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PubMed2001

Thyroid hormones regulate pituitary growth hormone secretagogue receptor gene expression.

Thyroid hormones regulate growth hormone (GH) secretion by actions both at the hypothalamus and at the pituitary gland. At the level of the pituitary, thyroid hormones increase GH and GH-releasing hormone receptor (GHRH-R) mRNA expression. To test if thyroid hormones might also regulate the pituitary expression of mRNA for the recently identified GH secretagogue (GHS) receptor, GHS-R, primary pituitary cell cultures from adult male rats were treated with triiodothyronine (T3) and GHS-R mRNA levels were assessed by reverse transcriptase-polymerase chain reaction. T3 increased pituitary GHS-R mRNA levels in a dose- and time-dependent manner. The stimulatory action of T3 on GHS-R mRNA levels was also observed in the presence of the RNA synthesis inhibitor, actinomycin D, indicating that gene transcription is not required. Closer examination of the decay rates of GHS-R mRNA in the presence of actinomycin D revealed T3 extended the half-life of the GHS-R mRNA from 8 h (basal) to15 h, demonstrating that T3 increases GHS-R mRNA levels in vitro by increasing message stability.

Animals↗
PubMed2025

Thyroid Hormone Action by Genomic and Nongenomic Molecular Mechanisms.

The thyroid hormones, thyroxine (T4) and triiodothyronine (T3), are pivotal in regulating various physiological processes including growth, development, and metabolism. The biological actions of thyroid hormones are primarily initiated by binding to nuclear thyroid hormone receptors (TRs). These receptors, belonging to the superfamily of nuclear receptors, act as ligand-dependent transcription factors. Transcriptional regulation by TRs is mediated by the recruitment of coregulators, governing activation and repression of target genes, thereby modulating cellular responses to thyroid hormones. Beyond this canonical genomic pathway, TH can regulate the expression of genes not directly bound by TRs through cross-talk mechanisms with other transcription factors and signaling pathways. Thyroid hormones can also elicit rapid non-genomic effects, potentially mediated by extranuclear TR proteins or by interactions with membrane receptors such as integrin αvβ3. This non-genomic mode of action adds another layer of complexity to the diverse array of physiological responses orchestrated by thyroid hormones, expanding our understanding of their multifaceted actions.

Animals↗
PubMed2001

A pituitary tumor in a patient with thyroid hormone resistance: a diagnostic dilemma.

Resistance to thyroid hormone (RTH) is due to mutations in the beta-isoform of the thyroid hormone receptor (TR-beta). RTH patients display inappropriate secretion of thyrotropin-releasing hormone (TRH) from the hypothalamus and thyrotropin (TSH) from the anterior pituitary, despite elevated levels of thyroid hormone thyroxine (T4) and triiodothyronine (T3). Thyrotropin-secreting tumors are presumed to represent clonal expansion of abnormal cells. Because the diagnosis of TSH-secreting tumors tends to be delayed and curative surgical resection remains under 50%, early diagnosis is paramount. Current diagnostic strategies suggest that RTH patients are distinguishable from patients with TSH-secreting pituitary tumors by the use of standard laboratory tests and imaging. Here, we present a woman in whom the standard evaluation for inappropriate TSH secretion was insufficient to distinguish these entities. The patient had a low-normal TRH stimulation test and an unmeasurable alpha-glycoprotein subunit level; however, a pituitary magnetic resonance imaging (MRI) revealed an adenoma. More testing using a T3 suppression test supported a RTH diagnosis and a R438H mutation was found in the TR-beta gene. To our knowledge, this represents the first report of an apparently incidental pituitary adenoma in the setting of documented resistance to thyroid hormone. As such, it raises the question of whether RTH predisposes to pituitary hyperplasia and adenoma development.

Adenoma↗
PubMed1996

Novel uses of thyroid hormones in patients with affective disorders.

Hormones of the thyroid axis have been used to treat patients with any of several mental illnesses. However, in recent decades interest has focused almost exclusively on depression, though thyroid hormones, mainly thyroxine (T4), are used with lithium in rapid cycling bipolar disorder, a condition in which depression and mania rapidly alternate. In depression L-triiodothyronine (T3) has been used in preference to T4 because of its rapid onset and offset of action. In women starting treatment, T3 hastens the onset of therapeutic action of standard antidepressant drugs. It fails to do so in depressed men, who anyway respond faster than women to standard antidepressants. Standard drugs fail to produce satisfactory improvement in one-quarter to one-third of depressed patients. Then, in both men and women, T3 converts about two-thirds of drug failures to successes in rapid fashion. Lithium, which has antithyroid properties, produces a similar conversion rate. The majority of depressed patients are grossly euthyroid, but many show one or another subtle change in thyroid axis activity. However, the thyroid state of patients has not been matched systematically with their response to thyroid hormone augmentation. It seems likely that a tendency toward hypothyroidism can predispose to depression, but when depression occurs in a euthyroid patient, the thyroid axis is often invoked in the process of restitution.

Antidepressive Agents↗
PubMed2000

The localization of thyroid hormone receptor mRNAs in human bone.

Thyroid hormones have well-documented effects on the skeleton although the mechanism of their action on bone is poorly understood. We have recently reported the presence of different thyroid hormone receptor isoforms in human bone. However, there is evidence to suggest that the expression of thyroid hormone receptor (TR) protein may not necessarily correlate with its mRNA. In this study, we used specific digoxigenin-labeled ribo probes to investigate the expression of TRalpha1, variant TRalpha2, TRbeta1, and in particular TRbeta2 mRNA in human osteophytic bone and osteoclastoma tissue in situ. The number of positive cells was expressed as the percentage of the total number of cells of the same phenotype. In osteophytes, at sites of endochondral ossification, TRalpha1, variant TRalpha2, TRbeta1, and TRbeta2 mRNA were widely distributed in undifferentiated, proliferating, mature and hypertrophic chondrocytes. At sites of bone remodeling, TRalpha1 mRNA was expressed in the majority (> 90%) of osteoblasts. TRbeta1 and the variant TR-alpha2 mRNA were moderately expressed in approximately 75% of cells with only a few osteoblasts (< 25%) expressing TRbeta2 mRNA. All the TR transcripts were highly expressed in multinucleated osteoclasts in osteoclastoma tissue. The distribution of TR mRNAs was similar to TR receptor protein expression (as we have previously reported) in both osteophytic bone and osteoclastoma tissue except TRalpha1 mRNA that was highly expressed in osteoclasts and in undifferentiated, proliferating, mature, and hypertrophic chondrocytes in contrast to its receptor protein expression. This study highlights the importance of studying both TR mRNA and receptor proteins in triiodothyronine (T3) responsive tissues. This is also the first demonstration of the presence of TRbeta2 mRNA in bone. The role of TRbeta2 in mediating the actions of thyroid hormones in bone is not known and requires further investigation.

Aged↗
PubMed2004

Dietary soy protein isolate and isoflavones modulate hepatic thyroid hormone receptors in rats.

Thyroid hormone receptors (TRs) are regulators of many genes involved in cholesterol and lipid metabolism. The purpose of this study was to examine the effect of soy protein isolate (SPI) and isoflavones on hepatic TRs in rats. In Expt. 1, Sprague-Dawley rats were fed diets containing either casein or alcohol-washed SPI with or without isoflavone supplementation (5-1250 mg/kg diet) for 70, 190, and 310 d. The offspring (F1) were fed the same diets as their parents (F0). In Expt. 2, Sprague-Dawley rats were fed diets containing casein or casein plus isoflavones (50-400 mg/kg diet) for 120 d. The mRNA and protein contents of the hepatic TRs were measured by semiquantitative RT-PCR and Western blot, respectively. TRalpha1, TRalpha2, and TRbeta2 contents were not affected by SPI. However, the content of the 52-kDa TRbeta1 protein, the major isoform present in the liver, was markedly increased by dietary SPI in both sexes of F0 and F1 compared with casein. The supplemental isoflavones had no effect on TRbeta1, whereas the high doses of isoflavones (250 and 1250 mg/kg diet) reduced the hepatic TRalpha1 protein content in F1 male rats on d 28. SPI had no effect on total T3 and T4 levels. However, higher dose of supplemental isoflavones markedly increased T4 level in female rats. Overall, this study demonstrates for the first time that SPI upregulates hepatic TRbeta1 expression, and that isoflavones reduce the hepatic TRalpha1 level in young male rats. The SPI-induced TRbeta1 may play a role in mediating the hypocholesterolemic and lipid-lowering actions of soy protein.

Animals↗
PubMed1994

Thyroid hormones, the brain, and affective disorders.

Clinical thyroid disorders are frequently associated with psychiatric symptomatology, thus supporting a role for thyroid hormones in the biological basis of psychiatric disorders, particularly mood disorders. Despite extensive literature documenting various abnormalities of thyroid function tests in primary major depression, the role of thyroid hormones in the pathophysiology of affective disorders remains to be clarified. In this review, we describe the various abnormalities of thyroid hormone levels reported in primary affective illness. We also review the competing hypothesis to explain the abnormalities of thyroid function observed. Although neither model can fully explain the role of thyroid hormones in depressive illness, they provide working hypotheses for further study. Additional research is required to clarify the regulation of thyroid hormones by mature brain and the role of these hormones in the biological basis of affective illness.

Brain↗
PubMed1994

Resistance to thyroid hormone and its molecular basis.

Generalized resistance to thyroid hormone (GRTH) is an inherited syndrome characterized by hyposensitivity of target tissues to thyroid hormone. The clinical presentation is variable. The syndrome is usually suspected when elevated serum thyroid hormone levels are associated with a non-suppressed thyroid-stimulating hormone (TSH). While goiter and thyroid test abnormalities have more often led to the suspicion of thyroid gland dysfunction, short stature, hyperactivity, learning disability and goiter in children or adolescents and recalcitrant goiter in adults, should raise the suspicion of GRTH. Hypothyroidism has been considered when growth or mental retardation was the presenting symptom and thyrotoxicosis when confronted with attention deficit, hyperactivity or tachycardia. Failure to recognize the inappropriate persistence of TSH secretion in spite of elevated thyroid hormone levels has commonly resulted in erroneous diagnosis leading to antithyroid treatment. More than 300 subjects with this syndrome have been identified. The mode of inheritance in the majority of families is autosomal dominant. Recessive transmission has been found in only one family. It has long been speculated that this defect is likely to be caused by an abnormal thyroid hormone receptor (TR), but this hypothesis could not be directly tested until the isolation of two TR genes, TR alpha and TR beta. Mutations in the TR beta gene have been identified in 42 families with GRTH. All are located in the T3-binding domain straddling the putative dimerization region and exhibit various degrees of hormone-binding impairment. This finding, and the fact that heterozygous subjects with complete TR deletion are not affected while those with point mutations are, indicates that interactions of a mutant TR with normal TR and with other factors are responsible for the dominant inheritance of GRTH and its heterogeneity. Elucidation of the etiology of GRTH has not only added a new means for the early diagnosis of the syndrome but provided new insights in the understanding of the mechanism of hormone action.

Diagnosis↗
PubMed1999

Novel insight from transgenic mice into thyroid hormone resistance and the regulation of thyrotropin.

Patients with resistance to thyroid hormone (RTH) exhibit elevated thyroid hormone levels and inappropriate thyrotropin (thyroid-stimulating hormone, or TSH) production. The molecular basis of this disorder resides in the dominant inhibition of endogenous thyroid hormone receptors (TRs) by a mutant receptor. To determine the relative contributions of pituitary versus hypothalamic resistance to the dysregulated production of thyroid hormone in these patients, we developed a transgenic mouse model with pituitary-specific expression of a mutant TR (Delta337T). The equivalent mutation in humans is associated with severe generalized RTH. Transgenic mice developed profound pituitary resistance to thyroid hormone, as demonstrated by markedly elevated baseline and non-triodothyronine (T3)-suppressible serum TSH and pituitary TSH-beta mRNA. Serum thyroxine (T4) levels were only marginally elevated in transgenic mice and thyrotropin-releasing hormone (TRH) gene expression in the paraventricular hypothalamus was downregulated. After TRH administration, T4 concentrations increased markedly in transgenic, but not in wild-type mice. Transgenic mice rendered hypothyroid exhibited a TSH response that was only 30% of the response observed in wild-type animals. These findings indicate that pituitary expression of this mutant TR impairs both T3-mediated suppression and T3-independent activation of TSH production in vivo. The discordance between basal TSH and T4 levels and the reversal with TRH administration demonstrates that resistance at the level of both the thyrotroph and the hypothalamic TRH neurons are required to elevate thyroid hormone levels in patients with RTH.

Animals↗
PubMed1981

Characteristics of active transport of thyroid hormone into rat hepatocytes.

Thyroid hormone uptake into primary cultured rat hepatocytes was studied using 1-min incubations with radio-iodine-labelled iodothyronines. (1) Uptake of thyroxine indicates two saturable sites with apparent Km values of 1.2 nM and 1.0 microM, and non-saturable uptake. Similar kinetics of triiodothyronine uptake have been observed. (2) The high-affinity systems of both hormones are energy-dependent (i.e., inhibited by KCN and oligomycin). It is postulated that these systems represent active transport of thyroid hormone into the cell. (3) Analysis of mutual inhibition by the substrates for the triiodothyronine and thyroxine transport systems indicates that triiodothyronine and thyroxine cross the cell membrane via separate transport systems. (4) Preincubation with ouabain resulted in a decrease in uptake of both triiodothyronine and thyroxine, suggesting that a sodium gradient is essential for this transport.

Animals↗
PubMed1991

Regulatory functions of a non-ligand-binding thyroid hormone receptor isoform.

Gene regulation by thyroid hormones is mediated through multiple nuclear receptors. Only some of these thyroid hormone receptor (TR) isoforms become transcriptional enhancers in the presence of the thyroid hormone T3. Here we analyze the regulatory function of the human TR alpha 2 isoform. This protein does not bind T3 and is not a transcriptional activator of thyroid hormone-responsive elements (TRE). Transfected TR alpha 2 functions as a constitutive repressor of the transcriptional activators TR alpha 1 and TR beta 1 but also represses heterologous receptors, including the retinoic acid receptor and the estrogen receptor, which can activate TRE-controlled genes. TR alpha 2 protein showed strongly reduced DNA binding to a palindromic TRE when compared with the active TRs. Hybrid receptor analysis revealed that the special properties of the TR alpha 2 protein, including its repressor function and DNA binding characteristics, are intrinsic properties of its carboxyterminus and can be transferred to other receptors. Although it has been shown that the active TRs can act as repressors and silencers due to their strong DNA binding in the absence of hormone, our data show that TR alpha 2 is unlikely to inhibit TRs and other receptors through a competitive DNA binding mechanism. Antibody gel shift experiments suggest that repression by TR alpha 2 might result from interaction with active receptors. Thus, the receptor-like TR alpha 2 isoform differs from typical nuclear receptors in its DNA-binding and ligand-binding properties and appears to regulate the activity of other receptors via protein-protein interaction.

Base Sequence↗
PubMed2000

Changes in thyroid hormones in the serum and the thyroid gland of hibernating frogs, Rana temporaria L.

The hypothalamo-pituitary-gonadal axis spontaneously activates in hibernating frogs, Rana temporaria, under constant conditions (0-4 degrees, darkness). The hypothesis that the spontaneous hibernatory activation involves other regulatory processes preparing the frogs for breeding and posthibernatory activity was tested. The serum concentrations and glandular contents of thyroid hormones (THs) were determined during hibernation. It was shown that (i) in both sexes, serum thyroxine and triiodothyronine levels significantly increased in the middle of January (week 13/14, between day 92 and 98 of hibernation); (ii) the peak of THs blood concentration was accompanied by a slow decrease of free forms of THs and the bound forms of both hormones dropped rapidly over this period; (iii) after a decrease on day 111, the low level of serum THs (but higher than before the peak) was sustained to the end of hibernation; (iv) the thyroid content of free THs significantly rose after their "surge" into the blood, reached maximal values in the middle of February, and remained at this level to the end of hibernation (last week of March); (v) in spring, after spawning, the THs levels in glands and in serum were much lower than those at the end of hibernation or were not detectable; and (vi) the results were confirmed during the second season, when the material in the period of expected elevation of serum THs was collected every other day.

Animals↗
PubMed1983

Failure to find evidence of immunoglobulin inhibitor(s) of thyroid hormone binding to serum proteins in non-thyroid illnesses.

In order to verify the hypothesis of the presence of IgM (or an IgM-like substance) capable of inhibiting thyroid hormone binding to serum proteins and, therefore, capable of enhancing serum free thyroid fractions in non-thyroid illnesses (NTI), we measured TBG and TBPA maximum binding capacities and TBG concentration by an immunoradiometric system in normal pooled sera (NPS) before and after enrichment with purified immunoglobulins (IgM and IgG) from euthyroid NTI sera (free T4, free T3 and TSH levels were normal). A known amount of TBG was diluted 1:2-1:6 with deionized water or with IgM from NPS or from each of 6 NTI sera; the measured values were not different from these expected on theoretical grounds. Likewise, IgM or IgG from normal or from each of 7 NTI sera failed to modify both TBG and TBPA capacities of different NPS, and NTI immunoglobulins showed no binding activity directed to [125I]T4, [125I]T3 or [125I]TBG. In addition, no inhibitory influence of TBG and TBPA capacities was observed when the whole euglobulin fraction obtained by precipitating the same 7 NTI sera by PEG was mixed with NPS. On the other hand, a significant IgM inhibitory effect on the binding of labelled T4 to TBG was found, only when IgM concentrations were experimentally rendered 41 times greater than that requested in the working mixtures. We conclude that no immunoglobulin inhibitor of thyroid hormone binding to transport proteins was evident in the NTI sera investigated.

Adolescent↗
PubMed1981

Development of support matrices for affinity chromatography of thyroid hormone receptors.

Certain cellular responses to thyroid hormones appear to be mediated by non-histone chromatin protein receptors. Purification of these proteins is important for an investigation of the detailed mechanisms of their regulatory role. In the present studies, we report the development of an affinity chromatographic system that can be used to purify thyroid hormone receptors solubilized from nuclei. Amine-substituted hormone analogs were prepared with D and L isomers of T3; these bind to the receptor. This finding supports the hypothesis that thyroid hormones fit into the receptor with the amino groups accessible from outside the binding site. Although L-triiodothyronine (LT3) (the naturally occurring isomer) binds more tightly (relative Kd = 1.0 nM) to the nuclear receptor than D-triiodothyronine (DT3) (relative Kd = 2.0 nM), the amine-substituted analog of DT3 binds more tightly than the LT3 analog (DT3 analog, relative Kd = 40 nM; LT3 analog, relative Kd = 1500 nM). Agarose-based gels containing DT3 and LT3 covalently coupled by their amino groups were also prepared. Binding of receptor to these gels was biospecific in that it could be inhibited by prior incubation of the receptors with LT3. In addition, as predicted by the analog studies, the DT3 affinity gels were more effective than LT3 gels in adsorbing receptor. Elution of receptor from the LT3-derived gels was achieved in a predicted volume and concentration of counter-ligand in elution buffer. These results suggest that affinity chromatography can be applied to the purification of thyroid hormone receptors.

Animals↗
PubMed1982

Syndromes of thyroid hormone resistance.

Resistance to the action of thyroid hormone can involve both peripheral tissues and the pituitary (global resistance), the pituitary only or peripheral tissues alone. Global resistance is of variable severity and has been observed in more than 60 individuals, the majority occurring in 17 families. Affected subjects are commonly eumetabolic and have goiters, elevated plasma levels of total and free thyroxine and triiodothyronine, normal thyroid hormone metabolism, and normal serum TSH levels (albeit high for the corresponding levels of thyroid hormone). A variable degree of delayed bone maturation, mental retardation, learning disabilities, and hearing defects have been reported; and a variety of treatment regimens, most of which are aimed at reducing the level of plasma hormones and/or goiter, have been attempted before the correct diagnosis has been reached. The clinical disorder is equally common in males and females and appears to be due to one or more autosomal gene mutations. The causes for the hormone resistance may be heterogeneous, either influencing the receptor for thyroid hormones or some unidentified steps in hormone action. At present, the diagnosis is one of exclusion; no effective therapy is available, and all measures designed to lower serum thyroid hormone levels should be avoided.

Adolescent↗
PubMed1994

Thyroid hormones and the central nervous system.

Thyroid hormones have a significant influence on the development and maturation of the central nervous system. Among their actions, T3 and T4 have effects on the differentiation of various cell types in the rat brain and cerebellum as well as on the process of myelination. Recently, several investigators have shown effects of thyroid hormones on myelin protein gene expression. Thyroid hormones seem to have a regulatory role with regard to life span. Hyperthyroid animals appear to have a shorter life and, at advanced age, show a myelin deficit. This may be due to the damage produced by the oxidative stress generated by an excess of thyroid hormones.

Aging↗
PubMedDate not supplied

Response of the rat heart to catecholamines and thyroid hormones.

Catecholamines and thyroid hormones have a similar influence on heart function and metabolism, but this may occur in a differential manner and to a different extent. In this study, the effects of norepinephrine (NE) and of triiodothyronine (T3) were studied in regard to the function of the left (LV) and right ventricle (RV) and to the oxidative pentose phosphate pathway (PPP). NE was applied in rats as continuous i.v. infusion (0.2 mg/kg/h) for three days. T3 was given as daily s.c. injections (0.2 mg/kg) for the same period of time. LV and RV function was measured in the closed-chest trapanal-anesthetized animals using special Millar ultraminature catheter pressure transducers. NE induced an increase in heart rate, in mean arterial pressure, and in total peripheral resistance (TPR). The cardiac RNA/DNA and the left ventricular weight/body weight ratios were increased by about 40%. These effects were prevented by simultaneous alpha- and beta-receptor blockade with prazosin and metoprolol, respectively, but not by verapamil which abolished the hemodynamic effects. RVSP was significantly elevated by NE in a dose-dependent manner. The functional effects of T3 on the LV were not as pronounced as those induced by NE. Heart rate and LV dp/dtmax were increased by T3, and this increase was prevented by concomitant beta-receptor blockade with metoprolol. In contrast to NE, T3 induced an increase in cardiac output and a concomitant decrease in TPR. The RNA/DNA ratio was elevated and cardiac hypertrophy had developed after treatment for three days with T3. These changes were not affected by beta-receptor blockade with metoprolol. RVSP was increased by T3 to a lesser extent than with NE. In metabolic terms it turned out that only NE, but not T3 had a stimulating effect on the cardiac PPP. NE increased the mRNA and activity of glucose-6-phosphate dehydrogenase (G-6-PD), the first and regulating enzyme of this pathway. However, there was no effect of T3 on G-6-PD activity nor on 6-phosphogluconate dehydrogenase activity, one of the following enzymes in the pathway within the first 5 days of T3 treatment. These results demonstrate that the functional effects of T3 were not as pronounced as or even different from those of NE, and that T3 lacked a stimulating effect on the cardiac PPP.

Adrenergic Antagonists↗
PubMed1997

Gender-specific induction of pituitary RNA by estrogen and its modification by thyroid hormone.

Estrogen and thyroid hormones play important roles in the regulation of pituitary function. We presently show that pituitary weight and total cellular RNA levels were significantly decreased by ovariectomy in female rats and were significantly increased by castration in males, without alterations in pituitary DNA levels as compared to intact animals. Treatment with a single dose of estrogen produced a significant increase in pituitary RNA in ovariectomized females but not castrated males. This effect was more obvious following multiple doses of estrogen, and was blocked by pretreatment with cycloheximide, or surprisingly by concomitant administration of triiodothyronine (T3). Analysis of estrogen response element (ERE) binding activity in pituitary nuclear protein extracts revealed that estrogen produced a rapid induction of a slow mobility complex of ERE binding in ovariectomized females much greater than in castrated males. Thus, estrogen-induced increases in pituitary total RNA levels are dependent on new protein synthesis, are gender-specific, are inhibited by T3, and may be mediated via specific estrogen-induced changes in protein-DNA interactions.

Animals↗