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PubMedDate not supplied

Effects of thyroid hormones on heart and kidney functions.

Thyroid hormones affect the functions of several organs including the heart and kidney. Using isolated left papillary muscles we have investigated the action of thyroid hormones on the mechanical and electrical properties of the heart. We found that pure hypothyroidism causes a depression in contractile and electrical parameters, but we noticed that superimposed hypoparathyroidism accounts for the marked prolongation in contractile kinetics and action potential duration. At kidney level we have shown that thyroid hormones affect proximal tubular sodium transport and this effect is only partially mediated by the action of thyroid hormones on Na-K-ATPase activity. Using the micropuncture technique, we hypothesized that the early effect of thyroid hormone action is on the potassium permeability of proximal tubular cell membrane. This latter effect would explain the increase in isotonic fluid reabsorption through an increase in the driving force for sodium. Finally, hypothyroid patients have a decrease in glomerular filtration rate and renal plasma flow that are completely reversed by thyroxine administration. On the other hand, hyperthyroid subjects exhibit a significant increase in both parameters.

Animals↗
PubMed1990

Growth hormone (GH) regulation of cytochrome P-450IIC12, insulin-like growth factor-I (IGF-I), and GH receptor messenger RNA expression in primary rat hepatocytes: a hormonal interplay with insulin, IGF-I, and thyroid hormone.

We have studied the GH-dependent expression of cytochrome P-450IIC12 (P-450(15)beta) mRNA and insulin-like growth factor-I (IGF-I) mRNA in primary adult rat hepatocytes. The GH receptor (GHR), being the common denominator for the GH response, was also studied. The respective mRNA levels were measured with specific solution hybridization assays. By investigating the effects of insulin, IGF-I, T3, and corticosterone, alone or in combinations, in the presence or absence of GH we concluded that GH is indeed the inducer of P-450(15)beta mRNA and IGF-I mRNA. However, insulin and IGF-I exerted a 2-fold potentiation of the GH-induced expression of the P-450(15)beta and IGF-I mRNA species. No significant effect of insulin was observed on GHR mRNA expression, but a translational or posttranslational effect on GHR was seen, in that insulin increased the binding of GH to the cells 4-fold. Furthermore, T3 caused a 9-fold increase in the GH-induced expression of IGF-I mRNA. These observations led us to postulate a possible mechanism of hormonal interplay between GH, thyroid hormone, and IGF-I in vivo, i.e. a thyroid hormone potentiation of the GH-induced IGF-I expression, which, in turn, leads to an increased GHR level and thereby a potentiation of the GH-induced expression of P-450(15)beta and, at least transiently, of IGF-I. A transcriptional mechanism of GH action on P-450(15)beta and IGF-I mRNA induction was indicated by the similar half-lives of respective mRNAs in the presence or absence of GH in cell cultures treated with actinomycin-D.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed2003

Effect of thyroid hormone on gene expression.

PURPOSE OF REVIEW: Thyroid hormones are key regulators of development and metabolism that modulate transcription via nuclear receptors. Although the molecular actions of thyroid hormones have been thoroughly studied, their pleiotropic effects are mediated by complex changes in expression of numerous, but still largely unknown, target genes. This review summarizes the recent advances in the characterization of target genes in different organs. RECENT FINDINGS: New patterns of gene expression regulation have been described in tissues with known physiological actions of thyroid hormone, that is brain, liver, skeletal and cardiac muscles, and brown and white adipose tissues. The studies have benefited from the numerous transgenic models with altered thyroid hormone receptor expression and the application of DNA microarray technology to mouse and human tissues. SUMMARY: Data on thyroid hormone-mediated control of gene expression and on the roles of the different thyroid hormone receptor isoforms bring new clues to our understanding of the molecular mechanisms of thyroid hormone action in physiological situations and, most importantly, in diseases associated with alterations of the thyroid status.

Adipose Tissue↗
PubMed1989

Limitations of interpretation of age-related changes in hormone levels: illustration by effects of thyroid hormones on cardiac and skeletal muscle.

Studies on age-related changes in hormone secretion or circulation are frequently interpreted to indicate changes in the functions of target tissues for that hormone. Such interpretations are not necessarily correct. For instance, the levels of thyroid hormone change modestly with age, and responses to this change differ dramatically in cardiac and skeletal muscles. There is a substantial change in myosin isozyme content of the heart, but little or no change in skeletal muscle fiber type distribution in specific pathogen free (SPF) barrier-protected rats. These changes (or lack of them) are reflected in functional differences (or lack of them) in the target tissues. The most obvious difference between the recent studies showing no differences with age in skeletal muscle fiber distribution and previous reports of general decreases with age in content of fast fibers is in animal housing conditions; all of the animals showing an age-related change had been housed in conventional colonies, while those exhibiting little or no change were in SPF barrier-protected facilities.

Aging↗
PubMed2003

Thyroid hormone deiodinases: physiology and clinical disorders.

Thyroid hormone action is achieved through the binding of 3,5,3'-triiodothyronine to its nuclear receptor, which results in alterations in gene expression. An impairment in thyroid hormone action during vertebrate development results in severe, irreversible abnormalities in tissue growth, maturation, and function. The deiodinases are a family of selenoproteins expressed in a number of fetal and adult tissues that catalyze the activation and inactivation of thyroid hormones. Their unique biochemical characteristics and tissue and developmental expression patterns suggest that deiodinases may control the concentration of active thyroid hormone available to specific tissues or cell types at certain stages of development. The deiodinases thus appear to play an important role in regulating thyroid hormone action at a prereceptor level. Current research focusing on a better understanding of the biochemistry, regulation, and physiologic role of these enzymes is the focus of this review.

Animals↗
PubMedDate not supplied

[Comparison of administration of rhTSH with withdrawal of thyroid hormone. Follow-up of patients with differentiated thyroid carcinoma].

UNLABELLED: Recombinant human thyrotropin (rhTSH) has been introduced recently in follow up of differentiated thyroid cancer (DTC) patients, as an alternative of thyroid hormone withdrawal. The aim of this retrospective study is to compare recombinant human thyrotropin versus endogenous stimulation. MATERIAL AND METHODS: Thirty-three patients with DTC with previous thyroidectomy and thyroid ablation were selected. All patients underwent whole-body radioiodine scanning and third day serum thyroglobulin (TG) measurement by two techniques, the first one after conventional thyroid hormone withdrawal (TSHe, TGe), and the second one after rhTSH stimulation (TSHr, TGr). Measurement of TG was performed on the third day due to the infrastructure. We only included patients with stable disease, without therapeutic interventions between two consecutive controls in an interval inferior to one year. Two qualitative categories were defined for TG (positive TG > 2 ng/ml or negative TG<2 ng/ml) and whole-body radioiodine scan (positive or negative). RESULTS: TSHe: 62.9 +/- 55.48; TSHr: 113.16 +/- 50.6; (p: ns); TGe: 62.5 +/- 115.7; TGr: 54.6 +/- 111.1; (p: 0.044). Quantitative data analysis showed significant differences between two techniques. Qualitative data analysis showed no significant differences in clinical setting based in TG and radioiodine scan. CONCLUSIONS: Administration of rhTSH produces a significantly higher increase of TSH than thyroid hormone withdrawal and lower increase in TG levels. There were no significant differences in the stage of disease (TG and whole-body radioiodine scan).

Adenocarcinoma, Follicular↗
PubMed2004

Human fetal and cord serum thyroid hormones: developmental trends and interrelationships.

Thyroid hormone is essential for fetal and neonatal development in particular of the brain, but little is known about regulation of fetal thyroid hormone levels throughout human gestation. The purpose of this study was to clarify developmental trends and interrelationships among T(4), free T(4) (FT4), thyroxine-binding globulin (TBG), TSH, T(3), rT(3), and T(4) sulfate (T4S) levels in cord and fetal blood sera (n = 639, 15-42 wk gestation) and correlate infant levels (23-42 wk gestation) to maternal values (n = 428, 16-45 yr) and those of nonpregnant women (n = 233, 16-46 yr). In cord and fetal serum, T(4), T(3), and TBG levels increase with gestation until term; TSH, FT4, T4S, and rT(3) levels increase and peak in the late second/early third trimester and then decline to term; T(4)/TBG ratios increase until late second trimester and plateau to term. Term cord sera TSH, TBG, and all iodothyronine levels, except T(3), are higher than nonpregnant women. In the third trimester, cord serum FT4, TSH, rT(3), and T4S levels are also higher than corresponding maternal levels, but T(4), T(3), and TBG levels are lower than maternal values. The late second/early third trimester is a critical transition period in fetal thyroid hormone metabolism, which may be interrupted by preterm birth and contribute to postnatal thyroid dysfunction.

Cohort Studies↗
PubMed2000

An element in the region responsible for premature termination of transcription mediates repression of c-myc gene expression by thyroid hormone in neuroblastoma cells.

The thyroid hormone (T3) blocks proliferation and induces differentiation of neuroblastoma N2a-beta cells that express the thyroid hormone receptor (TR) beta1 isoform. c-Myc is required for cell cycle progression, and this study shows that T3-induced neuronal differentiation is preceded by a rapid decrease of c-myc gene expression. A negative T3 responsive element (TRE), arranged as an inverted palindrome spaced by three nucleotides, has been identified within the first exon between nucleotides +237 and +268. The TRE is adjacent to the binding site for the transcriptional repressor CCCTC binding factor and maps precisely within the region of RNA polymerase II pausing and release, suggesting a direct implication of TR on premature termination of transcription. Furthermore, the TRE confers repression by T3 to an heterologous promoter only when inserted downstream of the transcription initiation site. Binding of CCCTC binding factor and TR to their cognate sites in the region of transcriptional attenuation, as well as direct interactions between both factors, could facilitate the formation of a repressor complex and the inhibition of c-myc gene expression. These studies provide insight into mechanisms by which TR mediate transcriptional repression and contribute to the understanding of the important effects of thyroid hormones on growth and differentiation of neuronal cells.

Animals↗
PubMed2001

Effects of thyroid hormones on cardiac structure: a tissue characterization study in patients with thyroid disorders before and after treatment.

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

Adult↗
PubMed1999

Promoting effects of kojic acid due to serum TSH elevation resulting from reduced serum thyroid hormone levels on development of thyroid proliferative lesions in rats initiated with N-bis(2-hydroxypropyl)nitrosamine.

In order to examine whether kojic acid (KA) exerts a promoting effect on thyroid carcinogenesis, male F344 rats were initiated with N-bis(2-hydroxypropyl)nitrosamine (BHP; 2800 mg/kg body wt, single s.c. injection) and, starting 1 week later, received pulverized basal diet containing 2 or 0% KA for 12 weeks. Untreated control rats were given basal diet for 13 weeks. As an additional experiment, two groups without BHP initiation received basal diet or diet containing 2% KA for 20 weeks. The serum triiodothyronine (T3) and thyroxine (T4) levels were significantly decreased (half to one-third of values of the BHP alone group) and serum thyroid-stimulating hormone (TSH) was markedly increased (13-19 times higher than the values of the BHP-alone group) in the BHP + KA group at weeks 4 and 12. Similar changes in serum thyroid-related hormones were observed in the group with 2% KA alone at week 4, but not at week 20. Thyroid weights were significantly increased in the BHP + KA and KA-alone groups. Focal thyroid follicular hyperplasias and adenomas were observed in 4/5 and 3/ 5 rats in the BHP + KA group at week 4, respectively. At weeks 12, these lesions were observed in all rats in the BHP + KA group. Animals of the KA alone group showed marked diffuse hypertrophy of follicular epithelial cells at weeks 4 and 20. No changes in thyroid-related hormone levels or thyroid histopathological lesions were observed in either the BHP alone or the untreated control groups. Measurement of liver T4-uridine diphosphate glucuronosyltransferase (UDP-GT) activity at week 4 revealed no significant intergroup differences. These results suggest that thyroid proliferative lesions were induced by KA administration due to continuous serum TSH stimulation through the negative feedback mechanism of the pituitary-thyroid axis, with decreases of T3 and T4 caused by a mechanism independent of T4-UDP-GT activity.

Adenoma↗
PubMed2004

[Familial generalized thyroid hormone resistance. Report of one case].

Thyroid hormone resistance is a rare autosomal dominant disease associated, in more than 90% of cases, to mutations in the beta thyroid hormone receptor. We report a 23 years old male that consulted for a psychiatric condition. Clinically, the patient was euthyroid in spite of high total and free T4 and T3 concentrations, while TSH remained normal. Also, TSH showed a five fold increase under TRH stimulation. The mother and one of his brothers had the same pattern of abnormal serum thyroid hormones. We discuss the diagnostic considerations and the protocol to study this rare pathology.

Adult↗
PubMed1999

Phenobarbital, beta-naphthoflavone, clofibrate, and pregnenolone-16alpha-carbonitrile do not affect hepatic thyroid hormone UDP-glucuronosyl transferase activity, and thyroid gland function in mice.

The effects of representative liver enzyme inducers such as clofibrate (CLO), phenobarbital (PB), pregnenolone-16alpha-carbonitrile (PCN), and beta-naphthoflavone (NF) on hepatic microsomal thyroxin (T4)- UDP-glucuronosyl transferase (UGT) and triiodothyronine (T3)- UGT activities and thyroid function were evaluated in OF-1 male mice after a 14-day po administration. CLO, PB, and PCN induced histological liver hypertrophy, increases in liver weights, in microsomal protein and cytochrome P450 contents as well as increases in specific UGT activities. Despite this, no significant changes in T4-UGT and T3-UGT activities occurred after treatment by any of these compounds. Furthermore, no significant changes in serum T4 and T3 levels were observed and thyroid histology was not affected. NF treatment induced microvacuolation of hepatocytes but did not affect any of the other tested parameters. The results show that, in contrast to the widely described effects in rats, liver enzyme inducers do not affect hepatic thyroid hormone metabolism and thyroid function in mice, suggesting that this species should be less sensitive to thyroid tumor promotion by hepatic microsomal enzyme inducers than rats.

Animals↗
PubMed2000

Thyroid hormone receptor, v-ErbA, and chromatin.

The thyroid hormone receptor and the highly related viral oncoprotein v-erbA are found exclusively in the nucleus as stable constituents of chromatin. Unlike most transcriptional regulators, the thyroid hormone receptor binds with comparable affinity to naked and nucleosomal DNA. In vitro reconstitution experiments and in vivo genomic footprinting have delineated the chromatin structural features that facilitate association with the receptor. Chromatin bound thyroid hormone receptor and v-erbA generate Dnase I hypersensitive sites independent of ligand. The unliganded thyroid hormone receptor and v-erbA associate with a corepressor complex containing NCoR, SIN3, and histone deacetylase. The enzymatic activity of the deacetylase and a chromatin environment are essential for the dominant repression of transcription by both the unliganded thyroid hormone receptor and v-erbA. In the presence of ligand, the thyroid hormone receptor undergoes a conformational change that weakens interactions with the corepressor complex while facilitating the recruitment of transcriptional coactivators such as p300 and PCAF possessing histone acetyltransferase activity. The ligand-bound thyroid hormone receptor directs chromatin disruption events in addition to histone acetylation. Thus, the thyroid hormone receptor and v-erbA make very effective use of their stable association with chromatin and their capacity to alter the chromatin environment as a major component of the transcription regulation process. This system provides an exceptionally useful paradigm for investigating the structural and functional consequences of targeted chromatin modification.

Animals↗
PubMed2003

Microarray analysis of knockout mice identifies cyclin D2 as a possible mediator for the action of thyroid hormone during the postnatal development of the cerebellum.

Thyroid hormone is a major regulator of postnatal brain development, but the precise molecular mechanisms underlying its action in this organ remain poorly understood. We used microarray analysis to identify new target genes in brain. Thyroid hormone treatment of hypothyroid Pax8(-/-) knockout mice, which lack thyroid follicular cells, had a very limited global effect on brain transcripts. This analysis mainly identified cyclin D2 as a new thyroid hormone target gene in the cerebellum of hypothyroid mice. Thyroid hormone receptor (TRalpha and/or TRbeta) knockout mice studies provided further genetic evidence that cyclin D2 is likely to mediate the antiapoptotic effect exerted by thyroid hormone on the cerebellum external granular layer neuroblasts but that this transcriptional activation is not directly exerted by the thyroid hormone receptors.

Animals↗
PubMed2000

Thyroid hormone action in neural development.

Effects of thyroid hormone on development of the brain have been documented for over a century. Although in many respects the hypothyroid brain appears morphologically normal, functional impairments include mental retardation, ataxia and spasticity. Keyed by the discovery of nuclear receptors for thyroid hormone that function as transcription factors, recent work has examined the mechanism of thyroid hormone action in brain development. The prediction that gene expression regulated by thyroid hormone is important for mediating brain development has spurred the search for thyroid hormone-responsive genes. Here we review some of the identified genes whose expression patterns correlate with the functional deficits observed in the hypothyroid brain. Recently identified thyroid hormone-responsive genes include synaptotagmin-related gene 1 (Srg1), a putative mediator of synaptic structure and/or activity, and hairless, a transcriptional cofactor that may influence the expression of other thyroid hormone-responsive genes.

Aging↗
PubMed1985

Autoantibodies against thyroid hormones or iodothyronine. Implications in diagnosis, thyroid function, treatment, and pathogenesis.

The presence of antithyroid hormone autoantibodies in the sera of patients with thyroid and nonthyroid disorders is a well-known condition. When circulating thyroid hormones bind to the patients' immunoglobulins, serum levels of total and free thyroid hormones are often in discordance with clinical features. This problem occurs because the autoantibodies can interfere with radioimmunoassays. To avoid inappropriate treatment of such patients, it is clinically important to consider the presence of autoantibodies in patients with unexpectedly high or low total and free thyroid hormone values. We have reviewed the English and Japanese literature, both case reports and basic works, and summarize the incidence of antithyroid hormone autoantibodies, clinical features, effects on appropriate testing of the hypothalamic-pituitary-thyroid axis, diagnostic methods for confirming their presence of autoantibodies, treatment of patients with these disorders, and possible pathogenetic mechanisms.

Autoantibodies↗
PubMed2003

Epidermal growth factor receptor expression is related to post-mitotic events in cerebellar development: regulation by thyroid hormone.

It has been established that thyroid hormone and neurotrophic factors both orchestrate developmental events in the brain. However, it is not clear how these two influences are related. In this study, we investigated the effects of thyroid hormone on cerebellar development and the coincident expression of transforming growth factor-alpha (TGF-alpha), a ligand in the epidermal growth factor (EGF) family, and the epidermal growth factor receptor (EGFR). Profiles of thyroid hormone expression were measured in postnatal animals and were found to peak at postnatal day 15 (P15). These levels dropped below detectable levels when mice were made hypothyroid with propylthiouracil (PTU). TGF-alpha and EGFR expression, as determined by RNAse protection assay, was maximal at P6 in normal animals, but remained low in hypothyroid animals, suggesting that thyroid hormone was responsible for their induction. In situ hybridization and immunohistochemical analysis of EGFR expression revealed that this receptor was present on granule cells within the inner zone of the external granule cell layer (EGL), suggesting that EGFR-ligands were not inducing granule cell proliferation. The persistence of EGFR expression on migrating granule cells and subsequent down-regulation of expression in the internal granule cell layer (IGL) implicates a role for EGFR-ligands in differentiation and/or migration. In hypothyroid animals, we observed a delayed progression of granule cell migration, consistent with the persistence of EGFR labeling in the EGL, and in the 'pile-up' of labeled cells at the interface between the molecular layer and the Purkinje cell layer. Taken together, these results implicate thyroid hormone in the coordinated expression of TGF-alpha and EGFR, which are positioned to play a role in post-mitotic developmental events in the cerebellum.

Aging↗