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PubMedDate not supplied

Thyroid hormone and the heart.

Thyroid hormone has important cardiovascular effects, and abnormalities of its production cause cardiovascular morbidity. The role of both excessive and insufficient thyroid hormone production in the pathogenesis of clinical cardiac diseases can be deduced from thyroid hormone-induced molecular changes. Thyroid hormone regulates the expression of myocardial genes regulating the handling of calcium, which affects both systolic and diastolic myocardial function. Thyroid hormone also has indirect and direct effects on peripheral vascular smooth muscle tone, and alters the coupling of the left ventricle and arterial system. Excessive production of thyroid hormone results in an increased cardiac output as well as increased cardiac work efficiency, but reduced cardiac reserve. Amiodarone therapy for cardiac rhythm can cause both hyper- and hypothyroidism. Amiodarone-induced thyrotoxicosis (AIT) can be due to either excessive thyroid hormone production (type I AIT) or thyroid hormone release due to an inflammatory condition (type II AIT). Classification of AIT is helpful in guiding therapy. Amiodarone causes changes in the thyroid function tests of euthyroid patients on therapy--it inhibits the conversion of T(4) and T(3), which results in decreased T(3) and slightly increased T(4) serum levels in euthyroid patients. Baseline thyroid functions should therefore be determined before starting amiodarone therapy, and at 6-monthly intervals thereafter.

Amiodarone↗
PubMed1996

Serum prolactin, growth hormone, total corticoids, thyroid hormones and thyrotropine during serial therapeutic sleep deprivation.

In 13 patients fulfilling DSM-III-R criteria for a major depressive episode, hormone serum levels were measured at 8 AM on the day before and on the first and second days after partial sleep deprivation (PSD) late in the night during a 4-week course of therapy with amitriptyline in combination with 6 PSDs. Prolactin, human growth hormone (HGH) and total corticoids were not influenced by PSD. In contrast, T3 and thyrotropine (TSH) were elevated significantly on the 1st day after PSD throughout the series, but T4 less regularly. Although TSH reverted regularly to baseline values on the 2nd day after PSD, i.e. after a full night's sleep, T3 remained elevated. The hormones under discussion do not predict the therapeutic PSD effect. Nor can any correlation be determined between endocrine and clinical changes on the 1st or 2nd day after PSD. In connection with findings from sleep deprivation research in animals and in healthy subjects, the results suggest that thyroid changes under PSD may be nonspecific and unrelated to antidepressive PSD effects.

Adrenal Cortex Hormones↗
PubMed1991

Inhibitory effects of ionophore A23187 on the release of thyroid hormone and colloid reabsorption in mouse thyroid glands.

The effect of the ionophore A23187 on a. the release of thyroid hormone from perifused mouse thyroid glands and b. the morphological changes in follicular epithelial cells was evaluated. A23187 at a concentration of 5 mumol/l significantly inhibited both the TSH- and the forskolin-stimulated release of T3 and T4. In the presence of 3-isobutyl-1-methylxanthine or (4-(3-butoxy-4-methoxybenzyl)-2-imidazolidinone) RO 20-1724, A23187 did not affect the forskolin-stimulated release of cAMP, but did inhibit the release of T3 and T4 stimulated by forskolin. Light and electron microscopic evaluation of the follicular epithelial cells of mouse thyroid tissues following 1-h stimulation with forskolin showed numerous pseudopods engulfing luminal colloid of various size and the presence of reabsorbed colloid droplets in the apical cytoplasm. Quantitative electron microscopic analysis revealed that the addition of the ionophore A23187 reduced the number of reabsorbed colloid droplets to one eighth in follicular epithelial cells. These observations suggest that the increase in intracellular Ca2+ induced by the ionophore A23187 inhibits the TSH-stimulated thyroid hormone release independently of the cAMP level, and that the suppression of thyroid hormone release may be due to an inhibition of colloid reabsorption.

1-Methyl-3-isobutylxanthine↗
PubMed2001

Chromatin remodeling by the thyroid hormone receptor in regulation of the thyroid-stimulating hormone alpha-subunit promoter.

The chromatin architecture of a promoter is an important determinant of its transcriptional response. For most target genes, the thyroid hormone receptor (TR) activates gene expression in response to thyroid hormone (T(3)). In contrast, the thyroid-stimulating hormone alpha-subunit (TSH alpha) gene promoter is down-regulated by TR in the presence of T(3). Here we utilize the capacity for the Xenopus oocyte to chromatinize exogenous nuclear- injected DNA to analyze the chromatin architecture of the TSH alpha promoter and how this changes upon TR-mediated regulation. Interestingly, in the oocyte, the TSH alpha promoter was positively regulated by T(3). In the inactive state, the promoter contained six loosely positioned nucleosomes. The addition of TR/retinoid X receptor together had no effect on the chromatin structure, but the inclusion of T(3) induced strong positioning of a dinucleosome in the TSH alpha proximal promoter that was bordered by regions that were hypersensitive to cleavage by methidiumpropyl EDTA. We identified a novel thyroid response element that coincided with the proximal hypersensitive region. Furthermore, we examined the consequences of mutations in TR that impaired coactivator recruitment. In a comparison with the Xenopus TR beta A promoter, we found that the effects of these mutations on transactivation and chromatin remodeling were significantly more severe on the TSH alpha promoter.

Animals↗
PubMed2005

Efficacy of thyroid hormone suppression for benign thyroid nodules: meta-analysis of randomized trials.

OBJECTIVE: To determine the efficacy of thyroid hormone suppressive therapy (THST) to decrease benign thyroid nodule volume. DESIGN: Meta-analysis. METHODS: Systematic search using electronic databases (PubMed, Medline, Cochrane Library) through August 2004, paper review, and contacting experts and drug manufacturers. Only randomized controlled studies of THST vs no treatment or placebo, for reduction of benign thyroid nodule volume, were included. Exclusion criteria were: <6-month treatment, lack of ultrasound volume measurement, and region of endemic goiter. Primary outcome was clinically relevant nodule volume reduction (>50%), with a random effects model (RevMan4.2). RESULTS: Nine randomized trials were included (609 subjects). Subjects were 88% more likely to experience >50% nodule volume reduction with THST than placebo or no treatment (relative risk = 1.88; 95% CI = 1.18-3.01; P = 0.008). However, 8 subjects must be subjected to the risk of cardiac and skeletal side effects from THST, for one to benefit from therapy (number needed to treat = 8, risk difference = 0.13; 95% CI = 0.06-0.19; P = 0.0003). Sensitivity analysis reveals that 15 null studies would have to have been missed to reverse statistical significance (fail-safe N = 15). Review of the only study with long-term treatment (5 years) suggests no significant difference in nodule volume reduction between THST and placebo. Further, studies with follow-up after THST withdrawal demonstrate rapid increase in thyroid nodule and goiter volumes. CONCLUSION: THST appears more likely than placebo or no treatment to significantly reduce benign thyroid nodule volume, but long-term treatment may be less effective and regrowth is likely following cessation of therapy. Given the risks of THST, routine use is not recommended for benign nodules.

Humans↗
PubMed1997

Hormone-activated phosphorylation of human beta1 thyroid hormone nuclear receptor.

To understand the role of phosphorylation in the hormone-dependent transcriptional activation of thyroid hormone receptors (TRs), the present study evaluated the effect of the thyroid hormone, 3,3',5-triiodo-L-thyronine (T3) on the phosphorylation of TR, human subtype beta1 (h-TRbeta1). The extent of phosphorylation was compared in cells cultured in T3-depleted (Td) or T3-supplemented medium (Td + T3). T3 was found to activate phosphorylation of h-TRbeta1 approximately threefold. Taking into account the T3-induced fourfold downregulation in the expression of h-TRbeta1 in the same period, the specific T3-activated phosphorylation was increased approximately twelvefold. Phosphoamino acid analysis indicates that the phosphorylation of serine and threonine in a ratio of approximately 10:1 was increased approximately threefold by T3. Comparison of the [32P]-labeled tryptic maps of h-TRbeta1 phosphorylated in cells cultured in Td medium or Td + T3 medium indicates that the latter had fewer fragments and changes of intensities in several common fragments, indicating that the phosphorylation sites activated by T3-treatment differed from those of basal phosphorylation. Partial V8 and chymotrypic proteolysis indicates that h-TRbeta1 phosphorylated in cells cultured in Td + T3 medium was more resistant to proteolysis. These results indicate that T3-activated phosphorylation altered the protease susceptibility of h-TRbeta1 that could reflect structural changes in h-TRbeta1. These results raise the possibility that T3-activated phosphorylation may play an important role in transcriptional activation of h-TRbeta1.

Cell Line↗
PubMed1988

Thyroid hormone down-regulates p55, a thyroid hormone-binding protein that is homologous to protein disulfide isomerase and the beta-subunit of prolyl-4-hydroxylase.

We have previously characterized a cellular thyroid hormone-binding protein (p55) that is found concentrated on the lumenal face of the endoplasmic reticulum and nuclear envelope (Cheng, S.-y., Hasumura, S., Willingham, M.C., and Pastan, I. (1986) Proc. Natl. Acad. Sci. U.S.A. 83, 947-951). To understand the role p55 plays in thyroid hormone action, we examined the regulation of p55 by 3,3',5-triiodo-L-thyronine (T3). Rat pituitary tumor GH3 cells cultured in regular medium, thyroid hormone-depleted medium (Td medium), or Td medium supplemented with 50 nM T3 (Td + T3 medium) were metabolically labeled with [35S]methionine and immunoprecipitated with antibodies against p55. Treatment with T3 caused a fall in p55 levels. Poly(A+) RNA from cells cultured in regular, Td, or Td + T3 medium was hybridized to a cDNA from p55. T3 withdrawal or addition had no effect on p55 mRNA levels. Furthermore, the initial rates of synthesis of p55 from cells cultured in regular, Td, and Td + T3 were found to be similar. However, analysis of the decay curves from cells in which p55 was pulse-labeled with [35S]methionine indicated that p55 is 2-fold less stable in T3 containing medium. These results indicated that down-regulation of p55 by T3 occurs at the post-translational level. Since DNA sequence analysis indicates that p55 is identical to protein disulfide isomerase and the beta-subunit of prolyl-4-hydroxylase, T3 may mediate its effects on the synthesis, secretion, and/or transport of proteins via p55.

Animals↗
PubMed1994

Evidence for the secretion of thyrotropin with enhanced bioactivity in syndromes of thyroid hormone resistance.

Resistance to thyroid hormone (RTH) is a rare genetic disorder associated with diverse mutations in the thyroid hormone receptor beta-gene. TSH-dependent thyroid hyperstimulation, leading to goiter and elevated thyroid hormone levels, is a characteristic feature of RTH. However, about 60% of untreated resistance patients have circulating TSH levels within the normal range, raising the possibility that the biological activity of TSH is altered. We, therefore, assayed the bioactivity of circulating TSH in 11 patients from 8 different kindreds with RTH, measuring cAMP production in Chinese hamster ovary cells transfected with the recombinant human TSH receptor as well as in FRTL-5 cells. The ratio of biologically active vs. immunoreactive TSH (B/I) was significantly higher in RTH patients than in 8 normal controls [TSH B/I, 4.2 +/- 0.9 (range, 2.2-11.9) vs. 1.3 +/- 0.2 (range, 0.6-2.1)]. TSH released in response to TRH had a bioactivity similar to that of circulating TSH under basal conditions. On the contrary, supraphysiological doses of T3 normalized the B/I ratio of circulating TSH. Concanavalin-A chromatography of TSH from RTH patients showed the presence of circulating forms with altered carbohydrate branching. Our data indicate that the bioactivity of circulating TSH in thyroid hormone resistance syndromes is enhanced and can be normalized after T3 administration. These findings may account for the occurrence of goiter and elevated thyroid hormone levels in RTH patients despite normal serum TSH concentrations.

Adult↗
PubMed2003

Successful therapy with L-T4 in a 5 year-old boy with generalized thyroid hormone resistance.

Resistance to thyroid hormone (RTH) is a rare dominantly inherited disorder caused by mutations in the thyroid hormone receptor beta gene which lead to impaired tissue responsiveness to thyroid hormone (TH). RTH is characterized by elevated free thyroid hormone and unsuppressed thyrotropin (TSH) levels. Two types of the disorder have been recognized: selective pituitary resistance and generalized resistance to TH (GRTH). Triiodothyroacetic acid has been used in patients showing hypermetabolism, and L-T4 treatment in high doses has been suggested in GRTH if patients have signs of clinical hypothyroidism such as growth retardation and developmental delay. The outcome of long-term treatment of GRTH with L-T4 has not yet been reported. We report a 5 year-old boy who presented with severe growth retardation, fatigue and speech delay. He had hyperactivity despite feeling tired easily. Elevated TH levels with unsuppressed TSH and delayed bone age were determined by laboratory evaluation and he was diagnosed as GRTH. There was no clinicical evidence of hypermetabolism. We could not demonstrate any mutation in thyroid receptor beta1, beta2 or alpha gene of this patient and his parents. L-T4 treatment was started at conventional doses (6 microg/kg), and after 3 months of treatment T4 and TSH levels were suppressed successfully. In 12 months of treatment, no side effects were detected and surprisingly clinical symptoms improved without requirement for high doses of L-T4.

Child, Preschool↗
PubMed2002

Endogenous excitatory amino acid neurotransmission regulates thyroid-stimulating hormone and thyroid hormone secretion in conscious freely moving male rats.

The role of neurotransmission of endogenous excitatory amino acid (EAA) on serum thyroid hormones and thyroid-stimulating hormone (TSH) levels was examined in conscious and freely moving adult male Sprague-Dawley rats. The rats were cannulated at the third ventricle 2 d before the experiments. Several glutamate receptor agonists, such as kainic acid and domoic acid, and antagonists, such as 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX) and dizocilpine (MK-801) were administered into the third ventricle. Serum TSH levels were assesed by radioimmunoassay, and serum thyroid hormone levels were assessed by enzyme immunoassay. The results showed that the administration of CNQX and MK-801 produced a decrease in serum levels of TSH and thyroid hormones. The administration of kainic acid and domoic acid increased TSH concentrations, whereas CNQX completely blocked the release of TSH induced by kainic acid and domoic acid. These results suggest the importance of endogenous EAA in the regulation of hormone secretion from the pituitary-thyroid axis, as well as the role of the N-methyl-D-aspartate (NMDA) and non-NMDA receptors in the stimulatory effect of EAAs on the pituitary-thyroid axis.

6-Cyano-7-nitroquinoxaline-2,3-dione↗
PubMed1995

Thyroid hormones and brain development.

Thyroid hormone is a major physiological regulator of mammalian brain development. Cell differentiation, migration and gene expression are altered as a consequence of thyroid hormone deficiency or excess. The physiological role of thyroid hormone can perhaps be defined so as to ensure the timed coordination of different developmental events through specific effects on the rate of cell differentiation and gene expression. All triiodothyronine (T3) receptor isoforms are expressed in the brain and their spatial and temporal patterns of expression suggest unique and complementary functions for the different isoforms. Cell biology studies suggest a role for T3 and its receptors in oligodendroglial and neuronal differentiation and the control of cell death. Some of the effects on neuronal differentiation might be due to an action of thyroid hormone on the production of neurotropins and their receptors. In recent years a number of T3-dependent genes have been identified in the rat brain, such as myelin protein-encoding genes or specific neuronal genes, and thyroid hormone-responsive elements have been demonstrated in some of these genes. The identification of the gene network regulated by thyroid hormone during brain development, the elucidation of the mechanism of regulation and the clarification of the physiological roles of the regulated genes remain major goals for future studies.

Animals↗
PubMed2005

Dual functions of the steroid hormone receptor coactivator 3 in modulating resistance to thyroid hormone.

Mutations of the thyroid hormone receptor beta (TRbeta) gene cause resistance to thyroid hormone (RTH). RTH is characterized by increased serum thyroid hormone associated with nonsuppressible thyroid-stimulating hormone (TSH) and impaired growth. It is unclear how the actions of TRbeta mutants are modulated in vivo to affect the manifestation of RTH. Using a mouse model of RTH that harbors a knockin mutation of the TRbeta gene (TRbetaPV mouse), we investigated the effect of the steroid hormone receptor coactivator 3 (SRC-3) on RTH. In TRbetaPV mice deficient in SRC-3, dysfunction of the pituitary-thyroid axis and hypercholesterolemia was lessened, but growth impairment of RTH was worsened. The lessened dysfunction of the pituitary-thyroid axis was attributed to a significant decrease in growth of the thyroid and pituitary. Serum insulin-like growth factor 1 (IGF-1) was further reduced in TRbetaPV mice deficient in SRC-3. This effect led to reduced signaling of the IGF-1/phosphatidylinositol 3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) pathway that is known to mediate cell growth and proliferation. Thus, SRC-3 modulates RTH by at least two mechanisms, one via its role as a receptor coregulator and the other via its growth regulatory role through the IGF-1/PI3K/AKT/mTOR signaling.

Body Weight↗
PubMed1981

Thyroid hormones and muscle protein turnover. The effect of thyroid-hormone deficiency and replacement in thryoidectomized and hypophysectomized rats.

We have investigated the effects of thyroidectomy, hypophysectomy and 3,3',5-tri-iodothyronine replacement on protein synthesis and degradation in skeletal muscle in vivo. Thyroidectomy resulted in a decrease in the rate of protein synthesis as a result of a loss of RNA. However, RNA activity, the rate of protein synthesis per unit of RNA, was not decreased. This was the case in both young growing rats and mature nongrowing rats. Tri-iodothyronine treatment of thyroidectomized rats increased protein synthesis by increasing RNA concentration without changes in RNA activity, and this occurred even when food intake was restricted to prevent any increase in growth. The rate of protein degradation was decreased by thyroidectomy and increased by tri-iodo-thyronine replacement in both animals fed ad libitum and food-restricted animals. Hypophysectomy decreased protein synthesis by decreasing both RNA concentration and activity. these changes were reversed by tri-iodothyronine treatment even in the presence of persistent marked hypoinsulinaemia. This indicates that tri-iodothyronine can activate athe translational phase of protein synthesis in muscle in the absence of significant quantities of insulin. However, tri-iodothyronine does not seem to be obligatory for the maintenance of normal RNA activity in muscle, since in the thyroidectomized rat, in which plasma insulin concentrations are normal, RNA activity is maintained. From a consideration of the magnitude of changes in RNA activity observed in these experiments, it would appear that alterations in rates of elongation as well as initiation are involved in the changes in RNA activity.

Animals↗
PubMed1983

Differences in iodinated peptides and thyroid hormone formation after chemical and thyroid peroxidase-catalyzed iodination of human thyroglobulin.

The distribution of iodine among the polypeptides of human goiter thyroglobulin (Tg) was examined. Tg was iodinated in vitro with 131I to levels of 2 to 84 gram atoms (g.a.)/mol using thyroid peroxidase (TPO) or a chemical iodination system. The samples were reduced, alkylated, and subjected to sodium dodecyl sulfate-polyacrylamide gel electrophoresis. Two low-molecular-weight peptides appeared preferentially in radioautograms of the sodium dodecyl sulfate (SDS) gels of TPO-iodinated samples. Iodination of these peptides increased sharply in the TPO-treated Tg as the level of total iodine/molecule rose. Radioiodine was incorporated into these same gel regions in the chemically treated Tg, but only after much higher levels of total iodination were reached. Differences in iodoamino acid distribution were also noted between the chemically and enzymatically iodinated thyroglobulins. In the chemically iodinated samples, little thyroxine (T4) was synthesized, even at high iodine levels. In the TPO-treated samples only small amounts of T4 were seen below 14 g.a. total I/mol, while at or above that level of iodination T4 formation increased sharply. To examine the coupling process, Tg was chemically iodinated, excess I- removed, and the samples treated with TPO and a H2O2-generating system in the absence of iodide. Radioautograms obtained from SDS-polyacrylamide gels of reduced and alkylated protein from such coupling assays showed an increase in the level of iodine in the low-molecular-weight peptides after TPO treatment. Thyroxine production also increased with TPO treatment. The addition of free DIT (a known coupling enhancer) to the [131I]Tg/TPO incubation increased both the production of T4 and the amount of iodine in the smaller polypeptides. Two-dimensional maps prepared from CNBr-digested TG showed differences between the coupled and uncoupled samples. Our observations confirm the importance of the low-molecular-weight peptides derived from Tg in thyroid hormone synthesis. At total iodine levels above 14 g.a./mol Tg in enzymatically treated samples there is selective incorporation of iodine into both the low-molecular-weight polypeptides and into thyroid hormone.

Adult↗
PubMed1991

Influence of thyroid hormone and retinoic acid on slow sarcoplasmic reticulum Ca2+ ATPase and myosin heavy chain alpha gene expression in cardiac myocytes. Delineation of cis-active DNA elements that confer responsiveness to thyroid hormone but not to retinoic acid.

The mRNA encoding the sarcoplasmic reticulum (SR) Ca2+ ATPase is highly influenced by thyroid hormone (T3) in the hearts of intact animals. We show here that this effect of T3 can be mimicked in primary neonatal rat cardiocytes, both in serum-containing and in serum-free media; the expression of SR Ca2+ ATPase mRNA is myocyte-specific and is also modulated by retinoic acid (RA). RA also induces myosin heavy chain (MHC) alpha-mRNA in this system. The induction of Ca2+ ATPase mRNA is sensitive to T3 (EC50 approximately 30 pM) and less sensitive to RA (EC50 approximately 2 nM). Transient transfection experiments utilizing various segments of the Ca2+ATPase promoter fused to the reporter gene chloramphenicol acetyltransferase (CAT) indicate a minimal thyroid hormone response element (TRE) between nucleotides -262 and -322, while sequences between -322 and -559 are required for maximal trans-activation. RA is not able to regulate these constructs. Likewise, a clear effect of T3 but no effect of RA was observed when the CAT gene was driven by a TRE derived from the rat alpha-MHC gene. In contrast, CAT expression was induced by either hormone when placed under the control of a synthetic palindromic TRE. Taken together, these results indicate that T3 and RA induce gene expression in primary cardiac myocytes, but through distinct response elements and/or mechanisms.

Animals↗