypothyroidism; Kinetics; Male; Middle Aged; Reference Values; Thyroxine; Triiodothyronine; Triiodothyronine, Reverse

A new sensitive radioimmunoassay method for measuring reverse triiodothyronine (rT3) concentrations in dried blood samples, designed to screen newborn infants for congenital hypothyroidism, has been developed. Paper strips are impregnated with cord blood and dried. Duplicate 5-mm diameter discs are punched from the paper strips and added directly to the radioimmunoassay reaction mixture. After incubation, bound and free hormone are separated by dextran-coated charcoal. The disc remains in the solution throughout the procedure and the assay can be completed within 24 hr. Recovery of rT3 is greater than 95% and coefficients of variation are 9.4% (intraassay) and 12.2% (interassay) at an rT3 concentration of 220 ng/dl. At very low rT3 concentrations (25 ng/dl), coefficients of variation are 14.2% (intraassay) and 18.7% (interassay). The method readily detects 12.5 ng/dl of rT3. With this paper disc method, rT3 was measured in 38 newborns and compared with serum rT3 measured in the same subjects by a standard radioimmunoassay method. The correlation between rT3 values measured in dried blood disc and in serum was very high (r = 0.918). The rT3 in dried blood discs from the cord blood of 745 normal newborns was 228.9 +/- 76.0 ng/dl (mean +/- SD). In contrast, two infants with proven congenital hypothyroidism had rT3 values of 35 and 75 ng/dl, respectively. This study indicates that rT3 can be easily measured in dried blood discs and suggests that the described method may be a useful screening procedure in a program for the detection of neonatal hypothyroidism.

Topics: Congenital Hypothyroidism; Fetal Blood; Humans; Hypothyroidism; Infant, Newborn; Infant, Newborn, Diseases; Paper; Radioimmunoassay; Statistics as Topic; Thyrotropin; Thyroxine; Triiodothyronine; Triiodothyronine, Reverse

Topics: Animals; Diiodothyronines; Dithiothreitol; Fasting; Hypothyroidism; Iodine; Liver; Male; Rats; Sulfhydryl Compounds; Thyroxine; Triiodothyronine; Triiodothyronine, Reverse

Amniotic fluid rT3 levels were measured during pregnancy in two women who previously gave birth to infants suffering from neonatal hypothyroidism. In the first case, hypothyroidism was strongly suspected because of repeated low levels of rT3 in the amniotic fluid (20-64 ng/dl) at 16 and 31 weeks of gestation. A normal infant was delivered. He is now 10 months old and taking no treatment; he has no clinical or laboratory signs of hypothyroidism. In the second case, amniotic rT3 levels (140-180 ng/dl) were well within the normal range for 15-19 weeks of pregnancy, but an affected hypothyroid infant was born. These data suggest that amniotic fluid rT3 levels may not be a reliable tool in diagnosing intrauterine hypothyroidism.

Topics: Adult; Amniotic Fluid; Congenital Hypothyroidism; Female; Gestational Age; Humans; Hypothyroidism; Infant, Newborn; Male; Prenatal Diagnosis; Triiodothyronine; Triiodothyronine, Reverse

Topics: Adolescent; Adult; Amniotic Fluid; Dexamethasone; Fasting; Female; Fetal Blood; Humans; Hyperthyroidism; Hypothyroidism; Ipodate; Middle Aged; Pregnancy; Radioimmunoassay; Thyroid Gland; Thyronines; Thyroxine; Triiodothyronine; Triiodothyronine, Reverse

Serum reverse triiodothyronine (reverse T3), triiodothyronine (T3), thyroxine (T4) and thyrotropin (TSH) concentrations were determined by radioimmunoassay in end-stage chronic renal failure, hypothyroidism and control subjects. In advanced chronic renal failure serum reverse T3 was normal or elevated and serum T3 concentrations were frequently, and serum T4 occasionally, lowered. Serum TSH was normal even where serum T3 and T4 concentrations were low. Normal or elevated serum reverse T3 associated with normal serum TSH in chronic renal failure clearly differentiates this disease from primary hypothyroidism in which low serum reverse T3 and high serum TSH are constantly found.

Topics: Adult; Female; Humans; Hypothyroidism; Kidney Failure, Chronic; Male; Middle Aged; Thyroid Gland; Thyrotropin; Thyroxine; Triiodothyronine; Triiodothyronine, Reverse

In order to investigate the effect of 3,5,3'L-triiodothyronine (T3) administration on thyroid hormone concentrations in serum, thyroxine (T4), T3, 3,3',5'L-triiodothyronine (reverse T3, rT3) and thyroid stimulating hormone (TSH) concentrations in serum were determined before and after T3 administration in 10 hypothyroid patients maintained on constant doses of T4. Ten hypothyroid patients given 100 micrograms of T4 for approximately 3 months had almost normal T4 and T3 concentrations in serum. Seven patients showed almost normal rT3 concentrations in serum and they were slightly diminished in the remaining 3 patients. TSH levels in serum were almost within the normal limit in 7 out of 10 patients. However, despite the elevation of T4 and T3 levels, 3 patients had markedly elevated TSH levels. Values for serum T4 concentrations were decreased 4 weeks after the administration of 50 micrograms T3 in all patients maintained on constant doses of T4, although they were almost within the normal range. T3 concentrations in serum, which was obtained just before the administration of the next daily doses of T3, were markedly elevated in 6 of 10 patients after T3 administration and the remaining 4 patients had also slightly higher T3 concentrations than those before T3 administration. On the other hand, serum rT3 concentrations were diminished in 5 patients during T3 ingestion. They were somewhat diminished or almost unchanged before and after T3 administration in the remai T3 administration and the remaining 4 patients had also slightly higher T3 concentrations than those before T3 administration. On the other hand, serum rT3 concentrations were diminished in 5 patients during T3 ingestion. They were somewhat diminished or almost unchanged before and after T3 administration in the remaining 5 patients. Moreover, 3 patients with elevated TSH levels during T4 administration showed almost normal TSH levels after T4 and T3 ingestion. The results showed the reciprocal relationship between T3 and rT3 levels in serum after T3 administration in hypothyroid patients maintained on constant doses of T4. Furthermore, the present findings suggest that the administration of both T4 and T3 might be a more suitable replacement therapy in the patients with hypothyroidism than T4 alone.

Topics: Drug Therapy, Combination; Humans; Hypothyroidism; Thyrotropin; Thyroxine; Triiodothyronine; Triiodothyronine, Reverse

Simple radioimmunoassays for 3,3',5-triiodothyronine (T3), 3,3',5'-reverse-triiodothyronine (r-T3) and 3,3'-diiodothyronine (r-T'2) in human serum are described. The princple of the methods is the same and based on a system using 8-anilino-1-naphthalene sulfonic acid as an inhibitor of nonspecific protein binding, a simultaneous addition of the antibody and the labelled hormone, an overnight incubation at room temperature and a separation of bound and free hormone with dextran-coated charcoal. The methods require 15 microliter, 50 microliter and 100 microliter (or 333 microliter for ethanol extraction) serum respectively. Serum concentrations (mean +/- SD) of T3, r-T3 and r-T'2 from normal subjects are 144 +/- 19 ng T3/100 ml (n = 52), 32 +/- 7 ng r-T3/100 ml (n = 36), 3.8 +/- 0.7 ng r-T'2/100 ml (ethanol extraction, n = 18) and 8.2 +/- 1.6 ng r-T'2/100 ml (unextracted, n = 16).

Topics: Diiodothyronines; Humans; Hyperthyroidism; Hypothyroidism; Radioimmunoassay; Reference Values; Thyronines; Thyroxine; Triiodothyronine; Triiodothyronine, Reverse

The effect of propranolol 80 mg daily on the metabolism of 3,3',5'-triiodothyronine (reverse T3, rT3), 3,3',5'-triiodothyronine (T3) and thyroxine (T4) was studied by means of a non compartmental kinetic method in seven females with severe pretreatment hypothyroidism. The patients were maintained euthyroid on a constant L-T4 replacement therapy. Serum rT3 levels increased significantly during propranolol (p less than 0.02). This increase was explained by a decrease in metabolic clearance rate (MCR) (p less than 0.02), since the conversion rate from T4 and the distribution volume of rT3 were unchanged. By contrast the decreased serum levels of T3 were due to a significant decreased conversion from T4 (p less than 0.02) in spite of a decreased MCR. The results are compatible with the assumption of two different monodeiodinating enzymes, a 5-deiodinase responsible for the diodination of T4 to rT3 and a 5'-deiodinase responsible for the deiodination of T4 to T3.

Topics: Female; Humans; Hypothyroidism; Propranolol; Thyroxine; Triiodothyronine; Triiodothyronine, Reverse

Topics: Congenital Hypothyroidism; Female; Humans; Hypothyroidism; Infant; Infant, Newborn; Male; Thyrotropin; Thyroxine; Triiodothyronine; Triiodothyronine, Reverse

Topics: Amniotic Fluid; Animals; Animals, Newborn; Diiodothyronines; Female; Hypothyroidism; Pregnancy; Sheep; Thyronines; Thyroxine; Triiodothyronine; Triiodothyronine, Reverse

Nonthyroidal illness is frequently associated with subnormal serum thyroxine (T4) and free T4 index. To unravel the resultant diagnostic problems, we have studied several variables of thyroid function in the sera of 47 patients hospitalized with nonthyroidal illnesses and seven hypothyroid patients encountered during the same period. Of the 47 euthyroid sick patients, 18 had low T4. Among these 18, free T4 index was normal in only five, whereas free T4 concentration measured by equilibrium dialysis was normal or high in 15 and 3,3',5'-triiodothyronine (reverse T3) normal or high in all 18. Reverse T3, free T4 concentration, and free T4 index were subnormal in all seven hypothyroid patients. Thus, measurement of free T4 index may be misleading in evaluation of thyroid function in patients with nonthyroidal illnesses, whereas measurement of serum concentration of reverse T3 and free T4 is quite discriminating.

Topics: Adult; Aged; Diagnosis, Differential; Diagnostic Errors; Evaluation Studies as Topic; Heart Diseases; Humans; Hypothyroidism; Middle Aged; Neoplasm Metastasis; Neoplasms; Pneumonia; Thyroid Gland; Thyroxine; Triiodothyronine; Triiodothyronine, Reverse; Uremia

Topics: Female; Humans; Hypothyroidism; Male; Thyroid Hormones; Thyrotropin; Thyroxine; Triiodothyronine; Triiodothyronine, Reverse

Propranolol alone was given to sixteen hyperthyroid, and concomitantly with thyroxine therapy to ten hypothyroid patients. Following treatment of the hyperthyroid group for 1-2 weeks there was a significant decrease in serum triiodothyronine (T3) which correlated with the plasma propranolol steady state concentration. The serum reverse T3 (rT3) rose significantly. Weight loss ceased in this group while weight gain occurred in patients who had a marked fall in serum T3. One patient with T3 toxicosis went into remission. The reduction in serum T3 was maintained in six patients receiving propranolol for more than 1 month. In the hypothyroid group the mean serum T3 level achieved with 0.15 mg thyroxine per day was significantly lower than in a control group who did not receive propranolol. In five patients following propranolol withdrawal there was a significant rise in T3, a fall in rT3 and TSH, and weight loss. Propranol may therefore have a clinically significant and direct action on the peripheral conversion of thyroxine to T3 and rT3.

Topics: Adolescent; Adult; Aged; Body Weight; Humans; Hyperthyroidism; Hypothyroidism; Middle Aged; Propranolol; Thyroxine; Triiodothyronine; Triiodothyronine, Reverse

Fourteen patients with Idiopathic Addison's disease (IAD) were studied in order to detect a possible subclinical hypothyroid state. All were clinically euthyroid with normal serum thyroxine (T4) and serum 3,5',5'-triiodothyronine (T3). Eleven had circulating thyroid microsomal antibodies in blood. The mean basal serum TSH was significantly higher than that of the control group but only three patients had values above the upper normal range. The mean value of serum T4 was decreased as compared to that of the normal persons, while serum 3,3',5'-triiodothyronine was elevated. 7.5 mU bovine thyrotrophin per kilogram body weight injected intravenously caused a rise in serum T3 not different from the response in normals. However, as well increasing serum TSH as increasing microsomal antibody titer correlated significantly to decreasing thyroidal release of T3. Our results suggest that clinically euthyroid patients suffering from IAD might have a beginning thyroidal insufficiency because of a progressive immunological damage of the thyroid.

Topics: Addison Disease; Adult; Aged; Antibodies; Female; Humans; Hypothyroidism; Male; Microsomes; Middle Aged; Thyroid Gland; Thyroid Hormones; Thyrotropin; Thyroxine; Triiodothyronine; Triiodothyronine, Reverse

As first described in serious systemic illnesses isolated decreased T3 plasma concentration was related to impaired peripheral conversion of T4, to T3 with preferential production of reverse T3 (rT3). A "low T3 syndrome" was seen in 47 out of 109 patients with extra-thyroidal diseases. Metabolic state, TSH and TSH responses to TRH were normal despite of low T3 concentration. Euthyroidism seems mainly due to T4 itself in these patients.

Topics: Aged; Anorexia Nervosa; Diet, Reducing; Humans; Hypothyroidism; Kidney Diseases; Liver Cirrhosis; Neoplasms; Obesity; Thyroid Function Tests; Thyrotropin; Thyroxine; Triiodothyronine; Triiodothyronine, Reverse

Topics: Diiodothyronines; Humans; Hypertension; Hyperthyroidism; Hypothyroidism; Infant, Newborn; Liver Cirrhosis; Thyronines; Thyroxine; Triiodothyronine; Triiodothyronine, Reverse

Topics: Adult; Female; Humans; Hyperthyroidism; Hypothyroidism; Male; Middle Aged; Thyrotropin-Releasing Hormone; Triiodothyronine; Triiodothyronine, Reverse

To further elucidate the peripheral metabolism of rT3 and to determine if rT3 production rates vary directly with thyroid function, we measured the disappearance of [125I]rT3 in thyrotoxic and hypothyroid subjects as well as in athyreotic patients maintained eumetabolic on exogenous T4. Kinetic parameters were determined by noncompartmental analysis, and serum concentrations of rT3 and T4 were determined by specific RIAs. In six hyperthyroid, seven euthyroid, and six hypothyroid subjects, the MCRs were 190.7 +/- 15.7, 111.7 +/- 13.2, and 71.8 +/- 7.0 liters/day kg, respectively (mean +/- SE). Production rates (PR) for these same groups were 271.3 +/- 40.5, 51.7 +/- 9.1, and 4.3 +/- 0.6 micrograms/day/70 kg. The observed differences in MCR and PR among the three study groups were highly significant (P less than 0.002). These data indicate that in comparison to euthyroid subjects, rT3 PR and MCR are increased in thyrotoxic and decreased in hypothyroid individuals.

Topics: Adult; Female; Humans; Hyperthyroidism; Hypothyroidism; Kinetics; Male; Metabolic Clearance Rate; Middle Aged; Thyroid Gland; Triiodothyronine; Triiodothyronine, Reverse

Kinetic studies of T4 and T3 using a noncompartmental approach were performed in seven patients with pretreatment severe hypothyroidism maintained on L-T4 replacement. Each subject received a combined tracer dose of labeled T4 and T3 as an iv bolus before and during peroral treatment with propranolol. Serum T4 was unchanged, while a significant decrease of 13% was found in serum T3. The disposal rates (DR) of T4 and T3 decreased significantly, and the ratio between the DR off T3 and the DR of T4, the conversion rate, was significantly reduced during propranolol treatment. The decrease in the DR of T4 suggests a reduction in the bioavailability of L-T4 during propranolol, possibly due to a decrease in intestinal absorption. The decrease in the conversion rate indicates a reduced extrathyroidal conversion of T4 to T3 during propranolol treatment.

Topics: Adult; Aged; Female; Humans; Hypothyroidism; Kinetics; Male; Metabolic Clearance Rate; Middle Aged; Propranolol; Thyroxine; Triiodothyronine; Triiodothyronine, Reverse

A simple and sensitive radioimmunoassay for reverse T3 in urine using small Sephadex G25 fine columns is described. The recovery of rT3 added to urine was on average 101.0 +/- 4.2% (mean +/- SEM). Detection limit was 4 pg/column. Urine excretion of rT3 (mean +/- SD) was 72.0 +/- 32.1 ng/24 h in 61 healthy euthyroid subjects with a slight increase with age (P less than 0.05), 28.8 +/- 18.2 ng/24 h in 12 hypothyroid patients and 183.6 +/- 79.7 ng/24 in 25 hyperthyroid patients.

Topics: Adolescent; Adult; Aged; Chromatography, Gel; Female; Humans; Hyperthyroidism; Hypothyroidism; Male; Middle Aged; Radioimmunoassay; Triiodothyronine; Triiodothyronine, Reverse

Topics: Energy Intake; Humans; Hyperthyroidism; Hypothyroidism; Infant, Newborn; Thyroxine; Triiodothyronine; Triiodothyronine, Reverse

In 17 hypothyroid patients serum T3: rT3 ratio was 7.5 /+- 1.1 which was significantly lower than in control subjects (12.2 /+- 0.6; p less than 0.001). The data suggest that in hypothyroidism the organism might shift conversion of T4 from biologically active T3 to biologically inactive rT3 which may not be a defense mechanism of the body, as it was found in chronic systemic illness.

Topics: Adult; Aged; Female; Humans; Hypothyroidism; Male; Middle Aged; Thyroxine; Triiodothyronine; Triiodothyronine, Reverse

Topics: Animals; Hyperthyroidism; Hypothyroidism; Kidney; Liver; Male; Rats; Thyroidectomy; Thyroxine; Triiodothyronine; Triiodothyronine, Reverse

Reverse triiodothyronine (rT3) was measured in cord serum from 5 infants with congenital hypothyroidism and compared with normal values in 70 euthyroid control infants. The mean (and SEM) value in the affected infants (135 +/- 12 ng/dl) was significantly lower than that in the control population (270 +/- 9 ng/dl). However, the large overlap in range of concentrations in affected and control infants indicates that newborn screening based on the determination of rT3 in cord blood specimens offers no advantage over present screening methods.

Topics: Congenital Hypothyroidism; Fetal Blood; Humans; Hypothyroidism; Infant, Newborn; Triiodothyronine; Triiodothyronine, Reverse

Topics: Birth Weight; Female; Fetal Blood; Gestational Age; Humans; Hypothyroidism; Infant, Newborn; Infant, Premature; Male; Thyrotropin; Thyroxine; Triiodothyronine; Triiodothyronine, Reverse

Topics: Congenital Hypothyroidism; False Negative Reactions; False Positive Reactions; Fetal Blood; Gestational Age; Humans; Hypothyroidism; Infant, Newborn; Thyrotropin; Thyroxine; Triiodothyronine; Triiodothyronine, Reverse