Defective thyroid hormone feedback regulation in the syndrome of peripheral resistance to thyroid hormone.
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Child↗
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Cloning of the alpha and beta ovine thyroid hormone receptor cDNAs.
Thyroid hormones modulate critical responses in a variety of tissues during development. While the mechanisms underlying many of these responses are uncertain, specific thyroid hormone nuclear receptor proteins likely play key roles in these processes. Many studies investigating the perinatal role of thyroid hormones in maturation have focused on events occurring in the developing rodent. However, the ovine fetus also serves as a useful model for human fetal thyroid system function. To extend the utility of the ovine model, the cDNAs representing the ovine family of nuclear thyroid receptors have been cloned, sequenced, and used to characterize mRNA species in ovine brain.
Amino Acid Sequence↗
Prolactin, growth hormone and thyrotropin-thyroid hormone secretion during stress states in man.
Changes in hormone secretion and/or metabolism almost constantly accompany stressful events. The hormonal response to stress is directly related to the intensity of the stimulus, and greatly depends on the individual's perception of potentially stressful situations. Hypoglycaemia, surgery and exercise represent physical, metabolic and psychological stressful events where the activation of the endocrine system plays a great role. These endocrine responses also include the secretion of GH and prolactin, but the response pattern varies with the stimulus. Hypoglycaemia, exercise and surgery are potent stimuli to GH and prolactin release, both in men and women. The available data suggest that prolactin is more responsive than GH to surgical stress, whereas physical exercise and hypoglycaemia preferentially stimulate GH secretion. Prolactin levels during hypoglycaemia rise solely when symptomatic neuroglycopenia is achieved. By contrast, prolactin and GH responses to purely psychological stress are rarely seen, although some forms of reproductive stress may potentiate prolactin release in women. A teleologically satisfactory rationale for the acute GH and prolactin rise in response to these stressful stimuli is not clearly apparent in man. No definite metabolic activity of prolactin on intermediate metabolism has been demonstrated, although prolactin is mildly diabetogenic. The known metabolic actions of GH do not appear to be critical during surgery or acute hypoglycaemia, although GH probably participates in the regulation of metabolic homeostasis during chronic hypoglycaemia and chronic exercise. Changes in secretion and/or metabolism of hypothalamic neurotransmitters can increase the secretion of GH by increasing the secretion of GHRH or by decreasing the secretion of somatostatin. The prolactin rise is brought about by either a decrease in dopamine activity, an increased secretion of a hypothetical PRF, or by both mechanisms. Since multiple neuronal pathways converge on the hypothalamus from many other parts of the brain, the pronounced effects of hypoglycaemia, exercise and surgery on the secretion of GH and prolactin also reflect the action of different and complex neural inputs on the activity of the hypothalamic-pituitary axis. However, the morpho-functional mapping of these excitatory pathways still remains incomplete. TSH secretion is tightly regulated by the negative feed-back mechanism exerted by thyroid hormones. The small changes in TSH level observed during surgery and physical exercise seem to reflect mainly alterations in peripheral T4 metabolism.(ABSTRACT TRUNCATED AT 400 WORDS)
Growth Hormone↗
Characteristics of a negative thyroid hormone response element.
Thyroid hormones may stimulate or repress transcriptional activity depending upon the specific gene. Whereas, a palindromic DNA sequence, TREpal, mediates positive regulation by thyroid hormone, the negative response element (nT3RE) remains undefined. Therefore, we have examined the DNA sequences that mediate the inhibitory effects of thyroid hormone on the transcription of the beta-subunit gene of rat thyrotropin (rTSH beta). In rat pituitary tumor cells (GH3), transient expression of plasmid constructs containing the putative nT3RE of rTSH beta mediated negative regulation by L-triiodothyronine (T3). Since this nT3RE contained sequences which resembled a half-site motif of the consensus T3RE and the idealized palindrome (TREpal), we tested a construct containing this half-site motif in the same cells. T3 decreased the activity of this plasmid. Cotransfection studies in T3-receptor (T3R)-deficient cells indicated that either alpha or beta isoforms of T3R were required for the inhibitory effects of the hormone. Both T3R isomers bind to DNA sequences containing the nT3RE from rTSH beta DNA or the half-site motif of TREpal. In summary, our results show that the repressive properties of T3 are mediated by a nT3RE from rTSH beta. Unexpectedly, this motif resembles a half-site component of TREpal which enhances promoter activity in response to T3.
Animals↗
Metabolism of thyroid hormones by rat thyroid tissue in vitro.
Rat thyroid lobes or hemilobes have been incubated in Krebs-Ringer phosphate buffer containing labeled T4 and/or T3, and the products were separated by paper chromatography. Labeled T4 was actively degraded; about half of the T4 metabolized was recovered as T3. Labeled T3 was also metabolized, but less rapidly than T4. Other than T3 produced from T4, the major products from both hormones were inorganic iodide and iodoprotein; the latter was presumably a secondary product of iodide organification because its formation was inhibited by hypoxia and methimazole. Feeding the animals a low iodine diet increased their hormone-metabolizing activity. Incubation under nitrogen did not affect the rate of T4 degradation, but partially inhibited T3 degradation. Degradation of both hormones was unchanged in the presence of methimazole and ascorbate, was markedly inhibited by 1 mM propylthiouracil (PTU), and was partially inhibited by azide and cyanide. Thyroid tissues concentrated both hormones, tissue to medium gradients averaging 5.4 for T4 and 20.7 for T3; none of the conditions affecting hormone degradation (incubation under nitrogen or with azide, cyanide, or PTU) significantly altered these gradients. It is concluded that the thyroid can metabolize both of its major hormones by a system distinct from thyroidal peroxidase. Hormone metabolism, therefore, is a potentially important factor in net hormone secretion. In its resistance to hypoxia, methimazole, and ascorbate and its sensitivity to PTU, the thyroid's system for generating T3 from T4 resembles T3-forming systems of liver and kidney. The thyroid, because T3 formation is its dominant pathway for T4 metabolism, may provide a useful model for study of this reaction.
Animals↗
Effects of thyroid hormones on amino acid and protein metabolism--IV. Effects of thyroid hormone on amino acid concentration and incorporation of [14C]L-valine in vivo and in vitro into proteins of the guinea-pig.
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Amino Acids↗
Negative regulation of the glycoprotein hormone alpha gene promoter by thyroid hormone: mutagenesis of a proximal receptor binding site preserves transcriptional repression.
Transcription of the glycoprotein hormone alpha gene is repressed by the thyroid hormone receptor (TR) in a hormone dependent manner. Previous studies identified a TR binding site immediately downstream of the TATA box. Site directed mutagenesis and transient gene expression studies were used to evaluate the role of this TR binding site as a negative thyroid response element (nTRE). Mutagenesis of the putative negative thyroid response element (nTRE) site eliminated TR binding but failed to eliminate negative regulation by T3. A mutation which converted the putative nTRE to a higher affinity palindromic element did not enhance repression, but rather eliminated thyroid hormone dependent negative regulation. Proximal alpha promoter sequences between -100 and +44 were replaced with a heterologous thymidine kinase promoter resulting in a construct that was not repressed by T3 treatment. This finding confirmed that repression required proximal alpha promoter sequences and also indicated that repression did not occur by interference with the function of upstream the alpha gene enhancers. These studies indicate that TR binding adjacent to the TATA box is not required for T3 mediated repression of the alpha promoter and suggest that negative regulation may involve protein-protein interactions with promoter-specific transcription factors.
Animals↗
Potent thyrotropic activity of human chorionic gonadotropin variants in terms of 125I incorporation and de novo synthesized thyroid hormone release in human thyroid follicles.
Using a highly sensitive bioassay for TSH, in which human thyroid follicles incorporate 125I and release de novo synthesized thyroid hormone into the culture medium, the thyrotropic activities of various hCG preparations were studied. Under the culture conditions employed, bovine TSH (bTSH) was approximately 6- to 9-fold more active than human TSH (hTSH). Highly purified hCG prepared from urine of normal pregnant women (CR 127) had only a trivial thyrotropic activity equipotent to 0.00022 microU bTSH/U hCG or 0.0013 microU hTSH/U hCG (19.7 microU hTSH/mg hCG). Hybrid hCG (AB1ER) also elicited low thyrotropic activity (14.0 microU hTSH/mg), whereas crude hCG had moderate thyrotropic activity (0.041 hTSH microU/U hCG or 127 microU/mg protein). Deglycosylated hCG, a very weak LH/hCG receptor agonist, was the most potent agonist in thyroid follicles (588 microU hTSH/mg protein). hCGs purified from urine of patients with trophoblastic tumors had greater TSH-like activity (37-84 microU hTSH/mg protein) than purified hCG. Asialo-hCG purified from a patient with choriocarcinoma had very potent TSH-like activity (468 microU hTSH/mg). Submaximal doses of bTSH and hCG variants produced additive stimulation of thyroid function. Furthermore, the thyrotropic effect of hCG was inhibited by anti-TSH receptor antibody obtained from patients with myxedema. These in vitro findings suggest that although hCG is reported to exert potent cAMP-stimulating activity on rat thyroid-like cells (FRTL-5) and Chinese hamster ovary cells transfected with hTSH receptor complementary DNA (0.092-0.72 microU hTSH/U hCG), the thyrotropic activity induced by authentic hCG in human thyroid follicles is too weak to cause hyperthyroidism in normal pregnancy. However, hCG produced by some trophoblastic tumors, particularly asialo-hCG, has potent thyrotropic activity sufficient to cause clinically overt hyperthyroidism when produced excessively.
Animals↗
Interaction of thyroid hormone and hemoglobin. I. Nature of the interaction and effect of hemoglobin on thyroid hormone radioimmunoassay.
Gel filtration of human RBC lysate incubated with labeled T4 or T3 revealed co-elution of a major iodothyronine-binding fraction (R-2) and hemoglobin. Solutions of purified human hemoglobin and T3 also showed co-elution of hormone and hemoglobin. Because hematin and protoporphyrin were shown to bind labeled T3, the oxygen-binding site on hemoglobin was excluded as the site of iodothyronine-hemoglobin interaction. Analysis of hormone binding by heme and globin moieties showed T3 binding to be limited to the heme fraction. Addition of excess unlabeled T3 to hemoglobin or heme incubated with labeled T3 indicated 75% to 90% of hormone binding was poorly dissociable. These observations suggested that the presence of hemoglobin in RBC lysate or in serum could influence the measurement of T4 and T3 by specific RIA. Subsequent studies of the addition to serum of human hemoglobin revealed a significant reduction in T3 and T4 detectable by RIA in the presence of this protein. The effect was influenced by the concentration of hemoglobin and by duration and temperature of incubations of hemoglobin and serum prior to RIA. Incubated for 5 days at 4 degrees C, 14 sera containing 10 gm/dl hemoglobin showed a mean decrease in T3 concentration of 40% compared to sera incubated in the absence of hemoglobin (160.1 to 93.9 ng/dl, p less than 0.001); detectable serum T4 fell by 50% in 13 sera incubated under the same conditions (5.40 micrograms/dl without hemoglobin to 2.55 micrograms/dl in the presence of hemoglobin, p less than 0.001). Hemoglobin concentrations in serum as low as 0.1 and 0.5 gm/dl affected the RIAs significantly. Thus a major fraction of thyroid hormone binding in human RBC cytoplasm is accounted for by an interaction with hemoglobin. This interaction in serum or RBC lysates is a significant variable affecting iodothyronine determinations.
Anilino Naphthalenesulfonates↗
The differential hormone-dependent transcriptional activation of thyroid hormone receptor isoforms is mediated by interplay of their domains.
Human thyroid hormone nuclear receptor isoforms (TRalpha1 and TRbeta1) express differentially in a tissue-specific and development-dependent manner. It is unclear whether these two isoforms have differential functions. We analyzed their interaction with a thyroid hormone response element with half-site binding motifs arranged in an everted repeat separated by six nucleotides (F2). Despite extensive sequence homologies, the two isoforms bound to F2 with different affinities and ratios of homodimer/monomer. Using F2-containing reporter gene, we found that the transcriptional activity of TRbeta1 was approximately 6-fold higher than that of TRalpha1. The lower activity of TRalpha1 was not due to differences in expression of the two isoforms because similar nuclear localization patterns were observed. To understand the structural determinants responsible for these differences, we constructed chimeric receptors in which hinge regions (domain D), hormone binding domains (domain E), and domains (D + E) were sequentially interchanged and their activities were compared. Chimeric TRs containing the domains D, E or (D + E) of TRbeta1 showed increased propensities to form homodimers and mediated higher transactivation activities than TRalpha1. Thus, differential transactivation activities of TR isoforms are mediated by interplay of their domains and could serve as an important regulatory mechanism to achieve diversity and specificity of pleiotropic T3 effect.
Binding Sites↗
Molecular and structural biology of thyroid hormone receptors.
1. Thyroid hormone receptors (TR) are expressed from two separate genes (alpha and beta) and belong to the nuclear receptor superfamily, which also contains receptors for steroids, vitamins and prostaglandins. 2. Unliganded TR are bound to DNA thyroid hormone response elements (TRE) predominantly as homodimers, or as heterodimers with retinoid X-receptors (RXR), and are associated with a complex of proteins containing corepressor proteins. Ligand binding promotes corepressor dissociation and binding of a coactivator. 3. Recent studies from our group have focused on the acquisition and use of X-ray crystallographic structures of ligand-binding domains (LBD) of both the rat (r) TR alpha and the human (h) TR beta bound to several different ligands. We have also developed ligands that bind selectively to the TR beta, which may provide ways to explore the differential functions of TR alpha compared with TR beta isoforms. 4. The LBD is comprised mostly of alpha-helices. The ligand is completely buried in the receptor and forms part of its hydrophobic core. Kinetic studies suggest that the limiting step in formation of high-affinity ligand-receptor complexes is the rate of folding of the receptor around the ligand. Ligands can be fitted tightly in the ligand-binding pocket and small differences in this fitting may explain many structure-activity relationships. Interestingly, analysis of the structures of antagonists suggests that they have chemical groups, 'extensions', that could impair receptor folding around them and, thus, prevent the agonist-induced conformation changes in the receptor. 5. The TR structures allowed us to see that the mutations that occur in the syndrome of generalized resistance to thyroid hormone are located in the vicinity of the ligand-binding pocket. 6. X-ray structure of the TR has also been used to guide construction of mutations in the TR surface that block binding of various proteins important for receptor function. Studies with these TR mutants reveal that the interfaces for homo- and heterodimerization map to similar residues in helix 10 and 11 and also allow the definition of the surface for binding of coactivators, which appears to be general for nuclear receptors. Formation of this surface, which involves packing of helix 12 of the TR into a scaffold formed by helices 3 and 5, appears to be the major change in the receptor structure induced by hormone occupancy.
Animals↗
Do clinical manifestations of resistance to thyroid hormone correlate with the functional alteration of the corresponding mutant thyroid hormone-beta receptors?
Resistance to thyroid hormone (RTH), a syndrome characterized by variable tissue hyposensitivity to thyroid hormone, is linked to mutations in the thyroid hormone receptor-beta (TR beta) gene. The purpose of this study was to determine whether the clinical phenotypes of RTH can be translated in terms of functional impairment of the corresponding mutant TR beta. Data from 124 subjects with RTH representing 18 different mutant TR beta s, showed that serum free T4 levels correlated with the degree of T3-binding impairment of the corresponding TR beta in 12 of these mutant TR beta s (group I), but not in the remaining 6 (group II). In subjects from both groups studied in detail by the administration of incremental doses of T3, the degree of thyrotroph resistance to T3 correlated with the magnitude of endogenous free T4 elevation at baseline, but did not parallel the resistance of peripheral tissues. In transfection studies, all group I mutant TR beta s inhibited positive transactivation by the wild type TR beta s to a similar degree in the presence of 1 nmol/L T3, whereas group II mutant TR beta s exerted a weaker inhibition that was not related to their T3-dependent trans-activation when tested alone. Similar results were obtained with negatively regulated reporter genes. It is concluded that the clinical severity of RTH, determined by thyrotroph resistance, can be predicted from the degree of T3 binding impairment and dominant negative potency of mutant TR beta s, but the degree of peripheral tissue resistance and related clinical manifestations is limited by putative genetic or environmental factors that modulate the effect of thyroid hormone.
Adolescent↗
[Study of hormone replacement therapy following total thyroidectomy in thyroid cancer--with special reference to the analysis of thyroid hormone peripheral effects, using indirect calorimetry].
Peripheral effects of thyroid hormones were examined using an indirect calorimetry in 18 patients with thyroid cancer before and after total thyroidectomy. Peripheral effects of exogenous thyroid hormones in TSH-suppression therapy after thyroidectomy were also studied. The subjects were maintained without hormone replacement for 3 weeks after total thyroidectomy. The ratio of resting energy expenditure to basal energy expenditure (REE/BEE) was determined before operation, before hormone replacement, and 1 and 5 weeks after the beginning of replacement, and the values were compared with changes in the blood thyroid hormone levels. Positive correlations were observed between the changes in endogenous thyroid hormone levels before and after total thyroidectomy and those in REE/BEE (free T3 vs. REE/BEE; r = 0.756, p less than 0.01), suggesting that evaluation of REE/BEE is clinically useful as an index of peripheral effects of thyroid hormones. Five weeks after the beginning of hormone replacement, T4 and free T4 were slightly range, and no enhancement of energy metabolism was noted. From these findings, the post-operative TSH suppression therapy carried out at our department is considered to be justifiable also from the viewpoint of energy metabolism.
Adult↗
[Symposium: Clinical aspects of steroid hormones. 6. Effect of thyroid hormones on the metabolism of adrenal cortex hormones].
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Adrenal Cortex Hormones↗
Comparison of administration of recombinant human thyrotropin with withdrawal of thyroid hormone for radioactive iodine scanning in patients with thyroid carcinoma.
BACKGROUND: To detect recurrent disease in patients who have had differentiated thyroid cancer, periodic withdrawal of thyroid hormone therapy may be required to raise serum thyrotropin concentrations to stimulate thyroid tissue so that radioiodine (iodine-131) scanning can be performed. However, withdrawal of thyroid hormone therapy causes hypothyroidism. Administration of recombinant human thyrotropin stimulates thyroid tissue without requiring the discontinuation of thyroid hormone therapy. METHODS: One hundred twenty-seven patients with thyroid cancer underwent whole-body radioiodine scanning by two techniques: first after receiving two doses of thyrotropin while thyroid hormone therapy was continued, and second after the withdrawal of thyroid hormone therapy. The scans were evaluated by reviewers unaware of the conditions of scanning. The serum thyroglobulin concentrations and the prevalence of symptoms of hypothyroidism and mood disorders were also determined. RESULTS: Sixty-two of the 127 patients had positive whole-body radioiodine scans by one or both techniques. The scans obtained after stimulation with thyrotropin were equivalent to the scans obtained after withdrawal of thyroid hormone in 41 of these patients (66 percent), superior in 3 (5 percent), and inferior in 18 (29 percent). When the 65 patients with concordant negative scans were included, the two scans were equivalent in 106 patients (83 percent). Eight patients (13 percent of those with at least one positive scan) were treated with radioiodine on the basis of superior scans done after withdrawal of thyroid hormone. Serum thyroglobulin concentrations increased in 15 of 35 tested patients: 14 after withdrawal of thyroid hormone and 13 after administration of thyrotropin. Patients had more symptoms of hypothyroidism (P<0.001) and dysphoric mood states (P<0.001) after withdrawal of thyroid hormone than after administration of thyrotropin. CONCLUSIONS: Thyrotropin stimulates radioiodine uptake for scanning in patients with thyroid cancer, but the sensitivity of scanning after the administration of thyrotropin is less than that after the withdrawal of thyroid hormone. Thyrotropin scanning is associated with fewer symptoms and dysphoric mood states.
Adult↗
Purification and characterization of rat liver nuclear thyroid hormone receptors.
Nuclear thyroid hormone receptor was purified to 904 pmol of L-3,5,3'-triiodothyronine (T3) binding capacity per mg of protein with 2.5-5.2% recovery by sequentially using hydroxylapatite column chromatography, ammonium sulfate precipitation, Sephadex G-150 gel filtration, DNA-cellulose column chromatography, DEAE-Sephadex column chromatography, and heparin-Sepharose column chromatography. Assuming that one T3 molecule binds to the 49,000-Da unit of the receptor, we reproducibly obtained 6.4-14.7 micrograms of receptor protein with 4.2-4.9% purity from 4-5 kg of rat liver. Elution of receptor from the heparin-Sepharose column was performed using 10 mM pyridoxal 5'-phosphate, which was observed to diminish binding of receptor to heparin-Sepharose or DNA-cellulose. This effect was specific for pyridoxal 5'-phosphate, since related compounds were not effective. Purified receptor bound T3 with high affinity (6.0 X 10(9) liter/mol), and the order of affinity of iodothyronine analogues to purified receptor was identical to that observed with crude receptor preparations [3,5,3'-triiodothyroacetic acid greater than L-T3 greater than D-3,5,3'-triiodothyronine (D-T3) greater than L-thyroxine greater than D-thyroxine]. Purified receptor had a sedimentation coefficient of 3.4 S, Stokes radius of 34 A, and calculated molecular mass of 49,000. Among several bands identified by silver staining after electrophoresis in NaDodSO4/polyacrylamide gels, one 49,000-Da protein showed photoaffinity labeling with [125I]thyroxine that was displaceable with excess unlabeled T3. The tryptic fragment and endogenous proteinase-digested fragment of the affinity-labeled receptor showed saturable binding in 27,000-Da and 36,000-Da peptides, respectively. These molecular masses are in agreement with estimates from gel filtration and gradient sedimentation, indicating that affinity labeling occurred at the hormone binding domain of nuclear thyroid hormone receptor. This procedure reproducibly provides classical native rat liver T3 nuclear receptor in useful quantity and purity and of the highest specific activity so far reported.
Animals↗
The influence of thiol derivatives on synthesis of thyroid hormones in human thyroid cultured cells.
The experiments were carried out on 26 lots of thyroid cell cultures treated with sodium sulphate, lithium sulphate, lithium carbonate, cystine, cysteine, and methionine, in 2 doses each, in the presence or absence of iodine in the culture medium. The monolayer culture was used in morphologic, cytochemical and cytoenzymatic studies, and the culture medium was used for assay of thyroglobulin and thyroxin. We found that addition of aminoacids with SH or S--S groups to the culture medium causes stimulation of protein synthesis overstrain on the oxydases system at the expense of dehydrogenases. Stimulation of protein synthesis in the thyroid cell cultures under study is not accompanied by a corresponding hormonal secretory activity, the process of hormonal biosynthesis being inhibited as compared to the control culture.
Cells, Cultured↗
Effect of post-operative thyroid hormone therapy on the recurrence of benign thyroid nodules. A study in Thai patients.
The efficacy of postoperative thyroid hormone treatment in prevention of recurrent thyroid nodule is still controversial. In order to investigate this effect in Thai patients, a retrospective study was performed on files of 321 post-operative patients with benign thyroid nodules, who were either on thyroid hormone treatment or not after surgery, and were followed-up for at least 1 year. The longest follow-up period was 15 years after surgery. The recurrence of nodules was determined by palpation. It was found that the recurrent rate in patients with adenoma who did not receive post-operative thyroid hormone treatment was 20 per cent (16/82 cases) while there was no recurrence at all (0/25 cases) in the treatment group (p < 0.05). The recurrent rate was 22 per cent (31/141 cases) in patients with nodular goitre who did not receive post-operative thyroid hormone treatment and 7 per cent (5/73 cases) in those with treatment (p < 0.001). In the group of patients without post-operative thyroid hormone treatment, for both the group of patients with adenoma and that with nodular goitres, the recurrence was found to occur as late as more than 10 years after surgery.
Adenoma↗