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Sample records for nongenomic thyroid hormone

  1. Overlapping nongenomic and genomic actions of thyroid hormone and steroids

    PubMed Central

    Hammes, Stephen R.; Davis, Paul J.

    2016-01-01

    The genomic actions of thyroid hormone and steroids depend upon primary interactions of the hormones with their specific nuclear receptor proteins. Formation of nuclear co-activator or co-repressor complexes involving the liganded receptors subsequently result in transcriptional events—either activation or suppression—at genes that are specific targets of thyroid hormone or steroids. Nongenomic actions of thyroid hormone and steroids are in contrast initiated at binding sites on the plasma membrane or in cytoplasm or organelles and do not primarily require formation of intranuclear receptor protein-hormone complexes. Importantly, hormonal actions that begin nongenomically outside the nucleus often culminate in changes in nuclear transcriptional events that are regulated by both traditional intranuclear receptors as well as other nuclear transcription factors. In the case of thyroid hormone, the extranuclear receptor can be the classical “nuclear” thyroid receptor (TR), a TR isoform, or integrin αvβ3. In the case of steroid hormones, the membrane receptor is usually, but not always, the classical “nuclear” steroid receptor. This concept defines the paradigm of overlapping nongenomic and genomic hormone mechanisms of action. Here we review some examples of how extranuclear signaling by thyroid hormone and by estrogens and androgens modulates intranuclear hormone signaling to regulate a number of vital biological processes both in normal physiology and in cancer progression. We also point out that nongenomic actions of thyroid hormone may mimic effects of estrogen in certain tumors. PMID:26303085

  2. Overlapping nongenomic and genomic actions of thyroid hormone and steroids.

    PubMed

    Davis, Paul J; Lin, Hung-Yun; Mousa, Shaker A; Luidens, Mary K; Hercbergs, Aleck A; Wehling, Martin; Davis, Faith B

    2011-08-01

    Nuclear receptors for thyroid hormone and steroids are members of a receptor superfamily with similar molecular organization, but discrete transcriptional functions that define genomic actions of these nonpeptide hormones. Nongenomic actions of thyroid hormone and estrogens and androgens are initiated outside the nucleus, at receptors in the plasma membrane or in cytoplasm; these actions are largely regarded to be unique to the respective hormones. However, there is an increasing number of descriptions of overlapping nongenomic and genomic effects of thyroid hormone and estrogens and testosterone. These effects are concentrated in tumor cells, where, for example, estrogens and thyroid hormone have similar mitogen-activate protein kinase (MAPK)-dependent proliferative actions on ERα-positive human breast cancer cells, and where dihydrotestosterone also can stimulate proliferation. Steroids and thyroid hormone have similar anti-apoptotic effects in certain tumors. But thyroid hormone and steroids also have overlapping or interacting nongenomic and genomic actions in heart and brain cells. These various effects of thyroid hormone and estrogens and androgens are reviewed here and their possible clinical consequences are enumerated. Copyright © 2011 Elsevier Inc. All rights reserved.

  3. Non-genomic actions of thyroid hormone in brain development.

    PubMed

    Leonard, Jack L

    2008-10-01

    Thyroid hormone (TH) is essential for neuronal migration and synaptogenesis in the developing brain. Assembly of neuronal circuits depends on guidance cues provided by the extracellular matrix. These cues are interpreted by the migrating neuron and its growing neurites through transmembrane signaling proteins anchored in place by the actin cytoskeleton. One of the best examples of a non-genomic action of thyroid hormone is its dynamic regulation of the number and quantity of actin fibers in astrocytes. Thyroxine (T4) and its transcriptionally inactive metabolite, 3',5',3-triiodothyronine (reverse T3) are responsible for modulating microfilament organization, while the transcriptional activator, 3',3,5-triiodothyronine (T3) is inert. The biological consequence of the loss of the actin filaments in astrocytes is the inability of the cell to anchor laminin, to its cell surface, and the loss of this key guidance molecule interrupts neurite pathfinding and neuronal migration. These data provide the essentials to construct a physiological pathway where TH-dependent regulation of the polymerization state of actin in the astrocyte and the developing neuron modulates the production and recognition of guidance cues--cues that if disrupted lead to abnormal neuronal migration and neuronal process formation--and lead to the morphological deficits observed in the cretinous brain.

  4. Nongenomic signaling pathways triggered by thyroid hormones and their metabolite 3-iodothyronamine on the cardiovascular system.

    PubMed

    Axelband, F; Dias, J; Ferrão, F M; Einicker-Lamas, M

    2011-01-01

    Thyroid hormones play a wide range of important physiological activities in almost all organism. As changes in these hormones levels-observed in hypothyroidism and hyperthyroidism-promote serious derangements of the cardiovascular system, it is important to know their mechanisms of action. Although the classic genomic actions which are dependent on interaction with nuclear receptors to modulate cardiac myocytes genes expression, there is growing evidence about T(3) and T(4)-triggered nongenomic pathways, resulted from their binding to plasma membrane, cytoplasm, or mitocondrial receptors that leads to a rapidly regulation of cardiac functions. Interestingly both actions converge to amplify thyroid hormone effects on cardiovascular system. T(3) and T(4) nongenomic actions modify inotropic and chronotropic effects, cardiac action potential duration, cardiac growth, and myocyte shape by protein translation through protein kinases-dependent signaling cascades, which include PKA, PKC, PI3K, and MAPK, and changes on ion channels and pumps activity. In respect to the decreased systemic vascular resistance seen in hyperthyroidism, T(3) appears to activate NOS or ATP-sensitive K(+) channels. In addition, a novel biologically active T(4)-derived metabolite has been described, 3-iodothyronamine, T(1)AM, which also acts through membrane receptors to mediate nongenomic cardiac effects. This metabolite influences the physiological manifestations of thyroid hormone actions by inducing opposite effects from those stimulated by T(3) and T(4), such as negative inotropic and chronotropic effects. Therefore, beyond genomic and nongenomic effects of thyroid hormones, it is crucial for there to be an equilibrium between T(3) or T(4) and T(1)AM levels for maintaining cardiac homeostasis.

  5. Nongenomic effect of thyroid hormone on free-radical production in human polymorphonuclear leukocytes.

    PubMed

    Mezosi, E; Szabo, J; Nagy, E V; Borbely, A; Varga, E; Paragh, G; Varga, Z

    2005-04-01

    Over the past few years increasing evidence has suggested the nongenomic effects of thyroid hormone, such as the activation of the signal transduction pathways and the activation of nuclear factor-kappaB by the induction of oxidative stress. The present study was undertaken to investigate the effect of thyroid hormone on human polymorphonuclear leukocytes (PMNLs) which are known as important sources of reactive oxygen species in the circulation. The production of superoxide anion (O2-) and the activity of myeloperoxidase were determined in the presence and absence of several inhibitors of the signalling pathway. L-thyroxine (T4) l-3,5,3'-tri-iodothyronine (T3) and L-3,5-di-iodothyronine (T2) stimulated O2- production in PMNLs in a dose-dependent manner within a few minutes of addition to cells. Thyroid hormone-stimulated O2- production was partially inhibited by pertussis toxin, an inhibitor of GTP-binding G protein, and was completely abolished by the protein kinase C inhibitors calphostin C and Ro-32-0432, and by a calcium chelator (BAPTA; bis-(o-aminophenoxy)ethane-N,N,N',N'-tetra-acetic acid). Thyroid hormone stimulated myeloperoxidase activity and induced 125I- incorporation into PMNLs. Furthermore, thyroid hormone pre-incubation enhanced O2- production for n-formyl-methionyl-leucyl- phenylalanine (FMLP) stimulation. In conclusion, novel nongenomic actions of thyroid hormone, the induction of superoxide anion production and the stimulation of myeloperoxidase activity in PMNLs were demonstrated. The induction of O2- production requires calcium and is mediated by a pertussis toxin-sensitive G protein via stimulation of protein kinase C(s). These results suggest the existence of a membrane-bound binding site for thyroid hormone in PMNLs and a physiological role for thyroid hormone in the cellular defence mechanisms by stimulating free-radical production.

  6. Low concentrations of bisphenol a suppress thyroid hormone receptor transcription through a nongenomic mechanism

    SciTech Connect

    Sheng, Zhi-Guo; Tang, Yuan; Liu, Yu-Xiang; Yuan, Ye; Zhao, Bao-Quan; Chao, Xi-Juan; Zhu, Ben-Zhan

    2012-02-15

    Bisphenol (BPA) is one of the highest-volume chemicals produced worldwide, and human exposure to BPA is thought to be ubiquitous. Various rodent and in vitro studies have shown that thyroid hormone (TH) function can be impaired by BPA. However, it is still unknown if low concentrations of BPA can suppress the thyroid hormone receptor (TR) transcription. The present study aims to investigate the possible suppressing effects of low concentrations of BPA on TR transcription and the involved mechanism(s) in CV-1 cells derived from cercopithecus aethiops monkey kidneys. Using gene reporter assays, BPA at concentrations as low as 10{sup −9} M suppresses TR or steroid receptor coactivator-1(SRC-1)-enhanced TR transcription, but not reducing TR/SRC-1 interaction in mammalian two-hybrid and glutathione S-transferase pull-down studies. It has been further shown that both nuclear receptor co-repressor (N-CoR) and silencing mediator for retinoid and thyroid hormone receptors (SMRT) are recruited to the TR-β1 by BPA in the presence of physiologic concentrations of T3 or T4. However, the overexpression of β3 integrin or c-Src significantly reduces BPA-induced recruitment of N-CoR/SMRT to TR or suppression of TR transcription. Furthermore, BPA inhibits the T3/T4-mediated interassociation of the β3 integrin/c-Src/MAPK/TR-β1 pathways by the co-immunoprecipitation. These results indicate that low concentrations of BPA suppress the TR transcription by disrupting physiologic concentrations of T3/T4-mediated β3 integrin/c-Src/MAPK/TR-β1 pathways, followed by recruiting N-CoR/SMRT to TR-β1, providing a novel insight regarding the TH disruption effects of low concentration BPA. -- Highlights: ► Environmentally relevant concentrations of BPA suppress TR transcription. ► BPA recruits the N-CoR/SMRT to TR under the physiologic concentrations of T3/T4. ► BPA disrupts T3/T4-mediated β3 integrin/c-Src/MAPK/TR-β1 pathways.

  7. Thyroid hormones affect the membrane dipolar organization. Is it a general event in their non-genomic action?

    PubMed

    Isse, B; Fidelio, G; Farías, R N

    2003-02-01

    The surface balance technique was employed to study the interactions of 3,5,3',5' tetraiodo L-thyronine, 3,5,3' triiodo L-thyronine, and 3,5-diiodothyronine with monomolecular phospholipid monolayers spread at the air-water interface. With this technique the insertion of thyroid hormones into egg yolk phosphatidylcholine was investigated. An increase of surface pressure and a substantial decrement in surface potential were observed after the injection of these hormones beneath a phospholipid monolayer. The negative dipole contribution upon hormone interaction opposes the well-known positive contribution of phospholipids. These effects correlated with iodo content of the thyroid molecule analogues 3,5,3',5' tetraiodo L-thyronine >3,5,3' triiodo L-thyronine >3,5-diiodothyronine. To our knowledge, these observations suggest a new and surprising effect of thyroid hormones on the regulation of transmembrane dipolar organization.

  8. [Thyroid hormone and the cardiovascular system].

    PubMed

    Fraczek, Magdalena Maria; Łacka, Katarzyna

    2014-09-01

    It is well established that thyroid hormones affect the cardiovascular system through genomic and nongenomic actions. TRalpha1 is the major thyroid hormone receptor in the heart. T3 suppresses increased mitotic activity of stimulated cardiomyocytes. Hyperthyroidism induces a hyperdynamic cardiovascular state, which is associated with enhanced left ventricular systolic and diastolic function and the chronotropic and inotropic properties of thyroid hormones. Hypothyroidism, however, is characterized by opposite changes. In addition, thyroid hormones decrease peripheral vascular resistance, influence the rennin-angiotensin system (RAS), and increase blood volume and erythropoetin secretion with subsequent increased preload and cardiac output. Thyroid hormones play an important role in cardiac electrophysiology and have both pro- and anti-arrhytmic potential. Thyroid hormone deficiency is associated with a less favorable lipid profile. Selective modulation of the TRbeta1 receptor is considered as a potential therapeutic target to treat dyslipidemia without cardiac side effects. Thyroid hormones have a beneficial effect on limiting myocardial ischemic injury, preventing and reversing cardiac remodeling and improving cardiac hemodynamics in endstage heart failure. This is crucial because a low T3 syndrome accompanies both acute and chronic cardiac diseases.

  9. [Thyroid hormone resistance syndromes].

    PubMed

    Bernal, Juan

    2011-04-01

    Thyroid hormone resistance syndromes are a group of genetic conditions characterized by decreased tissue sensitivity to thyroid hormones. Three syndromes, in which resistance to hormone action is respectively due to mutations in the gene encoding for thyroid hormone receptor TRβ, impaired T4 and T3 transport, and impaired conversion of T4 to T3 mediated by deiodinases. An updated review of each of these forms of resistance is provided, and their pathogenetic mechanisms and clinical approaches are discussed.

  10. Thyroid Stimulating Hormone Receptor

    PubMed Central

    Tuncel, Murat

    2017-01-01

    Thyroid stimulating hormone receptor (TSHR) plays a pivotal role in thyroid hormone metabolism. It is a major controller of thyroid cell function and growth. Mutations in TSHR may lead to several thyroid diseases, most commonly hyperthyroidism. Although its genetic and epigenetic alterations do not directly lead to carcinogenesis, it has a crucial role in tumor growth, which is initiated by several oncogenes. This article will provide a brief review of TSHR and related diseases. PMID:28117293

  11. Thyroid Stimulating Hormone Receptor.

    PubMed

    Tuncel, Murat

    2016-01-05

    Thyroid stimulating hormone receptor (TSHR) plays a pivotal role in thyroid hormone metabolism. It is a major controller of thyroid cell function and growth. Mutations in TSHR may lead to several thyroid diseases, most commonly hyperthyroidism. Although its genetic and epigenetic alterations do not directly lead to carcinogenesis, it has a crucial role in tumor growth, which is initiated by several oncogenes. This article will provide a brief review of TSHR and related diseases.

  12. [Thyroid hormones and cardiovascular system].

    PubMed

    Límanová, Zdeňka; Jiskra, Jan

    Cardiovascular system is essentially affected by thyroid hormones by way of their genomic and non-genomic effects. Untreated overt thyroid dysfunction is associated with higher cardiovascular risk. Although it has been studied more than 3 decades, in subclinical thyroid dysfunction the negative effect on cardiovascular system is much more controversial. Large meta-analyses within last 10 years have shown that subclinical hyperthyroidism is associated with higher cardiovascular risk than subclinical hypothyroidism. Conversely, in patients of age > 85 years subclinical hypothyroidism was linked with lower mortality. Therefore, subclinical hyperthyroidism should be rather treated in the elderly while subclinical hypothyroidism in the younger patients and the older may be just followed. An important problem on the border of endocrinology and cardiology is amiodarone thyroid dysfunction. Effective and safe treatment is preconditioned by distinguishing of type 1 and type 2 amiodarone induced hyperthyroidism. The type 1 should be treated with methimazol, therapeutic response is prolonged, according to recent knowledge immediate discontinuation of amiodarone is not routinely recommended and patient should be usually prepared to total thyroidectomy, or rather rarely 131I radioiodine ablation may be used if there is appropriate accumulation. In the type 2 there is a promt therapeutic response on glucocorticoids (within 1-2 weeks) with permanent remission or development of hypothyroidism. If it is not used for life-threatening arrhytmias, amiodarone may be discontinuated earlier (after several weeks). Amiodarone induced hypothyroidism is treated with levothyroxine without amiodarone interruption.Key words: amiodarone induced thyroid dysfunction - atrial fibrillation - cardiovascular risk - heart failure - hyperthyroidism - hypothyroidism - thyroid stimulating hormone.

  13. Thyroid hormone transporter defects.

    PubMed

    Grüters, Annette

    2007-01-01

    In in vitro experiments, active transport of thyroid hormones had been repeatedly demonstrated. The membrane transporters for thyroid hormones which have been identified include the organic anion transporting polypeptide, heterodimeric amino acid transporters and the monocarboxylate transporters (MCT) which are the focus of this chapter. The gene encoding MCT8 which was identified as a specific thyroid hormone transporter is located on chromosome Xq13.2. The expression pattern of MCT8 indicates that MCT8 plays an important role in the development of the central nervous system by transporting thyroid hormone into neurons as its main target cells. Mutational analysis of the MCT8 gene revealed mutations or deletions in the MCT8 gene in unrelated male patients with severe psychomotor retardation and biochemical findings consistent with thyroid hormone resistance. Indeed, thyroid function tests in patients with MCT8 mutations demonstrated marked elevations of serum T3 (in the thyrotoxic range), a significant decrease in serum T4 or fT4 and normal to elevated TSH levels.

  14. Membrane rafts as potential sites of nongenomic hormonal signaling in prostate cancer.

    PubMed

    Freeman, Michael R; Cinar, Bekir; Lu, Michael L

    2005-08-01

    Recent evidence indicates that nuclear receptors for steroid hormones can signal by nongenomic mechanisms that operate independently of their transcription function. These signal-transduction processes occur within seconds to minutes after initiation with agonist and involve interactions between nuclear receptors and other signaling proteins in the cytoplasm and at membrane surfaces. This review provides an overview of published information on possible nongenomic activities of the androgen receptor (AR) and other nuclear receptors, focusing on the potential involvement of these processes in prostate cancer. We discuss the hypothesis that the cholesterol-rich lipid-raft compartment(s) of cancer-cell membranes might provide privileged sites for nongenomic signals mediated by the AR.

  15. Thyroid hormones and the cardiovascular system: pathophysiology and interventions.

    PubMed

    Cini, G; Carpi, A; Mechanick, J; Cini, L; Camici, M; Galetta, F; Giardino, R; Russo, M A; Iervasi, G

    2009-12-01

    Thyroid dysfunction, however mild, can significantly affect the cardiovascular (CV) system. The effects of thyroid hormones may be viewed as genomic and non-genomic, with the former occurring over a longer time scale and both affecting structural and functional proteins in CV tissue. As the interplay between thyroid function and the CV system becomes elucidated, particularly in the context of a system biology approach, the heart failure phenotype is better understood. Symptomatology is related to disturbance in inotropic and chronotropic function. Moreover, biochemical changes reflected by thyroid function testing with the non-thyroidal illness syndrome can prognosticate and guide therapy in heart failure. In addition, empiric treatment with thyroid hormone analogues or T3 represent emergent and highly controversial interventions.

  16. Effects of thyroid hormones on the heart.

    PubMed

    Vargas-Uricoechea, Hernando; Bonelo-Perdomo, Anilsa; Sierra-Torres, Carlos Hernán

    2014-01-01

    Thyroid hormones have a significant impact on heart function, mediated by genomic and non-genomic effects. Consequently, thyroid hormone deficiencies, as well as excesses, are expected to result in profound changes in cardiac function regulation and cardiovascular hemodynamics. Thyroid hormones upregulate the expression of the sarcoplasmic reticulum calcium-activated ATPase and downregulate the expression of phospholamban. Overall, hyperthyroidism is characterized by an increase in resting heart rate, blood volume, stroke volume, myocardial contractility, and ejection fraction. The development of "high-output heart failure" in hyperthyroidism may be due to "tachycardia-mediated cardiomyopathy". On the other hand, in a hypothyroid state, thyroid hormone deficiency results in lower heart rate and weakening of myocardial contraction and relaxation, with prolonged systolic and early diastolic times. Cardiac preload is decreased due to impaired diastolic function. Cardiac afterload is increased, and chronotropic and inotropic functions are reduced. Subclinical thyroid dysfunction is relatively common in patients over 65 years of age. In general, subclinical hypothyroidism increases the risk of coronary heart disease (CHD) mortality and CHD events, but not of total mortality. The risk of CHD mortality and atrial fibrillation (but not other outcomes) in subclinical hyperthyroidism is higher among patients with very low levels of thyrotropin. Finally, medications such as amiodarone may induce hypothyroidism (mediated by the Wolff-Chaikoff), as well as hyperthyroidism (mediated by the Jod-Basedow effect). In both instances, the underlying cause is the high concentration of iodine in this medication. Copyright © 2014 Sociedad Española de Arteriosclerosis. Published by Elsevier España. All rights reserved.

  17. Thyroid hormone and the heart.

    PubMed

    Moolman, J A

    2002-01-01

    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.

  18. Thyroid Hormones and Methylmercury Toxicity

    PubMed Central

    O’Mara, Daniel M.; Aschner, Michael

    2013-01-01

    Thyroid hormones are essential for cellular metabolism, growth, and development. In particular, an adequate supply of thyroid hormones is critical for fetal neurodevelopment. Thyroid hormone tissue activation and inactivation in brain, liver, and other tissues is controlled by the deiodinases through the removal of iodine atoms. Selenium, an essential element critical for deiodinase activity, is sensitive to mercury and, therefore, when its availability is reduced, brain development might be altered. This review addresses the possibility that high exposures to the organometal, methylmercury (MeHg), may perturb neurodevelopmental processes by selectively affecting thyroid hormone homeostasis and function. PMID:18716716

  19. Thyroid hormones and cardiovascular disease.

    PubMed

    Jabbar, Avais; Pingitore, Alessandro; Pearce, Simon H S; Zaman, Azfar; Iervasi, Giorgio; Razvi, Salman

    2017-01-01

    Myocardial and vascular endothelial tissues have receptors for thyroid hormones and are sensitive to changes in the concentrations of circulating thyroid hormones. The importance of thyroid hormones in maintaining cardiovascular homeostasis can be deduced from clinical and experimental data showing that even subtle changes in thyroid hormone concentrations - such as those observed in subclinical hypothyroidism or hyperthyroidism, and low triiodothyronine syndrome - adversely influence the cardiovascular system. Some potential mechanisms linking the two conditions are dyslipidaemia, endothelial dysfunction, blood pressure changes, and direct effects of thyroid hormones on the myocardium. Several interventional trials showed that treatment of subclinical thyroid diseases improves cardiovascular risk factors, which implies potential benefits for reducing cardiovascular events. Over the past 2 decades, accumulating evidence supports the association between abnormal thyroid function at the time of an acute myocardial infarction (MI) and subsequent adverse cardiovascular outcomes. Furthermore, experimental studies showed that thyroid hormones can have an important therapeutic role in reducing infarct size and improving myocardial function after acute MI. In this Review, we summarize the literature on thyroid function in cardiovascular diseases, both as a risk factor as well as in the setting of cardiovascular diseases such as heart failure or acute MI, and outline the effect of thyroid hormone replacement therapy for reducing the risk of cardiovascular disease.

  20. Thyroid Hormone Deiodinases and Cancer

    PubMed Central

    Casula, Sabina; Bianco, Antonio C.

    2012-01-01

    Deiodinases constitute a group of thioredoxin fold-containing selenoenzymes that play an important function in thyroid hormone homeostasis and control of thyroid hormone action. There are three known deiodinases: D1 and D2 activate the pro-hormone thyroxine (T4) to T3, the most active form of thyroid hormone, while D3 inactivates thyroid hormone and terminates T3 action. A number of studies indicate that deiodinase expression is altered in several types of cancers, suggesting that (i) they may represent a useful cancer marker and/or (ii) could play a role in modulating cell proliferation – in different settings thyroid hormone modulates cell proliferation. For example, although D2 is minimally expressed in human and rodent skeletal muscle, its expression level in rhabdomyosarcoma (RMS)-13 cells is threefold to fourfold higher. In basal cell carcinoma (BCC) cells, sonic hedgehog (Shh)-induced cell proliferation is accompanied by induction of D3 and inactivation of D2. Interestingly a fivefold reduction in the growth of BCC in nude mice was observed if D3 expression was knocked down. A decrease in D1 activity has been described in renal clear cell carcinoma, primary liver cancer, lung cancer, and some pituitary tumors, while in breast cancer cells and tissue there is an increase in D1 activity. Furthermore D1 mRNA and activity were found to be decreased in papillary thyroid cancer while D1 and D2 activities were significantly higher in follicular thyroid cancer tissue, in follicular adenoma, and in anaplastic thyroid cancer. It is conceivable that understanding how deiodinase dysregulation in tumor cells affect thyroid hormone signaling and possibly interfere with tumor progression could lead to new antineoplastic approaches. PMID:22675319

  1. Modulation of angiogenesis by thyroid hormone and hormone analogues: implications for cancer management.

    PubMed

    Mousa, Shaker A; Lin, Hung-Yun; Tang, Heng Yuan; Hercbergs, Aleck; Luidens, Mary K; Davis, Paul J

    2014-07-01

    Acting via a cell surface receptor on integrin αvβ3, thyroid hormone is pro-angiogenic. Nongenomic mechanisms of actions of the hormone and hormone analogues at αvβ3 include modulation of activities of multiple vascular growth factor receptors and their ligands (vascular endothelial growth factor, basic fibroblast growth factor, platelet-derived growth factor, epidermal growth factor), as well as of angiogenic chemokines (CX3 family). Thyroid hormone also may increase activity of small molecules that support neovascularization (bradykinin, angiotensin II) and stimulate endothelial cell motility. Therapeutic angio-inhibition in the setting of cancer may be opposed by endogenous thyroid hormone, particularly when a single vascular growth factor is the treatment target. This may be a particular issue in management of aggressive or recurrent tumors. It is desirable to have access to chemotherapies that affect multiple steps in angiogenesis and to examine as alternatives in aggressive cancers the induction of subclinical hypothyroidism or use of antagonists of the αvβ3 thyroid hormone receptor that are under development.

  2. Thyroid Hormones as Renal Cell Cancer Regulators

    PubMed Central

    Matak, Damian; Bartnik, Ewa; Szczylik, Cezary; Czarnecka, Anna M.

    2016-01-01

    It is known that thyroid hormone is an important regulator of cancer development and metastasis. What is more, changes across the genome, as well as alternative splicing, may affect the activity of the thyroid hormone receptors. Mechanism of action of the thyroid hormone is different in every cancer; therefore in this review thyroid hormone and its receptor are presented as a regulator of renal cell carcinoma. PMID:27034829

  3. Thyroid hormone biosynthesis and release.

    PubMed

    Carvalho, Denise P; Dupuy, Corinne

    2017-01-31

    Thyroid hormones (TH) 3,5,3',5'- tetraiodothyronine or thyroxine (T4) and 3,5,3'- triiodothyronine (T3) contain iodine atoms as part of their structure, and their synthesis occur in the unique structures called thyroid follicles. Iodide reaches thyroid cells through the bloodstream that supplies the basolateral plasma membrane of thyrocytes, where it is avidly taken up through the sodium/iodide symporter (NIS). Thyrocytes are also specialized in the secretion of the high molecular weight protein thyroglobulin (TG) in the follicular lumen. The iodination of the tyrosyl residues of TG preceeds TH biosynthesis, which depends on the interaction of iodide, TG, hydrogen peroxide (H2O2) and thyroid peroxidase (TPO) at the apical plasma membrane of thyrocytes. Thyroid hormone biosynthesis is under the tonic control of thyrotropin (TSH), while the iodide recycling ability is very important for normal thyroid function. We discuss herein the biochemical aspects of TH biosynthesis and release, highlighting the novel molecules involved in the process.

  4. Thyroid hormone disorders and sepsis.

    PubMed

    Luo, Bin; Yu, Zhui; Li, Yinping

    2017-01-01

    Sepsis is a systemic inflammatory response syndrome with high mortality, which results from severe infection and can lead to secondary organ dysfunction. It is one of the most common cause of death in intensive care unit. Clinical reports have shown that sepsis was often accompanied by thyroid dysfunction, which is called "low triiodothyronine (T3)" syndrome and characterized by decreased blood total T3 and free T3, and by normal or decreased thyroxine (T4) and thyroid stimulating hormone (TSH). This syndrome may greatly affect the prognosis of patients with sepsis. The main purpose of this review is to illustrate the role of thyroid hormone disorder in the development and prognosis of sepsis.

  5. Thyroid hormones and heart failure.

    PubMed

    Martinez, Felipe

    2016-07-01

    Heart failure is a major health problem and its relationship to thyroid dysfunction has been increasingly investigated in recent years. Since it has been demonstrated that thyroid hormones (TH) and mainly T3 have cardioprotective effects, it is easy to understand that in the scenario of thyroid disorder, cardiac function may be damaged, and inversely in cardiac dysfunction thyroid dysregulation may be seen. The increase in plasma TH produces a clear neurohormonal activation which impacts negatively on cardiac function. In hypothyroidism, and in addition to extracardiac dysfunction, myocardial and vascular remodelling is altered and they contribute to cardiac failure. Abnormal low plasma TSH has also been shown to be a risk factor for developing HF in several recent studies, and they suggest that TSH is an independent predictor of clinical outcome including death and cardiac hospitalizations. Therefore, physicians should consider all these concepts when managing a patient with heart failure, not only for a clear diagnosis, but also for better and accurate treatment.

  6. Thyroid hormone and the cardiovascular system.

    PubMed

    Danzi, Sara; Klein, Irwin

    2012-03-01

    Thyroid hormone has profound effects on the heart and cardiovascular system. This article describes the cellular mechanisms by which thyroid hormone acts at the level of the cardiac myocyte and the vascular smooth muscle cell to alter phenotype and physiology. Because it is well established that thyroid hormone, specifically T(3), acts on almost every cell and organ in the body, studies on the regulation of thyroid hormone transport into cardiac and vascular tissue have added clinical significance. The characteristic changes in cardiovascular hemodynamics and metabolism that accompany thyroid disease states can then be best understood at the cellular level. Copyright © 2012 Elsevier Inc. All rights reserved.

  7. Thyroid Hormone Treatment

    MedlinePlus

    ... hormone for the body’s needs. This is called Hypothyroidism and may be caused by a non-functioning ... or by a non-functioning pituitary gland (see Hypothyroidism Brochure ). Hypothyroidism, is the most common reason for ...

  8. [Thyroid hormone treatment].

    PubMed

    Gärtner, R

    2013-07-01

    The autoimmune thyroiditis with overt or subclinical primary hypothyroidism is the most common endocrine disease. Although the diagnosis of hypothyroidism is not difficult, the question when a replacement therapy in subclinical hypothyroidism should be initiated is still under discussion. In patients with overt hypothyroidism defined as low FT4 and elevated TSH or TSH > 10 mU/L a replacement with levothyroxine is clearly indicated. In patients with subclinical hypothyroidism defined as a TSH between 4 and 10 mU/L and normal FT4, the treatment with Levothyroxine depends on the underlying disease and symptoms. Levothyroxine is a prohormone with is activated by deiodination in the organs to triiodothyronine. Therefore, levothyroxine for replacement therapy is mainly used. Some patients, however, do not feel well with this treatment and therefore studies with a combination therapy of levothyroxine and triiodothyronine had been performed and it could be shown that this might be related to a polymorphism in type 2 deiodinase in some patients, with the consequence of lower intracellular triodothyronine formation. In women on levothyroxine replacement therapy getting pregnant, the demand of levothyroxine increases up to 25-50 µg, especially in the early weeks of pregnancy. It also has to be considered that the resorption of levothyroxine depends on normal stomach acid and therefore patients on acid blockers or atrophic gastritis require higher dosages of levothyroxine. Only patients after thyroidectomy because of differentiated thyroid carcinoma with higher grad of malignancy need a TSH suppressive therapy, those with occult papillary thyroid carcinoma the TSH should be within the low normal range. © Georg Thieme Verlag KG Stuttgart · New York.

  9. IODIDE DEFICIENCY, THYROID HORMONES, AND NEURODEVELOPMENT

    EPA Science Inventory

    ABSTRACT BODY: Iodide is an essential nutrient for thyroid hormone synthesis. Severe iodide insufficiency during early development is associated with cognitive deficits. Environmental contaminants can perturb the thyroid axis and this perturbation may be more acute under conditio...

  10. IODIDE DEFICIENCY, THYROID HORMONES, AND NEURODEVELOPMENT

    EPA Science Inventory

    ABSTRACT BODY: Iodide is an essential nutrient for thyroid hormone synthesis. Severe iodide insufficiency during early development is associated with cognitive deficits. Environmental contaminants can perturb the thyroid axis and this perturbation may be more acute under conditio...

  11. Bromine and thyroid hormone activity.

    PubMed Central

    Allain, P; Berre, S; Krari, N; Laine, P; Barbot, N; Rohmer, V; Bigorgne, J C

    1993-01-01

    AIMS--To examine the possible consequences of high plasma concentrations of bromine on thyroid hormone. METHODS--Bromine was measured by inductively coupled plasma mass spectrometry in the plasma of 799 patients consulting for thyroid disorders. Because the mean (SD) bromine concentration in the plasma of healthy subjects is 4 (1) mg/l, concentrations above 6 mg/l were regarded as outside the normal range. Bromine, free thyroxine (FT4), and thyroid stimulating hormone (TSH) values were compared. RESULTS--The percentage of patients with normal, low, and high FT4 and TSH plasma activities, measured separately, did not differ between patients with low and high bromine concentrations. The percentage of patients with high TSH but normal FT4 values was significantly higher in the group with bromine values of more than 6 mg/l than in the group with bromine concentrations below this (p < 0.02). CONCLUSION--An increase in plasma bromine could potentiate an increase in plasma TSH concentration, probably as a consequence of a minor inhibitory effect on thyroid activity. PMID:8320326

  12. Thyroid hormone transporters in the brain.

    PubMed

    Suzuki, Takehiro; Abe, Takaaki

    2008-01-01

    Thyroid hormone plays an essential role in proper mammalian development of the central nervous system and peripheral tissues. Lack of sufficient thyroid hormone results in abnormal development of virtually all organ systems, a syndrome termed cretinism. In particular, hypothyroidism in the neonatal period causes serious damage to neural cells and leads to mental retardation. Although thyroxine is the major product secreted by the thyroid follicular cells, the action of thyroid hormone is mediated mainly through the deiodination of T(4) to the biologically active form 3,3', 5-triiodo-L-thyronine, followed by the binding of T(3) to a specific nuclear receptor. Before reaching the intracellular targets, thyroid hormone must cross the plasma membrane. Because of the lipophilic nature of thyroid hormone, it was thought that they traversed the plasma membrane by simple diffusion. However, in the past decade, a membrane transport system for thyroid hormone has been postulated to exist in various tissues. Several classes of transporters, organic anion transporter polypeptide (oatp) family, Na(+)/Taurocholate cotransporting polypeptide (ntcp) and amino acid transporters have been reported to transport thyroid hormones. Monocarboxylate transporter8 (MCT8) has recently been identified as an active and specific thyroid hormone transporter. Mutations in MCT8 are associated with severe X-linked psycomotor retardation and strongly elevated serum T3 levels in young male patients. Several other molecules should be contributed to exert the role of thyroid hormone in the central nervous system.

  13. Thyroid Hormone Regulation of Metabolism

    PubMed Central

    Mullur, Rashmi; Liu, Yan-Yun

    2014-01-01

    Thyroid hormone (TH) is required for normal development as well as regulating metabolism in the adult. The thyroid hormone receptor (TR) isoforms, α and β, are differentially expressed in tissues and have distinct roles in TH signaling. Local activation of thyroxine (T4), to the active form, triiodothyronine (T3), by 5′-deiodinase type 2 (D2) is a key mechanism of TH regulation of metabolism. D2 is expressed in the hypothalamus, white fat, brown adipose tissue (BAT), and skeletal muscle and is required for adaptive thermogenesis. The thyroid gland is regulated by thyrotropin releasing hormone (TRH) and thyroid stimulating hormone (TSH). In addition to TRH/TSH regulation by TH feedback, there is central modulation by nutritional signals, such as leptin, as well as peptides regulating appetite. The nutrient status of the cell provides feedback on TH signaling pathways through epigentic modification of histones. Integration of TH signaling with the adrenergic nervous system occurs peripherally, in liver, white fat, and BAT, but also centrally, in the hypothalamus. TR regulates cholesterol and carbohydrate metabolism through direct actions on gene expression as well as cross-talk with other nuclear receptors, including peroxisome proliferator-activated receptor (PPAR), liver X receptor (LXR), and bile acid signaling pathways. TH modulates hepatic insulin sensitivity, especially important for the suppression of hepatic gluconeogenesis. The role of TH in regulating metabolic pathways has led to several new therapeutic targets for metabolic disorders. Understanding the mechanisms and interactions of the various TH signaling pathways in metabolism will improve our likelihood of identifying effective and selective targets. PMID:24692351

  14. Thyroid hormone resistance and its management

    PubMed Central

    Lado-Abeal, Joaquin

    2016-01-01

    The syndrome of impaired sensitivity to thyroid hormone, also known as syndrome of thyroid hormone resistance, is an inherited condition that occurs in 1 of 40,000 live births characterized by a reduced responsiveness of target tissues to thyroid hormone due to mutations on the thyroid hormone receptor. Patients can present with symptoms of hyperthyroidism or hypothyroidism. They usually have elevated thyroid hormones and a normal or elevated thyroid-stimulating hormone level. Due to their nonspecific symptomatic presentation, these patients can be misdiagnosed if the primary care physician is not familiar with the condition. This can result in frustration for the patient and sometimes unnecessary invasive treatment such as radioactive iodine ablation, as in the case presented herein. PMID:27034574

  15. Endocrine disruptors and thyroid hormone physiology.

    PubMed

    Jugan, Mary-Line; Levi, Yves; Blondeau, Jean-Paul

    2010-04-01

    Endocrine disruptors are man-made chemicals that can disrupt the synthesis, circulating levels, and peripheral action of hormones. The disruption of sex hormones was subject of intensive research, but thyroid hormone synthesis and signaling are now also recognized as important targets of endocrine disruptors. The neurological development of mammals is largely dependent on normal thyroid hormone homeostasis, and it is likely to be particularly sensitive to disruption of the thyroid axis. Here, we survey the main thyroid-disrupting chemicals, such as polychlorinated biphenyls, perchlorates, and brominated flame-retardants, that are characteristic disruptors of thyroid hormone homeostasis, and look at their suspected relationships to impaired development of the human central nervous system. The review then focuses on disrupting mechanisms known to be directly or indirectly related to the transcriptional activity of the thyroid hormone receptors.

  16. Thyroid hormone antibodies and Hashimoto's thyroiditis in mongrel dogs

    SciTech Connect

    Rajatanavin, R.; Fang, S.L.; Pino, S.; Laurberg, P.; Braverman, L.E.; Smith, M.; Bullock, L.P.

    1989-05-01

    Abnormally elevated serum T3 concentrations measured by RIA were observed in 19 clinically euthyroid or hypothyroid mongrel dogs. The serum T4 concentrations in these sera were low, normal, or high. Measurement of the intensity of thyroid hormone binding to serum proteins was determined by equilibrium dialysis. A marked decrease in the percent free T3 was observed in these abnormal sera. Polyacrylamide gel electrophoresis, pH 7.4, of normal dog serum enriched with tracer /sup 125/I-labeled thyroid hormones demonstrated binding of (/sup 125/I)T4 to transthyretin, thyroid hormone-binding globulin, and albumin and of (/sup 125/I)T3 primarily to thyroid hormone-binding globulin. In all abnormal sera, polyacrylamide gel electrophoresis demonstrated strikingly higher binding of T3 to immunoglobulin (Ig). Eleven of 16 abnormal sera had minimal to moderate binding of T4 to Ig. The percent free T4 was lower only in dogs whose sera demonstrated markedly increased binding of T4 to Ig. All abnormal sera tested had positive antithyroglobulin antibodies, consistent with the diagnosis of autoimmune lymphocytic thyroiditis. As in humans, antibodies to thyroid hormones in dogs are more common in the presence of Hashimoto's thyroiditis and should be considered when elevated serum thyroid hormone concentrations are observed in the absence of clinical thyrotoxicosis. When an antibody to only one thyroid hormone is present, a marked discrepancy in the serum concentrations of T3 and T4 will be observed.

  17. [Thyroid hormone and the cardiovascular system].

    PubMed

    Takasu, Nobuyuki

    2006-12-01

    Thyroid hormone has many effects on the heart and vascular system. Many of the clinical manifestations of hyperthyroidism are due to the ability of thyroid hormone to alter cardiovascular hemodynamics. The hemodynamic effects of hypothyroidism are opposite to those of hyperthyroidism, although the clinical manifestations are less obvious. This review will integrate what is known about the mechanisms of thyroid hormone action on the heart with recent observations from both experimental and clinical studies of hyperthyroidism and hypothyroidism. Thyroid hormone has both direct and indirect actions on the cardiovascular system. Patients with thyroid disease, especially those with hyperthyroidism, often have symptoms and signs indicating changes in cardiovascular hemodynamics. Indeed, symptoms and signs referable to the cardiovascular system may be the only manifestations of thyroid dysfunction, and thyroid function should therefore be assessed by the measurement of serum thyrotropin concentrations in all patients with cardiovascular disease. Some suggest that the administration of triiodothyronine may benefit some patients with cardiovascular disease.

  18. Thyroid hormone, brain development, and the environment.

    PubMed Central

    Zoeller, Thomas R; Dowling, Amy L S; Herzig, Carolyn T A; Iannacone, Eric A; Gauger, Kelly J; Bansal, Ruby

    2002-01-01

    Thyroid hormone is essential for normal brain development. Therefore, it is a genuine concern that thyroid function can be altered by a very large number of chemicals routinely found in the environment and in samples of human and wildlife tissues. These chemicals range from natural to manufactured compounds. They can produce thyroid dysfunction when they are absent from the diet, as in the case of iodine, or when they are present in the diet, as in the case of thionamides. Recent clinical evidence strongly suggests that brain development is much more sensitive to thyroid hormone excess or deficit than previously believed. In addition, recent experimental research provides new insight into the developmental processes affected by thyroid hormone. Based on the authors' research focusing on the ability of polychlorinated biphenyls to alter the expression of thyroid hormone-responsive genes in the developing brain, this review provides background information supporting a new way of approaching risk analysis of thyroid disruptors. PMID:12060829

  19. Thyroid hormone deiodination in birds.

    PubMed

    Darras, Veerle M; Verhoelst, Carla H J; Reyns, Geert E; Kühn, Eduard R; Van der Geyten, Serge

    2006-01-01

    Because the avian thyroid gland secretes almost exclusively thyroxine (T4), the availability of receptor-active 3,3',5-triiodothyronine (T3) has to be regulated in the extrathyroidal tissues, essentially by deiodination. Like mammals and most other vertebrates, birds possess three types of iodothyronine deiodinases (D1, D2, and D3) that closely resemble their mammalian counterparts, as shown by biochemical characterization studies in several avian species and by cDNA cloning of the three enzymes in chicken. The tissue distribution of these deiodinases has been studied in detail in chicken at the level of activity and mRNA expression. More recently specific antibodies were used to study cellular localization at the protein level. The abundance and distribution of the different deiodinases shows substantial variation during embryonic development and postnatal life. Deiodination in birds is subject to regulation by hormones from several endocrine axes, including thyroid hormones, growth hormone and glucocorticoids. In addition, deiodination is also influenced by external parameters, such as nutrition, temperature, light and also a number of environmental pollutants. The balance between the outer and inner ring deiodination resulting from the impact of all these factors ultimately controls T3 availability.

  20. THYROID HORMONE DISRUPTION: FROM KINETICS TO DYNAMICS.

    EPA Science Inventory

    A wide range of chemicals with diverse structures act as thyroid disrupting chemicals (TDCs). Broadly defined, TDCs are chemicals that alter the structure or function of the thyroid gland, alter regulatory enzymes associated with thyroid hormones (THs), or change circulating or t...

  1. THYROID HORMONE DISRUPTION: FROM KINETICS TO DYNAMICS.

    EPA Science Inventory

    A wide range of chemicals with diverse structures act as thyroid disrupting chemicals (TDCs). Broadly defined, TDCs are chemicals that alter the structure or function of the thyroid gland, alter regulatory enzymes associated with thyroid hormones (THs), or change circulating or t...

  2. Thyroid hormone resistance: a novel mutation in thyroid hormone receptor beta (THRB) gene - case report.

    PubMed

    Işık, Emregül; Beck Peccoz, Paolo; Campi, Irene; Özön, Alev; Alikaşifoğlu, Ayfer; Gönç, Nazlı; Kandemir, Nurgün

    2013-01-01

    Thyroid hormone resistance (THR) is a dominantly inherited syndrome characterized by reduced sensitivity to thyroid hormones. It is usually caused by mutations in the thyroid hormone receptor beta (THRB) gene. In the present report, we describe the clinical and laboratory characteristics and genetic analysis of patients with a novel THRB gene mutation. The index patient had been misdiagnosed as hyperthyroidism and treated with antithyroid drugs since eight days of age. Thyroid hormone results showed that thyrotropin (thyroid-stimulating hormone, TSH) was never suppressed despite elevated thyroid hormone levels, and there was no symptom suggesting hyperthyroidism. A heterozygous mutation at codon 350 located in exon 9 of the THRB gene was detected in all the affected members of the family. It is important to consider thyroid hormone levels in association with TSH levels to prevent inappropriate treatment and the potential complications, such as clinical hypothyroidism or an increase in goiter size.

  3. Thyroid hormone and the growth plate.

    PubMed

    Shao, Yvonne Y; Wang, Lai; Ballock, R Tracy

    2006-12-01

    Thyroid hormone was first identified as a potent regulator of skeletal maturation at the growth plate more than forty years ago. Since that time, many in vitro and in vivo studies have confirmed that thyroid hormone regulates the critical transition between cell proliferation and terminal differentiation in the growth plate, specifically the maturation of growth plate chondrocytes into hypertrophic cells. However these studies have neither identified the molecular mechanisms involved in the regulation of skeletal maturation by thyroid hormone, nor demonstrated how the systemic actions of thyroid hormone interface with the local regulatory milieu of the growth plate. This article will review our current understanding of the role of thyroid hormone in regulating the process of endochondral ossification at the growth plate, as well as what is currently known about the molecular mechanisms involved in this regulation.

  4. Thyroid hormone dysfunction during pregnancy: A review

    PubMed Central

    Alemu, Aynadis; Terefe, Betelihem; Abebe, Molla; Biadgo, Belete

    2016-01-01

    Thyroid dysfunctions such as hypothyroidism, thyrotoxicosis and thyroid nodules may develop during pregnancy leading to abortion, placental abruptions, preeclampsia, preterm delivery and reduced intellectual function in the offspring. Epidemiological data have shown the significant role of maternal thyroid hormone in fetal neurologic development and maternal health. It has been suggested that the deleterious effects of thyroid dysfunction can also extend beyond pregnancy and delivery to affect neuro-intellectual development in the early life of the child. Pregnancy poses an important challenge to the maternal thyroid gland as hormone requirements are increased during gestation as a result of an increase in thyroid- binding globulin, the stimulatory effect of HCG on TSH receptors, and increased peripheral thyroid hormone requirements. Maternal thyroid dysfunction is associated with increased risk for early abortion, preterm delivery, neonatal morbidity and other obstetrical complications. Early diagnosis for thyroid dysfunction of pregnant women and treatment of thyroid dysfunction during pregnancy is important and cost effective to avoid both fetal and maternal complications secondary to thyroid dysfunction. Therefore the aim of this review was to assess the thyroid function changes occurring during pregnancy, the different disorders with their maternal and fetal implications, the laboratory diagnosis and the best ways of management of these conditions. PMID:27981252

  5. Thyroid hormone deiodination in fish.

    PubMed

    Orozco, Aurea; Valverde-R, Carlos

    2005-08-01

    We review the experimental evidence accumulated within the past decade regarding the physiologic, biochemical, and molecular characterization of iodothyronine deiodinases (IDs) in piscine species. Agnathans, chondrichthyes, and teleosts express the three isotypes of IDs: ID1, ID2, and ID3, which are responsible for the peripheral fine-tuning of thyroid hormone (TH) bioactivity. At the molecular and operational level, fish IDs share properties with their corresponding vertebrate counterparts. However, fish IDs also exhibit discrete features that seem to be distinctive for piscine species. Indeed, teleostean ID1 is conspicuously resistant to propylthiouracil (PTU) inhibition, and its response to thyroidal status differs from that exhibited by other ID1s. Moreover, both the high level of ID2 activity and its expression in the liver of teleosts are unique among vertebrates. The physiologic role of iodothyronine deiodination in functions regulated by TH in fish is not entirely clear. Nevertheless, current experimental evidence suggests that IDs may coordinate and facilitate, in a tissue-specific fashion, the action of iodothyronines and other hormones involved in such processes.

  6. Minireview: Pathophysiological importance of thyroid hormone transporters.

    PubMed

    Heuer, Heike; Visser, Theo J

    2009-03-01

    Thyroid hormone metabolism and action are largely intracellular events that require transport of iodothyronines across the plasma membrane. It has been assumed for a long time that this occurs by passive diffusion, but it has become increasingly clear that cellular uptake and efflux of thyroid hormone is mediated by transporter proteins. Recently, several active and specific thyroid hormone transporters have been identified, including monocarboxylate transporter 8 (MCT8), MCT10, and organic anion transporting polypeptide 1C1 (OATP1C1). The latter is expressed predominantly in brain capillaries and transports preferentially T(4), whereas MCT8 and MCT10 are expressed in multiple tissues and are capable of transporting different iodothyronines. The pathophysiological importance of thyroid hormone transporters has been established by the demonstration of MCT8 mutations in patients with severe psychomotor retardation and elevated serum T(3) levels. MCT8 appears to play an important role in the transport of thyroid hormone in the brain, which is essential for the crucial action of the hormone during brain development. It is expected that more specific thyroid hormone transporters will be discovered in the near future, which will lead to a better understanding of the tissue-specific regulation of thyroid hormone bioavailability.

  7. Thyroid Hormone Function in the Rat Testis

    PubMed Central

    Gao, Ying; Lee, Will M.; Cheng, C. Yan

    2014-01-01

    Thyroid hormones are emerging regulators of testicular function since Sertoli, germ, and Leydig cells are found to express thyroid hormone receptors (TRs). These testicular cells also express deiodinases, which are capable of converting the pro-hormone T4 to the active thyroid hormone T3, or inactivating T3 or T4 to a non-biologically active form. Furthermore, thyroid hormone transporters are also found in the testis. Thus, the testis is equipped with the transporters and the enzymes necessary to maintain the optimal level of thyroid hormone in the seminiferous epithelium, as well as the specific TRs to execute thyroid hormone action in response to different stages of the epithelial cycle of spermatogenesis. Studies using genetic models and/or goitrogens (e.g., propylthiouracil) have illustrated a tight physiological relationship between thyroid hormone and testicular function, in particular, Sertoli cell differentiation status, mitotic activity, gap junction function, and blood–testis barrier assembly. These findings are briefly summarized and discussed herein. PMID:25414694

  8. 21 CFR 862.1690 - Thyroid stimulating hormone test system.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... 21 Food and Drugs 8 2011-04-01 2011-04-01 false Thyroid stimulating hormone test system. 862.1690... Systems § 862.1690 Thyroid stimulating hormone test system. (a) Identification. A thyroid stimulating hormone test system is a device intended to measure thyroid stimulating hormone, also known...

  9. 21 CFR 862.1690 - Thyroid stimulating hormone test system.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... 21 Food and Drugs 8 2012-04-01 2012-04-01 false Thyroid stimulating hormone test system. 862.1690... Systems § 862.1690 Thyroid stimulating hormone test system. (a) Identification. A thyroid stimulating hormone test system is a device intended to measure thyroid stimulating hormone, also known...

  10. 21 CFR 862.1690 - Thyroid stimulating hormone test system.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... 21 Food and Drugs 8 2014-04-01 2014-04-01 false Thyroid stimulating hormone test system. 862.1690... Systems § 862.1690 Thyroid stimulating hormone test system. (a) Identification. A thyroid stimulating hormone test system is a device intended to measure thyroid stimulating hormone, also known...

  11. 21 CFR 862.1690 - Thyroid stimulating hormone test system.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... 21 Food and Drugs 8 2013-04-01 2013-04-01 false Thyroid stimulating hormone test system. 862.1690... Systems § 862.1690 Thyroid stimulating hormone test system. (a) Identification. A thyroid stimulating hormone test system is a device intended to measure thyroid stimulating hormone, also known...

  12. 21 CFR 862.1690 - Thyroid stimulating hormone test system.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 21 Food and Drugs 8 2010-04-01 2010-04-01 false Thyroid stimulating hormone test system. 862.1690... Systems § 862.1690 Thyroid stimulating hormone test system. (a) Identification. A thyroid stimulating hormone test system is a device intended to measure thyroid stimulating hormone, also known...

  13. Adipose tissues and thyroid hormones

    PubMed Central

    Obregon, Maria-Jesus

    2014-01-01

    The maintenance of energy balance is regulated by complex homeostatic mechanisms, including those emanating from adipose tissue. The main function of the adipose tissue is to store the excess of metabolic energy in the form of fat. The energy stored as fat can be mobilized during periods of energy deprivation (hunger, fasting, diseases). The adipose tissue has also a homeostatic role regulating energy balance and functioning as endocrine organ that secretes substances that control body homeostasis. Two adipose tissues have been identified: white and brown adipose tissues (WAT and BAT) with different phenotype, function and regulation. WAT stores energy, while BAT dissipates energy as heat. Brown and white adipocytes have different ontogenetic origin and lineage and specific markers of WAT and BAT have been identified. “Brite” or beige adipose tissue has been identified in WAT with some properties of BAT. Thyroid hormones exert pleiotropic actions, regulating the differentiation process in many tissues including the adipose tissue. Adipogenesis gives raise to mature adipocytes and is regulated by several transcription factors (c/EBPs, PPARs) that coordinately activate specific genes, resulting in the adipocyte phenotype. T3 regulates several genes involved in lipid mobilization and storage and in thermogenesis. Both WAT and BAT are targets of thyroid hormones, which regulate genes crucial for their proper function: lipogenesis, lipolysis, thermogenesis, mitochondrial function, transcription factors, the availability of nutrients. T3 acts directly through specific TREs in the gene promoters, regulating transcription factors. The deiodinases D3, D2, and D1 regulate the availability of T3. D3 is activated during proliferation, while D2 is linked to the adipocyte differentiation program, providing T3 needed for lipogenesis and thermogenesis. We examine the differences between BAT, WAT and brite/beige adipocytes and the process that lead to activation of UCP1 in WAT

  14. Thyroid hormone, neural tissue and mood modulation.

    PubMed

    Bauer, M; Whybrow, P C

    2001-04-01

    The successful treatment of affective disorders with thyroid hormone exemplifies the suggested inter-relationship between endocrine and neuronal systems in these disorders. Thyroid hormones have a profound influence on behaviour and appear to be capable of modulating the phenotypic expression of major affective illness. Specifically, there is good evidence that triiodothyronine (T3) may accelerate the antidepressant response to tricylic antidepressants, and some studies suggest that T3 may augment the therapeutic response to antidepressants in refractory depressed patients. Open studies have also indicated that adjunctive supraphysiological doses of thyroxine (T4) can ameliorate depressive symptomatology and help stabilize the long-term course of illness in bipolar and unipolar patients, especially women refractory to standard medications. Despite acceptance of the essential role of thyroid hormone on brain maturation and differentiation, and the clinical and therapeutic observations in association with mood disorders, the molecular action that may underlie the mood-modulating properties of thyroid hormone in the adult brain has only recently become the focus of research. The identification of nuclear T3 receptors, the region-specific expression of deiodinase isoenzymes and the molecular analyses of thyroid-responsive genes in the adult brain have provided the biological bases for a better understanding of thyroid hormone action in mature neurons. Also the influence of thyroid hormones on the putative neurotransmitter systems that regulate mood and behaviour, serotonin and norepinephrine, may be helpful in explaining their mood-modulating effects.

  15. Thyroid Hormone Replacement in Patients Following Thyroidectomy for Thyroid Cancer

    PubMed Central

    Hannoush, Zeina C.; Weiss, Roy E.

    2016-01-01

    Thyroid hormone replacement therapy in patients following thyroidectomy for thyroid cancer, although a potentially straightforward clinical problem, can present the clinician and patient with a variety of challenges. Most often the problems are related to the dose and preparation of thyroid hormone (TH) to use. Some patients feel less well following thyroidectomy and/or radioiodine ablation than they did before their diagnosis. We present evidence that levothyroxine (L-T4) is the preparation of choice, and keeping the thyroid-stimulating hormone (TSH) between detectable and 0.1 mU/L should be the standard of care in most cases. In unusual circumstances, when the patient remains clinically hypothyroid despite a suppressed TSH, we acknowledge there may be as yet unidentified factors influencing the body’s response to TH, and individualized therapy may be necessary in such patients. PMID:26886951

  16. [Thyroid hormone and the cardiovascular system].

    PubMed

    Weinbrenner, C; Gerbert, B; Strasser, R H

    2005-09-30

    Thyroid hormone has many effects on the heart and vascular system. In hyperthyroidism changes in cardiovascular hemodynamics explain many of the clinical manifestations induced by thyroid hormones. In hypothyroidism the cardiovascular effects are opposite to those observed in hyperthyroidism, although the clinical manifestations are less obvious. This review will focus on the cardiovascular system in hyperthyroidism and hypothyroidism. In particular the subclinical dysfunctions of the thyroid gland, which occurs especially in older age, will be discussed. The clinical relevance and the necessity of diagnostic and therapy in subclinical thyroid disease are not clarified yet. In the United States an expert group has published a scientific review and guideline for the diagnosis and management of subclinical thyroid disease in 2004, which will also be outlined.

  17. Control of Pituitary Thyroid-stimulating Hormone Synthesis and Secretion by Thyroid Hormones during Xenopus Metamorphosis

    EPA Science Inventory

    Serum thyroid hormone (TH) concentrations in anuran larvae rise rapidly during metamorphosis. Such a rise in an adult anuran would inevitably trigger a negative feedback response resulting in decreased synthesis and secretion of thyroid-stimulating hormone (TSH) by the pituitary....

  18. Control of Pituitary Thyroid-stimulating Hormone Synthesis and Secretion by Thyroid Hormones during Xenopus Metamorphosis

    EPA Science Inventory

    Serum thyroid hormone (TH) concentrations in anuran larvae rise rapidly during metamorphosis. Such a rise in an adult anuran would inevitably trigger a negative feedback response resulting in decreased synthesis and secretion of thyroid-stimulating hormone (TSH) by the pituitary....

  19. New insights into thyroid hormone action.

    PubMed

    Mendoza, Arturo; Hollenberg, Anthony N

    2017-05-01

    Thyroid hormones (TH) are endocrine messengers essential for normal development and function of virtually every vertebrate. The hypothalamic-pituitary-thyroid axis is exquisitely modulated to maintain nearly constant TH (T4 and T3) levels in circulation. However peripheral tissues and the CNS control the intracellular availability of TH, suggesting that circulating concentrations of TH are not fully representative of what each cell type sees. Indeed, recent work in the field has identified that TH transporters, deiodinases and thyroid hormone receptor coregulators can strongly control tissue-specific sensitivity to a set amount of TH. Furthermore, the mechanism by which the thyroid hormone receptors regulate target gene expression can vary by gene, tissue and cellular context. This review will highlight novel insights into the machinery that controls the cellular response to TH, which include unique signaling cascades. These findings shed new light into the pathophysiology of human diseases caused by abnormal TH signaling. Copyright © 2017 Elsevier Inc. All rights reserved.

  20. Thyroid Hormone and Seasonal Rhythmicity

    PubMed Central

    Dardente, Hugues; Hazlerigg, David G.; Ebling, Francis J. P.

    2014-01-01

    Living organisms show seasonality in a wide array of functions such as reproduction, fattening, hibernation, and migration. At temperate latitudes, changes in photoperiod maintain the alignment of annual rhythms with predictable changes in the environment. The appropriate physiological response to changing photoperiod in mammals requires retinal detection of light and pineal secretion of melatonin, but extraretinal detection of light occurs in birds. A common mechanism across all vertebrates is that these photoperiod-regulated systems alter hypothalamic thyroid hormone (TH) conversion. Here, we review the evidence that a circadian clock within the pars tuberalis of the adenohypophysis links photoperiod decoding to local changes of TH signaling within the medio-basal hypothalamus (MBH) through a conserved thyrotropin/deiodinase axis. We also focus on recent findings which indicate that, beyond the photoperiodic control of its conversion, TH might also be involved in longer-term timing processes of seasonal programs. Finally, we examine the potential implication of kisspeptin and RFRP3, two RF-amide peptides expressed within the MBH, in seasonal rhythmicity. PMID:24616714

  1. Thyroid hormones and renin secretion.

    PubMed

    Ganong, W F

    Circulating angiotensin is produced by the action of renin from the kidneys on circulating angiotensinogen. There are other renin-angiotensin systems in various organs in the body, and recent observations raise the intriguing possibility that angiotensin II is produced by a totally intracellular pathway in the juxtaglomerular cells, the gonadotrops of the anterior pituitary, neurons, in the brain, salivary duct cells, and neuroblastoma cells. Circulating angiotensin II levels depend in large part on the plasma concentration of angiotensinogen, which is hormonally regulated, and on the rate of renin secretion. Renin secretion is regulated by an intrarenal baroreceptor mechanism, a macula densa mechanism, angiotensin II, vasopressin, and the sympathetic nervous system. The increase in renin secretion produced by sympathetic discharge is mediated for the most part by beta-adrenergic receptors, which are probably located on the juxtaglomerular cells. Hyperthyroidism would be expected to be associated with increased renin secretion in view of the increased beta-adrenergic activity in this condition, and hypothyroidism would be associated with decreased plasma renin activity due to decreased beta-adrenergic activity. Our recent research on serotonin-mediated increases in renin secretion that depend on the integrity of the dorsal raphe nucleus and the mediobasal hypothalamus has led us to investigate the effect of the pituitary on the renin response to p-chloroamphetamine. The response is potentiated immediately after hypophysectomy, but 22 days after the operation, it is abolished. This slowly developing decrease in responsiveness may be due to decreased thyroid function.

  2. New avenues for regulation of lipid metabolism by thyroid hormones and analogs.

    PubMed

    Senese, Rosalba; Lasala, Pasquale; Leanza, Cristina; de Lange, Pieter

    2014-01-01

    Weight loss due to negative energy balance is a goal in counteracting obesity and type 2 diabetes mellitus. The thyroid is known to be an important regulator of energy metabolism through the action of thyroid hormones (THs). The classic, active TH, 3,5,3'-triiodo-L-thyronine (T3) acts predominantly by binding to nuclear receptors termed TH receptors (TRs), that recognize TH response elements (TREs) on the DNA, and so regulate transcription. T3 also acts through "non-genomic" pathways that do not necessarily involve TRs. Lipid-lowering therapies have been suggested to have potential benefits, however, the establishment of comprehensive therapeutic strategies is still awaited. One drawback of using T3 in counteracting obesity has been the occurrence of heart rhythm disturbances. These are mediated through one TR, termed TRα. The end of the previous century saw the exploration of TH mimetics that specifically bind to TR beta in order to prevent cardiac disturbances, and TH derivatives such as 3,5-diiodo-L-thyronine (T2), that possess interesting biological activities. Several TH derivatives and functional analogs have low affinity for the TRs, and are suggested to act predominantly through non-genomic pathways. All this has opened new perspectives in thyroid physiology and TH derivative usage as anti-obesity therapies. This review addresses the pros and cons of these compounds, in light of their effects on energy balance regulation and on lipid/cholesterol metabolism.

  3. Thyroid hormone signaling in energy homeostasis and energy metabolism

    PubMed Central

    McAninch, Elizabeth A.; Bianco, Antonio C.

    2014-01-01

    The thyroid hormone plays a significant role in diverse processes related to growth, development, differentiation, and metabolism. Thyroid hormone signaling modulates energy expenditure through both central and peripheral pathways. At the cellular level, the thyroid hormone exerts its effects after concerted mechanisms facilitate binding to the thyroid hormone receptor. In the hypothalamus, signals from a range of metabolic pathways, including appetite, temperature, afferent stimuli via the autonomic nervous system, availability of energy substrates, hormones, and other biologically active molecules, converge to maintain plasma thyroid hormone at the appropriate level to preserve energy homeostasis. At the tissue level, thyroid hormone actions on metabolism are controlled by transmembrane transporters, deiodinases, and thyroid hormone receptors. In the modern environment, humans are susceptible to an energy surplus, which has resulted in an obesity epidemic and thus understanding the contribution of the thyroid hormone to cellular and organism metabolism is increasingly relevant. PMID:24697152

  4. Hypothalamic effects of thyroid hormones on metabolism.

    PubMed

    Martínez-Sánchez, Noelia; Alvarez, Clara V; Fernø, Johan; Nogueiras, Rubén; Diéguez, Carlos; López, Miguel

    2014-10-01

    Over the past few decades, obesity and its related metabolic disorders have increased at an epidemic rate in the developed and developing world. New signals and factors involved in the modulation of energy balance and metabolism are continuously being discovered, providing potential novel drug targets for the treatment of metabolic disease. A parallel strategy is to better understand how hormonal signals, with an already established role in energy metabolism, work, and how manipulation of the pathways involved may lead to amelioration of metabolic dysfunction. The thyroid hormones belong to the latter category, with dysregulation of the thyroid axis leading to marked alterations in energy balance. The potential of thyroid hormones in the treatment of obesity has been known for decades, but their therapeutic use has been hampered because of side-effects. Data gleaned over the past few years, however, have uncovered new features at the mechanisms of action involved in thyroid hormones. Sophisticated neurobiological approaches have allowed the identification of specific energy sensors, such as AMP-activated protein kinase and mechanistic target of rapamycin, acting in specific groups of hypothalamic neurons, mediating many of the effects of thyroid hormones on food intake, energy expenditure, glucose, lipid metabolism, and cardiovascular function. More extensive knowledge about these molecular mechanisms will be of great relevance for the treatment of obesity and metabolic syndrome.

  5. Coexistence of resistance to thyroid hormone and papillary thyroid carcinoma

    PubMed Central

    Igata, Motoyuki; Tsuruzoe, Kaku; Kawashima, Junji; Kukidome, Daisuke; Kondo, Tatsuya; Motoshima, Hiroyuki; Shimoda, Seiya; Furukawa, Noboru; Nishikawa, Takeshi; Miyamura, Nobuhiro

    2016-01-01

    Summary Resistance to thyroid hormone (RTH) is a syndrome of reduced tissue responsiveness to thyroid hormones. RTH is majorly caused by mutations in the thyroid hormone receptor beta (THRB) gene. Recent studies indicated a close association of THRB mutations with human cancers, but the role of THRB mutation in carcinogenesis is still unclear. Here, we report a rare case of RTH with a papillary thyroid carcinoma (PTC). A 26-year-old woman was referred to our hospital due to a thyroid tumor and hormonal abnormality. She had elevated serum thyroid hormones and non-suppressed TSH levels. Genetic analysis of THRB identified a missense mutation, P452L, leading to a diagnosis of RTH. Ultrasound-guided fine-needle aspiration biopsy of the tumor and lymph nodes enabled the cytological diagnosis of PTC with lymph node metastases. Total thyroidectomy and neck lymph nodes dissection were performed. Following surgery, thyroxine replacement (≥500 μg) was necessary to avoid the symptoms of hypothyroidism and to maintain her TSH levels within the same range as before the operation. During the follow-up, basal thyroglobulin (Tg) levels were around 6 ng/ml and TSH-stimulated Tg levels were between 12 and 20 ng/ml. Up to present, the patient has had no recurrence of PTC. This indicates that these Tg values are consistent with a biochemical incomplete response or an indeterminate response. There is no consensus regarding the management of thyroid carcinoma in patients with RTH, but aggressive treatments such as total thyroidectomy followed by radioiodine (RAI) and TSH suppression therapy are recommended. Learning points There are only a few cases reporting the coexistence of RTH and thyroid carcinoma. Moreover, our case would be the first case presenting one with lymph node metastases. Recent studies indicated a close association of THRB mutations with human cancers, but the role of THRB mutation in carcinogenesis is still unclear. When total thyroidectomy is performed in

  6. Effects of phenobarbital on thyroid hormone contabolism in rat hepatocytes

    EPA Science Inventory

    Hepatic enzyme inducers such as phenobarbital (PB) decrease circulating thyroid hormone (TH) concentrations in rodents. PB induction of hepatic xenobiotic metabolizing enzymes increases thyroid hormones catabolism and biliary elimination. This study examines the catabolism and cl...

  7. Effects of phenobarbital on thyroid hormone contabolism in rat hepatocytes

    EPA Science Inventory

    Hepatic enzyme inducers such as phenobarbital (PB) decrease circulating thyroid hormone (TH) concentrations in rodents. PB induction of hepatic xenobiotic metabolizing enzymes increases thyroid hormones catabolism and biliary elimination. This study examines the catabolism and cl...

  8. Thyroid hormones states and brain development interactions.

    PubMed

    Ahmed, Osama M; El-Gareib, A W; El-Bakry, A M; Abd El-Tawab, S M; Ahmed, R G

    2008-04-01

    The action of thyroid hormones (THs) in the brain is strictly regulated, since these hormones play a crucial role in the development and physiological functioning of the central nervous system (CNS). Disorders of the thyroid gland are among the most common endocrine maladies. Therefore, the objective of this study was to identify in broad terms the interactions between thyroid hormone states or actions and brain development. THs regulate the neuronal cytoarchitecture, neuronal growth and synaptogenesis, and their receptors are widely distributed in the CNS. Any deficiency or increase of them (hypo- or hyperthyroidism) during these periods may result in an irreversible impairment, morphological and cytoarchitecture abnormalities, disorganization, maldevelopment and physical retardation. This includes abnormal neuronal proliferation, migration, decreased dendritic densities and dendritic arborizations. This drastic effect may be responsible for the loss of neurons vital functions and may lead, in turn, to the biochemical dysfunctions. This could explain the physiological and behavioral changes observed in the animals or human during thyroid dysfunction. It can be hypothesized that the sensitive to the thyroid hormones is not only remarked in the neonatal period but also prior to birth, and THs change during the development may lead to the brain damage if not corrected shortly after the birth. Thus, the hypothesis that neurodevelopmental abnormalities might be related to the thyroid hormones is plausible. Taken together, the alterations of neurotransmitters and disturbance in the GABA, adenosine and pro/antioxidant systems in CNS due to the thyroid dysfunction may retard the neurogenesis and CNS growth and the reverse is true. In general, THs disorder during early life may lead to distortions rather than synchronized shifts in the relative development of several central transmitter systems that leads to a multitude of irreversible morphological and biochemical

  9. Modification of Chromatin Structure by the Thyroid Hormone Receptor.

    PubMed

    Li; Sachs; Shi; Wolffe

    1999-05-01

    Pioneering experiments and recent observations have established the thyroid hormone receptor as a master manipulator of the chromosomal environment in targeting the activation and repression of transcription. Here we review how the thyroid hormone receptor is assembled into chromatin, where in the absence of thyroid hormone the receptor recruits histone deacetylase to silence transcription. On addition of hormone, the receptor undergoes a conformational change that leads to the release of deacetylase, while facilitating the recruitment of transcriptional coactivators that act as histone acetyltransferases. We discuss the biological importance of these observations for gene control by the thyroid hormone receptor and for oncogenic transformation by the mutated thyroid hormone receptor, v-ErbA.

  10. Thyroid hormone transporters in health and disease: advances in thyroid hormone deiodination.

    PubMed

    Köhrle, Josef

    2007-06-01

    Thyroid hormone metabolism by the three deiodinase selenoproteins -- DIO1, DIO2, and DIO3 -- regulates the local availability of various iodothyronine metabolites and thus mediates their effects on gene expression, thermoregulation, energy metabolism, and many key reactions during the development and maintenance of an adult organism. Circulating serum levels of thyroid hormone and thyroid-stimulating hormone, used as a combined indicator of thyroid hormone status, reflect a composite picture of: thyroid secretion; tissue-specific production of T(3) by DIO1 and DIO2 activity, which both contribute to circulating levels of T(3); and degradation of the prohormone T4, of the thyromimetically active T(3), of the inactive rT(3), of other iodothyronines metabolites with a lower iodine content and of thyroid hormone conjugates. Degradation reactions are catalyzed by either DIO1 or DIO3. Aberrant expression of individual deiodinases in disease, single nucleotide polymorphisms in their genes, and novel regulators of DIO gene expression (such as bile acids) provide a more complex picture of the fine tuning and the adaptation of systemic and local bioavailability of thyroid hormones.

  11. Thyroid Hormones and Growth in Health and Disease

    PubMed Central

    Tarım, Ömer

    2011-01-01

    Thyroid hormones regulate growth by several mechanisms. In addition to their negative feedback effect on the stimulatory hormones thyrotropin-releasing hormone (TRH) and thyrotropin (TSH), thyroid hormones also regulate their receptors in various physiological and pathological conditions. Up-regulation and down-regulation of the thyroid receptors fine-tune the biological effects exerted by the thyroid hormones. Interestingly, the deiodinase enzyme system is another intrinsic regulator of thyroid physiology that adjusts the availability of thyroid hormones to the tissues, which is essential for normal growth and development. Almost all chronic diseases of childhood impair growth and development. Every disease may have a unique mechanism to halt linear growth, but reduced serum concentration or diminished local availability of thyroid hormones seems to be a common pathway. Therefore, the effects of systemic diseases on thyroid physiology must be taken into consideration in the evaluation of growth retardation in affected children. Conflict of interest:None declared. PMID:21750631

  12. Thyroid hormones and growth in health and disease.

    PubMed

    Tarım, Ömer

    2011-01-01

    Thyroid hormones regulate growth by several mechanisms. In addition to their negative feedback effect on the stimulatory hormones thyrotropin-releasing hormone (TRH) and thyrotropin (TSH), thyroid hormones also regulate their receptors in various physiological and pathological conditions. Up-regulation and down-regulation of the thyroid receptors fine-tune the biological effects exerted by the thyroid hormones. Interestingly, the deiodinase enzyme system is another intrinsic regulator of thyroid physiology that adjusts the availability of thyroid hormones to the tissues, which is essential for normal growth and development. Almost all chronic diseases of childhood impair growth and development. Every disease may have a unique mechanism to halt linear growth, but reduced serum concentration or diminished local availability of thyroid hormones seems to be a common pathway. Therefore, the effects of systemic diseases on thyroid physiology must be taken into consideration in the evaluation of growth retardation in affected children.

  13. Actions of Thyroid Hormone Analogues on Chemokines

    PubMed Central

    Glinsky, Gennadi V.

    2016-01-01

    The extracellular domain of plasma membrane integrin αvβ3 contains a receptor for thyroid hormone (L-thyroxine, T4; 3,5,3′-triiodo-L-thyronine, T3); this receptor also binds tetraiodothyroacetic acid (tetrac), a derivative of T4. Tetrac inhibits the binding of T4 and T3 to the integrin. Fractalkine (CX3CL1) is a chemokine relevant to inflammatory processes in the CNS that are microglia-dependent but also important to normal brain development. Expression of the CX3CL1 gene is downregulated by tetrac, suggesting that T4 and T3 may stimulate fractalkine expression. Independently of its specific receptor (CX3CR1), fractalkine binds to αvβ3 at a site proximal to the thyroid hormone-tetrac receptor and changes the physical state of the integrin. Tetrac also affects expression of the genes for other CNS-relevant chemokines, including CCL20, CCL26, CXCL2, CXCL3, and CXCL10. The chemokine products of these genes are important to vascularity of the brain, particularly of the choroid plexus, to inflammatory processes in the CNS and, in certain cases, to neuroprotection. Thyroid hormones are known to contribute to regulation of each of these CNS functions. We propose that actions of thyroid hormone and hormone analogues on chemokine gene expression contribute to regulation of inflammatory processes in brain and of brain blood vessel formation and maintenance. PMID:27493972

  14. Biochemical mechanisms of thyroid hormone deiodination.

    PubMed

    Kuiper, George G J M; Kester, Monique H A; Peeters, Robin P; Visser, Theo J

    2005-08-01

    Deiodination is the foremost pathway of thyroid hormone metabolism not only in quantitative terms but also because thyroxine (T(4)) is activated by outer ring deiodination (ORD) to 3,3',5-triiodothyronine (T(3)), whereas both T(4) and T(3) are inactivated by inner ring deiodination (IRD) to 3,3',5-triiodothyronine and 3,3'-diiodothyronine, respectively. These reactions are catalyzed by three iodothyronine deiodinases, D1-3. Although they are homologous selenoproteins, they differ in important respects such as catalysis of ORD and/or IRD, deiodination of sulfated iodothyronines, inhibition by the thyrostatic drug propylthiouracil, and regulation during fetal and neonatal development, by thyroid state, and during illness. In this review we will briefly discuss recent developments in these different areas. These have resulted in the emerging view that the biological activity of thyroid hormone is regulated locally by tissue-specific regulation of the different deiodinases.

  15. Thyroid Hormones, Metabolic Syndrome and Its Components.

    PubMed

    Delitala, Alessandro P; Fanciulli, Giuseppe; Pes, Giovanni M; Maioli, Margherita; Delitala, Giuseppe

    2017-03-20

    Metabolic syndrome is a clustering of various metabolic parameters, which included diabetes, low high-density lipoprotein cholesterol, elevated triglycerides, abdominal obesity, and hypertension. It has merged as a worldwide epidemic and a major public health care concern. However, due to the different criteria used for the assessment, the frequency of metabolic syndrome in the general population is variable but it more common in the older people. Metabolic syndrome is closely linked to cardiovascular risk and increases cardiovascular outcomes and all-cause mortality. Recent evidences showed that alterations of the thyroid function could have an impact on the components of the metabolic syndrome, suggesting that thyroid hormones have a variety of effects on energy homeostasis, lipid and glucose metabolism, and blood pressure. In this review we summarize available data on the action of thyroid hormone on the components of metabolic syndrome.

  16. Thyroid hormone transporters in health and disease.

    PubMed

    Jansen, Jurgen; Friesema, Edith C H; Milici, Carmelina; Visser, Theo J

    2005-08-01

    Cellular entry is required for conversion of thyroid hormone by the intracellular deiodinases and for binding of 3,3',5-triiodothyronine (T(3)) to its nuclear receptors. Recently, several transporters capable of thyroid hormone transport have been identified. Functional expression studies using Xenopus laevis oocytes have demonstrated that organic anion transporters (e.g., OATPs), and L-type amino acid transporters (LATs) facilitate thyroid hormone uptake. Among these, OATP1C1 has a high affinity and specificity for thyroxine (T(4)). OATP1C1 is expressed in capillaries throughout the brain, suggesting it is critical for transport of T(4) over the blood-brain barrier. We have also characterized a member of the monocarboxylate transporter family, MCT8, as a very active and specific thyroid hormone transporter. Human MCT8 shows preference for T(3) as the ligand. MCT8 is highly expressed in liver and brain but is also widely distributed in other tissues. The MCT8 gene is located on the X chromosome. Recently, mutations in MCT8 have been found to be associated with severe X-linked psychomotor retardation and strongly elevated serum T(3) levels.

  17. Thyroid hormone and the cardiovascular system.

    PubMed

    Danzi, S; Klein, I

    2004-09-01

    Thyroid hormone is an important regulator of cardiac function and cardiovascular hemodynamics. Triiodothyronine, (T(3)), the physiologically active form of thyroid hormone, binds to nuclear receptor proteins and mediates the expression of several important cardiac genes, inducing transcription of the positively regulated genes including alpha-myosin heavy chain (MHC) and the sarcoplasmic reticulum calcium ATPase. Negatively regulated genes include beta-MHC and phospholamban, which are down regulated in the presence of normal serum levels of thyroid hormone. T(3) mediated effects on the systemic vasculature include relaxation of vascular smooth muscle resulting in decreased arterial resistance and diastolic blood pressure. In hyperthyroidism, cardiac contractility and cardiac output are enhanced and systemic vascular resistance is decreased, while in hypothyroidism, the opposite is true. Patients with subclinical hypothyroidism manifest many of the same cardiovascular changes, but to a lesser degree than that which occurs in overt hypothyroidism. Cardiac disease states are sometimes associated with the low T(3) syndrome. The phenotype of the failing heart resembles that of the hypothyroid heart, both in cardiac physiology and in gene expression. Changes in serum T(3) levels in patients with chronic congestive heart failure are caused by alterations in thyroid hormone metabolism suggesting that patients may benefit from T(3) replacement in this setting.

  18. Abnormal serum thyroid hormones concentration with healthy functional gland: a review on the metabolic role of thyroid hormones transporter proteins.

    PubMed

    Azad, Reza Mansourian

    2011-03-01

    Laboratory findings can definitely help the patients not to enter into status, where the damage might be happen due to a miss-diagnosis based on clinical assessment alone. The secondary disease accompanied with thyroid patients should also carefully check out due to the interference which some diseases can cause in the amount of serum thyroid hormone, particularly the free thyroxin. The dilemma over thyroid clinical diagnosis occur due to variation on serum thyroid hormone which initiated by other non-thyroidal disorders which can play an important roles in metabolic disorders of thyroid hormone due to the alteration which occur on the serum level of thyroid hormone transporter proteins. The majority of serum thyroid hormones of up to 95-99% are bound to the carrier proteins mainly to Thyroxin-Binding Globulins (TBG), some transthyretin already known as pre-albumin and albumin which are all synthesis in the liver and any modification which alter their production may alter the status of thyroid hormones. It seems TBG, transthyretin and albumin carries 75, 20, 5% of thyroid hormones within blood circulation, respectively. The dilemma facing the thyroid hormones following disruption of thyroid hormone transporter protein synthesis originate from this fact that any alteration of these protein contribute to the alteration of total thyroid and free serum thyroid hormones which are in fact the biologically active form of thyroid hormones. The subsequent of latter implication result in miss-understanding and miss-diagnosis of thyroid function tests, with possible wrongly thyroid clinical care, followed by undesired therapy of otherwise healthy thyroid.

  19. Thyroid hormone and seasonal regulation of reproduction.

    PubMed

    Yoshimura, Takashi

    2013-08-01

    Organisms living outside the tropics use changes in photoperiod to adapt to seasonal changes in the environment. Several models have contributed to an understanding of this mechanism at the molecular and endocrine levels. Subtropical birds are excellent models for the study of these mechanisms because of their rapid and dramatic response to changes in photoperiod. Studies of birds have demonstrated that light is perceived by a deep brain photoreceptor and long day-induced thyrotropin (TSH) from the pars tuberalis (PT) of the pituitary gland causes local thyroid hormone activation within the mediobasal hypothalamus (MBH). The locally generated bioactive thyroid hormone, T₃, regulates seasonal gonadotropin-releasing hormone (GnRH) secretion, and hence gonadotropin secretion. In mammals, the eyes are the only photoreceptor involved in photoperiodic time perception and nocturnal melatonin secretion provides an endocrine signal of photoperiod to the PT to regulate TSH. Here, I review the current understanding of the hypothalamic mechanisms controlling seasonal reproduction in mammals and birds.

  20. Growth and development in a child with resistance to thyroid hormone and ectopic thyroid gland.

    PubMed

    Heather, Natasha; Hall, Kate; Neas, Katherine; Potter, Howard; Wiltshire, Esko

    2012-03-01

    Resistance to thyroid hormone is an uncommon problem, which has rarely been associated with thyroid dysgenesis. We report a case with both thyroid gland ectopy and resistance to thyroid hormone and, thus, a reduced capacity to produce and respond to thyroid hormone. The patient presented at 2 years of age with developmental delay, dysmorphic features, and elevation in both thyroxine and thyrotropin. We document her response to therapy with thyroxine, with particular regard to her growth and development. Persistent elevation of thyrotropin is commonly recognized during treatment of congenital hypothyroidism. Resistance to thyroid hormone may be an important additional diagnosis to consider in cases where thyrotropin remains persistently elevated.

  1. Thyroid Hormone Signaling in the Mouse Retina

    PubMed Central

    Arbogast, Patrick; Flamant, Frédéric; Godement, Pierre; Glösmann, Martin

    2016-01-01

    Thyroid hormone is a crucial regulator of gene expression in the developing and adult retina. Here we sought to map sites of thyroid hormone signaling at the cellular level using the transgenic FINDT3 reporter mouse model in which neurons express β-galactosidase (β-gal) under the control of a hybrid Gal4-TRα receptor when triiodothyronine (T3) and cofactors of thyroid receptor signaling are present. In the adult retina, nearly all neurons of the ganglion cell layer (GCL, ganglion cells and displaced amacrine cells) showed strong β-gal labeling. In the inner nuclear layer (INL), a minority of glycineric and GABAergic amacrine cells showed β-gal labeling, whereas the majority of amacrine cells were unlabeled. At the level of amacrine types, β-gal labeling was found in a large proportion of the glycinergic AII amacrines, but only in a small proportion of the cholinergic/GABAergic ‘starburst’ amacrines. At postnatal day 10, there also was a high density of strongly β-gal-labeled neurons in the GCL, but only few amacrine cells were labeled in the INL. There was no labeling of bipolar cells, horizontal cells and Müller glia cells at both stages. Most surprisingly, the photoreceptor somata in the outer nuclear layer also showed no β-gal label, although thyroid hormone is known to control cone opsin expression. This is the first record of thyroid hormone signaling in the inner retina of an adult mammal. We hypothesize that T3 levels in photoreceptors are below the detection threshold of the reporter system. The topographical distribution of β-gal-positive cells in the GCL follows the overall neuron distribution in that layer, with more T3-signaling cells in the ventral than the dorsal half-retina. PMID:27942035

  2. Pituitary resistance to thyroid hormones: pathophysiology and therapeutic options.

    PubMed

    Suzuki, Satoru; Shigematsu, Satoshi; Inaba, Hidefumi; Takei, Masahiro; Takeda, Teiji; Komatsu, Mitsuhisa

    2011-12-01

    Thyroid hormone secretion suppresses the expression of thyroid stimulating hormone (TSH), both of which are strictly controlled by a negative feedback loop between the hypothalamus-pituitary and thyroid. Pituitary resistance to thyroid hormone (PRTH) is defined as resistance to the action of thyroid hormone that is more severe in the pituitary than at the peripheral tissue level. Although the molecular basis of PRTH is not well understood, the clinical issue mainly involves imbalance between the hypothalamus-pituitary and peripheral thyroid hormone responsivity, which may induce peripheral thyrotoxic phenomena. Here, we review the pathogenesis and molecular aspects of PRTH, present a single case with inappropriate TSH secretion suffering from thyrotoxicosis treated with PTU, and discuss the possible choice of therapeutic options to correct the imbalance of thyroid hormone responsivity in both the hypothalamus-pituitary and peripheral tissues.

  3. Does normal thyroid gland by ultrasonography match with normal serum thyroid hormones and negative thyroid antibodies?

    PubMed

    Trimboli, P; Rossi, F; Condorelli, E; Laurenti, O; Ventura, C; Nigri, G; Romanelli, F; Guarino, M; Valabrega, S

    2010-10-01

    Few papers have shown that a hypoechoic appearance of the thyroid gland at ultrasonography (US) is related to a hypofunction and serum positivity of thyroid antibodies (T-Ab). However, it is not ascertained if normal thyroid appearance at US correspond to normal thyroid laboratory tests. The aim of this study was to assess the value of normal thyroid at US in predicting normal thyroid hormones and negative T-Ab in a cohort of 48 adult patients. All patients (37 females and 11 males) were referred to our hospital to undergo their first thyroid US examination, followed by a thyroid function evaluation. All subjects had normal thyroid gland at US. As a control group 65 patients with hypoechoic and inhomogeneous thyroid gland were enrolled. All 48 patients had normal free-T (3) and free-T (4) levels. While 41 patients (85.4%) showed normal TSH, in 7 subjects (14.6%) TSH was elevated and a significant (p < 0.001) difference was recorded between the two groups in mean TSH value. Positive T-Ab value was found in 5 patients (10.4%) and the remaining 43 patients (89.6%) had negative T-Ab. TSH was not significantly correlated with age, thyroid volume or BMI. The multivariate model showed that only BMI was significantly correlated to thyroid volume (p < 0.01, r(2)=0.31). These results showed that normal thyroid recorded by US matches with normal thyroid laboratory assessment to a large degree. These preliminary data need to be confirmed in a prospective study and in a larger series and should suggest the evaluation of thyrotropin and thyroid antibodies in subjects with normal thyroid gland as assessed by US.

  4. Animal models to study thyroid hormone action in cerebellum.

    PubMed

    Koibuchi, Noriyuki

    2009-06-01

    Thyroid hormone plays a crucial role in the development and functional maintenance of the central nervous system including the cerebellum. To study the molecular mechanisms of thyroid hormone action, various animal models have been used. These are classified: (1) congenital hypothyroid animals due to thyroid gland dysgenesis or thyroid dyshormonogenesis, (2) thyroid hormone receptor (TR) gene-mutated animals, and (3) thyroid hormone transport or metabolism-modified animals. TR is a ligand-activated transcription factor. In the presence of ligand, it activates transcription of target gene, whereas it represses the transcription without ligand. Thus, phenotype of TR-knockout mouse is different from that of hypothyroid animal (low thyroid hormone level), in which unliganded TR actively represses the transcription. On the other hand, human patient harboring mutant TR expresses different phenotypes depending on the function of mutated TR. To mimic this phenotype, other animal models are generated. In addition, recent human studies have shown that thyroid hormone transporters such as monocarboxylate transporter (MCT) 8 may play an important role in thyroid hormone-mediated brain development. However, MCT8 knockout mouse show different phenotypes from a human patient. This article introduces representative animal models currently used to study various aspects of thyroid hormone, particularly to study the involvement of the thyroid hormone system on the development and functional maintenance of the cerebellum.

  5. H9c2 cardiomyoblasts produce thyroid hormone.

    PubMed

    Meischl, Christof; Buermans, Henk P; Hazes, Thierry; Zuidwijk, Marian J; Musters, René J P; Boer, Christa; van Lingen, Arthur; Simonides, Warner S; Blankenstein, Marinus A; Dupuy, Corrine; Paulus, Walter J; Hack, C Erik; Ris-Stalpers, Carrie; Roos, Dirk; Niessen, Hans W M

    2008-05-01

    Thyroid hormone acts on a wide range of tissues. In the cardiovascular system, thyroid hormone is an important regulator of cardiac function and cardiovascular hemodynamics. Although some early reports in the literature suggested an unknown extrathyroidal source of thyroid hormone, it is currently thought to be produced exclusively in the thyroid gland, a highly specialized organ with the sole function of generating, storing, and secreting thyroid hormone. Whereas most of the proteins necessary for thyroid hormone synthesis are thought to be expressed exclusively in the thyroid gland, we now have found evidence that all of these proteins, i.e., thyroglobulin, DUOX1, DUOX2, the sodium-iodide symporter, pendrin, thyroid peroxidase, and thyroid-stimulating hormone receptor, are also expressed in cardiomyocytes. Furthermore, we found thyroglobulin to be transiently upregulated in an in vitro model of ischemia. When performing these experiments in the presence of 125 I, we found that 125 I was integrated into thyroglobulin and that under ischemia-like conditions the radioactive signal in thyroglobulin was reduced. Concomitantly we observed an increase of intracellularly produced, 125 I-labeled thyroid hormone. In conclusion, our findings demonstrate for the first time that cardiomyocytes produce thyroid hormone in a manner adapted to the cell's environment.

  6. Hormone replacement after thyroid and parathyroid surgery.

    PubMed

    Schäffler, Andreas

    2010-11-01

    Hypothyroidism and hypocalcemia are common after thyroid and parathyroid surgery. In this article, the authors provide clinically-oriented recommendations to help surgeons, general practitioners, internists, and endocrinologists give their affected patients adequate hormone replacement therapy. Selective evaluation of original articles and reviews that were retrieved by a PubMed search over the years 1980 to 2010, as well as of the recommendations of medical societies including the Endocrine Society (USA), the German Society for Endocrinology (Deutsche Gesellschaft für Endokrinologie), and the American and European Thyroid Associations. Important issues in L-thyroxine replacement therapy include: the selection of the hormone preparation (T4 or T4/T3), combination with iodine (yes/no), the definition of therapeutic TSH ranges (particularly after surgery for thyroid cancer), the extent of remaining thyroid tissue after goiter surgery and its significance, underlying diseases, and drug interactions. The major issues in the treatment of postoperative hypoparathyroidism are: the selection of suitable calcium and vitamin D preparations, the definition of therapeutic goals, the treatment of hypercalciuria and hyperphosphatemia, and the option of recombinant parathormone therapy. Effective treatment requires an appropriate choice of medication and an understanding of its pharmacokinetics as well as of the possible effects of the patient's underlying disease, comorbidities, and other medications on its absorption and metabolism.

  7. An improved thyroid hormone reporter assay to determine the thyroid hormone-like activity of amiodarone, bithionol, closantel and rafoxanide.

    PubMed

    Matsubara, Kana; Sanoh, Seigo; Ohta, Shigeru; Kitamura, Shigeyuki; Sugihara, Kazumi; Fujimoto, Nariaki

    2012-01-05

    A number of environmental chemicals have been reported to exhibit thyroid hormone-like activity. Since thyroid hormones play a crucial role in development, it is important to identify chemicals in the environment that are capable of endocrine disruption of thyroid hormone homeostasis. In order to detect thyroid hormone-like activity, the growth of pituitary cell lines has been commonly used as a sensitive marker, albeit with limited specificity to thyroid hormones. Reporter gene assays using the thyroid hormone responsive element (TRE) connected to the luciferase reporter gene have also been developed. Thus far however, this type of assay appears to have limited sensitivity compared to cell growth assays. In the present study, we developed a highly sensitive TRE reporter gene assay by using a pituitary cell line, MtT/E-2, and by culturing cells in a serum-free medium. Our assay was developed in order to detect T3 activity at a concentration of 10(-11)M. This assay identified thyroid hormone-like activity from the antiarrhythmic drug, amiodarone, and from three anti-parasitic drugs, bithionol, closantel and rafoxanide, all commonly used in veterinary medicine. Thyroid hormone-like activity of these compounds was further confirmed by the induction of BCL3 gene expression in MtT/E-2, which is known to be regulated by thyroid hormones. Our improved assay was proved to be a sensitive tool for assessing thyroid hormone-like activity of environmental chemicals. Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.

  8. Cardiac specific effects of thyroid hormone analogues.

    PubMed

    Danzi, S; Klein, I

    2011-10-01

    There is significant interest in development of thyroid hormone analogues to harness specific properties as therapeutic agents for a variety of clinical indications including obesity, hypercholesterolemia, heart failure, and thyrotoxicosis. To date, most analogues have been designed to target liver specific effects, which can promote weight loss and lipid lowering through either tissue specific uptake or thyroid hormone receptor (TR) β isoform selectivity at the same time minimizing the unwanted cardiac and bone effects. We have developed a molecular biomarker assay to study the induction of the transcription of the cardiac specific α-myosin heavy chain (MHC) gene as a more sensitive and specific measure of thyroid hormone action on cardiac myocytes. We tested 5 TRβ and 1 TRα selective agonists as well as 2 putative TR antagonists in our α-MHC hnRNA assay. Using reverse transcription and polymerase chain reaction, we measured the induction of the α-MHC primary transcript in response to administration of drug. The TRα and only 2 of the TRβ agonists were highly active, when compared to the effect of T3, at the level of the cardiac myocyte. In addition, our data suggests that the reason that the antagonist NH-3 is not able to block the T3-mediated induction of α-MHC is that it does not get transported into the cardiac myocyte. Our data suggest that this assay will be useful in preclinical studies of the potential cardiac specific effects of thyroid hormone analogues and that predictions of function based on structure are not necessarily accurate or complete. © Georg Thieme Verlag KG Stuttgart · New York.

  9. Resistance to thyroid hormone due to defective thyroid receptor alpha

    PubMed Central

    Moran, Carla; Chatterjee, Krishna

    2015-01-01

    Thyroid hormones act via nuclear receptors (TRα1, TRβ1, TRβ2) with differing tissue distribution; the role of α2 protein, derived from the same gene locus as TRα1, is unclear. Resistance to thyroid hormone alpha (RTHα) is characterised by tissue-specific hypothyroidism associated with near-normal thyroid function tests. Clinical features include dysmorphic facies, skeletal dysplasia (macrocephaly, epiphyseal dysgenesis), growth retardation, constipation, dyspraxia and intellectual deficit. Biochemical abnormalities include low/low-normal T4 and high/high-normal T3 concentrations, a subnormal T4/T3 ratio, variably reduced reverse T3, raised muscle creatine kinase and mild anaemia. The disorder is mediated by heterozygous, loss-of-function, mutations involving either TRα1 alone or both TRα1 and α2, with no discernible phenotype attributable to defective α2. Whole exome sequencing and diagnostic biomarkers may enable greater ascertainment of RTHα, which is important as thyroxine therapy reverses some metabolic abnormalities and improves growth, constipation, dyspraxia and wellbeing. The genetic and phenotypic heterogeneity of RTHα and its optimal management remain to be elucidated. PMID:26303090

  10. Transport of thyroid hormones via the choroid plexus into the brain: the roles of transthyretin and thyroid hormone transmembrane transporters

    PubMed Central

    Richardson, Samantha J.; Wijayagunaratne, Roshen C.; D'Souza, Damian G.; Darras, Veerle M.; Van Herck, Stijn L. J.

    2015-01-01

    Thyroid hormones are key players in regulating brain development. Thus, transfer of appropriate quantities of thyroid hormones from the blood into the brain at specific stages of development is critical. The choroid plexus forms the blood-cerebrospinal fluid barrier. In reptiles, birds and mammals, the main protein synthesized and secreted by the choroid plexus is a thyroid hormone distributor protein: transthyretin. This transthyretin is secreted into the cerebrospinal fluid and moves thyroid hormones from the blood into the cerebrospinal fluid. Maximal transthyretin synthesis in the choroid plexus occurs just prior to the period of rapid brain growth, suggesting that choroid plexus-derived transthyretin moves thyroid hormones from blood into cerebrospinal fluid just prior to when thyroid hormones are required for rapid brain growth. The structure of transthyretin has been highly conserved, implying strong selection pressure and an important function. In mammals, transthyretin binds T4 (precursor form of thyroid hormone) with higher affinity than T3 (active form of thyroid hormone). In all other vertebrates, transthyretin binds T3 with higher affinity than T4. As mammals are the exception, we should not base our thinking about the role of transthyretin in the choroid plexus solely on mammalian data. Thyroid hormone transmembrane transporters are involved in moving thyroid hormones into and out of cells and have been identified in many tissues, including the choroid plexus. Thyroid hormones enter the choroid plexus via thyroid hormone transmembrane transporters and leave the choroid plexus to enter the cerebrospinal fluid via either thyroid hormone transmembrane transporters or via choroid plexus-derived transthyretin secreted into the cerebrospinal fluid. The quantitative contribution of each route during development remains to be elucidated. This is part of a review series on ontogeny and phylogeny of brain barrier mechanisms. PMID:25784853

  11. Transport of thyroid hormones via the choroid plexus into the brain: the roles of transthyretin and thyroid hormone transmembrane transporters.

    PubMed

    Richardson, Samantha J; Wijayagunaratne, Roshen C; D'Souza, Damian G; Darras, Veerle M; Van Herck, Stijn L J

    2015-01-01

    Thyroid hormones are key players in regulating brain development. Thus, transfer of appropriate quantities of thyroid hormones from the blood into the brain at specific stages of development is critical. The choroid plexus forms the blood-cerebrospinal fluid barrier. In reptiles, birds and mammals, the main protein synthesized and secreted by the choroid plexus is a thyroid hormone distributor protein: transthyretin. This transthyretin is secreted into the cerebrospinal fluid and moves thyroid hormones from the blood into the cerebrospinal fluid. Maximal transthyretin synthesis in the choroid plexus occurs just prior to the period of rapid brain growth, suggesting that choroid plexus-derived transthyretin moves thyroid hormones from blood into cerebrospinal fluid just prior to when thyroid hormones are required for rapid brain growth. The structure of transthyretin has been highly conserved, implying strong selection pressure and an important function. In mammals, transthyretin binds T4 (precursor form of thyroid hormone) with higher affinity than T3 (active form of thyroid hormone). In all other vertebrates, transthyretin binds T3 with higher affinity than T4. As mammals are the exception, we should not base our thinking about the role of transthyretin in the choroid plexus solely on mammalian data. Thyroid hormone transmembrane transporters are involved in moving thyroid hormones into and out of cells and have been identified in many tissues, including the choroid plexus. Thyroid hormones enter the choroid plexus via thyroid hormone transmembrane transporters and leave the choroid plexus to enter the cerebrospinal fluid via either thyroid hormone transmembrane transporters or via choroid plexus-derived transthyretin secreted into the cerebrospinal fluid. The quantitative contribution of each route during development remains to be elucidated. This is part of a review series on ontogeny and phylogeny of brain barrier mechanisms.

  12. Thyroid hormone determines the start of the sensitive period of imprinting and primes later learning.

    PubMed

    Yamaguchi, Shinji; Aoki, Naoya; Kitajima, Takaaki; Iikubo, Eiji; Katagiri, Sachiko; Matsushima, Toshiya; Homma, Koichi J

    2012-01-01

    Filial imprinting in precocial birds is the process of forming a social attachment during a sensitive or critical period, restricted to the first few days after hatching. Imprinting is considered to be part of early learning to aid the survival of juveniles by securing maternal care. Here we show that the thyroid hormone 3,5,3'-triiodothyronine (T(3)) determines the start of the sensitive period. Imprinting training in chicks causes rapid inflow of T(3), converted from circulating plasma thyroxine by Dio2, type 2 iodothyronine deiodinase, in brain vascular endothelial cells. The T(3) thus initiates and extends the sensitive period to last more than 1 week via non-genomic mechanisms and primes subsequent learning. Even in non-imprinted chicks whose sensitive period has ended, exogenous T(3) enables imprinting. Our findings indicate that T(3) determines the start of the sensitive period for imprinting and has a critical role in later learning.

  13. Thyroid hormone determines the start of the sensitive period of imprinting and primes later learning

    PubMed Central

    Yamaguchi, Shinji; Aoki, Naoya; Kitajima, Takaaki; Iikubo, Eiji; Katagiri, Sachiko; Matsushima, Toshiya; Homma, Koichi J.

    2012-01-01

    Filial imprinting in precocial birds is the process of forming a social attachment during a sensitive or critical period, restricted to the first few days after hatching. Imprinting is considered to be part of early learning to aid the survival of juveniles by securing maternal care. Here we show that the thyroid hormone 3,5,3′-triiodothyronine (T3) determines the start of the sensitive period. Imprinting training in chicks causes rapid inflow of T3, converted from circulating plasma thyroxine by Dio2, type 2 iodothyronine deiodinase, in brain vascular endothelial cells. The T3 thus initiates and extends the sensitive period to last more than 1 week via non-genomic mechanisms and primes subsequent learning. Even in non-imprinted chicks whose sensitive period has ended, exogenous T3 enables imprinting. Our findings indicate that T3 determines the start of the sensitive period for imprinting and has a critical role in later learning. PMID:23011135

  14. Thyroid hormone and the central control of homeostasis.

    PubMed

    Warner, Amy; Mittag, Jens

    2012-08-01

    It has long been known that thyroid hormone has profound direct effects on metabolism and cardiovascular function. More recently, it was shown that the hormone also modulates these systems by actions on the central autonomic control. Recent studies that either manipulated thyroid hormone signalling in anatomical areas of the brain or analysed seasonal models with an endogenous fluctuation in hypothalamic thyroid hormone levels revealed that the hormone controls energy turnover. However, most of these studies did not progress beyond the level of anatomical nuclei; thus, the neuronal substrates as well as the molecular mechanisms remain largely enigmatic. This review summarises the evidence for a role of thyroid hormone in the central autonomic control of peripheral homeostasis and advocates novel strategies to address thyroid hormone action in the brain on a cellular level.

  15. Clinical implications of thyroid hormones effects on nervous system development.

    PubMed

    Carreón-Rodríguez, Alfonso; Pérez-Martínez, Leonor

    2012-03-01

    Thyroid hormones have an important role throughout prenatal and postnatal nervous system development. They are involved in several processes such as neurogenesis, gliogenesis, myelination, synaptogenesis, etc., as shown in many cases of deficiency like congenital hypothyroidism or hypothyroxinemia. Those pathologies if untreated could lead to severe damages in cognitive, motor, neudoendocrine functions among other effects. Some could be reversed after adequate supplementation of thyroid hormones at birth, however there are other cellular processes highly sensitive to low levels of thyroid hormones and lasting a limited period of time during which if thyroid hormone action is lacking or deficient, the functional and structural damages would produce permanent defects.

  16. ON THE EFFECT OF NEUROHYPOPHYSIAL HORMONE ON THYROID ACTIVITY.

    DTIC Science & Technology

    THYROID GLAND, BIOCHEMISTRY, HORMONES , INJECTION, DRUGS, CARDIOVASCULAR AGENTS, SECRETION, THYROXINE, EXPOSURE(PHYSIOLOGY), THYROTROPIN, STIMULATION(PHYSIOLOGY), TEMPERATURE, BODY WEIGHT, PATHOLOGY, HISTOLOGY.

  17. Thyroid Hormone Enhances Nitric Oxide-Mediated Bacterial Clearance and Promotes Survival after Meningococcal Infection

    PubMed Central

    Wang, Xiao; Altenbacher, Georg; Hagner, Matthias; Berglund, Pernilla; Gao, Yumin; Lu, Ting; Jonsson, Ann-Beth; Sjölinder, Hong

    2012-01-01

    Euthyroid sick syndrome characterized by reduced levels of thyroid hormones (THs) is observed in patients with meningococcal shock. It has been found that the level of THs reflects disease severity and is predictive for mortality. The present study was conducted to investigate the impact of THs on host defense during meningococcal infection. We found that supplementation of thyroxine to mice infected with Neisseria meningitidis enhanced bacterial clearance, attenuated the inflammatory responses and promoted survival. In vitro studies with macrophages revealed that THs enhanced bacteria-cell interaction and intracellular killing of meningococci by stimulating inducible nitric oxide synthase (iNos)-mediated NO production. TH treatment did not activate expression of TH receptors in macrophages. Instead, the observed TH-directed actions were mediated through nongenomic pathways involving the protein kinases PI3K and ERK1/2 and initiated at the membrane receptor integrin αvβ3. Inhibition of nongenomic TH signaling prevented iNos induction, NO production and subsequent intracellular bacterial killing by macrophages. These data demonstrate a beneficial role of THs in macrophage-mediated N. meningitidis clearance. TH replacement might be a novel option to control meningococcal septicemia. PMID:22844479

  18. Thyroid Hormones, Oxidative Stress, and Inflammation.

    PubMed

    Mancini, Antonio; Di Segni, Chantal; Raimondo, Sebastiano; Olivieri, Giulio; Silvestrini, Andrea; Meucci, Elisabetta; Currò, Diego

    2016-01-01

    Inflammation and oxidative stress (OS) are closely related processes, as well exemplified in obesity and cardiovascular diseases. OS is also related to hormonal derangement in a reciprocal way. Among the various hormonal influences that operate on the antioxidant balance, thyroid hormones play particularly important roles, since both hyperthyroidism and hypothyroidism have been shown to be associated with OS in animals and humans. In this context, the nonthyroidal illness syndrome (NTIS) that typically manifests as reduced conversion of thyroxine (T4) to triiodothyronine (T3) in different acute and chronic systemic conditions is still a debated topic. The pathophysiological mechanisms of this syndrome are reviewed, together with the roles of deiodinases, the enzymes responsible for the conversion of T4 to T3, in both physiological and pathological situations. The presence of OS indexes in NTIS supports the hypothesis that it represents a condition of hypothyroidism at the tissue level and not only an adaptive mechanism to diseases.

  19. Thyroid Hormones, Oxidative Stress, and Inflammation

    PubMed Central

    Raimondo, Sebastiano; Olivieri, Giulio; Meucci, Elisabetta; Currò, Diego

    2016-01-01

    Inflammation and oxidative stress (OS) are closely related processes, as well exemplified in obesity and cardiovascular diseases. OS is also related to hormonal derangement in a reciprocal way. Among the various hormonal influences that operate on the antioxidant balance, thyroid hormones play particularly important roles, since both hyperthyroidism and hypothyroidism have been shown to be associated with OS in animals and humans. In this context, the nonthyroidal illness syndrome (NTIS) that typically manifests as reduced conversion of thyroxine (T4) to triiodothyronine (T3) in different acute and chronic systemic conditions is still a debated topic. The pathophysiological mechanisms of this syndrome are reviewed, together with the roles of deiodinases, the enzymes responsible for the conversion of T4 to T3, in both physiological and pathological situations. The presence of OS indexes in NTIS supports the hypothesis that it represents a condition of hypothyroidism at the tissue level and not only an adaptive mechanism to diseases. PMID:27051079

  20. Chronic exposure to pentachlorophenol alters thyroid hormones and thyroid hormone pathway mRNAs in zebrafish.

    PubMed

    Yu, Li-Qin; Zhao, Gao-Feng; Feng, Min; Wen, Wu; Li, Kun; Zhang, Pan-Wei; Peng, Xi; Huo, Wei-Jie; Zhou, Huai-Dong

    2014-01-01

    Pentachlorophenol (PCP) is frequently detected in the aquatic environment and has been implicated as an endocrine disruptor in fish. In the present study, 4-month-old zebrafish (Danio rerio) were exposed to 1 of 4 concentrations of PCP (0.1, 1, 9, and 27 µg/L) for 70 d. The effects of PCP exposure on plasma thyroid hormone levels, and the expression levels of selected genes, were measured in the brain and liver. The PCP exposure at 27 µg/L resulted in elevated plasma thyroxine concentrations in male and female zebrafish and depressed 3, 5, 3'-triiodothyronine concentrations in males only. In both sexes, PCP exposure resulted in decreased messenger RNA (mRNA) expression levels of thyroid-stimulating hormone β-subunit (tshβ) and thyroid hormone receptor β (trβ) in the brain, as well as increased liver levels of uridine diphosphoglucuronosyl transferase (ugt1ab) and decreased deiodinase 1 (dio1). The authors also identified several sex-specific effects of PCP exposure, including changes in mRNA levels for deiodinase 2 (dio2), cytosolic sulfotransferase (sult1 st5), and transthyretin (ttr) genes in the liver. Environmental PCP exposure also caused an increased malformation rate in offspring that received maternal exposure to PCP. The present study demonstrates that chronic exposure to environmental levels of PCP alters plasma thyroid hormone levels, as well as the expression of genes associated with thyroid hormone signaling and metabolism in the hypothalamic-pituitary-thyroid (HPT) axis and liver, resulting in abnormal zebrafish development.

  1. The role of thyroid hormone in sleep deprivation.

    PubMed

    Pereira, José Carlos; Andersen, Mônica Levy

    2014-03-01

    Sleep deprivation is a stressful condition, as the subject experiences feelings of inadequate well-being and exhibits impairments in his/her functioning. However, in some circumstances sleep deprivation may be crucial for survival of the individual. Most likely, complex neural circuits and hormones play a role in allowing sleep deprivation to occur. For instance, thyroid hormone activity sharply increases when an individual is in a state of sleep deprivation. We believe that this increase is central to sleep deprivation physiology. During sleep deprivation, the hypothalamic-pituitary-thyroid axis initially increases as a consequence of increased release of thyroid stimulating hormone from the pituitary. Subsequently, as sleep deprivation continues, the sympathetic nervous system is recruited through its anatomical connection with the thyroid gland. While thyroid stimulating hormone levels markedly increase during sleep deprivation, it has been suggested that these increases are secondary to sleep deprivation. However, there is little evidence to support this assumption. We believe that the physiology of the thyroid axis during sleep deprivation and the actions of the effector hormone thyroid hormone suggest that thyroid hormone inhibits sleep and not the contrary. To our knowledge, few studies have addressed the possible neural functions that enable sleep deprivation. In this article, we discuss the hypothesis that an augmentation in the thyroid hormone axis is central to a subject's ability to curtail sleep.

  2. Thyroid hormone receptors bind to defined regions of the growth hormone and placental lactogen genes.

    PubMed Central

    Barlow, J W; Voz, M L; Eliard, P H; Mathy-Harter, M; De Nayer, P; Economidis, I V; Belayew, A; Martial, J A; Rousseau, G G

    1986-01-01

    The intracellular receptor for thyroid hormone is a protein found in chromatin. Since thyroid hormone stimulates transcription of the growth hormone gene through an unknown mechanism, the hypothesis that the thyroid hormone-receptor complex interacts with defined regions of this gene has been investigated in a cell-free system. Nuclear extracts from human lymphoblastoid IM-9 cells containing thyroid hormone receptors were incubated with L-3,5,3'-tri[125I]iodothyronine and calf thymus DNA-cellulose. Restriction fragments of the human growth hormone gene were added to determine their ability to inhibit labeled receptor binding to DNA-cellulose. These fragments encompassed nucleotide sequences from about three kilobase pairs upstream to about four kilobase pairs downstream from the transcription initiation site. The thyroid hormone-receptor complex bound preferentially to the 5'-flanking sequences of the growth hormone gene in a region between nucleotide coordinates -290 and -129. The receptor also bound to an analogous promoter region in the human placental lactogen gene, which has 92% nucleotide sequence homology with the growth hormone gene. These binding regions appear to be distinct from those that are recognized by the receptor for glucocorticoids, which stimulate growth hormone gene expression synergistically with thyroid hormone. The presence of thyroid hormone was required for binding of its receptor to the growth hormone gene promoter, suggesting that thyroid hormone renders the receptor capable of recognizing specific gene regions. PMID:3466175

  3. Thyroid hormone receptors bind to defined regions of the growth hormone and placental lactogen genes.

    PubMed

    Barlow, J W; Voz, M L; Eliard, P H; Mathy-Harter, M; De Nayer, P; Economidis, I V; Belayew, A; Martial, J A; Rousseau, G G

    1986-12-01

    The intracellular receptor for thyroid hormone is a protein found in chromatin. Since thyroid hormone stimulates transcription of the growth hormone gene through an unknown mechanism, the hypothesis that the thyroid hormone-receptor complex interacts with defined regions of this gene has been investigated in a cell-free system. Nuclear extracts from human lymphoblastoid IM-9 cells containing thyroid hormone receptors were incubated with L-3,5,3'-tri[125I]iodothyronine and calf thymus DNA-cellulose. Restriction fragments of the human growth hormone gene were added to determine their ability to inhibit labeled receptor binding to DNA-cellulose. These fragments encompassed nucleotide sequences from about three kilobase pairs upstream to about four kilobase pairs downstream from the transcription initiation site. The thyroid hormone-receptor complex bound preferentially to the 5'-flanking sequences of the growth hormone gene in a region between nucleotide coordinates -290 and -129. The receptor also bound to an analogous promoter region in the human placental lactogen gene, which has 92% nucleotide sequence homology with the growth hormone gene. These binding regions appear to be distinct from those that are recognized by the receptor for glucocorticoids, which stimulate growth hormone gene expression synergistically with thyroid hormone. The presence of thyroid hormone was required for binding of its receptor to the growth hormone gene promoter, suggesting that thyroid hormone renders the receptor capable of recognizing specific gene regions.

  4. Thyroid Hormone Signaling and Cone Photoreceptor Viability.

    PubMed

    Ma, Hongwei; Ding, Xi-Qin

    2016-01-01

    Thyroid hormone (TH) signaling regulates cell proliferation, differentiation, and apoptosis. In the retina, TH signaling plays a central role in cone opsin expression. TH signaling inhibits S opsin expression, stimulates M opsin expression, and promotes dorsal-ventral opsin patterning. TH signaling has also been associated with cone photoreceptor viability. Treatment with thyroid hormone triiodothyronine (T3) or induction of high T3 by deleting the hormone-inactivating enzyme type 3 iodothyronine deiodinase (DIO3) causes cone death in mice. This effect is reversed by deletion of the TH receptor (TR) gene. Consistent with the T3 treatment effect, suppressing TH signaling preserves cones in mouse models of retinal degeneration. The regulation of cone survival by TH signaling appears to be independent of its regulatory role in cone opsin expression. The mechanism by which TH signaling regulates cone viability remains to be identified. The current understanding of TH signaling regulation in photoreceptor viability suggests that suppressing TH signaling locally in the retina may represent a novel strategy for retinal degeneration management.

  5. TSH (Thyroid-Stimulating Hormone) Test

    MedlinePlus

    ... symptoms of a thyroid disorder , including hyperthyroidism or hypothyroidism . TSH is produced by the pituitary gland , a ... thyroid Monitor thyroid replacement therapy in people with hypothyroidism Monitor anti-thyroid treatment in people with hyperthyroidism ...

  6. American Thyroid Association Guide to Investigating Thyroid Hormone Economy and Action in Rodent and Cell Models

    PubMed Central

    Anderson, Grant; Forrest, Douglas; Galton, Valerie Anne; Gereben, Balázs; Kim, Brian W.; Kopp, Peter A.; Liao, Xiao Hui; Obregon, Maria Jesus; Peeters, Robin P.; Refetoff, Samuel; Sharlin, David S.; Simonides, Warner S.; Weiss, Roy E.; Williams, Graham R.

    2014-01-01

    Background: An in-depth understanding of the fundamental principles that regulate thyroid hormone homeostasis is critical for the development of new diagnostic and treatment approaches for patients with thyroid disease. Summary: Important clinical practices in use today for the treatment of patients with hypothyroidism, hyperthyroidism, or thyroid cancer are the result of laboratory discoveries made by scientists investigating the most basic aspects of thyroid structure and molecular biology. In this document, a panel of experts commissioned by the American Thyroid Association makes a series of recommendations related to the study of thyroid hormone economy and action. These recommendations are intended to promote standardization of study design, which should in turn increase the comparability and reproducibility of experimental findings. Conclusions: It is expected that adherence to these recommendations by investigators in the field will facilitate progress towards a better understanding of the thyroid gland and thyroid hormone dependent processes. PMID:24001133

  7. Alternate pathways of thyroid hormone metabolism.

    PubMed

    Wu, Sing-Yung; Green, William L; Huang, Wen-Sheng; Hays, Marguerite T; Chopra, Inder J

    2005-08-01

    The major thyroid hormone (TH) secreted by the thyroid gland is thyroxine (T(4)). Triiodothyronine (T(3)), formed chiefly by deiodination of T(4), is the active hormone at the nuclear receptor, and it is generally accepted that deiodination is the major pathway regulating T(3) bioavailability in mammalian tissues. The alternate pathways, sulfation and glucuronidation of the phenolic hydroxyl group of iodothyronines, the oxidative deamination and decarboxylation of the alanine side chain to form iodothyroacetic acids, and ether link cleavage provide additional mechanisms for regulating the supply of active hormone. Sulfation may play a general role in regulation of iodothyronine metabolism, since sulfation of T(4) and T(3) markedly accelerates deiodination to the inactive metabolites, reverse triiodothyronine (rT(3)) and T(2). Sulfoconjugation is prominent during intrauterine development, particularly in the precocial species in the last trimester including humans and sheep, where it may serve both to regulate the supply of T(3), via sulfation followed by deiodination, and to facilitate maternal-fetal exchange of sulfated iodothyronines (e.g., 3,3'-diiodothyronine sulfate [T(2)S]). The resulting low serum T(3) may be important for normal fetal development in the late gestation. The possibility that T(2)S or its derivative, transferred from the fetus and appearing in maternal serum or urine, can serve as a marker of fetal thyroid function is being studied. Glucuronidation of TH often precedes biliary-fecal excretion of hormone. In rats, stimulation of glucuronidation by various drugs and toxins may lead to lower T(4) and T(3) levels, provocation of thyrotropin (TSH) secretion, and goiter. In man, drug induced stimulation of glucuronidation is limited to T(4), and does not usually compromise normal thyroid function. However, in hypothyroid subjects, higher doses of TH may be required to maintain euthyroidism when these drugs are given. In addition, glucuronidates and

  8. New avenues for regulation of lipid metabolism by thyroid hormones and analogs

    PubMed Central

    Senese, Rosalba; Lasala, Pasquale; Leanza, Cristina; de Lange, Pieter

    2014-01-01

    Weight loss due to negative energy balance is a goal in counteracting obesity and type 2 diabetes mellitus. The thyroid is known to be an important regulator of energy metabolism through the action of thyroid hormones (THs). The classic, active TH, 3,5,3′-triiodo-L-thyronine (T3) acts predominantly by binding to nuclear receptors termed TH receptors (TRs), that recognize TH response elements (TREs) on the DNA, and so regulate transcription. T3 also acts through “non-genomic” pathways that do not necessarily involve TRs. Lipid-lowering therapies have been suggested to have potential benefits, however, the establishment of comprehensive therapeutic strategies is still awaited. One drawback of using T3 in counteracting obesity has been the occurrence of heart rhythm disturbances. These are mediated through one TR, termed TRα. The end of the previous century saw the exploration of TH mimetics that specifically bind to TR beta in order to prevent cardiac disturbances, and TH derivatives such as 3,5-diiodo-L-thyronine (T2), that possess interesting biological activities. Several TH derivatives and functional analogs have low affinity for the TRs, and are suggested to act predominantly through non-genomic pathways. All this has opened new perspectives in thyroid physiology and TH derivative usage as anti-obesity therapies. This review addresses the pros and cons of these compounds, in light of their effects on energy balance regulation and on lipid/cholesterol metabolism. PMID:25538628

  9. Diagnostic Dilemma in Discordant Thyroid Function Tests Due to Thyroid Hormone Autoantibodies

    PubMed Central

    Srichomkwun, Panudda; Scherberg, Neal H.; Jakšić, Jasminka; Refetoff, Samuel

    2016-01-01

    Objective Assay interference could be the cause of abnormal thyroid function tests. Early recognition prevents inappropriate patient management. The objective of this report is to present a case with discordant thyroid function tests in different thyroid assay platforms due to thyroid autoantibodies. Methods We present a case her family, laboratory data and methods that investigate immunoassay interference. Results A 21-year-old woman with autoimmune thyroid disease was treated for hypothyroidism with levothyroxine and noted to have elevated total and free thyroxine, free triiodothyronine but normal thyroid-stimulating hormone. Repeat thyroid function tests using different platforms revealed discrepant results. Further investigation showed that the patient had positive thyroid hormone autoantibodies (THAAbs). Conclusion We demonstrates abnormal thyroid function tests caused by THAAbs. The latter were the cause of interference with assays resulting in discrepant test results inconsistent with the clinical presentation. Early recognition would prevent inappropriate patient management. PMID:28078322

  10. Illness-induced changes in thyroid hormone metabolism: focus on the tissue level.

    PubMed

    Kwakkel, J; Fliers, E; Boelen, A

    2011-05-01

    During illness changes in thyroid hormone metabolism occur, collectively known as the non-thyroidal illness syndrome (NTIS). NTIS is characterised by low serum thyroid hormone levels without the expected rise in serum thyroid-stimulating hormone, indicating a major change in thyroid hormone feedback regulation. Recent studies have made clear that during NTIS differential changes in thyroid hormone metabolism occur in various tissues, the net effect of which may be either activation or inhibition of thyroid hormone action. In this review we discuss systemic and local changes in thyroid hormone metabolism during illness, highlighting their physiological implications in terms of disease course.

  11. Thyroid hormone action at the nuclear level.

    PubMed

    Oppenheimer, J H

    1985-03-01

    Recent findings have led to a greater understanding of thyroid hormone action. The nuclear receptor for triiodothyronine is an integral component of a larger chromatin fragment. A stereospecific energy-dependent transport system appears responsible for translocation of triiodothyronine from cytosol to nucleus. In the liver, a multiplicative interaction between a signal from the triiodothyronine-nuclear receptor complex and a signal generated from carbohydrate metabolism results in the induction of specific mRNAs. Two-dimensional mRNA activity profiles suggest that approximately 8% of the visible mRNA sequences are differentially affected by alterations in thyroid states. Almost 30% to 40% of these changes are mediated by an increase in pituitary growth hormone induced by triiodothyronine. Sequential analyses of mRNA activity profiles have identified an mRNA sequence (mRNAs14) coding for a protein (S14) with Mr 17 010 and pI 4.9 which responds to triiodothyronine with a lag time of less than 20 minutes. The coordinate regulation of mRNAs14 by carbohydrate and triiodothyronine and its presence in lipogenic tissues (fat, liver, lactating mammary tissue) suggests that S14 is involved in some aspect of fatty acid synthesis degradation or storage.

  12. [Thyroid hormones and their precursors I. Biochemical properties].

    PubMed

    Tóth, Gergo; Noszál, Béla

    2013-01-01

    This paper and the following one (see the next issue of Acta Pharmaceutica Hungarica) survey the biological roles and the related site-specific physico-chemical parameters (basicity and lipophilicity) of the presently known thyroid hormones (thyroxine, liothyronine and reverse liothyronine) and their biological precursors (monoiodotyrosine and diiodotyrosine). Here the literature of the thyroid hormone biochemistry, biosynthesis, plasma- and membrane transport is summarized, focusing on the pH-dependent processes. Biosyntheses of the thyroid hormones take place by oxidative coupling of two iodotyrosine residues catalyzed by thyreoperoxidase in thyreoglobulin. The protonation state of the precursors, especially that of the phenolic OH is crucial for the biosynthesis, since anionic iodotyrosine residues can only be coupled in the thyroid hormone biosyntheses. In the blood more than 99% of the circulating thyroid hormone is bound to plasma proteins among which the thyroxine-binding globulin and transthyretin are crucial. The amphiphilic character of the hormones is assumed to be the reason why their membrane transport is an energy-dependent, transport-mediated process, in which the organic anion transporter family, mainly OATP1C1, and the amino acid transporters, such as MCT8 play important roles. Liothyronine is the biologically active hormone; it binds the thyroid hormone receptor, a type of nuclear receptor. There are two major thyroid hormone receptor (TR) isoforms, alfa (TRalpha) and beta (TRbeta). The activation of the TRalpha is associated with modifications in cardiac behavior, while activation of the TRbeta is associated with increasing metabolic rates, resulting in weight loss and reduction of blood plasma lipid levels. The affinity of the thyroid hormones for different proteins depends on the ionization state of the ligands. The site-specific physico-chemical characterization of the thyroid hormones is of fundamental importance to understand their (patho

  13. Thyroid disease and the cardiovascular system.

    PubMed

    Danzi, Sara; Klein, Irwin

    2014-06-01

    Thyroid hormones, specifically triiodothyronine (T3), have significant effects on the heart and cardiovascular system. Hypothyroidism, hyperthyroidism, subclinical thyroid disease, and low T3 syndrome each cause cardiac and cardiovascular abnormalities through both genomic and nongenomic effects on cardiac myocytes and vascular smooth muscle cells. In compromised health, such as occurs in heart disease, alterations in thyroid hormone metabolism may further impair cardiac and cardiovascular function. Diagnosis and treatment of cardiac disease may benefit from including analysis of thyroid hormone status, including serum total T3 levels. Copyright © 2014 Elsevier Inc. All rights reserved.

  14. Thyroid profiles in a patient with resistance to thyroid hormone and episodes of thyrotoxicosis, including repeated painless thyroiditis.

    PubMed

    Taniyama, Matsuo; Otsuka, Fumiko; Tozaki, Teruaki; Ban, Yoshiyuki

    2013-07-01

    Thyrotoxic disease can be difficult to recognize in patients with resistance to thyroid hormone (RTH) because the clinical symptoms of thyrotoxicosis cannot be observed, and thyrotropin (TSH) may not be suppressed because of hormone resistance. Painless thyroiditis is a relatively common cause of thyrotoxicosis, but its occurrence in RTH has not been reported. We assessed the thyroid profile in a patient with RTH and episodes of thyrotoxicosis who experienced repeated painless thyroiditis. A 44-year-old Japanese woman with RTH, which was confirmed by the presence of a P453A mutation in the thyroid hormone receptor β (TRβ) gene, showed a slight elevation of the basal levels of thyroid hormones, which indicated that her pituitary RTH was mild. She experienced a slight exacerbation of hyperthyroxinemia concomitant with TSH suppression. A diagnosis of painless thyroiditis was made because of the absence of TSH receptor antibodies, low Tc-99m pertechnetate uptake by the thyroid gland, and transient suppression followed by a slight elevation of TSH following the elevation of thyroid hormones. The patient's complaints of general malaise and occasional palpitations did not change throughout the course of painless thyroiditis. Three years later, painless thyroiditis occurred again without any deterioration of the clinical manifestations. Mild pituitary RTH can be overcome by slight exacerbation of hyperthyroxinemia during mild thyrotoxicosis. When pituitary resistance is severe and TSH is not suppressed, thyrotoxicosis may be overlooked.

  15. The effects of thyroid hormone abnormalities on periodontal disease status.

    PubMed

    Zahid, Talal M; Wang, Bing-Yan; Cohen, Robert E

    2011-10-01

    Thyroid hormones play an important role in the regulation of physiologic processes. Thyroid disease can lead to imbalance in the homeostasis of the body and affect the healing capacity of tissues. However, limited data are available regarding the relationship between thyroid hormone imbalance (thyroid disease) and periodontal health. This review is carried out to summarize the relationship between thyroid disease and periodontal status. PUBMED and MEDLINE searches of both human and animal studies were performed to investigate the relationship between thyroid disease, periodontal status, and dental implants. Results suggest that thyroid diseases may affect the status of periodontal diseases, especially in hypothyroid conditions. The duration from disease onset to treatment of thyroid disorders may be critical, since uncontrolled thyroid disease may result in destruction of the periodontium. Further controlled studies are needed to explore the relationship between thyroid hormone imbalance and periodontal status. Periodontal therapies, including dental implant placement, appear to be safe with no increase in treatment failure, so long as the status of the thyroid gland is controlled.

  16. Neurodevelopmental Consequences of Low-Level Thyroid Hormone Disruption Induced by Environmental Contaminants

    EPA Science Inventory

    Inadequate levels of thyroid hormone during critical developmental periods lead to stunted growth, mental retardation, and neurological 'cretinism'. Animal models of developmental thyroid hormone deficiency mirror well the impact of severe insults to the thyroid system. However, ...

  17. Neurodevelopmental Consequences of Low-Level Thyroid Hormone Disruption Induced by Environmental Contaminants

    EPA Science Inventory

    Inadequate levels of thyroid hormone during critical developmental periods lead to stunted growth, mental retardation, and neurological 'cretinism'. Animal models of developmental thyroid hormone deficiency mirror well the impact of severe insults to the thyroid system. However, ...

  18. Thyroid Hormone and Leptin in the Testis

    PubMed Central

    Ramos, Cristiane Fonte; Zamoner, Ariane

    2014-01-01

    Leptin is primarily expressed in white adipose tissue; however, it is expressed in the hypothalamus and reproductive tissues as well. Leptin acts by activating the leptin receptors (Ob-Rs). Additionally, the regulation of several neuroendocrine and reproductive functions, including the inhibition of glucocorticoids and enhancement of thyroxine and sex hormone concentrations in human beings and mice are leptin functions. It has been suggested that thyroid hormones (TH) could directly regulate leptin expression. Additionally, hypothyroidism compromises the intracellular integration of leptin signaling specifically in the arcuate nucleus. Two TH receptor isoforms are expressed in the testis, TRa and TRb, with TRa being the predominant one that is present in all stages of development. The effects of TH involve the proliferation and differentiation of Sertoli and Leydig cells during development, spermatogenesis, and steroidogenesis. In this context, TH disorders are associated with sexual dysfunction. An endocrine and/or direct paracrine effect of leptin on the gonads inhibits testosterone production in Leydig cells. Further studies are necessary to clarify the effects of both hormones in the testis during hypothyroidism. The goal of this review is to highlight the current knowledge regarding leptin and TH in the testis. PMID:25505448

  19. New Approaches to Thyroid Hormones and Purinergic Signaling

    PubMed Central

    Silveira, Gabriel Fernandes; Buffon, Andréia; Bruno, Alessandra Nejar

    2013-01-01

    It is known that thyroid hormones influence a wide variety of events at the molecular, cellular, and functional levels. Thyroid hormones (TH) play pivotal roles in growth, cell proliferation, differentiation, apoptosis, development, and metabolic homeostasis via thyroid hormone receptors (TRs) by controlling the expression of TR target genes. Most of these effects result in pathological and physiological events and are already well described in the literature. Even so, many recent studies have been devoted to bringing new information on problems in controlling the synthesis and release of these hormones and to elucidating mechanisms of the action of these hormones unconventionally. The purinergic system was recently linked to thyroid diseases, including enzymes, receptors, and enzyme products related to neurotransmitter release, nociception, behavior, and other vascular systems. Thus, throughout this text we intend to relate the relationship between the TH in physiological and pathological situations with the purinergic signaling. PMID:23956925

  20. New approaches to thyroid hormones and purinergic signaling.

    PubMed

    Silveira, Gabriel Fernandes; Buffon, Andréia; Bruno, Alessandra Nejar

    2013-01-01

    It is known that thyroid hormones influence a wide variety of events at the molecular, cellular, and functional levels. Thyroid hormones (TH) play pivotal roles in growth, cell proliferation, differentiation, apoptosis, development, and metabolic homeostasis via thyroid hormone receptors (TRs) by controlling the expression of TR target genes. Most of these effects result in pathological and physiological events and are already well described in the literature. Even so, many recent studies have been devoted to bringing new information on problems in controlling the synthesis and release of these hormones and to elucidating mechanisms of the action of these hormones unconventionally. The purinergic system was recently linked to thyroid diseases, including enzymes, receptors, and enzyme products related to neurotransmitter release, nociception, behavior, and other vascular systems. Thus, throughout this text we intend to relate the relationship between the TH in physiological and pathological situations with the purinergic signaling.

  1. Generalized resistance to thyroid hormone associated with a mutation in the ligand-binding domain of the human thyroid hormone receptor. beta

    SciTech Connect

    Sakurai, A.; Takeda, K.; Ain, K.; Ceccarelli, P.; Nakai, A.; Seino, S.; Bell, G.I.; Refetoff, S.; DeGroot, L.J. )

    1989-11-01

    The syndrome of generalized resistance to thyroid hormone is characterized by elevated circulating levels of thyroid hormone in the presence of an overall eumetabolic state and failure to respond normally to triiodothyronine. The authors have evaluated a family with inherited generalized resistance to thyroid hormone for abnormalities in the thyroid hormone nuclear receptors. A single guanine {yields} cytosine replacement in the codon for amino acid 340 resulted in a glycine {yields} arginine substitution in the hormone-binding domain of one of two alleles of the patient's thyroid hormone nuclear receptor {beta} gene. In vitro translation products of this mutant human thyroid hormone nuclear receptor {beta} gene did not bind triiodothyronine. Thus, generalized resistance to thyroid hormone can result from expression of an abnormal thyroid hormone nuclear receptor molecule.

  2. Thyroiditis

    MedlinePlus

    ... Hashimoto’s thyroiditis is the most common cause of hypothyroidism in the United States. Postpartum thyroiditis, which causes ... hormone levels in the blood) followed by temporary hypothyroidism, is a common cause of thyroid problems after ...

  3. Thyroid

    MedlinePlus

    Thyroid is used to treat the symptoms of hypothyroidism (a condition where the thyroid gland does not produce enough thyroid hormone). Symptoms of hypothyroidism include lack of energy, depression, constipation, weight gain, ...

  4. Circulating thyroid hormone levels in children

    PubMed Central

    Corcoran, J. M.; Eastman, C. J.; Carter, J. N.; Lazarus, L.

    1977-01-01

    Extensive use of radioimmunoassay for routine measurement of serum thyroid hormones in paediatric thyroid disorders showed inconsistencies between laboratory results based upon adult criteria and clinical observation. To resolve this disparity, serum triiodothyronine (T3) and thyroxine (T4) levels were measured by radioimmunoassay in 354 healthy children aged between 3 weeks and 17 years. The mean serum T3 concentration in children up to 10 years of age was 1·94±0·35 ng/ml (SD) which was higher than the mean serum T3 of 1·37±0·25 ng/ml in healthy adults. Similarly, the mean serum T4 of 10±2·5 μg/100 ml was higher than the adult mean serum T4 of 8·5±1·5 μg/100 ml. Neither concentration changed significantly from 3 weeks to 10 years of age, nor was there any sex difference. In girls serum T3 and T4 concentrations declined gradually from age 10 to maturity. A perimenarcheal nadir observed in the T4 data was thought to reflect the joint effects of the age-dependent fall in circulating T4 and the concomitant oestrogen-dependent rise in thyroxine-binding globulin. In boys the decline in serum T3 occurred approximately 2 years later than in the girls. These observations show that the normal ranges for serum T3 and T4 in children are higher than those in adults and that reference to normal adult ranges may lead to misclassification in diagnosis and monitoring of paediatric thyroid disorders. PMID:921322

  5. Multiple exportins influence thyroid hormone receptor localization

    PubMed Central

    Subramanian, Kelly S.; Dziedzic, Rose C.; Nelson, Hallie N.; Stern, Mary E.; Roggero, Vincent R.; Bondzi, Cornelius; Allison, Lizabeth A.

    2015-01-01

    The thyroid hormone receptor (TR) undergoes nucleocytoplasmic shuttling and regulates target genes involved in metabolism and development. Previously, we showed that TR follows a CRM1/calreticulin-mediated nuclear export pathway. However, two lines of evidence suggest TR also follows another pathway: export is only partially blocked by leptomycin B (LMB), a CRM1-specific inhibitor; and we identified nuclear export signals in TR that are LMB-resistant. To determine whether other exportins are involved in TR shuttling, we used RNA interference and fluorescence recovery after photobleaching shuttling assays in transfected cells. Knockdown of exportins 4, 5, and 7 altered TR shuttling dynamics, and when exportins 5 and 7 were overexpressed, TR distribution shifted towards the cytosol. To further assess the effects of exportin overexpression, we examined transactivation of a TR-responsive reporter gene. Our data indicate that multiple exportins influence TR localization, highlighting a fine balance of nuclear import, retention, and export that modulates TR function. PMID:25911113

  6. Multiple exportins influence thyroid hormone receptor localization.

    PubMed

    Subramanian, Kelly S; Dziedzic, Rose C; Nelson, Hallie N; Stern, Mary E; Roggero, Vincent R; Bondzi, Cornelius; Allison, Lizabeth A

    2015-08-15

    The thyroid hormone receptor (TR) undergoes nucleocytoplasmic shuttling and regulates target genes involved in metabolism and development. Previously, we showed that TR follows a CRM1/calreticulin-mediated nuclear export pathway. However, two lines of evidence suggest TR also follows another pathway: export is only partially blocked by leptomycin B (LMB), a CRM1-specific inhibitor; and we identified nuclear export signals in TR that are LMB-resistant. To determine whether other exportins are involved in TR shuttling, we used RNA interference and fluorescence recovery after photobleaching shuttling assays in transfected cells. Knockdown of exportins 4, 5, and 7 altered TR shuttling dynamics, and when exportins 5 and 7 were overexpressed, TR distribution shifted toward the cytosol. To further assess the effects of exportin overexpression, we examined transactivation of a TR-responsive reporter gene. Our data indicate that multiple exportins influence TR localization, highlighting a fine balance of nuclear import, retention, and export that modulates TR function.

  7. Role of thyroid hormones in ventricular remodeling.

    PubMed

    Rajagopalan, Viswanathan; Gerdes, A Martin

    2015-04-01

    Cardiac remodeling includes alterations in molecular, cellular, and interstitial systems contributing to changes in size, shape, and function of the heart. This may be the result of injury, alterations in hemodynamic load, neurohormonal effects, electrical abnormalities, metabolic changes, etc. Thyroid hormones (THs) serve as master regulators for diverse remodeling processes of the cardiovascular system-from the prenatal period to death. THs promote a beneficial cardiomyocyte shape and improve contractility, relaxation, and survival via reversal of molecular remodeling. THs reduce fibrosis by decreasing interstitial collagen and reduce the incidence and duration of arrhythmias via remodeling ion channel expression and function. THs restore metabolic function and also improve blood flow both by direct effects on the vessel architecture and decreasing atherosclerosis. Optimal levels of THs both in the circulation and in cardiac tissues are critical for normal homeostasis. This review highlights TH-based remodeling and clinically translatable strategies for diverse cardiovascular disorders.

  8. Thyroid hormone transport by monocarboxylate transporters.

    PubMed

    Visser, W Edward; Friesema, Edith C H; Jansen, Jurgen; Visser, Theo J

    2007-06-01

    Thyroid hormone (TH) is essential for the normal development and metabolism of different tissues. TH action and metabolism take place intracellularly, which requires cellular uptake via transporters. Several transporter families have been identified, of which the monocarboxylate transporter (MCT) family deserves special attention. So far, only MCT1, MCT2, MCT3, MCT4 and MCT6 have been demonstrated to transport monocarboxylates; MCT8 has been identified as a specific TH transporter. MCT8 mutations in humans are associated with severe psychomotor retardation and elevated 3,3',5-triiodothyronine (T(3)) levels. Recently, MCT8 knockout mice have been shown to perfectly imitate the thyroid state in patients with MCT8 mutations; however, they lack the neurological defects. Although it was long hypothesized that a T-type amino acid transporter also transports iodothyronines, it only recently became clear that MCT10 is involved in the bidirectional transport of aromatic amino acids and iodothyronines. MCT10 preferentially transports T(3) even more effectively than does MCT8. However, its precise function in the human body is poorly understood.

  9. Low Thyroid Hormone Levels Disrupt Thyrotrope Development.

    PubMed

    Tonyushkina, Ksenia N; Krug, Stefanie; Ortiz-Toro, Theresa; Mascari, Tibor; Karlstrom, Rolf O

    2017-09-01

    Low thyroid hormone (TH) conditions caused by a variety of prenatal and perinatal problems have been shown to alter postnatal regulatory thyrotropin (TSH) responsiveness to TH in humans and rodents. The mechanisms underlying this pituitary TH resistance remain unknown. Here we use the evolutionarily conserved zebrafish model to examine the effects of low TH on thyrotrope development and function. Zebrafish were exposed to the goitrogen 6-propyl-2-thiouracil (PTU) to block TH synthesis, and this led to an approximately 50% increase in thyrotrope numbers and an 8- to 10-fold increase in tshb mRNA abundance in 2-week-old larvae and 1-month-old juveniles. Thyrotrope numbers returned to normal 3 weeks after cessation of PTU treatment, demonstrating that these effects were reversible and revealing substantial plasticity in pituitary-thyroid axis regulation. Using a T4 challenge assay, we found that development under low-TH conditions did not affect the ability of T4 to suppress tshb mRNA levels despite the thyrotrope hyperplasia that resulted from temporary low-TH conditions. Together, these studies show that low developmental TH levels can lead to changes in thyrotrope number and function, providing a possible cellular mechanism underlying elevated TSH levels seen in neonates with either permanent or transient congenital hypothyroidism. Copyright © 2017 Endocrine Society.

  10. Receptors for thyrotropin-releasing hormone, thyroid-stimulating hormone, and thyroid hormones in the macaque uterus: effects of long-term sex hormone treatment.

    PubMed

    Hulchiy, Mariana; Zhang, Hua; Cline, J Mark; Hirschberg, Angelica Lindén; Sahlin, Lena

    2012-11-01

    Thyroid gland dysfunction is associated with menstrual cycle disturbances, infertility, and increased risk of miscarriage, but the mechanisms are poorly understood. However, little is known about the regulation of these receptors in the uterus. The aim of this study was to determine the effects of long-term treatment with steroid hormones on the expression, distribution, and regulation of the receptors for thyrotropin-releasing hormone (TRHR) and thyroid-stimulating hormone (TSHR), thyroid hormone receptor α1/α2 (THRα1/α2), and THRβ1 in the uterus of surgically menopausal monkeys. Eighty-eight cynomolgus macaques were ovariectomized and treated orally with conjugated equine estrogens (CEE; n = 20), a combination of CEE and medroxyprogesterone acetate (MPA; n = 20), or tibolone (n = 28) for 2 years. The control group (OvxC; n = 20) received no treatment. Immunohistochemistry was used to evaluate the protein expression and distribution of the receptors in luminal epithelium, glands, stroma, and myometrium of the uterus. Immunostaining of TRHR, TSHR, and THRs was detected in all uterine compartments. Epithelial immunostaining of TRHR was down-regulated in the CEE + MPA group, whereas in stroma, both TRHR and TSHR were increased by CEE + MPA treatment as compared with OvxC. TRHR immunoreactivity was up-regulated, but THRα and THRβ were down-regulated, in the myometrium of the CEE and CEE + MPA groups. The thyroid-stimulating hormone level was higher in the CEE and tibolone groups as compared with OvxC, but the level of free thyroxin did not differ between groups. All receptors involved in thyroid hormone function are expressed in monkey uterus, and they are all regulated by long-term steroid hormone treatment. These findings suggest that there is a possibility of direct actions of thyroid hormones, thyroid-stimulating hormone and thyrotropin-releasing hormone on uterine function.

  11. [Thyroid hormone action beyond classical concepts. The priority programme "Thyroid Trans Act" (SPP 1629) of the German Research Foundation].

    PubMed

    Führer, D; Brix, K; Biebermann, H

    2014-03-01

    Thyroid hormones are of crucial importance for the function of nearly all organ systems. In case of dysfunction of thyroid hormone production and function many organ systems may be affected. The estimation of normal thyroid function is based on determination of TSH and the thyroid hormones T3 and T4. However, international conventions about the normal TSH range are still lacking which bears consequences for patient`s treatment. Hence not unexpected, many patients complain although their thyroid hormone status is in the normal range by clinical estimation. Here, more precise parameters are needed for a better definition of the healthy thyroid status of an individual. Recently, new key players in the system of thyroid hormone action were detected, like specific transporters for uptake of thyroid hormones and thyroid hormone derivatives. DFG, the German Research Foundation supports the priority program Thyroid Trans Act to find answers to the main question: what defines the healthy thyroid status of an individual. The overall aim of this interdisciplinary research consortium is to specify physiological and pathophysiological functions of thyroid hormone transporters and thyroid hormone derivative as new players in thyroid regulation in order to better evaluate, treat, and prevent thyroid-related disease.

  12. Hyponatremia after thyroid hormone withdrawal in a patient with papillary thyroid carcinoma.

    PubMed

    Jo, Hyo Jin; Kim, Yong Hyun; Shin, Dong Hyun; Kim, Mi Jeoung; Lee, Sang Jin; Jeon, Dong Ok; Im, Sung Gyu; Jang, Sun Kyung; Choi, Jin Young

    2014-03-01

    Hyponatremia is an electrolyte abnormality commonly found in clinical practice. It is important to diagnose the underlying etiology of the hyponatremia and correct it appropriately because severe hyponatremia can cause serious complications and substantially increase the risk of mortality. Although hypothyroidism is known to be a cause of hyponatremia, it is rare that hyponatremia occurs in relation to hypothyroidism induced by thyroid hormone withdrawal in patients with differentiated thyroid cancer. We report a case of a 76-year-old woman with papillary thyroid carcinoma presenting with severe hyponatremia related to hypothyroidism induced by thyroid hormone withdrawal for radio-active iodine whole-body scanning, who was treated by thyroid hormone replacement and hydration. Considering that the incidence of differentiated thyroid cancer is rapidly increasing, physicians should be aware that, although uncommon, hyponatremia can occur in patients undergoing radioiodine therapy or diagnostic testing.

  13. The relationships between thyroid hormones and thyroid-stimulating hormone with lipid profile in euthyroid men.

    PubMed

    Chin, Kok-Yong; Ima-Nirwana, Soelaiman; Mohamed, Isa Naina; Aminuddin, Amilia; Johari, Mohamad Hanapi; Ngah, Wan Zurinah Wan

    2014-01-01

    Alteration in lipid profile is a common observation in patients with thyroid dysfunction, but the current knowledge on the relationship between lipids and thyroid hormone levels in euthyroid state is insufficient. The current study aimed to determine the association between thyroid hormones and thyroid-stimulating hormone (TSH) with lipid profile in a euthyroid male population. A total of 708 Chinese and Malay men aged 20 years and above were recruited in this cross-sectional study. Their blood was collected for the determination of total cholesterol (TC), low density lipoprotein cholesterol (LDL-C), high density lipoprotein cholesterol (HDL-C), triglyceride (TG), free thyroxine (FT4), free triiodothyronine (FT3) and TSH levels. The association was analyzed using multiple regression and logistic regression models with adjustment for age, ethnicity, body mass index and FT4/FT3/TSH levels. In multiple regression models, TSH was positively and significantly associated with TG (p<0.05). Free T4 was positively and significantly associated with TC, LDL-C and HDL-C (p<0.05). Free T3 was negatively and significantly associated with HDL-C (p<0.05). In binary logistic models, an increase in TSH was significantly associated with higher prevalence of elevated TG in the subjects (p<0.05), while an increase in FT4 was significantly associated with higher prevalence of elevated TC but a lower prevalence of subnormal HDL in the subjects (p<0.05). Free T3 was not associated with any lipid variables in the logistic regression (p>0.05). In euthyroid Malaysian men, there are positive and significant relationships between TSH level and TG level, and between FT4 level and cholesterol levels.

  14. Type 2 deiodinase at the crossroads of thyroid hormone action

    PubMed Central

    Arrojo e Drigo, Rafael; Bianco, Antonio C.

    2011-01-01

    Thyroid hormone action can be customiZed on a cell-specific fashion through the controlled action of the deiodinase group of enzymes, which are homodimeric thioredoxin fold containing selenoproteins. Whereas the type II deiodinase (D2) initiates thyroid hormone signaling by activating the pro-hormone thyroxine (T4) to the biologically active T3 molecule, the type III deiodinase (D3) terminates thyroid hormone action by catalyzing the inactivation of both T4 and T3 molecules. Deiodinases play a role in thyroid hormone homeostasis, development, growth and metabolic control by affecting the intracellular levels of T3 and thus gene expression on a cell-specific basis. Whereas both Dio2 and Dio3 are transcriptionally regulated, ubiquitination of D2 is a switch mechanism that controls D2 activity and intracellular T3 production. The hedgehog-inducible WSB-1 and the yeast Doa10 mammalian ortholog TEB4 are two E3 ligases that inactivate D2 via ubiquitination. Inactivation involves disruption of the D2:D2 dimer and can be reversed via two ubiquitin-specific proteases, USP20 and USP33, rescuing catalytic activity and T3 production. The ubiquitin-based switch mechanism that controls D2 activity illustrates how different cell types fine-tune thyroid hormone signaling, making D2 a suitable target for pharmacological intervention. This article reviews the cellular and molecular aspects of D2 regulation and the current models of D2-mediated thyroid hormone signaling. PMID:21679772

  15. Transport of thyroid hormone in brain.

    PubMed

    Wirth, Eva K; Schweizer, Ulrich; Köhrle, Josef

    2014-01-01

    Thyroid hormone (TH) transport into the brain is not only pivotal for development and differentiation, but also for maintenance and regulation of adult central nervous system (CNS) function. In this review, we highlight some key factors and structures regulating TH uptake and distribution. Serum TH binding proteins play a major role for the availability of TH since only free hormone concentrations may dictate cellular uptake. One of these proteins, transthyretin is also present in the cerebrospinal fluid (CSF) after being secreted by the choroid plexus. Entry routes into the brain like the blood-brain-barrier (BBB) and the blood-CSF-barrier will be explicated regarding fetal and adult status. Recently identified TH transmembrane transporters (THTT) like monocarboxylate transporter 8 (Mct8) play a major role in uptake of TH across the BBB but as well in transport between cells like astrocytes and neurons within the brain. Species differences in transporter expression will be presented and interference of TH transport by endogenous and exogenous compounds including endocrine disruptors and drugs will be discussed.

  16. Transport of Thyroid Hormone in Brain

    PubMed Central

    Wirth, Eva K.; Schweizer, Ulrich; Köhrle, Josef

    2014-01-01

    Thyroid hormone (TH) transport into the brain is not only pivotal for development and differentiation, but also for maintenance and regulation of adult central nervous system (CNS) function. In this review, we highlight some key factors and structures regulating TH uptake and distribution. Serum TH binding proteins play a major role for the availability of TH since only free hormone concentrations may dictate cellular uptake. One of these proteins, transthyretin is also present in the cerebrospinal fluid (CSF) after being secreted by the choroid plexus. Entry routes into the brain like the blood–brain-barrier (BBB) and the blood–CSF-barrier will be explicated regarding fetal and adult status. Recently identified TH transmembrane transporters (THTT) like monocarboxylate transporter 8 (Mct8) play a major role in uptake of TH across the BBB but as well in transport between cells like astrocytes and neurons within the brain. Species differences in transporter expression will be presented and interference of TH transport by endogenous and exogenous compounds including endocrine disruptors and drugs will be discussed. PMID:25009532

  17. Developmental Thyroid Hormone Disruption: Prevalence, Environmental Contaminants and Neurodevelopmental Consequences

    EPA Science Inventory

    Thyroid hormones (TH) are critical for growth and development and particularly brain development. There are numerous environmental agents that lead to marginal reductions of circulating TH. Although it is clear that severe developmental hypothyroidism is profoundly detrimental to...

  18. Developmental Thyroid Hormone Disruption: Prevalence, Environmental Contaminants and Neurodevelopmental Consequences

    EPA Science Inventory

    Thyroid hormones (TH) are critical for growth and development and particularly brain development. There are numerous environmental agents that lead to marginal reductions of circulating TH. Although it is clear that severe developmental hypothyroidism is profoundly detrimental to...

  19. Thyroid hormone metabolism and the developing human lung.

    PubMed

    Hume, R; Richard, K; Kaptein, E; Stanley, E L; Visser, T J; Coughtrie, M W

    2001-05-01

    Thyroid hormones are involved in the regulation of fetal lung development, and maturation is accelerated in animal models by antepartum exposure to raised concentrations of the receptor-active thyroid hormone triiodothyronine and glucocorticoids. It is essential that the nature of the regulation of the spatial and temporal metabolism of iodothyronines in the human fetus and infant is known before effective therapies can be developed to modify human lung maturation. Thyroid hormone bioavailability to the human fetus is regulated in part by enzymatic deiodination and reversible sulfation of iodothyronines, with contributions from other factors such as fetomaternal and fetoamniotic hormone transfers, fetal thyroid gland production, and the activities of plasma membrane transporters mediating uptake of iodothyronines from plasma into tissues. Copyright 2001 S. Karger AG, Basel.

  20. Regulation of Seasonal Reproduction by Hypothalamic Activation of Thyroid Hormone

    PubMed Central

    Shinomiya, Ai; Shimmura, Tsuyoshi; Nishiwaki-Ohkawa, Taeko; Yoshimura, Takashi

    2014-01-01

    Organisms living outside the tropics measure the changes in the length of the day to adapt to seasonal changes in the environment. Animals that breed during spring and summer are called long-day breeders, while those that breed during fall are called short-day breeders. Although the influence of thyroid hormone in the regulation of seasonal reproduction has been known for several decades, its precise mechanism remained unknown. Recent studies revealed that the activation of thyroid hormone within the mediobasal hypothalamus plays a key role in this phenomenon. This localized activation of the thyroid hormone is controlled by thyrotropin (thyroid-stimulating hormone) secreted from the pars tuberalis of the pituitary gland. Although seasonal reproduction is a rate-limiting factor in animal production, genes involved in photoperiodic signal transduction pathway could emerge as potential targets to facilitate domestication. PMID:24600435

  1. Inhibition of the Thyroid Hormone Pathway in Xenopus by Mercaptobenzothiazole

    EPA Science Inventory

    Amphibian metamorphosis is a thyroid hormone-dependent process that provides a potential model system to assess chemicals for their ability to disrupt the hypothalamic-pituitary-thyroid (HPT) axis. Several studies have demonstrated the sensitivity of this system to a variety of ...

  2. Thyroid Hormone-disrupting Effects and the Amphibian Metamorphosis Assay.

    PubMed

    Miyata, Kaori; Ose, Keiko

    2012-03-01

    There are continued concerns about endocrine-disrupting chemical effects, and appropriate vertebrate models for assessment of risk are a high priority. Frog tadpoles are very sensitive to environmental substances because of their habitat and the complex processes of metamorphosis regulated by the endocrine system, mainly thyroid hormones. During metamorphosis, marked alteration in hormonal factors occurs, as well as dramatic structural and functional changes in larval tissues. There are a variety of mechanisms determining thyroid hormone balance or disruption directly or indirectly. Direct-acting agents can cause changes in thyroxine synthesis and/or secretion in thyroid through effects on peroxidases, thyroidal iodide uptake, deiodinase, and proteolysis. At the same time, indirect action may result from biochemical processes such as sulfation, deiodination and glucuronidation. Because their potential to disrupt thyroid hormones has been identified as an important consideration for the regulation of chemicals, the OECD and the EPA have each established guidelines that make use of larval African clawed frogs (Xenopus laevis) and frog metamorphosis for screening and testing of potential endocrine disrupters. The guidelines are based on evaluation of alteration in the hypothalamic-pituitary-thyroid axis. One of the primary endpoints is thyroid gland histopathology. Others are mortality, developmental stage, hind limb length, snout-vent length and wet body weight. Regarding histopathological features, the guidelines include core criteria and additional qualitative parameters along with grading. Taking into account the difficulties in evaluating amphibian thyroid glands, which change continuously throughout metamorphosis, histopathological examination has been shown to be a very sensitive approach.

  3. Inhibition of the Thyroid Hormone Pathway in Xenopus by Mercaptobenzothiazole

    EPA Science Inventory

    Amphibian metamorphosis is a thyroid hormone-dependent process that provides a potential model system to assess chemicals for their ability to disrupt the hypothalamic-pituitary-thyroid (HPT) axis. Several studies have demonstrated the sensitivity of this system to a variety of ...

  4. Selenium and the control of thyroid hormone metabolism.

    PubMed

    Köhrle, Josef

    2005-08-01

    Thyroid hormone synthesis, metabolism and action require adequate availability of the essential trace elements iodine and selenium, which affect homeostasis of thyroid hormone-dependent metabolic pathways. The three selenocysteine-containing iodothyronine deiodinases constitute a novel gene family. Selenium is retained and deiodinase expression is maintained at almost normal levels in the thyroid gland, the brain and several other endocrine tissues during selenium deficiency, thus guaranteeing adequate local and systemic levels of the active thyroid hormone T(3). Due to their low tissue concentrations and their mRNA SECIS elements deiodinases rank high in the cellular and tissue-specific hierarchy of selenium distribution among various selenoproteins. While systemic selenium status and expression of abundant selenoproteins (glutathione peroxidase or selenoprotein P) is already impaired in patients with cancer, disturbed gastrointestinal resorption, unbalanced nutrition or patients requiring intensive care treatment, selenium-dependent deiodinase function might still be adequate. However, disease-associated alterations in proinflammatory cytokines, growth factors, hormones and pharmaceuticals modulate deiodinase isoenzyme expression independent from altered selenium status and might thus pretend causal relationships between systemic selenium status and altered thyroid hormone metabolism. Limited or inadequate supply of both trace elements, iodine and selenium, leads to complex rearrangements of thyroid hormone metabolism enabling adaptation to unfavorable conditions.

  5. Thyroid hormones in fetal growth and prepartum maturation.

    PubMed

    Forhead, A J; Fowden, A L

    2014-06-01

    The thyroid hormones, thyroxine (T4) and triiodothyronine (T3), are essential for normal growth and development of the fetus. Their bioavailability in utero depends on development of the fetal hypothalamic-pituitary-thyroid gland axis and the abundance of thyroid hormone transporters and deiodinases that influence tissue levels of bioactive hormone. Fetal T4 and T3 concentrations are also affected by gestational age, nutritional and endocrine conditions in utero, and placental permeability to maternal thyroid hormones, which varies among species with placental morphology. Thyroid hormones are required for the general accretion of fetal mass and to trigger discrete developmental events in the fetal brain and somatic tissues from early in gestation. They also promote terminal differentiation of fetal tissues closer to term and are important in mediating the prepartum maturational effects of the glucocorticoids that ensure neonatal viability. Thyroid hormones act directly through anabolic effects on fetal metabolism and the stimulation of fetal oxygen consumption. They also act indirectly by controlling the bioavailability and effectiveness of other hormones and growth factors that influence fetal development such as the catecholamines and insulin-like growth factors (IGFs). By regulating tissue accretion and differentiation near term, fetal thyroid hormones ensure activation of physiological processes essential for survival at birth such as pulmonary gas exchange, thermogenesis, hepatic glucogenesis, and cardiac adaptations. This review examines the developmental control of fetal T4 and T3 bioavailability and discusses the role of these hormones in fetal growth and development with particular emphasis on maturation of somatic tissues critical for survival immediately at birth.

  6. Thyroid hormone and the developing hypothalamus

    PubMed Central

    Alkemade, Anneke

    2015-01-01

    Thyroid hormone (TH) plays an essential role in normal brain development and function. Both TH excess and insufficiency during development lead to structural brain abnormalities. Proper TH signaling is dependent on active transport of the prohormone thyroxine (T4) across the blood-brain-barrier and into brain cells. In the brain T4 undergoes local deiodination into the more active 3,3′,5-triiodothyronine (T3), which binds to nuclear TH receptors (TRs). TRs are already expressed during the first trimester of pregnancy, even before the fetal thyroid becomes functional. Throughout pregnancy, the fetus is largely dependent on the maternal TH supply. Recent studies in mice have shown that normal hypothalamic development requires intact TH signaling. In addition, the development of the human lateral hypothalamic zone coincides with a strong increase in T3 and TR mRNA concentrations in the brain. During this time the fetal hypothalamus already shows evidence for TH signaling. Expression of components crucial for central TH signaling show a specific developmental timing in the human hypothalamus. A coordinated expression of deiodinases in combination with TH transporters suggests that TH concentrations are regulated to prevent untimely maturation of brain cells. Even though the fetus depends on the maternal TH supply, there is evidence suggesting a role for the fetal hypothalamus in the regulation of TH serum concentrations. A decrease in expression of proteins involved in TH signaling towards the end of pregnancy may indicate a lower fetal TH demand. This may be relevant for the thyrotropin (TSH) surge that is usually observed after birth, and supports a role for the hypothalamus in the regulation of TH concentrations during the fetal period anticipating birth. PMID:25750617

  7. The thyroid gland and thyroid hormones in sheepshead minnow (Cyprinodon variegatus) during early development and metamorphosis.

    PubMed

    Schnitzler, Joseph G; Klaren, Peter H M; Mariavelle, Emeline; Das, Krishna

    2016-04-01

    The sheepshead minnow is widely used in ecotoxicological studies that only recently have begun to focus on disruption of the thyroid axis by xenobiotics and endocrine disrupting compounds. However, reference levels of the thyroid prohormone thyroxine (T4) and biologically active hormone 3,5,3'-triiodothyronine (T3) and their developmental patterns are unknown. This study set out to describe the ontogeny and morphology of the thyroid gland in sheepshead minnow, and to correlate these with whole-body concentrations of thyroid hormones during early development and metamorphosis. Eggs were collected by natural spawning in our laboratory. T4 and T3 were extracted from embryos, larvae and juveniles and an enzyme-linked immunoassay was used to measure whole-body hormone levels. Length and body mass, hatching success, gross morphology, thyroid hormone levels and histology were measured. The onset of metamorphosis at 12-day post-hatching coincided with surges in whole-body T4 and T3 concentrations. Thyroid follicles were first observed in pre-metamorphic larvae at hatching and were detected exclusively in the subpharyngeal region, surrounding the ventral aorta. Follicle size and thyrocyte epithelial cell heights varied during development, indicating fluctuations in thyroid hormone synthesis activity. The increase in the whole-body T3/T4 ratio was indicative of an increase in outer ring deiodination activity. This study establishes a baseline for thyroid hormones in sheepshead minnows, which will be useful for the understanding of thyroid hormone functions and in future studies of thyroid toxicants in this species.

  8. Prolonged weightlessness effect on postflight plasma thyroid hormones

    NASA Technical Reports Server (NTRS)

    Leach, C. S.; Johnson, P. C.; Driscoll, T. B.

    1977-01-01

    Blood drawn before and after spaceflight from the nine Skylab astronauts showed a statistically significant increase in mean plasma thyroxine (T-4) of 1.4 micro g/dl and in thyroid-stimulating hormone (TSH) of 4 microunits ml. Concurrent triiodothyronine (T-3) levels decreased 27 ng/dl indicating inhibited conversion of T-4 to T-3. The T-3 decrease is postulated to be a result of the increased cortisol levels noted during and following each mission. These results confirm the thyroidal changes noted after the shorter Apollo flights and show that thyroid hormone levels change during spaceflight.

  9. Prolonged weightlessness effect on postflight plasma thyroid hormones

    NASA Technical Reports Server (NTRS)

    Leach, C. S.; Johnson, P. C.; Driscoll, T. B.

    1977-01-01

    Blood drawn before and after spaceflight from the nine Skylab astronauts showed a statistically significant increase in mean plasma thyroxine (T-4) of 1.4 micro g/dl and in thyroid-stimulating hormone (TSH) of 4 microunits ml. Concurrent triiodothyronine (T-3) levels decreased 27 ng/dl indicating inhibited conversion of T-4 to T-3. The T-3 decrease is postulated to be a result of the increased cortisol levels noted during and following each mission. These results confirm the thyroidal changes noted after the shorter Apollo flights and show that thyroid hormone levels change during spaceflight.

  10. Expression of thyroid hormone receptor isoforms down-regulated by thyroid hormone in human medulloblastoma cells.

    PubMed

    Monden, Tsuyoshi; Nakajima, Yasuyo; Hashida, Tetsu; Ishii, Sumiyasu; Tomaru, Takuya; Shibusawa, Nobuyuki; Hashimoto, Koshi; Satoh, Teturou; Yamada, Masanobu; Mori, Masatomo; Kasai, Kikuo

    2006-04-01

    The role of thyroid hormone (T3) in the regulation of growth and development of the central nervous system including the cerebellum has been well established. However, the effects of thyroid hormone on malignant tumors derived from the cerebellum remain poorly understood. Our analysis mainly focused on expression levels of TR isoforms and the effects of thyroid hormone in human medulloblastoma HTB-185 cells. Northern blot analysis revealed TRalpha2 mRNA but not TRalpha1, beta1 or beta2 mRNA in the cell. The TRalpha1 and TRbeta1 mRNAs were detected only by RT-PCR method and TRbeta2 was not expressed. Incubation of T3 for 24 h decreased TRalpha1, TRalpha2 and TRbeta1 mRNA. Addition of actinomycin D caused an acute increase in the basal TR mRNA levels and the rate of decrease of all kinds of TR isoform mRNA was accelerated in the T3-treated groups compared to controls, indicating that the stability of TR mRNA was affected by T3. Incubation with cycloheximide also blocked a decrease in TR mRNA levels in the T3-treated HTB-185 cells suggesting that down-regulation of TR mRNA required the synthesis of new protein. Our data provide novel evidence for the expression of TRs down-regulated by T3 in HTB-185 cells, suggesting that TR expression is post-transcriptionally regulated by T3 at the level of RNA stability.

  11. Do thyroid hormones function in insects?

    PubMed

    Davey, K G

    2000-01-01

    Earlier work demonstrated that phenoxy-phenyl compounds such as fenoxycarb and thyroxine mimicked the effects of JH III in causing a reduction in volume of the follicle cells of Locusta migratoria. While these compounds were only moderately effective, a derivative of thyroxine, 3,3',5-triiodothyronine (T3) was as effective as JH III, and T3 has been shown to bind to the same membrane receptor and activate the same pathway as JH III. The current paper shows that other thyroxine derivatives vary in activity. 3,3', 5'-Triiodothyronine (reverse T3) is inactive. 3,5-Diiodothyronine (T2) is more active than JH III, while its relatives (iodines at 3', 5' or at 3,3') are inactive. When follicles are exposed in vitro to rhodamine conjugated T3, the fluorescent compound can be seen to enter the cells and accumulate there: this process is inhibited by cycloheximide or by a temperature of 0 degrees C. The accumulation is antagonised by JH III but not JH I (which does not bind to the JH III membrane receptor) and by an antiserum raised against the putative membrane receptor protein. The action of T3, but not T2, is inhibited by 6-n-propyl-2-thiouracil or by aurothioglucose, both known to inhibit deiodinases. The activity of T3, but not of T2, increases with time of exposure to the follicle cells. These facts suggest that T3 enters the cells by receptor mediated endocytosis and is converted to a more active compound. Immunoreactivity to T3, but not thyroxine, can be detected in the haemolymph of locusts, and the titre varies slightly with the gonotrophic cycle. The food shows immunoreactivity for both thyroxine and T3. These findings suggest that thyroid hormones are ingested by locusts and have the potential to be used as hormonal signals in the control of egg production.

  12. Reference intervals for thyroid hormones in pregnant Chinese women.

    PubMed

    Panesar, N S; Li, C Y; Rogers, M S

    2001-07-01

    To establish gestation-related reference intervals for thyroid hormones in a Chinese population. A prospective study with 343 healthy pregnant women (5-41 weeks) and 63 non-pregnant controls. Thyroid stimulating hormone (TSH), free thyroxine (T4) and tri-iodothyronine (T3) (and human chorionic gonadotrophin) were measured by immunoassays. The median, 2.5th and 97.5th percentiles at 4-week intervals were calculated. Data were also analysed for significant trends using ANOVA. Free T3 decreased during pregnancy, whereas free T4 initially increased, peaking between 9-13 weeks and then decreased, the decline becoming significant by week 21. TSH mirrored changes in free T4. The gestation-related reference intervals for thyroid hormones should alleviate the misinterpretation of thyroid function in pregnancy.

  13. Thyroid hormone receptors in brain development and function.

    PubMed

    Bernal, Juan

    2007-03-01

    Thyroid hormones are important during development of the mammalian brain, acting on migration and differentiation of neural cells, synaptogenesis, and myelination. The actions of thyroid hormones are mediated through nuclear thyroid hormone receptors (TRs) and regulation of gene expression. The purpose of this article is to review the role of TRs in brain maturation. In developing humans maternal and fetal thyroid glands provide thyroid hormones to the fetal brain, but the timing of receptor ontogeny agrees with clinical data on the importance of the maternal thyroid gland before midgestation. Several TR isoforms, which are encoded by the THRA and THRB genes, are expressed in the brain, with the most common being TRalpha1. Deletion of TRalpha1 in rodents is not, however, equivalent to hormone deprivation and, paradoxically, even prevents the effects of hypothyroidism. Unliganded receptor activity is, therefore, probably an important factor in causing the harmful effects of hypothyroidism. Accordingly, expression of a mutant receptor with impaired triiodothyronine (T(3)) binding and dominant negative activity affected cerebellar development and motor performance. TRs are also involved in adult brain function. TRalpha1 deletion, or expression of a dominant negative mutant receptor, induces consistent behavioral changes in adult mice, leading to severe anxiety and morphological changes in the hippocampus.

  14. Thyroid-stimulating Hormone (TSH): Measurement of Intracellular, Secreted, and Circulating Hormone in Xenopus laevis and Xenopus tropicalis.

    EPA Science Inventory

    Thyroid Stimulating Hormone (TSH) is a hormone produced in the pituitary that stimulates the thyroid gland to grow and produce thyroid hormone (TH). The concentration of TH controls developmental changes that take place in a wide variety of organisms. Many use the metaphoric ch...

  15. Thyroid-stimulating Hormone (TSH): Measurement of Intracellular, Secreted, and Circulating Hormone in Xenopus laevis and Xenopus tropicalis.

    EPA Science Inventory

    Thyroid Stimulating Hormone (TSH) is a hormone produced in the pituitary that stimulates the thyroid gland to grow and produce thyroid hormone (TH). The concentration of TH controls developmental changes that take place in a wide variety of organisms. Many use the metaphoric ch...

  16. Thyroid Hormone Action: Astrocyte–Neuron Communication

    PubMed Central

    Morte, Beatriz; Bernal, Juan

    2014-01-01

    Thyroid hormone (TH) action is exerted mainly through regulation of gene expression by binding of T3 to the nuclear receptors. T4 plays an important role as a source of intracellular T3 in the central nervous system via the action of the type 2 deiodinase (D2), expressed in the astrocytes. A model of T3 availability to neural cells has been proposed and validated. The model contemplates that brain T3 has a double origin: a fraction is available directly from the circulation, and another is produced locally from T4 in the astrocytes by D2. The fetal brain depends almost entirely on the T3 generated locally. The contribution of systemic T3 increases subsequently during development to account for approximately 50% of total brain T3 in the late postnatal and adult stages. In this article, we review the experimental data in support of this model, and how the factors affecting T3 availability in the brain, such as deiodinases and transporters, play a decisive role in modulating local TH action during development. PMID:24910631

  17. Thyroid hormones induce browning of white fat

    PubMed Central

    Martínez-Sánchez, Noelia; Moreno-Navarrete, José M; Contreras, Cristina; Rial-Pensado, Eva; Fernø, Johan; Nogueiras, Rubén; Diéguez, Carlos

    2016-01-01

    The canonical view about the effect of thyroid hormones (THs) on thermogenesis assumes that the hypothalamus acts merely as a modulator of the sympathetic outflow on brown adipose tissue (BAT). Recent data have challenged that vision by demonstrating that THs act on the ventromedial nucleus of the hypothalamus (VMH) to inhibit AMP-activated protein kinase (AMPK), which regulates the thermogenic program in BAT, leading to increased thermogenesis and weight loss. Current data have shown that in addition to activation of brown fat, the browning of white adipose tissue (WAT) might also be an important thermogenic mechanism. However, the possible central effects of THs on the browning of white fat remain unclear. Here, we show that 3,3′,5,5′ tetraiodothyroxyne (T4)-induced hyperthyroidism promotes a marked browning of WAT. Of note, central or VMH-specific administration of 3,3′,5-triiodothyronine (T3) recapitulates that effect. The specific genetic activation of hypothalamic AMPK in the VMH reversed the central effect of T3 on browning. Finally, we also showed that the expression of browning genes in human WAT correlates with serum T4. Overall, these data indicate that THs induce browning of WAT and that this mechanism is mediated via the central effects of THs on energy balance. PMID:27913573

  18. Oncogenic mutations of thyroid hormone receptor β

    PubMed Central

    Park, Jeong Won; Zhao, Li; Willingham, Mark; Cheng, Sheue-yann

    2015-01-01

    The C-terminal frame-shift mutant of the thyroid hormone receptor TRβ1, PV, functions as an oncogene. An important question is whether the oncogenic activity of mutated TRβ1 is uniquely dependent on the PV mutated sequence. Using four C-terminal frame-shift mutants—PV, Mkar, Mdbs, and AM—we examined that region in the oncogenic actions of TRβ1 mutants. Remarkably, these C-terminal mutants induced similar growth of tumors in mouse xenograft models. Molecular analyses showed that they physically interacted with the p85α regulatory subunit of PI3K similarly in cells. In vitro GST-binding assay showed that they bound to the C-terminal Src-homology 2 (CSH2) of p85α with markedly higher avidity. The sustained association of mutants with p85α led to activation of the common PI3K-AKT-ERK/STAT3 signaling to promote cell proliferation and invasion and to inhibit apoptosis. Thus, these results argue against the oncogenic activity of PV being uniquely dependent on the PV mutated sequence. Rather, these four mutants could favor a C-terminal conformation that interacted with the CSH2 domain of p85α to initiate activation of PI3K to relay downstream signaling to promote tumorigenesis. Thus, we propose that the mutated C-terminal region of TRβ1 could function as an “onco-domain” and TRβ1 is a potential therapeutic target. PMID:25924236

  19. BRAIN, LIVER AND THYROID BIOMARKERS REFLECT ENHANCED SENSITIVITY OF THE DEVELOPING RAT TO THYROID HORMONE DEPLETION.

    EPA Science Inventory

    Many developmental events are regulated at least in part by thyroid hormones. It was hypothesized that tissue biomarkers of thyroid status would be more accurate predictors of neurotoxicity than serum biomarkers in rats treated with the goitrogen propylthiouracil (PTU). Over seve...

  20. Control of pituitary thyroid-stimulating hormone synthesis and secretion by thyroid hormones during Xenopus metamorphosis.

    PubMed

    Sternberg, Robin M; Thoemke, Kara R; Korte, Joseph J; Moen, Scott M; Olson, Jessica M; Korte, Lisa; Tietge, Joseph E; Degitz, Sigmund J

    2011-09-15

    We used ex vivo and in vivo experiments with Xenopus laevis tadpoles to examine the hypothesis that the set-point for negative feedback on pituitary thyroid-stimulating hormone (TSH) synthesis and secretion by thyroid hormones (THs) increases as metamorphosis progresses to allow for the previously documented concomitant increase in serum TH concentrations and pituitary TSH mRNA expression during this transformative process. First, pituitaries from climactic tadpoles were cultured for up to 96 h to characterize the ability of pituitary explants to synthesize and secrete TSHβ in the absence of hypothalamic and circulating hormones. Next, pituitary explants from tadpoles NF stages 54-66 were exposed to physiologically-relevant concentrations of THs to determine whether stage-specific differences exist in pituitary sensitivity to negative feedback by THs. Finally, in vivo exposures of tadpoles to THs were conducted to confirm the results of the ex vivo experiments. When pituitaries from climactic tadpoles were removed from the influence of endogenous hormones, TSHβ mRNA expression increased late or not at all whereas the rate of TSHβ secreted into media increased dramatically, suggesting that TSH secretion, but not TSH mRNA expression, is under the negative regulation of an endogenous signal during the climactic stages of metamorphosis. Pituitaries from pre- and prometamorphic tadpoles were more sensitive to TH-induced inhibition of TSHβ mRNA expression and secretion than pituitaries from climactic tadpoles. The observed decrease in sensitivity of pituitary TSHβ mRNA expression to negative feedback by THs from premetamorphosis to metamorphic climax was confirmed by in vivo experiments in which tadpoles were reared in water containing THs. Based on the results of this study, a model is proposed to explain the seemingly paradoxical, concurrent rise in serum TH concentrations and pituitary TSH mRNA expression during metamorphosis in larval anurans.

  1. Deiodination as an index of chemical disruption of thyroid hormone homeostasis and thyroidal status in fish

    SciTech Connect

    Eales, J.G.; Brown, S.B.; Cyr, D.G.; Adams, B.A.; Finnson, K.R.

    1999-07-01

    Commonly used indices of fish thyroidal status are based on thyroxine (T4) secretion by thyroid tissue under control of the central brain-pituitary-thyroid axis. However, much of the control of the fish thyroid system also occurs in peripheral tissues, such as liver, by regulating T4 prohormone conversion to biologically active 3,5,3{prime}-triiodothyronine (T3) or to biologically inactive 3,3{prime},5{prime}-triiodothyronine and by regulating T3 conversion to inactive 3,3{prime}-diiodothyronine. These extrathyroidal conversions depend on a family of independently-regulated selenocysteine-containing microsomal deiodinases. The authors describe deiodination assays and evaluate their potential as biomarkers for exposure to chemicals that directly or indirectly disrupt thyroid hormone homeostasis or thyroidal status. The authors conclude that deiodination be included in a minimum suite of assays to detect xenobiotic effects on the fish thyroid system.

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

    PubMed

    Arufe, M C; Durán, R; Perez-Vences, D; Alfonso, M

    2002-04-01

    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.

  3. Primary and secondary thyroid hormone transporters

    PubMed Central

    2011-01-01

    Thyroid hormones (TH) are essential for the development of the human brain, growth and cellular metabolism. Investigation of TH transporters became one of the emerging fields in thyroid research after the discovery of inactivating mutations in the Monocarboxylate transporter 8 (MCT8), which was found to be highly specific for TH transport. However, additional transmembrane transporters are also very important for TH uptake and efflux in different cell types. They transport TH as secondary substrates and include the aromatic amino acid transporting MCT10, the organic anion transporting polypeptides (e.g. OATP1C1, OATP1A2, OPTP1A4) and the large neutral amino acid transporters (LAT1 and LAT2). These TH transporters characteristically possess 12 transmembrane spanners but due to the strong differing sequences between the three transporter families we assume an identical conformation is not very likely. In contrast to the others, the LAT family members form a heterodimer with the escort protein 4F2hc/CD98. A comparison of sequence proportions, locations and types of functional sensitive features for TH transport discovered by mutations, revealed that transport sensitive charged residues occur as conserved amino acids only within each family of the transporter types but not in all putative TH transporters. Based on the lack of highly conserved sensitive charged residues throughout the three transporter families as a common counterpart for the amino acid moiety of the substrates, we conclude that the molecular transport mechanism is likely organized either a) by different molecular determinants in the divergent transporter types or b) the counterparts for the substrates` amino acid moiety at the transporter are not any charged side chains but other proton acceptors or donators. However, positions of transport sensitive residues coincide at transmembrane helix 8 in the TH transporter MCT8, OATP1C1 and another amino acid transporter, the L-cystine and L-glutamate exchanger

  4. Trends in thyroid hormone prescribing and consumption in the UK

    PubMed Central

    Mitchell, Anna L; Hickey, Bryan; Hickey, Janis L; Pearce, Simon HS

    2009-01-01

    Background Thyroid hormone replacement is one of the most commonly prescribed and cost effective treatments for a chronic disease. There have been recent changes in community prescribing policies in many areas of the UK that have changed patient access to necessary medications. This study aimed to provide a picture of thyroid hormone usage in the UK and to survey patient opinion about current community prescribing policies for levothyroxine. Methods Data on community prescriptions for thyroid hormones in England between 1998 and 2007, provided by the Department of Health, were collated and analysed. A survey of UK members of a patient support organisation (the British Thyroid Foundation) who were taking levothyroxine was carried out. Results The amount of prescribed thyroid hormones used in England has more than doubled, from 7 to almost 19 million prescriptions, over the last 10 years. The duration of prescriptions has reduced from 60 to 45 days, on average over the same time. Two thousand five hundred and fifty one responses to the patient survey were received. Thirty eight percent of levothyroxine users reported receiving prescriptions of 28 days' duration. 59% of respondents reported being dissatisfied with 28-day prescribing. Conclusion Amongst users of levothyroxine, there is widespread patient dissatisfaction with 28-day prescription duration. Analysis of the full costs of 28-day dispensing balanced against the potential savings of reduced wastage of thyroid medications, suggests that this is unlikely to be an economically effective public health policy. PMID:19432950

  5. Tissue specific regulation of lipogenesis by thyroid hormone

    SciTech Connect

    Blennemann, B.; Freake, H. )

    1990-02-26

    Thyroid hormone stimulates long chain fatty acid synthesis in rat liver by increasing the amounts of key lipogenic enzymes. Sparse and conflicting data exist concerning its action on this pathway in other tissues. The authors recently showed that, in contrast to liver, hypothyroidism stimulates lipogenesis in brown adipose tissue and have now systematically examined the effects of thyroid state on fatty acid synthesis in other rat tissues. Lipogenesis was assessed by tritiated water incorporation. Euthyroid hepatic fatty acid synthesis (16.6um H/g/h) was reduced to 30% in hypothyroid rats and increased 3 fold in hyperthyroidism. Lipogenesis was detected in euthyroid kidney and heart and these levels were also stimulated by thyroid hormone treatment. Brown adipose tissue was unique in showing increased lipogenesis in the hypothyroid state. Hyperthyroid levels were not different from euthyroid. Effects in white adipose tissue were small and inconsistent. Brain, skin and lung were all lipogenically active, but did not respond to changes in thyroid state. Low but detectable levels of fatty acid synthesis were measured in muscle, which also were non-responsive. A wide spectrum of responses to thyroid hormone are seen in different rat tissues and thus the pathway of long chain fatty acid synthesis would appear to be an excellent model for examining the tissue specific regulation of gene expression by thyroid hormone.

  6. Early Temporal Effects of Three Thyroid Hormone Synthesis Inhibitors in Xenopus laevis

    EPA Science Inventory

    Thyroid axis disruption is an important consideration when evaluating the risks associated with chemicals. Bioassay methods that include thyroid-related endpoints have been developed in a variety of species, including amphibians, whose metamorphic development is thyroid hormone ...

  7. Early Temporal Effects of Three Thyroid Hormone Synthesis Inhibitors in Xenopus laevis

    EPA Science Inventory

    Thyroid axis disruption is an important consideration when evaluating the risks associated with chemicals. Bioassay methods that include thyroid-related endpoints have been developed in a variety of species, including amphibians, whose metamorphic development is thyroid hormone ...

  8. Thyroid hormone transporters--functions and clinical implications.

    PubMed

    Bernal, Juan; Guadaño-Ferraz, Ana; Morte, Beatriz

    2015-07-01

    The cellular influx and efflux of thyroid hormones are facilitated by transmembrane protein transporters. Of these transporters, monocarboxylate transporter 8 (MCT8) is the only one specific for the transport of thyroid hormones and some of their derivatives. Mutations in SLC16A2, the gene that encodes MCT8, lead to an X-linked syndrome with severe neurological impairment and altered concentrations of thyroid hormones. Histopathological analysis of brain tissue from patients who have impaired MCT8 function indicates that brain lesions start prenatally, and are most probably the result of cerebral hypothyroidism. A Slc16a2 knockout mouse model has revealed that Mct8 is an important mediator of thyroid hormone transport, especially T3, through the blood-brain barrier. However, unlike humans with an MCT8 deficiency, these mice do not have neurological impairment. One explanation for this discrepancy could be differences in expression of the T4 transporter OATP1C1 in the blood-brain barrier; OATP1C1 is more abundant in rodents than in primates and permits the passage of T4 in the absence of T3 transport, thus preventing full cerebral hypothyroidism. In this Review, we discuss the relevance of thyroid hormone transporters in health and disease, with a particular focus on the pathophysiology of MCT8 mutations.

  9. Molecular basis of thyrotropin and thyroid hormone action during implantation and early development.

    PubMed

    Colicchia, Martina; Campagnolo, Luisa; Baldini, Enke; Ulisse, Salvatore; Valensise, Herbert; Moretti, Costanzo

    2014-01-01

    Implantation and early embryo development are finely regulated processes in which several molecules are involved. Evidence that thyroid hormones (TH: T4 and T3) might be part of this machinery is emerging. An increased demand for TH occurs during gestation, and any alteration in maternal thyroid physiology has significant implications for both maternal and fetal health. Not only overt but also subclinical hypothyroidism is associated with infertility as well as with obstetric complications, including disruptions and disorders of pregnancy, labor, delivery, and troubles in early neonatal life. We searched the PubMed and Google Scholar databases for articles related to TH action on ovary, endometrium, trophoblast maturation and embryo implantation. In addition, articles on the regulation of TH activity at cellular level have been reviewed. The findings are hereby summarized and critically discussed. TH have been shown to influence endometrial, ovarian and placental physiology. TH receptors (TR) and thyrotropin (thyroid-stimulating hormone: TSH) receptors (TSHR) are widely expressed in the feto-maternal unit during implantation, and both the endometrium and the trophoblast might be influenced by TH either directly or through TH effects on the synthesis and activity of implantation-mediating molecules. Interestingly, due to the multiplicity of mechanisms involved in TH action (e.g. differential expression of TR isoforms, heterodimeric receptor partners, interacting cellular proteins, and regulating enzymes), the TH concentration in blood is not always predictive of their cellular availability and activity at both genomic and nongenomic level. In addition to the known role of TH on the hormonal milieu of the ovarian follicle cycle, which is essential for a woman's fertility, evidence is emerging on the importance of TH signaling during implantation and early pregnancy. Based on recent observations, a local action of TH on female reproductive organs and the embryo during

  10. Maternal iron deficiency alters circulating thyroid hormone levels in developing neonatal rats

    EPA Science Inventory

    Thyroid hormone insufficiency and iron deficiency (FeD) during fetal and neonatal life are both similarly deleterious to mammalian development suggesting a possible linkage between iron and thyroid hormone insufficiencies. Recent published data from our laboratory demonstrate a r...

  11. Establishing Adverse Outcome Pathways of Thyroid Hormone Disruption in an Amphibian Model

    EPA Science Inventory

    The Adverse Outcome Pathway (AOP) provides a framework for understanding the relevance of toxicology data in ecotoxicological hazard assessments. The AOP concept can be applied to many toxicological pathways including thyroid hormone disruption. Thyroid hormones play a critical r...

  12. Maternal iron deficiency alters circulating thyroid hormone levels in developing neonatal rats

    EPA Science Inventory

    Thyroid hormone insufficiency and iron deficiency (FeD) during fetal and neonatal life are both similarly deleterious to mammalian development suggesting a possible linkage between iron and thyroid hormone insufficiencies. Recent published data from our laboratory demonstrate a r...

  13. Establishing Adverse Outcome Pathways of Thyroid Hormone Disruption in an Amphibian Model

    EPA Science Inventory

    The Adverse Outcome Pathway (AOP) provides a framework for understanding the relevance of toxicology data in ecotoxicological hazard assessments. The AOP concept can be applied to many toxicological pathways including thyroid hormone disruption. Thyroid hormones play a critical r...

  14. [Current status of the treatment with thyroid hormones].

    PubMed

    Laudo Pardos, C; Puigdevall Gallego, V; del Río Mayor, M J; Velasco Martín, A

    1996-11-01

    The main indication of thyroid hormone preparations is the treatment of hypothyroidism, ideally the goal of therapy is to restore the serum thyrotropin (TSH) concentration to a normal value. The optimal doses used to be stable, but several conditions may alter their requirements (reduced intestinal absorption, pregnancy,...). Levothyroxine therapy is also used in the benign nodular disease and after surgery in patients with thyroid cancer. The overtreatment with thyroxine and the problems related to bone mineral density seems of special importance.

  15. Thyroid Hormone-disrupting Effects and the Amphibian Metamorphosis Assay

    PubMed Central

    Miyata, Kaori; Ose, Keiko

    2012-01-01

    There are continued concerns about endocrine-disrupting chemical effects, and appropriate vertebrate models for assessment of risk are a high priority. Frog tadpoles are very sensitive to environmental substances because of their habitat and the complex processes of metamorphosis regulated by the endocrine system, mainly thyroid hormones. During metamorphosis, marked alteration in hormonal factors occurs, as well as dramatic structural and functional changes in larval tissues. There are a variety of mechanisms determining thyroid hormone balance or disruption directly or indirectly. Direct-acting agents can cause changes in thyroxine synthesis and/or secretion in thyroid through effects on peroxidases, thyroidal iodide uptake, deiodinase, and proteolysis. At the same time, indirect action may result from biochemical processes such as sulfation, deiodination and glucuronidation. Because their potential to disrupt thyroid hormones has been identified as an important consideration for the regulation of chemicals, the OECD and the EPA have each established guidelines that make use of larval African clawed frogs (Xenopus laevis) and frog metamorphosis for screening and testing of potential endocrine disrupters. The guidelines are based on evaluation of alteration in the hypothalamic-pituitary-thyroid axis. One of the primary endpoints is thyroid gland histopathology. Others are mortality, developmental stage, hind limb length, snout-vent length and wet body weight. Regarding histopathological features, the guidelines include core criteria and additional qualitative parameters along with grading. Taking into account the difficulties in evaluating amphibian thyroid glands, which change continuously throughout metamorphosis, histopathological examination has been shown to be a very sensitive approach. PMID:22481853

  16. Effects of thyroid hormone on the cardiovascular system.

    PubMed

    Fazio, Serafino; Palmieri, Emiliano A; Lombardi, Gaetano; Biondi, Bernadette

    2004-01-01

    Increased or reduced action of thyroid hormone on certain molecular pathways in the heart and vasculature causes relevant cardiovascular derangements. It is well established that overt hyperthyroidism induces a hyperdynamic cardiovascular state (high cardiac output with low systemic vascular resistance), which is associated with a faster heart rate, enhanced left ventricular (LV) systolic and diastolic function, and increased prevalence of supraventricular tachyarrhythmias - namely, atrial fibrillation - whereas overt hypothyroidism is characterized by the opposite changes. However, whether changes in cardiac performance associated with overt thyroid dysfunction are due mainly to alterations of myocardial contractility or to loading conditions remains unclear. Extensive evidence indicates that the cardiovascular system responds to the minimal but persistent changes in circulating thyroid hormone levels, which are typical of individuals with subclinical thyroid dysfunction. Subclinical hyperthyroidism is associated with increased heart rate, atrial arrhythmias, increased LV mass, impaired ventricular relaxation, reduced exercise performance, and increased risk of cardiovascular mortality. Subclinical hypothyroidism is associated with impaired LV diastolic function and subtle systolic dysfunction and an enhanced risk for atherosclerosis and myocardial infarction. Because all cardiovascular abnormalities are reversed by restoration of euthyroidism ("subclinical hypothyroidism") or blunted by beta-blockade and L-thyroxine (L-T4) dose tailoring ("subclinical hyperthyroidism"), timely treatment is advisable in an attempt to avoid adverse cardiovascular effects. Interestingly, some data indicate that patients with acute and chronic cardiovascular disorders and those undergoing cardiac surgery may have altered peripheral thyroid hormone metabolism that, in turn, may contribute to altered cardiac function. Preliminary clinical investigations suggest that administration of

  17. Neonatal detection of generalized resistance to thyroid hormone

    SciTech Connect

    Weiss, R.E.; Balzano, S.; Scherberg, N.H.; Refetoff, S. )

    1990-11-07

    Generalized resistance to thyroid hormone (GRTH) is an inherited disease that is usually suspected when elevated serum thyroid hormone levels are associated with nonsuppressed thyrotropin. Often these test results are obtained because of short stature, decreased intelligence, and/or hyperactivity with learning disability noted in childhood and adolescence, or because of goiter in adulthood. The authors detected GRTH at birth by analysis of blood obtained during routine neonatal screening. The proposita, born to a mother with GRTH, had a thyrotropin level of 26 mU/L and a corresponding thyroxine concentration of 656 nmol/L. Administration of thyroid hormone in doses eightfold to 10-fold above replacement levels were required to reduce serum thyrotropin to normal levels without induction of hypermetabolism. This case, and the retrospective finding of high thyroxine levels in five newborns subsequently diagnosed as having GRTH, suggest that measurement of thyroxine at birth, in conjunction with thyrotropin, could allow the early detection of GRTH.

  18. Thyroid Hormone and the Neuroglia: Both Source and Target

    PubMed Central

    Mohácsik, Petra; Zeöld, Anikó; Bianco, Antonio C.; Gereben, Balázs

    2011-01-01

    Thyroid hormone plays a crucial role in the development and function of the nervous system. In order to bind to its nuclear receptor and regulate gene transcription thyroxine needs to be activated in the brain. This activation occurs via conversion of thyroxine to T3, which is catalyzed by the type 2 iodothyronine deiodinase (D2) in glial cells, in astrocytes, and tanycytes in the mediobasal hypothalamus. We discuss how thyroid hormone affects glial cell function followed by an overview on the fine-tuned regulation of T3 generation by D2 in different glial subtypes. Recent evidence on the direct paracrine impact of glial D2 on neuronal gene expression underlines the importance of glial-neuronal interaction in thyroid hormone regulation as a major regulatory pathway in the brain in health and disease. PMID:21876836

  19. Marsupial models for understanding evolution of thyroid hormone distributor proteins.

    PubMed

    Richardson, Samantha J

    2008-10-10

    Marsupials are a group of mammals that are under-exploited, in particular in developmental and evolutionary studies of biological systems. In this review, the roles that marsupials have played in elucidating the evolution of thyroid hormone distribution systems are summarised. Marsupials are born at very early developmental stages, and most development occurs during lactation rather than in utero. Studying thyroid hormone distribution systems during marsupial development, in addition to comparing the two Orders of marsupials, gave clues as to the selection pressures acting on the hepatic gene expression of transthyretin (TTR), one of the major thyroid hormone distributor proteins in blood. The structure of TTR in marsupials is intermediate between that of avian/reptilian TTRs and eutherian ("placental mammalian") TTRs. Consequently, the function of marsupial TTR is intermediate between those of avian/reptilian TTRs and eutherian TTRs. Thus, in some respects marsupials can be considered as "missing links" in vertebrate evolution.

  20. Multiple genetic factors in the heterogeneity of thyroid hormone resistance

    SciTech Connect

    Weiss, R.E.; Refetoff, S. ); Marcocci, C.; Bruno-Bossio, G. )

    1993-01-01

    Generalized resistance to thyroid hormone (GRTH), a syndrome of inherited tissue hyposensitivity to thyroid hormone, is linked to thyroid hormone receptor (TR) mutations. A typical feature of GRTH is variable severity of organ involvement among families that, surprisingly, does not correlate with the degree of T[sub 3]-binding impairment of the corresponding in vitro synthesized mutant TRs. Furthermore, variations in the clinical severity among family members harboring identical TR[beta] mutations have been reported. The authors compared serum levels of thyroid hormones that maintained a normal TSH in members of a large family with GRTH divided in three groups: Group A, 8 affected subjects with a mutation replacing arginine-320 with a histidine in the T[sub 3]-binding domain of TR[beta]; Group B, 11 first degree relatives (sibs and children of affected subjects) with no TR[beta] mutation; Group C, 16 controls related by marriage. TSH values were not different among the three groups. As expected, total and free T[sub 4] and T[sub 3], and rT[sub 3] levels were significantly higher in Group A vs Groups B and C. However, with the exception of T[sub 3], the same tests were also significantly higher in Group B vs Group C. The latter differences are not due to thyroid hormone transport in serum since TBG concentrations were not different. It is postulated that genetic variability of factors that contribute to the action of thyroid hormone modulate the phenotype of GRTH associated with TR[beta] mutations. 23 refs., 2 figs., 1 tab.

  1. Thyroid Hormone Signaling and Adult Neurogenesis in Mammals

    PubMed Central

    Remaud, Sylvie; Gothié, Jean-David; Morvan-Dubois, Ghislaine; Demeneix, Barbara A.

    2014-01-01

    The vital roles of thyroid hormone in multiple aspects of perinatal brain development have been known for over a century. In the last decades, the molecular mechanisms underlying effects of thyroid hormone on proliferation, differentiation, migration, synaptogenesis, and myelination in the developing nervous system have been gradually dissected. However, recent data reveal that thyroid signaling influences neuronal development throughout life, from early embryogenesis to the neurogenesis in the adult brain. This review deals with the latter phase and analyses current knowledge on the role of T3, the active form of thyroid hormone, and its receptors in regulating neural stem cell function in the hippocampus and the subventricular zone, the two principal sites harboring neurogenesis in the adult mammalian brain. In particular, we discuss the critical roles of T3 and TRα1 in commitment to a neuronal phenotype, a process that entails the repression of a number of genes notably that encoding the pluripotency factor, Sox2. Furthermore, the question of the relevance of thyroid hormone control of adult neurogenesis is considered in the context of brain aging, cognitive decline, and neurodegenerative disease. PMID:24808891

  2. Role of Thyroid Hormones in Skeletal Development and Bone Maintenance

    PubMed Central

    Bassett, J. H. Duncan

    2016-01-01

    The skeleton is an exquisitely sensitive and archetypal T3-target tissue that demonstrates the critical role for thyroid hormones during development, linear growth, and adult bone turnover and maintenance. Thyrotoxicosis is an established cause of secondary osteoporosis, and abnormal thyroid hormone signaling has recently been identified as a novel risk factor for osteoarthritis. Skeletal phenotypes in genetically modified mice have faithfully reproduced genetic disorders in humans, revealing the complex physiological relationship between centrally regulated thyroid status and the peripheral actions of thyroid hormones. Studies in mutant mice also established the paradigm that T3 exerts anabolic actions during growth and catabolic effects on adult bone. Thus, the skeleton represents an ideal physiological system in which to characterize thyroid hormone transport, metabolism, and action during development and adulthood and in response to injury. Future analysis of T3 action in individual skeletal cell lineages will provide new insights into cell-specific molecular mechanisms and may ultimately identify novel therapeutic targets for chronic degenerative diseases such as osteoporosis and osteoarthritis. This review provides a comprehensive analysis of the current state of the art. PMID:26862888

  3. Thyroid hormone action: identification of the mitochondrial thyroid hormone receptor as adenine nucleotide translocase.

    PubMed

    Sterling, K

    1991-01-01

    A preliminary report from our laboratory suggested that the thyroid hormone triiodothyronine (T3) is bound with an association constant (Ka) approximating 2 x 10(11) M-1 by adenine nucleotide translocase (AdNT) purified from beef heart mitochondria. We now report that [125I]T3 is capable of photoaffinity labeling not only purified AdNT but also the carrier in intact beef heart mitochondria. Photoaffinity labeling in intact mitochondria was appreciably greater than that observed with purified AdNT. The covalently labeled AdNT was identified by 2-dimensional electrophoresis with pI of 10 on electrofocusing and M(r) of 31,000 on SDS gel. Identification of the covalently labeled protein as authentic AdNT was substantiated by its interaction with a specific monoclonal antibody preparation.

  4. Deiodinases: implications of the local control of thyroid hormone action

    PubMed Central

    Bianco, Antonio C.; Kim, Brian W.

    2006-01-01

    The deiodinases activate or inactivate thyroid hormone, and their importance in thyroid hormone homeostasis has become increasingly clear with the availability of deiodinase-deficient animals. At the same time, heightened interest in the field has been generated following the discovery that the type 2 deiodinase can be an important component in both the Hedgehog signaling pathway and the G protein–coupled bile acid receptor 1–mediated (GPBAR1-mediated) signaling cascade. The discovery of these new roles for the deiodinases indicates that tissue-specific deiodination plays a much broader role than once thought, extending into the realms of developmental biology and metabolism. PMID:17016550

  5. [Pediatric reference intervals : retrospective study on thyroid hormone levels].

    PubMed

    Ladang, A; Vranken, L; Luyckx, F; Lebrethon, M-C; Cavalier, E

    2017-01-01

    Defining reference range is an essential tool for diagnostic. Age and sexe influences on thyroid hormone levels have been already discussed. In this study, we are defining a new pediatric reference range for TSH, FT3 and FT4 for Cobas C6000 analyzer. To do so, we have taken in account 0 to 18 year old outclinic patients. During the first year of life, thyroid hormone levels change dramatically before getting stabilized around 3 years old. We also compared our results to those obtained in a Canadian large-scale prospective study (the CALIPER initiative).

  6. [Thyroid hormones and their precursors. II. Species-specific properties].

    PubMed

    Tóth, Gergo; Noszál, Béla

    2014-01-01

    This paper surveys the species-specific physico-chemical parameters (basicity and lipophilicity) and related biological functions of thyroid hormones (thyroxine, liothyronine and reverse liothyronine) and their biological precursors (tyrosine, monoiodotyrosine and diiodotyrosine). The protonation macroconstants were determined by 1H NMR-pH titrations while the microconstants were determined by a multimodal spectroscopic-deductive methodology using auxiliary derivatives of reduced complexity. Our results show that the different number and/or position of iodine are the key factors to influence the phenolate basicity. The ionization state of the phenolate site is crucial in the biosynthesis and protein binding of thyroid hormones. The role of the protonation state in the receptor binding was investigated by an in silico docking method. Microspecies of thyroid hormones were docked to the thyroid hormone receptor isoforms. Our results quantitate at the molecular level how the ionization stage and the charge distribution influence the protein binding. The anionic form of the carboxyl group is essential for the protein binding, whereas the protonated form of the amino group loosens it. The protonation state of the phenolate plays a role of secondary importance in the receptor binding. The combined results of docking and microspeciation studies show that microspecies of the highest concentration at the pH of blood are not the strongest binding ones. The site-specific lipophilicity of our investigated molecules was determined with the measurement of distribution coefficients at different pH using carboxymethyl- and O-methyl-derivatives to mimic the partition of some of the individual microspecies. Correction factors were determined and introduced. Our data show that the iodinated aromatic ring system is the definitive structural element that fundamentally determines the lipophilicity of thyroid hormones, whereas the protonation state of the aliphatic part is essential in

  7. 21 CFR 201.316 - Drugs with thyroid hormone activity for human use; required warning.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... 21 Food and Drugs 4 2013-04-01 2013-04-01 false Drugs with thyroid hormone activity for human use... Drug Products § 201.316 Drugs with thyroid hormone activity for human use; required warning. (a) Drugs with thyroid hormone activity have been promoted for, and continue to be dispensed and prescribed...

  8. 21 CFR 201.316 - Drugs with thyroid hormone activity for human use; required warning.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... 21 Food and Drugs 4 2014-04-01 2014-04-01 false Drugs with thyroid hormone activity for human use... Drug Products § 201.316 Drugs with thyroid hormone activity for human use; required warning. (a) Drugs with thyroid hormone activity have been promoted for, and continue to be dispensed and prescribed...

  9. Regulation of Mammary Gland Sensitivity to Thyroid Hormones during the Transition from Pregnancy to Lactation

    USDA-ARS?s Scientific Manuscript database

    Thyroid hormones are galactopoietic and appear to assist in establishing the mammary gland’s metabolic priority during lactation. Expression patterns for genes that can alter tissue sensitivity to thyroid hormones and thyroid hormone activity were evaluated in the mammary gland and liver of Holstei...

  10. [Reference Intervals of Thyroid Hormones in Normal Pregnant Women and Effects of Thyroid Autoantibodies on Thyroid Hormone Levels in Pregnant Women in Chengdu Area].

    PubMed

    Chen, Yu-Min; Zeng, Jing; Yan, Yue-Rong; Luo, Dan; Huang, Lu; Huang, Hui

    2017-05-01

    To establish the reference intervals of thyroid hormones in normal pregnant women in Chengdu area of China, and to investigate the effects of thyroid autoantibodies on thyroid function in pregnant women. We included 696 pregnant women who had gestation data from June 2013 to March 2014 in Chengdu Women & Children's Central Hospital. Every subject under went questionnaire survey, physical examination, thyroid ultrasound and measurement of thyroid hormone and thyroid autoantibodies. The normal reference intervals were established according to the percentiles (P2.5-P97.5) of the healthy pregnant women in the same trimester. Another 50 non-pregnant women were selected as the control group. Of the 696 pregnant women, 579 subjects had negative thyroid autoantibodies and 117 subjects had positive thyroid autoantibodies. The positive rate of thyroid autoantibodies was 16.81%. Of the 579 subjects with negative thyroid autoantibodies, 257 were in the first trimester, 202 in the second trimester and 120 in the third trimester. In the first trimester of normal pregnancy, the reference intervals of serum thyrotropin (TSH) , free triiodothyronine (FT3) and free thyroxine (FT4) were 0.02-4.03 mIU/L, 3.85-6.27 pmol/L and 11.93-21.04 pmol/L respectively. In the second trimester, the reference intervals of serum TSH, FT3 and FT4 were 0.02-4.05 mIU/L, 3.51-5.82 pmol/L and 11.23-19.22 pmol/L respectively. In the thirdtrimester, the reference intervals for serum TSH, FT3 and FT4 were 0.24-5.41 mIU/L, 3.18-4.97 pmol/L and 11.10-17.00 pmol/L, respectively. When compared with non-pregnant women, the median TSH value was increasingly consisted with the progress of pregnancy period, while the median FT4 and FT3 values were decreasing accordingly. The similar tendencies of TSH, FT3, and FT4 were found in pregnant women with positive thyroid autoantibodies, but the trends were more remarkable when compared with those with negative thyroid autoantibodies. In pregnant women with positive

  11. Metabolic effects of thyroid hormone derivatives.

    PubMed

    Moreno, Maria; de Lange, Pieter; Lombardi, Assunta; Silvestri, Elena; Lanni, Antonia; Goglia, Fernando

    2008-02-01

    The processes and pathways mediating the intermediary metabolism of carbohydrates, lipids, and proteins are all affected by thyroid hormones (THs) in almost all tissues. Particular attention has been devoted by scientists to the effects of THs on lipid metabolism. Among others, effects related to cholesterol, lipid handling, and cardiac performance have been the subject of study. Many reports are present in the literature concerning the calorigenic effect of THs, with most of them aimed at identifying the molecular basis of this effect. However, at the moment the mechanism(s) underlying the metabolic effects of THs remain to be elucidated. THs exert most of their effects though TH receptors (TRs). However, some effects of THs cannot be explained by a nuclear-mediated pathway, and recently an increasing number of nonnuclear actions have been described, which can provide a regulatory system of which the effects differ from those mediated on the transcriptional level by TRs. Some of the TH derivatives (naturally occurring metabolites and analogs) possess biological activities. TH-related biological effects have been described for physiological products such as tetraiodothyroacetic acid (Tetrac) and triiodothyroacetic acid (Triac) (via oxidative deamination and decarboxylation of thyroxine [T4] and triiodothyronine [T3] alanine chain), 3,3',5'-triiodothyronine (rT3) (via T4 and T3 deiodination), 3,3'-diiodothyronine (3,3'-T2) and 3,5-diiodothyronine (T2) (via T4, T3, and rT3 deiodination), and 3-iodothyronamine (T1AM) and thyronamine (T0AM) (via T4 and T3 deiodination and amino acid decarboxylation), as well as for TH structural analogs, such as 3,5,3'-triiodothyropropionic acid (Triprop), 3,5-dibromo-3-pyridazinone-l-thyronine (L-940901), N-[3,5-dimethyl-4-(4'-hydroxy-3'-isopropylphenoxy)-phenyl]-oxamic acid (CGS 23425), 3,5-dimethyl-4[(4'-hydroxy-3'-isopropylbenzyl)-phenoxy] acetic acid (GC-1), 3,5-dichloro-4[(4-hydroxy-3-isopropylphenoxy)phenyl] acetic acid (KB-141

  12. Thyroid Hormone Receptor Binds to a Site in the Rat Growth Hormone Promoter Required for Induction by Thyroid Hormone

    NASA Astrophysics Data System (ADS)

    Koenig, Ronald J.; Brent, Gregory A.; Warne, Robert L.; Reed Larsen, P.; Moore, David D.

    1987-08-01

    Transcription of the rat growth hormone (rGH) gene in pituitary cells is increased by addition of thyroid hormone (T3). This induction is dependent on the presence of specific sequences just upstream of the rGH promoter. We have partially purified T3 receptor from rat liver and examined its interaction with these rGH sequences. We show here that T3 receptor binds specifically to a site just upstream of the basal rGH promoter. This binding site includes two copies of a 7-base-pair direct repeat, the centers of which are separated by 10 base pairs. Deletions that specifically remove the T3 receptor binding site drastically reduce response to T3 in transient transfection experiments. These results demonstrate that T3 receptor can recognize specific DNA sequences and suggest that it can act directly as a positive transcriptional regulatory factor.

  13. Thyroid hormone testing in the 21st century.

    PubMed

    Singh, Ravinder J; Kaur, Parmpreet

    2016-08-01

    Thyroid dysfunction and treatment follow up require accurate measurement of thyroid hormones. Most thyroid disease is treated on an outpatient basis; thus, assays have to be rapid and cost effective for optimal patient care. There are no rapid or point-of-care thyroid tests yet available, which could replace centralized automated thyroid testing. With the high population of thyroid dysfunction, it is important for thyroid assays to be available widely and locally. Immunoassays are most commonly used due to their ease and availability, but are limited in their accuracy. MS assays are much more specific, but are laborious with a high machine cost. Many hospitals may not be able to afford the machines and lack technical expertise. Sensitivity, specificity and standardization issues still result in substantial differences between various tests currently used for this population. To address these issues, new performance standards are being established by the professional organizations and technological advancements are being undertaken by instrument manufacturers. Automation solution is provided by various manufacturers and offers a choice for the hospital labs to select a platform which helps in their workflow and other chemistry testing. This has also resulted in decentralization and easy access to the thyroid testing. Even with these advancements, it is understandably confusing for clinicians to choose an assay for various clinical scenarios (20). As it becomes more available and standardized, LC-MS will continue to demonstrate its superiority to immunoassay.

  14. DEHP reduces thyroid hormones via interacting with hormone synthesis-related proteins, deiodinases, transthyretin, receptors, and hepatic enzymes in rats.

    PubMed

    Liu, Changjiang; Zhao, Letian; Wei, Li; Li, Lianbing

    2015-08-01

    Di-(2-ethylhexyl) phthalate (DEHP) is used extensively in many personal care and consumer products, resulting in widespread nonoccupational human exposure through multiple routes and media. Limited studies suggest that exposure to DEHP may be associated with altered thyroid function, but detailed mechanisms are unclear. In order to elucidate potential mechanisms by which DEHP disturbs thyroid hormone homeostasis, Sprague-Dawley (SD) rats were dosed with DEHP by gavage at 0, 250, 500, and 750 mg/kg/day for 30 days and sacrificed within 24 h after the last dose. Gene expressions of thyroid hormone receptors, deiodinases, transthyretin, and hepatic enzymes were measured by RT-PCR; protein levels of transthyretin were also analyzed by Western blot. Results showed that DEHP caused histological changes in the thyroid and follicular epithelial cell hypertrophy and hyperplasia were observed. DEHP significantly reduced thyroid hormones (T3, T4) and thyrotropin releasing hormone (TRH) levels, whereas thyroid stimulating hormone (TSH) was not affected. After exposure to DEHP, biosynthesis of thyroid hormones was suppressed, and sodium iodide symporter (NIS) and thyroid peroxidase (TPO) levels were significantly reduced. Additionally, levels of deiodinases and transthyretin were also affected. TSH receptor (TSHr) level was downregulated, while TRH receptor (TRHr) level was upregulated. Metabolism of thyroid hormones was accelerated due to elevated gene expression of hepatic enzymes (UDPGTs and CYP2B1) by DEHP. Taken together, observed findings indicate that DEHP could reduce thyroid hormones through influencing biosynthesis, biotransformation, biotransport, receptor levels, and metabolism of thyroid hormones.

  15. 2,4,6-Tribromophenol Interferes with the Thyroid Hormone System by Regulating Thyroid Hormones and the Responsible Genes in Mice

    PubMed Central

    Lee, Dongoh; Ahn, Changhwan; Hong, Eui-Ju; An, Beum-Soo; Hyun, Sang-Hwan; Choi, Kyung-Chul; Jeung, Eui-Bae

    2016-01-01

    2,4,6-Tribromophenol (TBP) is a brominated flame retardant (BFR). Based on its affinity for transthyretin, TBP could compete with endogenous thyroid hormone. In this study, the effects of TBP on the thyroid hormone system were assessed in mice. Briefly, animals were exposed to 40 and 250 mg/kg TBP. Thyroid hormones were also administered with or without TBP. When mice were treated with TBP, deiodinase 1 (Dio1) and thyroid hormone receptor β isoform 2 (Thrβ2) decreased in the pituitary gland. The levels of deiodinase 2 (Dio2) and growth hormone (Gh) mRNA increased in response to 250 mg/kg of TBP, and the relative mRNA level of thyroid stimulating hormone β (Tshβ) increased in the pituitary gland. Dio1 and Thrβ1 expression in the liver were not altered, while Dio1 decreased in response to co-treatment with thyroid hormones. The thyroid gland activity decreased in response to TBP, as did the levels of free triiodothyronine and free thyroxine in serum. Taken together, these findings indicate that TBP can disrupt thyroid hormone homeostasis and the presence of TBP influenced thyroid actions as regulators of gene expression. These data suggest that TBP interferes with thyroid hormone systems PMID:27420076

  16. 2,4,6-Tribromophenol Interferes with the Thyroid Hormone System by Regulating Thyroid Hormones and the Responsible Genes in Mice.

    PubMed

    Lee, Dongoh; Ahn, Changhwan; Hong, Eui-Ju; An, Beum-Soo; Hyun, Sang-Hwan; Choi, Kyung-Chul; Jeung, Eui-Bae

    2016-07-12

    2,4,6-Tribromophenol (TBP) is a brominated flame retardant (BFR). Based on its affinity for transthyretin, TBP could compete with endogenous thyroid hormone. In this study, the effects of TBP on the thyroid hormone system were assessed in mice. Briefly, animals were exposed to 40 and 250 mg/kg TBP. Thyroid hormones were also administered with or without TBP. When mice were treated with TBP, deiodinase 1 (Dio1) and thyroid hormone receptor β isoform 2 (Thrβ2) decreased in the pituitary gland. The levels of deiodinase 2 (Dio2) and growth hormone (Gh) mRNA increased in response to 250 mg/kg of TBP, and the relative mRNA level of thyroid stimulating hormone β (Tshβ) increased in the pituitary gland. Dio1 and Thrβ1 expression in the liver were not altered, while Dio1 decreased in response to co-treatment with thyroid hormones. The thyroid gland activity decreased in response to TBP, as did the levels of free triiodothyronine and free thyroxine in serum. Taken together, these findings indicate that TBP can disrupt thyroid hormone homeostasis and the presence of TBP influenced thyroid actions as regulators of gene expression. These data suggest that TBP interferes with thyroid hormone systems.

  17. Perfluoroalkyl substances and thyroid hormones in cord blood.

    PubMed

    Tsai, Meng-Shan; Lin, Ching-Chun; Chen, Mei-Huei; Hsieh, Wu-Shiun; Chen, Pau-Chung

    2017-03-01

    Perfluoroalkyl substances (PFASs) are pollutants that tend to accumulate in the environment and organisms. The animal and human studies to date have focused on thyroid function, but the results are inconsistent. A sample of 118 mother-infant pairs was obtained from the Taiwan Birth Panel Study (TBPS). Cord blood PFASs levels were evaluated using the Waters ACQUITY UPLC system coupled with a Waters Quattro Premier XE triple quadrupole mass spectrometer, and cord blood thyroid hormones were assessed using a Roche Analytics E170 modular analyser (Roche Diagnostics, Mannheim, Germany). PFASs concentrations were analysed in the final models to examine the associations between cord blood PFASs levels and thyroid hormone concentrations. The cord blood perfluorooctane sulfonate (PFOS) concentration was negatively associated with the cord blood thyroxine (T4) concentration [per ln unit: adjusted β (95% confidence interval, CI) = -0.458(-0.916, -0.001)]. Moreover, the level of cord blood thyroid stimulating hormone (TSH) was positively associated with the cord blood PFOS concentration [per ln unit: adjusted β (95% confidence interval, CI) = 0.346(0.101, 0.592)]. The sex stratified effects of PFOS on T4 were suggestive of differential effects in high-exposure groups compared with low-exposure group in boys. We found that cord blood thyroid hormone levels are affected by PFASs, with a negative association between T4 and PFOS and a positive association between TSH and PFOS. The causal associations of thyroid hormones and PFASs require further exploration. Copyright © 2016 Elsevier Ltd. All rights reserved.

  18. A developmental switch induced by thyroid hormone: Xenopus laevis metamorphosis.

    PubMed

    Furlow, J David; Neff, Eric S

    2006-03-01

    Thyroid hormone induces the complete metamorphosis of anuran tadpoles into juvenile frogs. Arguably, anuran metamorphosis is the most dramatic effect of a hormone in any vertebrate. Recent advances in pharmacology and molecular biology have made the study of this remarkable process in the frog Xenopus laevis attractive to developmental biologists and endocrinologists alike. In particular, the availability of a straightforward transgenesis assay and the near completion of the Xenopus tropicalis genome are enabling significant advances to be made in our understanding of the major remaining problems of metamorphosis: the extraordinary tissue specificity of responses, the precise timing of morphological changes, the degree of cell autonomy of hormone responses and developmental competence. We argue that X. laevis metamorphosis presents an exciting opportunity for understanding the role of thyroid hormone in vertebrate development.

  19. Role of maternal thyroid hormones in the developing neocortex and during human evolution

    PubMed Central

    Stenzel, Denise; Huttner, Wieland B.

    2013-01-01

    The importance of thyroid hormones during brain development has been appreciated for many decades. In humans, low levels of circulating maternal thyroid hormones, e.g., caused by maternal hypothyroidism or lack of iodine in diet, results in a wide spectrum of severe neurological defects, including neurological cretinism characterized by profound neurologic impairment and mental retardation, underlining the importance of the maternal thyroid hormone contribution. In fact, iodine intake, which is essential for thyroid hormone production in the thyroid gland, has been related to the expansion of the brain, associated with the increased cognitive capacities during human evolution. Because thyroid hormones regulate transcriptional activity of target genes via their nuclear thyroid hormone receptors (THRs), even mild and transient changes in maternal thyroid hormone levels can directly affect and alter the gene expression profile, and thus disturb fetal brain development. Here we summarize how thyroid hormones may have influenced human brain evolution through the adaptation to new habitats, concomitant with changes in diet and, therefore, iodine intake. Further, we review the current picture we gained from experimental studies in rodents on the function of maternal thyroid hormones during developmental neurogenesis. We aim to evaluate the effects of maternal thyroid hormone deficiency as well as lack of THRs and transporters on brain development and function, shedding light on the cellular behavior conducted by thyroid hormones. PMID:23882187

  20. Role and Mechanisms of Actions of Thyroid Hormone on the Skeletal Development

    PubMed Central

    Kim, Ha-Young; Mohan, Subburaman

    2013-01-01

    The importance of the thyroid hormone axis in the regulation of skeletal growth and maintenance has been well established from clinical studies involving patients with mutations in proteins that regulate synthesis and/or actions of thyroid hormone. Data from genetic mouse models involving disruption and overexpression of components of the thyroid hormone axis also provide direct support for a key role for thyroid hormone in the regulation of bone metabolism. Thyroid hormone regulates proliferation and/or differentiated actions of multiple cell types in bone including chondrocytes, osteoblasts and osteoclasts. Thyroid hormone effects on the target cells are mediated via ligand-inducible nuclear receptors/transcription factors, thyroid hormone receptor (TR) α and β, of which TRα seems to be critically important in regulating bone cell functions. In terms of mechanisms for thyroid hormone action, studies suggest that thyroid hormone regulates a number of key growth factor signaling pathways including insulin-like growth factor-I, parathyroid hormone related protein, fibroblast growth factor, Indian hedgehog and Wnt to influence skeletal growth. In this review we describe findings from various genetic mouse models and clinical mutations of thyroid hormone signaling related mutations in humans that pertain to the role and mechanism of action of thyroid hormone in the regulation of skeletal growth and maintenance. PMID:26273499

  1. Role of thyroid hormone deiodination in the hypothalamus.

    PubMed

    Lechan, Ronald M; Fekete, Csaba

    2005-08-01

    Iodothyronine deiodinases (D1, D2, and D3) comprise a family of selenoproteins that are involved in the conversion of thyroxine (T(4)) to active triiodothyronine (T(3)), and also the inactivation of both thyroid hormones. The deiodinase enzymes are of critical importance for the normal development and function of the central nervous system. D1 is absent from the human brain, suggesting that D2 and D3 are the two main enzymes involved in the maintenance of thyroid hormone homeostasis in the central nervous system, D2 as the primary T(3)-producing enzyme, and D3 as the primary inactivating enzyme. While the coordinated action of D2 and D3 maintain constant T(3) levels in the cortex independently from the circulating thyroid hormone levels, the role of deiodinases in the hypothalamus may be more complex, as suggested by the regulation of D2 activity in the hypothalamus by infection, fasting and changes in photoperiod. Tanycytes, the primary source of D2 activity in the hypothalamus, integrate hormonal and probably neuronal signals, and under specific conditions, may influence neuroendocrine functions by altering local T(3) tissue concentrations. This function may be of particular importance in the regulation of the hypothalamic-pituitary-thyroid axis during fasting and infection, and in the regulation of appetite and reproductive function. Transient expression of D3 in the preoptic region during a critical time of development suggests a special role for this deiodinase in sexual differentiation of the brain.

  2. Association between thyroid hormones, insulin resistance, and metabolic syndrome.

    PubMed

    Kumar, Hari K; Yadav, Raj K; Prajapati, Jayaram; Reddy, Challa V K; Raghunath, Manchala; Modi, Kirtikumar D

    2009-07-01

    To determine the association between thyroid hormones, insulin resistance, and metabolic syndrome in euthyroid women. Forty-five women with no past medical history were studied in this cross-sectional study at the Department of Endocrinology, Medwin Hospitals, Hyderabad, India, from August 2008 to September 2008. The body fat was estimated using bio-impedance method, and fasting blood sample was analyzed for total triiodothyronine (T3), total thyroxine (T4), thyroid-stimulating hormone (TSH), free triiodothyronine (FT3), lipid profile, insulin, and glucose. The mean age of the participants was 32.6 +/= 9.6 years with a body mass index (BMI) of 29.9 +/= 3.8 kg/m2. Evidence of homeostasis model assessment index for insulin resistance (HOMA-IR) more than 3 was seen in 34 (75%) and metabolic syndrome in 29 (64%) participants. Total T3 showed a positive correlation with triglycerides, low density lipoprotein- cholesterol (LDL-C), total cholesterol, insulin, HOMA-IR and negatively with body fat. Thyroid-stimulating hormone correlated positively with BMI, insulin, HOMA-IR, LDL-C and negatively with HDL-cholesterol (p<0.05). Free triiodothyronine correlated positively with waist circumference and T4 did not correlate with metabolic syndrome parameters. Our preliminary data show an association between thyroid hormones and some components specific of the metabolic syndrome in euthyroid women. Total triiodothyronine and TSH correlated more with variables of metabolic syndrome than FT3 and T4.

  3. μ-Crystallin controls muscle function through thyroid hormone action.

    PubMed

    Seko, Daiki; Ogawa, Shizuka; Li, Tao-Sheng; Taimura, Akihiro; Ono, Yusuke

    2016-05-01

    μ-Crystallin (Crym), a thyroid hormone-binding protein, is abnormally up-regulated in the muscles of patients with facioscapulohumeral muscular dystrophy, a dominantly inherited progressive myopathy. However, the physiologic function of Crym in skeletal muscle remains to be elucidated. In this study, Crym was preferentially expressed in skeletal muscle throughout the body. Crym-knockout mice exhibited a significant hypertrophy of fast-twitch glycolytic type IIb fibers, causing an increase in grip strength and high intensity running ability in Crym-null mice. Genetic inactivation of Crym or blockade of Crym by siRNA-mediated knockdown up-regulated the gene expression of fast-glycolytic contractile fibers in satellite cell-derived myotubes in vitro These alterations in Crym-inactivated muscle were rescued by inhibition of thyroid hormone, even though Crym is a positive regulator of thyroid hormone action in nonmuscle cells. The results demonstrated that Crym is a crucial regulator of muscle plasticity, controlling metabolic and contractile properties of myofibers, and thus the selective inactivation of Crym may be a potential therapeutic target for muscle-wasting diseases, such as muscular dystrophies and age-related sarcopenia.-Seko, D., Ogawa, S., Li, T.-S., Taimura, A., Ono, Y. μ-Crystallin controls muscle function through thyroid hormone action.

  4. Effects of microsomal enzyme inducers on thyroid follicular cell proliferation and thyroid hormone metabolism.

    PubMed

    Klaassen, C D; Hood, A M

    2001-01-01

    The effects of microsomal enzyme inducers on thyroid hormone homeostasis and the thyroid gland are of concern. We have investigated the effects of microsomal enzyme inducers on thyroid follicular cell proliferation and thyroid hormone metabolism in rats. We have shown that small increases in serum TSH can result in large increases in thyroid follicular cell proliferation. Furthermore, only those microsomal enzyme inducers that increase serum TSH--that is, phenobarbital (PB) and pregnenolone-16alpha-carbonitrile (PCN)-increase thyroid follicular cell proliferation, whereas those microsomal enzyme inducers that do not increase serum TSH--that is, 3-methylcholanthrene (3MC) and Aroclor 1254 (PCB)-do not increase thyroid follicular cell proliferation. Deiodination does not appear to be the reason why serum T3 concentrations are maintained in microsomal enzyme inducer-treated rats. We have also shown that those microsomal enzyme inducers that increase serum TSH increase T3 UDP-glucuronosyltransferase (UGT) activity, whereas those microsomal enzyme inducers that do not increase serum TSH do not increase T3 UGT activity. This finding suggests that induction of T3 glucuronidation, rather than T4 glucuronidation, mediates increases in serum TSH of microsomal enzyme inducer treated rats.

  5. Effects of TCDD on thyroid hormone homeostasis in the rat.

    PubMed

    Kohn, M C

    2000-02-01

    A physiological dosimetric model was constructed to describe the effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) on circulating thyroid hormones in the rat and to test the hypothesis that these hormonal changes cause chronically elevated serum thyrotropin (thyroid stimulating hormone, TSH), which mediates growth promotion and may lead to thyroid tumors in TCDD-treated rats. The model included diffusion restricted distribution of TCDD among compartments for liver, kidney, white fat, slowly and rapidly perfused tissues, and the thyroxine-sensitive tissues brown fat, pituitary, and thyroid. Blood was distributed among major vessels and the capillary beds of the tissues. Metabolism of TCDD was limited to the liver. Secretion of 3,5,3'-triiodothyronine (T3) and thyroxine (3,5,3',5'-tetraiodothyronine, T4) from the thyroid was modeled as stimulated by circulating TSH, whose release from the pituitary was regulated by the hypothalamic peptides thyrotropin releasing hormone (activating) and somatostatin (inhibiting). Release of these peptides was represented as inhibited and activated, respectively, by circulating T4. Binding proteins for T3 and T4 and metabolism of the hormones by deiodination were included in thyroxine-sensitive tissues. Induction of hepatic UDP-glucuronosyltransferase-1*6 (UGT), the enzyme which glucuronidates T4, was modeled as induced by the complex formed between TCDD and the aryl hydrocarbon receptor. The computed extent of deiodination, primacy of the thyroid in generating T3 from T4, dependence of liver and kidney on locally produced T3, and export of T3 formed in the pituitary agreed with experimental observations. The model reproduced the observed decrease in circulating T4 and elevated serum TSH following chronic administration of TCDD. The altered levels were attributed to the increased clearance of T4 by the induced UGT and the consequent modification of feedback control of hormone releases. These results are consistent with the

  6. Thyroid stimulating hormone and prospective memory functioning in old age.

    PubMed

    Livner, Asa; Wahlin, Ake; Bäckman, Lars

    2009-11-01

    Alterations of thyroid functioning are common in old age. Even among persons free from thyroid disorders, subclinical variations in thyroid functioning may affect cognitive performance. However, it is unknown whether prospective memory (ProM) is related to thyroid stimulating hormone (TSH) variations. An association could be expected, as changes in the thyroid gland have been linked to alterations in frontal brain regions that play a key role in prospective remembering. Thus, the aim of this study was to examine whether subclinical variations in thyroid functioning affect ProM performance. We studied 103 participants, 75 years and older, who were free from thyroid disorders and had serum levels of TSH and thyroxine (T4) within normal ranges. Interestingly, we found a non-linear association between TSH and ProM performance, where persons with TSH levels above the fourth quartile performed substantially better than persons in the other quartiles. T4 levels were unrelated to ProM performance. This pattern suggests that the previously identified "normal-range" interval for TSH should be moved further up in old age, at least when cognitive functioning is considered.

  7. Thyroid hormone status regulates the expression of secretory phospholipases.

    PubMed

    Sharma, Pragya; Levesque, Tania; Boilard, Eric; Park, Edwards A

    2014-01-31

    Thyroid hormone (T3) stimulates various metabolic pathways and the hepatic actions of T3 are mediated primarily through the thyroid hormone receptor beta (TRβ). Hypothyroidism has been linked with low grade inflammation, elevated risk of hepatic steatosis and atherosclerosis. Secretory phospholipases (sPLA2) are associated with inflammation, hyperlipidemia and atherosclerosis. Due to potential linkage between thyroid hormone and sPLA2, we investigated the effect of thyroid hormone status on the regulation of secretory phospholipases in mice, rats and human liver. T3 suppressed the expression of the sPLA2 group IIa (PLA2g2a) gene in the liver of BALB/c mice and C57BL/6 transgenic mice expressing the human PLA2g2a. PLA2g2a was elevated with hypothyroidism and high fat diets which may contribute to the low grade inflammation associated with hypothyroidism and diet induced obesity. We also examined the effects of the TRβ agonist eprotirome on hepatic gene regulation. We observed that eprotirome inhibited the expression of selected sPLA2 genes and furthermore the cytokine mediated induction PLA2g2a was suppressed. In addition, eprotirome induced genes involved in fatty acid oxidation and cholesterol clearance while inhibiting lipogenic genes. Our results indicate that in vivo thyroid hormone status regulates the abundance of sPLA2 and the inhibition of PLA2g2a by T3 is conserved across species. By regulating sPLA2 genes, T3 may impact processes associated with atherosclerosis and inflammation and TRβ agonists may ameliorate inflammation and hyperlipidemia.

  8. Thyroid hormone status regulates the expression of secretory phospholipases

    PubMed Central

    Sharma, Pragya; Levesque, Tania; Boilard, Eric; Park, Edwards A.

    2014-01-01

    Thyroid hormone (T3) stimulates various metabolic pathways and the hepatic actions of T3 are mediated primarily through the thyroid hormone receptor beta (TRβ). Hypothyroidism has been linked with low grade inflammation, elevated risk of hepatic steatosis and atherosclerosis. Secretory phospholipases (sPLA2) are associated with inflammation, hyperlipidemia and atherosclerosis. Due to potential linkage between thyroid hormone and sPLA2, we investigated the effect of thyroid hormone status on the regulation of secretory phospholipases in mice, rats and human liver. T3 suppressed the expression of the sPLA2 group IIa (PLA2g2a) gene in the liver of BALB/c mice and C57BL/6 transgenic mice expressing the human PLA2g2a. PLA2g2a was elevated with hypothyroidism and high fat diets which may contribute to the low grade inflammation associated with hypothyroidism and diet induced obesity. We also examined the effects of the TRβ agonist eprotirome on hepatic gene regulation. We observed that eprotirome inhibited the expression of selected sPLA2 genes and furthermore the cytokine mediated induction PLA2g2a was suppressed. In addition, eprotirome induced genes involved in fatty acid oxidation and cholesterol clearance while inhibiting lipogenic genes. Our results indicate that in vivo thyroid hormone status regulates the abundance of sPLA2 and the inhibition of PLA2g2a by T3 is conserved across species. By regulating sPLA2 genes, T3 may impact processes associated with atherosclerosis and inflammation and TRβ agonists may ameliorate inflammation and hyperlipidemia. PMID:24440706

  9. Thyroid hormone is required for hypothalamic neurons regulating cardiovascular functions.

    PubMed

    Mittag, Jens; Lyons, David J; Sällström, Johan; Vujovic, Milica; Dudazy-Gralla, Susi; Warner, Amy; Wallis, Karin; Alkemade, Anneke; Nordström, Kristina; Monyer, Hannah; Broberger, Christian; Arner, Anders; Vennström, Björn

    2013-01-01

    Thyroid hormone is well known for its profound direct effects on cardiovascular function and metabolism. Recent evidence, however, suggests that the hormone also regulates these systems indirectly through the central nervous system. While some of the molecular mechanisms underlying the hormone's central control of metabolism have been identified, its actions in the central cardiovascular control have remained enigmatic. Here, we describe a previously unknown population of parvalbuminergic neurons in the anterior hypothalamus that requires thyroid hormone receptor signaling for proper development. Specific stereotaxic ablation of these cells in the mouse resulted in hypertension and temperature-dependent tachycardia, indicating a role in the central autonomic control of blood pressure and heart rate. Moreover, the neurons exhibited intrinsic temperature sensitivity in patch-clamping experiments, providing a new connection between cardiovascular function and core temperature. Thus, the data identify what we believe to be a novel hypothalamic cell population potentially important for understanding hypertension and indicate developmental hypothyroidism as an epigenetic risk factor for cardiovascular disorders. Furthermore, the findings may be beneficial for treatment of the recently identified patients that have a mutation in thyroid hormone receptor α1.

  10. THE THYROID HORMONE TRANSPORTER, MCT8, SELECTIVELY RESPONDS TO THYROID HORMONE INSUFFICIENCY IN THE DEVELOPMENT RAT BRAIN.

    EPA Science Inventory

    Thyroid hormone (TH) is essential for normal brain development. Therefore, it is not surprising that a variety of adaptive mechanisms are activated in response to TH insufficiency. However, not all brain regions respond in the same fashion to TH insufficiency. This observation...

  11. Effect of thyroid hormones on pituitary neuromedin B and possible interaction between thyroid hormones and neuromedin B on thyrotropin secretion.

    PubMed

    Ortiga-Carvalho, T M; Polak, J; McCann, S; Pazos-Moura, C C

    1996-11-14

    Neuromedin B (NB), a bombesin-like peptide, has been recently characterized as a physiological paracrine/autocrine inhibitor of thyrotropin (TSH) secretion. We hypothesized on the basis of our prior experiments that thyroid hormones stimulate pituitary NB secretion which mediates, at least in part, the TSH-suppressive effect of thyroid hormone. Here, we evaluated the time-course of the effect of thyroid hormones administration to eu- and hypothyroid rats on the anterior pituitary content of NB and on serum TSH. As previously reported, the pituitary content of NB increased in hyperthyroidism and decreased in hypothyroidism. Chronic treatment of hypothyroid rats with a physiological dose of thyroxine (0.8 microgram/100 g b.w. s.c, for 3 or 5 days) normalized pituitary NB content, while 5 days of treatment with a pharmacological dose of thriiodothyronine (0.4 microgram/100 g b.w.) induced an increase above that of normal pituitaries. Thyroxine and triiodothyronine injected once, s.c., into hypothyroid rats required 30 min to normalize NB content, which reached higher than normal values in 3-6 h. At these times, the increment in NB preceded or was simultaneous with the suppression of serum TSH. This rapid and marked effect on pituitary neuromedin B content, associated in time with TSH suppression, is in agreement with the hypothesis that neuromedin B may mediate at least in part, the acute suppression of TSH release by thyroid hormone, a hypothesis that still needs further verification.

  12. THE THYROID HORMONE TRANSPORTER, MCT8, SELECTIVELY RESPONDS TO THYROID HORMONE INSUFFICIENCY IN THE DEVELOPMENT RAT BRAIN.

    EPA Science Inventory

    Thyroid hormone (TH) is essential for normal brain development. Therefore, it is not surprising that a variety of adaptive mechanisms are activated in response to TH insufficiency. However, not all brain regions respond in the same fashion to TH insufficiency. This observation...

  13. Neither bovine somatotropin nor growth hormone-releasing factor alters expression of thyroid hormone receptors in liver and mammary tissues.

    PubMed

    Capuco, A V; Binelli, M; Tucker, H A

    2011-10-01

    Physiological effects of thyroid hormones are mediated primarily by binding of triiodothyronine to specific nuclear receptors. Organ-specific changes in production of triiodothyronine from its prohormone, thyroxine, have been hypothesized to target the action of thyroid hormones on the mammary gland and play a role in mediating or augmenting a galactopoietic response to bovine somatotropin (bST). Additionally, tissue responsiveness to thyroid hormones may be altered by changes in the number or affinity of nuclear receptors for thyroid hormones. In the present study, effects of bST and bovine growth hormone-releasing factor (bGRF) on thyroid hormone receptors in liver and mammary gland were studied. Lactating Holstein cows received continuous infusions of bST or bGRF for 63 d or served as uninfused controls. Nuclei were isolated from harvested mammary and liver tissues and incubated with [(125)I]-triiodothyronine. Treatments did not alter the capacity or affinity of specific binding sites for triiodothyronine in liver or mammary nuclei. Evaluation of transcript abundance for thyroid hormone receptors showed that isoforms of thyroid hormone receptor or retinoid receptor (which may influence thyroid receptor action) expressed in the mammary gland were not altered by bST or bGRF treatment. Data do not support the hypothesis that administration of bST or bGRF alters sensitivity of mammary tissue by changing expression of thyroid hormone receptors.

  14. Thyroid stimulating hormone and cognition during severe, transient hypothyroidism.

    PubMed

    Schraml, Frank V; Goslar, Pamela W; Baxter, Leslie; Beason-Held, Lori L

    2011-01-01

    The purpose of our pilot study was to explore the relationship between serum thyroid stimulating hormone (TSH) levels during overt hypothyroidism (OH) and hypothyroid-related neuropsychological symptoms. We hypothesized that TSH level may reflect the degree of 'brain hypothyroidism' such that an inverse correlation may exist between serum TSH and cognitive function in patients experiencing overt hypothyroidism (OH), and sought to explore this hypothesis. Eleven thyroidectomized patients underwent neuropsychological and thyroid function testing while overtly hypothyroid, and again following thyroid hormone replacement. Their test performance was compared with that of eleven healthy controls at a similarly separated two points in time, and the change over time for the patient group and the controls was likewise assessed and compared. The patients' neuropsychological test scores were then correlated with their serum TSH levels while hypothyroid. The patients' performance while hypothyroid was worse than that of the controls in only one neurocognitive measure--Working Memory Index. The subjects improved similarly or to a greater degree than the controls, when the subjects were thyroid hormone replaced, on all but one neurocognitive measure - Thurstone Word Fluency. TSH level during hypothyroidism was inversely proportional to the patients' performance on these same two measures, but no others. Serum TSH level during hypothyroidism was inversely proportional to performance on the only two neurocognitive measures evidencing an adverse effect from hypothyroidism in our cohort. This suggests that serum TSH level may reflect the severity of 'brain hypothyroidism' during the overt stage of this condition.

  15. The thyroid gland and thyroid hormones in Senegalese sole (Solea senegalensis) during early development and metamorphosis.

    PubMed

    Klaren, Peter H M; Wunderink, Yvette S; Yúfera, Manuel; Mancera, Juan M; Flik, Gert

    2008-02-01

    We here describe the ontogeny and morphology of the thyroid gland in Senegalese sole (Solea senegalensis), and correlate these with whole body concentrations of thyroid hormones during early development and metamorphosis. Under our rearing conditions at 19.5 degrees C, most larvae entered metamorphosis in stage 1 at 15 days post-hatching (dph), and completed metamorphosis in stage 4 at 25dph. The onset of metamorphosis coincided with surges in whole body T4 and T3 concentrations. Crossmon's trichrome stain colored the lumen of follicular structures brightly red, and this co-localized with a T4-immunoreactivity. Thyroid follicles were first observed in stage 0 pre-metamorphic larvae at 5dph of age, and were detected exclusively in the subpharyngeal region, surrounding the ventral aorta. Increases in whole body thyroid hormone levels coincided with a 2(1/2)-fold increase in the total thyroidal colloid area in stage 1 larvae (aged 15dph) compared to stage 0 larvae (12dph). This was preceded by an approximately 40%-increase in the follicles' epithelial cell height in stage 0 larvae at 12dph compared to larvae at 5dph, and by an increase in the whole body T3/T4 ratio, indicative of an increase in outer ring deiodination. We conclude that in S. senegalensis there is a clear chronology in the activation of the thyroid gland that starts in early pre-metamorphic larvae.

  16. Thyroid Hormones and Thyroid Disease in Relation to Perchlorate Dose and Residence Near a Superfund Site

    PubMed Central

    Gold, Ellen B.; Blount, Benjamin C.; Rasor, Marianne O’Neill; Lee, Jennifer S.; Alwis, Udeni; Srivastav, Anup; Kim, Kyoungmi

    2013-01-01

    Background Perchlorate is a widely occurring contaminant, which can competitively inhibit iodide uptake and thus thyroid hormone production. The health effects of chronic low dose perchlorate exposure are largely unknown. Objectives In a community-based study, we compared thyroid function and disease in women with differing likelihoods of prior and current perchlorate exposure. Methods Residential blocks were randomly selected from areas: 1) with potential perchlorate exposure via drinking water; 2) with potential exposure to environmental contaminants; and 3) neighboring but without such exposures. Eligibility included having lived in the area for ≥6 months and aged 20–50 years during 1988–1996 (during documented drinking water well contamination). We interviewed 814 women and collected blood samples (assayed for thyroid stimulating hormone [TSH] and free thyroxine [fT4]) from 431 interviewed women. Daily urine samples were assayed for perchlorate and iodide for 178 premenopausal women with blood samples. We performed multivariable regression analyses comparing thyroid function and disease by residential area and by urinary perchlorate dose adjusted for urinary iodide levels. Results Residential location and current perchlorate dose were not associated with thyroid function or disease. Conclusions No persistent effect of perchlorate on thyroid function or disease was found several years after contaminated wells were capped. PMID:22968349

  17. Thyroid hormones and thyroid disease in relation to perchlorate dose and residence near a superfund site.

    PubMed

    Gold, Ellen B; Blount, Benjamin C; O'Neill Rasor, Marianne; Lee, Jennifer S; Alwis, Udeni; Srivastav, Anup; Kim, Kyoungmi

    2013-07-01

    Perchlorate is a widely occurring contaminant, which can competitively inhibit iodide uptake and thus thyroid hormone production. The health effects of chronic low dose perchlorate exposure are largely unknown. In a community-based study, we compared thyroid function and disease in women with differing likelihoods of prior and current perchlorate exposure. Residential blocks were randomly selected from areas: (1) with potential perchlorate exposure via drinking water; (2) with potential exposure to environmental contaminants; and (3) neighboring but without such exposures. Eligibility included having lived in the area for ≥6 months and aged 20-50 years during 1988-1996 (during documented drinking water well contamination). We interviewed 814 women and collected blood samples (assayed for thyroid stimulating hormone and free thyroxine) from 431 interviewed women. Daily urine samples were assayed for perchlorate and iodide for 178 premenopausal women with blood samples. We performed multivariable regression analyses comparing thyroid function and disease by residential area and by urinary perchlorate dose adjusted for urinary iodide levels. Residential location and current perchlorate dose were not associated with thyroid function or disease. No persistent effect of perchlorate on thyroid function or disease was found several years after contaminated wells were capped.

  18. Sleep deprivation alters thyroid hormone economy in rats.

    PubMed

    Rodrigues, Nayana Coutinho; da Cruz, Natália Santos; de Paula Nascimento, Cristine; da Conceição, Rodrigo Rodrigues; da Silva, Alba Cenélia Matos; Olivares, Emerson Lopes; Marassi, Michelle Porto

    2015-02-01

    What is the central question of this study? The relationship between the thyroid system and sleep deprivation has seldom been assessed in the literature, and mounting evidence exists that sleep disturbances influence human lifestyles. The aim of this study was to investigate the hypothalamic-pituitary-thyroid axis and thyroid hormone metabolism in sleep-deprived and sleep-restricted rats. What is the main finding and its importance? Central hypothyroidism and high thyroxine (T4 ) to 3,5,3'-triiodothyronine (T3 ) activation in brown adipose tissue were observed following sleep deprivation. Sleep-restricted rats exhibited normal thyroid-stimulating hormone and T4 concentrations despite increased circulating T3 . Sleep recovery for 24 h did not normalize the high T3 concentrations, suggesting that high T3 is a powerful counterregulatory mechanism activated following sleep deprivation. Modern life has shortened sleep time, and the consequences of sleep deprivation have been examined in both human subjects and animal models. As the relationship between thyroid function and sleep deprivation has not been fully investigated, the aim of this study was to assess the hypothalamic-pituitary-thyroid axis and thyroid hormone metabolism following paradoxical sleep deprivation (PSD) and sleep restriction (SR) in rats. The effects of a 24 h rebound period were also studied. Male Wistar rats (200-250 g, n = 10 per group) were subjected to sleep deprivation via the modified multiple platform method. Rats were assigned to the following seven groups: control, PSD for 24 or 96 h, 24 or 96 h of sleep deprivation with rebound (PSD24R and PSD96R), SR for 21 days (SR21) and SR21 with rebound (SR21R). Blood samples were collected to determine the 3,5,3'-triiodothyronine (T3 ), thyroxine (T4 ) and thyroid-stimulating hormone concentrations. Brown adipose tissue iodothyronine deiodinase type 2 (D2) activity was also evaluated. Body weight gain was dramatically reduced (by ∼50-100%) in all

  19. Glucocorticoids, thyroid hormones, and iodothyronine deiodinases in embryonic saltwater crocodiles.

    PubMed

    Shepherdley, Caroline A; Daniels, Christopher B; Orgeig, Sandra; Richardson, Samantha J; Evans, Barbara K; Darras, Veerle M

    2002-11-01

    We investigated the relationship between glucocorticoids, thyroid hormones, and outer ring and inner ring deiodinases (ORD and IRD) during embryonic development in the saltwater crocodile (Crocodylus porosus). We treated the embryos with the synthetic glucocorticoid dexamethasone (Dex), 3,3',5-triiodothyronine (T(3)), and a combination of these two hormones (Dex + T(3)). The effects of these treatments were specific in different tissues and at different stages of development and also brought about changes in plasma concentrations of free thyroid hormones and corticosterone. Administration of Dex to crocodile eggs resulted in a decrease in 3,3',5,5'-tetraiodothyronine (T(4)) ORD activities in liver and kidney microsomes, and a decrease in the high-K(m) rT(3) ORD activity in kidney microsomes, on day 60 of incubation. Dex treatment increased the T(4) ORD activity in liver microsomes, but not kidney microsomes, on day 75 of incubation. Dex administration decreased T(3) IRD activity in liver microsomes. However, this decrease did not change plasma-free T(3) concentrations, which suggests that free thyroid hormone levels are likely to be tightly regulated during development.

  20. Nanostructured sensors containing immobilized nuclear receptors for thyroid hormone detection.

    PubMed

    Bendo, Luana; Casanova, Monise; Figueira, Ana Carolina M; Polikarpov, Igor; Zucolotto, Valtencir

    2014-05-01

    Thyroid hormone receptors (TRs) are members of the nuclear receptors (NRs) superfamily, being encoded by two genes: TRa and TRbeta. In this paper, the ligand-binding domain (LBD) of the TRbeta1 isoform was immobilized on the surface of nanostructured electrodes for TR detection. The platforms containing TRbeta1-LBD were applied to the detection of specific ligand agonists, including the natural hormones T3 (triiodothyronine) and T4 (thyroxine), and the synthetic agonists TRIAC (3,5,3'-triiodothyroacetic acid) and GC-1 [3,5-dimethyl-4-(4'-hydroxy-3'-isopropylbenzyl phenoxy) acetic acid]. Detection was performed via impedance spectroscopy. The biosensors were capable of distinguishing between the thyroid hormones T3 and T4, and/or the analogues TRIAC and GC-1 at concentrations as low as 50 nM. The detection and separation of thyroid hormones and analogue ligands by impedance techniques represents an innovative tool in the field of nanomedicine because it allows the design of inexpensive devices for the rapid and real-time detection of distinct ligand/receptor systems.

  1. Thyroid hormone is required for hypothalamic neurons regulating cardiovascular functions

    PubMed Central

    Mittag, Jens; Lyons, David J.; Sällström, Johan; Vujovic, Milica; Dudazy-Gralla, Susi; Warner, Amy; Wallis, Karin; Alkemade, Anneke; Nordström, Kristina; Monyer, Hannah; Broberger, Christian; Arner, Anders; Vennström, Björn

    2012-01-01

    Thyroid hormone is well known for its profound direct effects on cardiovascular function and metabolism. Recent evidence, however, suggests that the hormone also regulates these systems indirectly through the central nervous system. While some of the molecular mechanisms underlying the hormone’s central control of metabolism have been identified, its actions in the central cardiovascular control have remained enigmatic. Here, we describe a previously unknown population of parvalbuminergic neurons in the anterior hypothalamus that requires thyroid hormone receptor signaling for proper development. Specific stereotaxic ablation of these cells in the mouse resulted in hypertension and temperature-dependent tachycardia, indicating a role in the central autonomic control of blood pressure and heart rate. Moreover, the neurons exhibited intrinsic temperature sensitivity in patch-clamping experiments, providing a new connection between cardiovascular function and core temperature. Thus, the data identify what we believe to be a novel hypothalamic cell population potentially important for understanding hypertension and indicate developmental hypothyroidism as an epigenetic risk factor for cardiovascular disorders. Furthermore, the findings may be beneficial for treatment of the recently identified patients that have a mutation in thyroid hormone receptor α1. PMID:23257356

  2. Free and total thyroid hormones in humans at extreme altitude

    NASA Astrophysics Data System (ADS)

    Basu, Minakshi; Pal, K.; Malhotra, A. S.; Prasad, R.; Sawhney, R. C.

    1995-03-01

    Alterations in circulatory levels of total T4 (TT4), total T3 (TT3), free T4 (FT4), free T3 (FT3), thyrotropin (TSH) and T3 uptake (T3U) were studied in male and female sea-level residents (SLR) at sea level, in Armed forces personnel staying at high altitude (3750 m) for prolonged duration (acclimatized lowlanders, ALL) and in high-altitude natives (HAN). Identical studies were also performed on male ALL who trekked to an extreme altitude of 5080 m and stayed at an altitude of more than 6300 m for about 6 months. The total as well as free thyroid hormones were found to be significantly higher in ALL and HAN as compared to SLR values. Both male as well as female HAN had higher levels of thyroid hormones. The rise in hormone levels in different ALL ethnic groups drawn from amongst the southern and northern parts of the country was more or less identical. In both HAN and ALL a decline in FT3 and FT4 occurred when these subjects trekked at subzero temperatures to extreme altitude of 5080 m but the levels were found to be higher in ALL who stayed at 6300 m for a prolonged duration. Plasma TSH did not show any appreciable change at lower altitudes but was found to be decreased at extreme altitude. The increase in thyroid hormones at high altitude was not due to an increase in hormone binding proteins, since T3U was found to be higher at high altitudes. A decline in TSH and hormone binding proteins and an increase in the free moiety of the hormones is indicative of a subtle degree of tissue hyperthyroidism which may be playing an important role in combating the extreme cold and hypoxic environment of high altitudes.

  3. The role of thyroid hormones in stress response of fish.

    PubMed

    Peter, M C Subhash

    2011-06-01

    Thyroxine (T(4)) and triiodothyronine (T(3)), the principal thyroid hormones (THs) secreted from the hypothalamic-pituitary-thyroid (HPT) axis, produce a plethora of physiologic actions in fish. The diverse actions of THs in fishes are primarily due to the sensitivity of thyroid axis to many physical, chemical and biological factors of both intrinsic and extrinsic origins. The regulation of THs homeostasis becomes more complex due to extrathyroidal deiodination pathways by which the delivery of biologically active T(3) to target cells has been controlled. As primary stress hormones and the end products of hypothalamic-pituitary-interrenal (HPI) and brain-sympathetic-chromaffin (BSC) axes, cortisol and adrenaline exert its actions on its target tissues where it promote and integrate osmotic and metabolic competence. Despite possessing specific osmoregulatory and metabolic actions at cellular and whole-body levels, THs may fine-tune these processes in accordance with the actions of hormones like cortisol and adrenaline. Evidences are presented that THs can modify the pattern and magnitude of stress response in fishes as it modifies either its own actions or the actions of stress hormones. In addition, multiple lines of evidence indicate that hypothalamic and pituitary hormones of thyroid and interrenal axes can interact with each other which in turn may regulate THs/cortisol-mediated actions. Even though it is hard to define these interactions, the magnitude of stress response in fish has been shown to be modified by the changes in the status of THs, pointing to its functional relationship with endocrine stress axes particularly with the interrenal axis. The fine-tuned mechanism that operates in fish during stressor-challenge drives the THs to play both fundamental and modulator roles in stress response by controlling osmoregulation and metabolic regulation. A major role of THs in stress response is thus evident in fish.

  4. Circulating thyroid stimulating hormone receptor messenger RNA and differentiated thyroid cancer: A diagnostic meta-analysis

    PubMed Central

    Kong, Chao-Yue; Li, Zhan-Ming; Wang, Li-Shun

    2017-01-01

    Thyroid stimulating hormone receptor messenger RNA (TSHR-mRNA) is over-expressed in thyroid cancer patients, which indicates that TSHR-mRNA is a potential biomarker of thyroid cancer. However, system evaluation for TSHR-mRNA as a diagnostic biomarker of thyroid cancer is deficient. The performance of TSHR-mRNA for thyroid cancer diagnosis was evaluated in this study. Three common international databases as well as a Chinese database were applied for literature researching. Quality assessment of the included literatures was conducted by the QUADAS-2 tool. Totally, 1027 patients from nine studies eligible for the meta-analysis were included in this study. Global sensitivity and specificity for the positivity of TSHR-mRNA in the thyroid cancer diagnosis is 72% and 82%. The value of AUC for this test performance was 0.84. Our meta-analysis suggests that TSHR-mRNA might be a potential biomarker to complete present diagnostic methods for early and precision diagnosis of thyroid cancer. Notably, this findings need validation thorough large-scale clinical studies. PMID:28036261

  5. Local activation and inactivation of thyroid hormones: the deiodinase family.

    PubMed

    Köhrle, J

    1999-05-25

    Tissue-specific activation and inactivation of ligands of nuclear receptors which belong to the steroid retinoid-thyroid hormone superfamily of transcription factors represents an important principle of development- and tissue-specific local modulation of hormone action. Recently, several enzyme families have been identified which act as 'guardians of the gate' of ligand-activated transcription modulation. Three monodeiodinase isoenzymes which are involved in activation the 'prohormone' L-thyroxine (T4), the main secretory product of the thyroid gland, have been identified, characterized, and cloned. Both, type I and type II 5'-deiodinase generate the thyromimetically active hormone 3,3',5-triiodothyronine (T3) by reductive deiodination of the phenolic ring of T4. Inactivation of T4 and its product T3 occurs by deiodination of iodothyronines at the tyrosyl ring. This reaction is catalyzed both the type III 5-deiodinase and also by the type I enzyme, which has a broader substrate specificity. The three deiodinases appear to constitute a newly discovered family of selenocysteine-containing proteins and the presence of selenocysteine in the protein is critical for enzyme activity. Whereas the selenoenzyme characteristics of the type I and type III deiodinases are definitively established some controversy still exists for the type II 5'-deiodinase in mammals. The mRNA probably encoding the type II 5'-deiodinase subunit is markedly longer than those of the two other deiodinases and its selenocysteine-insertion element is located more than 5 kB downstream of the UGA-codon in the 3'-untranslated region. The three deiodinase isoenzymes show a distinct development- and tissue-specific pattern of expression, operate at individual optimal substrate levels, are differently regulated and modulated by hormones, cytokines, signaling pathways, natural factors, and pharmaceuticals. Whereas circulating T3 mainly originates from hepatic production via the type I 5'-deiodinase, the

  6. Visualisation of thyroid hormone synthesis by ion imaging

    NASA Astrophysics Data System (ADS)

    Audinot, J. N.; Senou, M.; Migeon, H.-N.; Many, M.-C.

    2008-12-01

    The main function of the thyroid gland is to make hormones, T4 and T3, which are essential for the regulation of metabolic processes throughout the body. Caveolae harbour is the key enzymes involved in this iodide organification. The analyses of thyroids from normal mice and caveolin-1 Knockout mice (mice deficient in caveolin) have been performed using the SIMS imaging. In the thyroid of control mice, the epithelium is homogeneous and iodine ( 127I) is observed in the follicle lumen. In Knockout mice, we observe an accumulation of intracellular vesicles and apoptotic nuclei resulting from oxidative stress due to H 2O 2 overproduction also inducing apical lesions of the thyrocytes, at the site of iodine organification and H 2O 2 generation. We also observe in the Knockout mice an accumulation of 127I in the cellular cytoplasm and an absence of the iodine in some follicular lumina, indicating a problem at the level of iodine organification.

  7. Lamprey metamorphosis: Thyroid hormone signaling in a basal vertebrate.

    PubMed

    Manzon, Richard G; Manzon, Lori A

    2017-06-16

    As one of the most basal living vertebrates, lampreys represent an excellent model system to study the evolution of thyroid hormone (TH) signaling. The lamprey hypothalamic-pituitary-thyroid and reproductive axes overlap functionally. Lampreys have 3 gonadotropin-releasing hormones and a single glycoprotein hormone from the hypothalamus and pituitary, respectively, that regulate both the reproductive and thyroid axes. TH synthesis in larval lampreys takes place in an endostyle that transforms into typical vertebrate thyroid tissue during metamorphosis; both the endostyle and follicular tissue have all the typical TH synthetic components found in other vertebrates. Furthermore, lampreys also have the vertebrate suite of peripheral regulators including TH distributor proteins (THDPs), deiodinases and TH receptors (TRs). Although at the molecular level the components of the lamprey thyroid system are ancestral to other vertebrates, their functions have been largely conserved. TH signaling as it relates to lamprey metamorphosis represents a particularly interesting phenomenon. Unlike other metamorphosing vertebrates, lamprey THs increase throughout the larval period, peak prior to metamorphosis and decline rapidly at the onset of metamorphosis; patterns of deiodinase activity are consistent with these increases and declines. Moreover, goitrogens (which suppress TH levels) initiate precocious metamorphosis, and exogenous TH treatment blocks goitrogen-induced metamorphosis and disrupts natural metamorphosis. Despite this clear physiological difference, TH action via TRs is consistent with higher vertebrates. Based on observations that TRs are upregulated in a tissue-specific fashion during morphogenesis and the finding that lamprey TRs upregulate genes via THs in a fashion similar to higher vertebrates, we propose the following hypothesis for further testing. THs have a dual role in lampreys where high TH levels promote larval feeding and growth and then at the onset of

  8. Thyroid hormone status and pituitary function in adult rats given oral doses of perfluorooctanesulfonate (PFOS)

    EPA Science Inventory

    Perfluorooctanesulfonate (PFOS) is widely distributed and persistent in humans and wildlife. Prior toxicological studies have reported decreased total and free thyroid hormones in serum without a major compensatory rise in thyrotropin (TSH) or altered thyroid gland histology. Alt...

  9. Developmental thyroid hormone insufficiency and brain development: A role for brain-derived neurotrophic factor (BDNF)?*

    EPA Science Inventory

    Thyroid hormones (TH) are essential for normal brain development. Even subclinical hypothyroidism experienced in utero can result in neuropsychological deficits in children despite normal thyroid status at birth. Neurotrophins have been implicated in a host of brain cellular func...

  10. Thyroid hormone status and pituitary function in adult rats given oral doses of perfluorooctanesulfonate (PFOS)

    EPA Science Inventory

    Perfluorooctanesulfonate (PFOS) is widely distributed and persistent in humans and wildlife. Prior toxicological studies have reported decreased total and free thyroid hormones in serum without a major compensatory rise in thyrotropin (TSH) or altered thyroid gland histology. Alt...

  11. Developmental thyroid hormone insufficiency and brain development: A role for brain-derived neurotrophic factor (BDNF)?*

    EPA Science Inventory

    Thyroid hormones (TH) are essential for normal brain development. Even subclinical hypothyroidism experienced in utero can result in neuropsychological deficits in children despite normal thyroid status at birth. Neurotrophins have been implicated in a host of brain cellular func...

  12. Thyroid hormone availability and activity in avian species: a review.

    PubMed

    Decuypere, E; Van As, P; Van der Geyten, S; Darras, V M

    2005-07-01

    The intracellular thyroid hormone (TH) availability is influenced by different metabolic pathways. Some of the changes in intracellular TH availability can be linked to changes in local deiodination and sulfation capacities. The secretion of the chicken thyroid consists predominantly of thyroxine (T4). TH receptors (TRs) preferentially bind 3,5,3'-triiodothyronine (T3). Therefore, the metabolism of T4 secreted by the thyroid gland in peripheral tissues, resulting in the production and degradation of receptor-active T3, plays a major role in thyroid function. Food restriction in growing chickens increases hepatic type III deiodinase (D3) levels but decreases growth hormone (GH)-dependent variables such as plasma insulin-like growth factor-I (IGF-I) and T3 concentrations. Refeeding restores hepatic D3 and plasma T3 to control levels within a few hours. It can be concluded that the tissue and time dependent regulation of the balance between TH activating and inactivating enzymes plays an essential role in the control of local T3 availability and hence in TH activity. Two separate genes encode multiple TR isoforms, i.e. TRalpha and TRbeta. These TRs consist of a DNA-binding domain, a ligand-binding domain, a hinge region and an amino-terminal (A/B) domain. TRs mediate their effects on transcription by binding as homodimers or heterodimers to the TH response elements (TREs). Also, unliganded TRs can bind to TREs and may so modulate transcription of target genes.

  13. Thyroid hormone increases bulk histones expression by enhancing translational efficiency.

    PubMed

    Zambrano, Alberto; García-Carpizo, Verónica; Villamuera, Raquel; Aranda, Ana

    2015-01-01

    The expression of canonical histones is normally coupled to DNA synthesis during the S phase of the cell cycle. Replication-dependent histone mRNAs do not contain a poly(A) tail at their 3' terminus, but instead possess a stem-loop motif, the binding site for the stem-loop binding protein (SLBP), which regulates mRNA processing, stability, and relocation to polysomes. Here we show that the thyroid hormone can increase the levels of canonical histones independent of DNA replication. Incubation of mouse embryonic fibroblasts with T3 increases the total levels of histones, and expression of the thyroid hormone receptor β induces a further increase. This is not restricted to mouse embryonic fibroblasts, because T3 also raises histone expression in other cell lines. T3 does not increase histone mRNA or SLBP levels, suggesting that T3 regulates histone expression by a posttranscriptional mechanism. Indeed, T3 enhanced translational efficiency, inducing relocation of histone mRNA to heavy polysomes. Increased translation was associated with augmented transcription of the eukaryotic translation initiation factor 4 γ2 (EIF4G2). T3 induced EIF4G2 protein and mRNA levels and the thyroid hormone receptor bound to the promoter region of the Eif4g2 gene. Induction of EIF4G2 was essential for T3-dependent histone induction, because depletion of this factor abolished histone increase. These results point out the importance of the thyroid hormones on the posttranscriptional regulation of histone biosynthesis in a cell cycle-independent manner and also suggest the potential regulation of eukaryotic translation by the modulation of the initiation factor EIF4G2, which also operates in the translation of canonical mRNAs.

  14. The menace of endocrine disruptors on thyroid hormone physiology and their impact on intrauterine development.

    PubMed

    Mastorakos, George; Karoutsou, Eftychia I; Mizamtsidi, Maria; Creatsas, George

    2007-06-01

    The delivery of the appropriate thyroid hormones quantity to target tissues in euthyroidism is the result of unopposed synthesis, transport, metabolism, and excretion of these hormones. Thyroid hormones homeostasis depends on the maintenance of the circulating 'free' thyroid hormone reserves and on the development of a dynamic balance between the 'free' hormones reserves and those of the 'bound' hormones with the transport proteins. Disturbance of this hormone system, which is in constant interaction with other hormone systems, leads to an adaptational counter-response targeting to re-establish a new homeostatic equilibrium. An excessive disturbance is likely to result, however, in hypo- or hyper- thyroid clinical states. Endocrine disruptors are chemical substances forming part of 'natural' contaminating agents found in most ecosystems. There is abundant evidence that several key components of the thyroid hormones homeostasis are susceptible to the action of endocrine disruptors. These chemicals include some chlorinated organic compounds, polycyclic aromatic hydrocarbons, herbicides, and pharmaceutical agents. Intrauterine exposure to endocrine disruptors that either mimic or antagonize thyroid hormones can produce permanent developmental disorders in the structure and functioning of the brain, leading to behavioral changes. Steroid receptors are important determinants of the consequences of endocrine disruptors. Their interaction with thyroid hormones complicates the effect of endocrine disruptors. The aim of this review is to present the effect of endocrine disruptors on thyroid hormones physiology and their potential impact on intrauterine development.

  15. Coupling between Nutrient Availability and Thyroid Hormone Activation*

    PubMed Central

    Lartey, Lattoya J.; Werneck-de-Castro, João Pedro; O-Sullivan, InSug; Unterman, Terry G.; Bianco, Antonio C.

    2015-01-01

    The activity of the thyroid gland is stimulated by food availability via leptin-induced thyrotropin-releasing hormone/thyroid-stimulating hormone expression. Here we show that food availability also stimulates thyroid hormone activation by accelerating the conversion of thyroxine to triiodothyronine via type 2 deiodinase in mouse skeletal muscle and in a cell model transitioning from 0.1 to 10% FBS. The underlying mechanism is transcriptional derepression of DIO2 through the mTORC2 pathway as defined in rictor knockdown cells. In cells kept in 0.1% FBS, there is DIO2 inhibition via FOXO1 binding to the DIO2 promoter. Repression of DIO2 by FOXO1 was confirmed using its specific inhibitor AS1842856 or adenoviral infection of constitutively active FOXO1. ChIP studies indicate that 4 h after 10% FBS-containing medium, FOXO1 binding markedly decreases, and the DIO2 promoter is activated. Studies in the insulin receptor FOXO1 KO mouse indicate that insulin is a key signaling molecule in this process. We conclude that FOXO1 represses DIO2 during fasting and that derepression occurs via nutritional activation of the PI3K-mTORC2-Akt pathway. PMID:26499800

  16. Novel biological and clinical aspects of thyroid hormone metabolism.

    PubMed

    Dumitrescu, Alexandra M; Refetoff, Samuel

    2007-01-01

    Intracellular metabolism of thyroid hormone (TH) and availability of the active hormone T3 is regulated by three selenoprotein iodothyronine deiodinases (Ds). D1 and D2 convert the precursor T4 into the active hormone, T3. D3 is the principal inactivator of T4 and T3 to their respective metabolites, rT3 and T2. While acquired changes in D activities are common, inherited defects in humans were not known. Recently, two families with abnormal thyroid function tests, high serum T4, high rT3, low T3 and slightly increased TSH, were identified. Linkage analysis and sequencing excluded abnormalities in all 3 DIO genes, yet clinical studies showed reduced responsiveness to T4 but not to T3. Extensive search for putative defects in genes involved in D2 metabolism led to the identification of mutations in the Sec insertion sequence binding protein (SBP)2 gene, involved in the synthesis of selenoproteins, including Ds. Affected children were either homozygous or compound heterozygous for these mutations. Other selenoproteins, including glutathione peroxidase, were also reduced in affected subjects, confirming a generalized effect of the SBP2 defect. Opposite thyroid test abnormalities are found in mutations of the TH transporter MCT8, and appear to be caused by the resulting increases in D2 and D1 activities.

  17. Atherogenic diet induced diabetes mellitus: involvement of thyroid hormones.

    PubMed

    Parmar, Hamendra Singh; Kar, Anand

    2007-09-10

    An investigation was made to reveal the possible involvement of thyroid hormones in the progression of diabetes mellitus in response to an atherogenic diet; CCT (4% cholesterol, 1% cholic acid and 0.5% 2-thiouracil). Following the intake of CCT diet for 14 consecutive days a decrease in the serum levels of insulin, both the thyroid hormones, triiodothyronine (T(3)) and thyroxine (T(4)); hepatic glycogen content, hepatic type-1 iodothyronine 5'-mono-deiodinase (5'D) and serum alpha-amylase activities were observed, while there was an increase in the levels of serum glucose and nitrite and in lipid peroxidation of heart, liver and kidney tissues as well as in serum. However, simultaneous administration of L-thyroxine (500 microg/kg/day, s.c.) to CCT-diet fed animals resulted in the amelioration of all the aforesaid adverse changes including that of serum glucose, insulin, alpha-amylase, hepatic glycogen content and nitrite levels, suggesting the involvement of thyroid hormones in the progression of CCT-diet induced diabetes mellitus.

  18. Secretion of Parathyroid Hormone in Patients with Medullary Thyroid Carcinoma

    PubMed Central

    Deftos, Leonard J.; Parthemore, Jacqueline G.

    1974-01-01

    The secretion of parathyroid hormone (PTH) and calcitonin (CT) was studied in 30 patients with medullary thyroid carcinoma. Most patients with elevated levels of CT were normocalcemic and also had normal basal levels of PTH. Five of six patients with associated hyperparathyroidism were hypercalcemic and had elevated basal PTH levels. Hormone secretion was also studied during infusions with standard and low doses of calcium. PTH unexpectedly increased during 12 of 18 calcium infusions. Such a paradoxical increase in PTH was seen in those patients with the greatest increase in CT and the least increase in calcium during the calcium infusion. Accordingly, increases in PTH concentration during the calcium infusions could be correlated directly with increases in CT and correlated inversely with increases in calcium. These observations suggest that, in some patients with medullary thyroid carcinoma, a further increase in the abnormally elevated CT levels may stimulate PTH secretion. Therefore, at least in acute studies, there may be a functional, as well as a genetic, relationship between the secretion of these two hormones in patients with this thyroid tumor. PMID:4847251

  19. Thyroid hormone regulated genes in cerebral cortex development.

    PubMed

    Bernal, Juan

    2017-02-01

    The physiological and developmental effects of thyroid hormones are mainly due to the control of gene expression after interaction of T3 with the nuclear receptors. To understand the role of thyroid hormones on cerebral cortex development, knowledge of the genes regulated by T3 during specific stages of development is required. In our laboratory, we previously identified genes regulated by T3 in primary cerebrocortical cells in culture. By comparing these data with transcriptomics of purified cell types from the developing cortex, the cellular targets of T3 can be identified. In addition, many of the genes regulated transcriptionally by T3 have defined roles in cortex development, from which the role of T3 can be derived. This review analyzes the specific roles of T3-regulated genes in the different stages of cortex development within the physiological frame of the developmental changes of thyroid hormones and receptor concentrations in the human cerebral cortex during fetal development. These data indicate an increase in the sensitivity to T3 during the second trimester of fetal development. The main cellular targets of T3 appear to be the Cajal-Retzius and the subplate neurons. On the other hand, T3 regulates transcriptionally genes encoding extracellular matrix proteins, involved in cell migration and the control of diverse signaling pathways.

  20. Does Ventriculoperitoneal Shunting Improve Thyroid Hormone Levels in Hydrocephalic Newborns?

    PubMed

    Ucler, Necati; Erol, Fatih Serhat; Ozturk, Sait; Akgun, Bekir; Kaplan, Metin; Sen, Yasar

    2017-01-01

    The aim of this report was to investigate the effect of ventriculoperitoneal shunt insertion for the treatment of hydrocephalus on thyroid hormones in the first 3 months of life. Thyroid-stimulating hormone (TSH), free T3 (fT3), and free T4 (fT4) levels were compared at 7 days (preoperatively) and at 30 and 90 days (postoperatively) after birth between 25 ventriculoperitoneal shunt-inserted hydrocephalic newborns and 20 healthy newborns. The TSH level at 7 days was higher in the hydrocephalic patient group (6.33 µIU) compared to the control group (3.76 µIU). This value was significantly decreased at 90 days in the ventriculoperitoneal shunt-inserted newborns (2.35 µIU) compared to the control group (3.33 µIU; p < 0.05). There were no significant differences between time points for fT4 and fT3 values in the patient group or for TSH, fT4, and fT3 values in the control group. We propose that a ventriculoperitoneal shunt inserted in the early period of life may have beneficial effects on thyroid hormones. © 2016 S. Karger AG, Basel.

  1. Thyroid hormones and personality traits in attempted suicide.

    PubMed

    Sinai, Cave; Hirvikoski, Tatja; Vansvik, Eva Dencker; Nordström, Anna-Lena; Linder, Jürgen; Nordström, Peter; Jokinen, Jussi

    2009-11-01

    The research on thyroid hormones and personality traits is quite sparse and mainly focused on male forensic psychiatric populations in which the relationship between thyroid hormones and psychopathy and aggression-related personality traits has been reported. The suicidal temperament hypothesis suggests that certain personality traits such as aggression, anxiety proneness, impulsivity, and low socialization may render an individual vulnerable to the risk of suicide. The aim of this study was to investigate personality traits assessed by the Karolinska Scales of Personality (KSP) in relation to hormones in the hypothalamic-pituitary-thyroid (HPT) axis in 100 euthyroid suicide attempters. Standard multiple regression analyses were performed with TSH, T3, T4, and the T3/T4 ratio, respectively, as the dependent variable and KSP factors (Anxiety Proneness, Aggressiveness, and Impulsivity) and subscales (Detachment, Social Desirability, and Socialization) as independent variables. In men, but not in women, the regression model of the T3/T4 ratio was significant and the results suggested that high scores on Aggressiveness and low ones on Detachment were associated with a low T3/T4 ratio. These results indicate that HPT function may be related to Aggressiveness and Detachment in male suicide attempters.

  2. Quantitative Proteomics of an Amphibian Pathogen, Batrachochytrium dendrobatidis, following Exposure to Thyroid Hormone.

    PubMed

    Thekkiniath, Jose; Zabet-Moghaddam, Masoud; Kottapalli, Kameswara Rao; Pasham, Mithun R; San Francisco, Susan; San Francisco, Michael

    2015-01-01

    Batrachochytrium dendrobatidis (Bd), a chytrid fungus, has increasingly been implicated as a major factor in the worldwide decline of amphibian populations. The fungus causes chytridiomycosis in susceptible species leading to massive die-offs of adult amphibians. Although Bd infects the keratinized mouthparts of tadpoles and negatively affects foraging behavior, these infections are non-lethal. An important morphogen controlling amphibian metamorphosis is thyroid hormone (T3). Tadpoles may be infected with Bd and the fungus may be exposed to T3 during metamorphosis. We hypothesize that exposure of Bd to T3 may induce the expression of factors associated with host colonization and pathogenicity. We utilized a proteomics approach to better understand the dynamics of the Bd-T3 interaction. Using liquid chromatography-mass spectrometry (LC-MS), we generated a data set of a large number of cytoplasmic and membrane proteins following exposure of Bd to T3. From these data, we identified a total of 263 proteins whose expression was significantly changed following T3 exposure. We provide evidence for expression of an array of proteins that may play key roles in both genomic and non-genomic actions of T3 in Bd. Additionally, our proteomics study shows an increase in several proteins including proteases and a class of uncommon crinkler and crinkler-like effector proteins suggesting their importance in Bd pathogenicity as well as those involved in metabolism and energy transfer, protein fate, transport and stress responses. This approach provides insights into the mechanistic basis of the Bd-amphibian interaction following T3 exposure.

  3. Quantitative Proteomics of an Amphibian Pathogen, Batrachochytrium dendrobatidis, following Exposure to Thyroid Hormone

    PubMed Central

    Thekkiniath, Jose; Zabet-Moghaddam, Masoud; Kottapalli, Kameswara Rao; Pasham, Mithun R.; San Francisco, Susan; San Francisco, Michael

    2015-01-01

    Batrachochytrium dendrobatidis (Bd), a chytrid fungus, has increasingly been implicated as a major factor in the worldwide decline of amphibian populations. The fungus causes chytridiomycosis in susceptible species leading to massive die-offs of adult amphibians. Although Bd infects the keratinized mouthparts of tadpoles and negatively affects foraging behavior, these infections are non-lethal. An important morphogen controlling amphibian metamorphosis is thyroid hormone (T3). Tadpoles may be infected with Bd and the fungus may be exposed to T3 during metamorphosis. We hypothesize that exposure of Bd to T3 may induce the expression of factors associated with host colonization and pathogenicity. We utilized a proteomics approach to better understand the dynamics of the Bd-T3 interaction. Using liquid chromatography-mass spectrometry (LC-MS), we generated a data set of a large number of cytoplasmic and membrane proteins following exposure of Bd to T3. From these data, we identified a total of 263 proteins whose expression was significantly changed following T3 exposure. We provide evidence for expression of an array of proteins that may play key roles in both genomic and non-genomic actions of T3 in Bd. Additionally, our proteomics study shows an increase in several proteins including proteases and a class of uncommon crinkler and crinkler-like effector proteins suggesting their importance in Bd pathogenicity as well as those involved in metabolism and energy transfer, protein fate, transport and stress responses. This approach provides insights into the mechanistic basis of the Bd-amphibian interaction following T3 exposure. PMID:26046527

  4. Neither bST nor Growth Hormone Releasing Factor Alter Expression of Thyroid Hormone Receptors in Liver and Mammary Tissues

    USDA-ARS?s Scientific Manuscript database

    Physiological effects of thyroid hormones are mediated primarily by binding of triiodothyronine, to specific nuclear receptors. It has been hypothesized that organ-specific changes in production of triiodothyronine from its prohormone, thyroxine, target the action of thyroid hormones to the mammary...

  5. Evaluation of thyroid hormones in children receiving carbamazepine or valproate: a prospective study.

    PubMed

    Kafadar, İhsan; Kılıç, Betül Aydın; Arapoglu, Mujde; Yalçın, Koray; Dalgıç, Nazan

    2015-01-01

    The aim of this study was to determine the alterations in thyroid function during carbamazepine or valproate monotherapy in a prospective study. Forty patients treated with valproate, 33 patients treated with carbamazepine, and 36 control patients, all aged between 2 and 18 years, were enrolled in our study. Serum levels of thyroid hormones were measured before the beginning of the antiepileptic therapy and at 6 and 12 months of treatment. Carbamazepine-treated patients showed mean serum thyroid hormone levels significantly lower than baseline evaluation and the control group. Thyroid-stimulating hormone levels at 6 and 12 months were not significantly different in carbamazepine treated patients. Serum hormone levels did not change during valproate treatment. Thyroid-stimulating hormone levels were significantly higher at the 12th month of valproate treatment. Our data suggest that although carbamazepine causes significant alterations in thyroid hormone levels, these changes do not lead to clinical symptoms at the follow-up period of 12 months.

  6. Thyroid-stimulating hormone increases active transport of perchlorate into thyroid cells.

    PubMed

    Tran, Neil; Valentín-Blasini, Liza; Blount, Benjamin C; McCuistion, Caroline Gibbs; Fenton, Mike S; Gin, Eric; Salem, Andrew; Hershman, Jerome M

    2008-04-01

    Perchlorate blocks thyroidal iodide transport in a dose-dependent manner. The human sodium/iodide symporter (NIS) has a 30-fold higher affinity for perchlorate than for iodide. However, active transport of perchlorate into thyroid cells has not previously been demonstrated by direct measurement techniques. To demonstrate intracellular perchlorate accumulation, we incubated NIS-expressing FRTL-5 rat thyroid cells in various concentrations of perchlorate, and we used a sensitive ion chromatography tandem mass spectrometry method to measure perchlorate accumulation in the cells. Perchlorate caused a dose-related inhibition of 125-iodide uptake at 1-10 microM. The perchlorate content from cell lysate was analyzed, showing a higher amount of perchlorate in cells that were incubated in medium with higher perchlorate concentration. Thyroid-stimulating hormone increased perchlorate uptake in a dose-related manner, thus supporting the hypothesis that perchlorate is actively transported into thyroid cells. Incubation with nonradiolabeled iodide led to a dose-related reduction of intracellular accumulation of perchlorate. To determine potential toxicity of perchlorate, the cells were incubated in 1 nM to 100 microM perchlorate and cell proliferation was measured. Even the highest concentration of perchlorate (100 microM) did not inhibit cell proliferation after 72 h of incubation. In conclusion, perchlorate is actively transported into thyroid cells and does not inhibit cell proliferation.

  7. Changes in thyroid hormone concentrations during neonatal extracorporeal membrane oxygenation.

    PubMed

    Leeuwen, L; van Heijst, A F J; van Rosmalen, J; de Rijke, Y B; Beurskens, L W J E; Tibboel, D; van den Akker, E L T; IJsselstijn, H

    2017-08-01

    Thyroid hormone concentrations can be disturbed during critical illness. Our aim was to determine changes in thyroid hormone concentrations during neonatal extracorporeal membrane oxygenation (ECMO). We included 21 ECMO-treated neonates. Age-specific s.d. scores (SDS) of free and total thyroxine (FT4; TT4), reverse and total triiodothyronine (rT3; TT3), thyroid-stimulating hormone (TSH) and thyroxine-binding globulin (TBG) were determined at six fixed time-points. Data were analyzed using general linear models. At baseline, mean SDS FT4 (-0.78, 95% CI: -1.37 to -0.19), TT4 (-1.97, 95% CI: -2.76 to -1.18), TT3 (-0.88, 95% CI: -1.13 to -0.63), TSH (-2.14, 95% CI: -2.93 to -1.35) and TBG (-3.52, 95% CI: -4.55 to -2.50) were low with high mean SDS rT3 (0.53, 95% CI: 0.28 to 0.78). One hour after start ECMO, TT4, TSH and TBG had further declined; 12 h after start ECMO TT3 had declined (all P<0.05). After this decline, mean SDS TSH increased to the baseline level 12 h after start ECMO (-2.50, 95% CI: -3.22 to -1.79), and was higher than baseline 48 h after start ECMO (-0.56, 95% CI: -1.29 to 0.17). This TSH increase was followed by increases in TT4 and TT3. FT4 remained constant within the normal range during ECMO. Thyroid hormone concentrations before ECMO were suggestive of non-thyroidal illness syndrome (NTIS). During ECMO, increases in TSH, TT4 and TT3 after an initial decline possibly reflect spontaneous restoration of the hypothalamic-pituitary-thyroid axis. FT4 remained constant within the normal range. This suggests that thyroxine therapy is not required during ECMO.

  8. THYROID HORMONE INSUFFICIENCY AND BRAIN DEVELOPMENT -- DETERMINATION OF NEUROTOXICITY AT LOW LEVELS OF HORMONE DISRUPTION.

    EPA Science Inventory

    Thyroid hormone (TH) deficiencies during development produce deleterious effects on brain structure and function. The degree to which TH must be perturbed to induce neurotoxicity remains unclear. The present study was conducted as part of a Cooperative Agreement between US EPA, U...

  9. THYROID HORMONE INSUFFICIENCY AND BRAIN DEVELOPMENT -- DETERMINATION OF NEUROTOXICITY AT LOW LEVELS OF HORMONE DISRUPTION.

    EPA Science Inventory

    Thyroid hormone (TH) deficiencies during development produce deleterious effects on brain structure and function. The degree to which TH must be perturbed to induce neurotoxicity remains unclear. The present study was conducted as part of a Cooperative Agreement between US EPA, U...

  10. Thyroid function and stress hormones in children with stress hyperglycemia.

    PubMed

    Bordbar, Mohammad Reza; Taj-Aldini, Reza; Karamizadeh, Zohre; Haghpanah, Sezaneh; Karimi, Mehran; Omrani, Gholam Hossein

    2012-12-01

    The purpose of the study is to determine the prevalence of stress hyperglycemia and to investigate how thyroid and stress hormones alter during stress hyperglycemia in children admitted to pediatric emergency wards. A prospective cross-sectional study was conducted in children, less than 19 years old, who were admitted to pediatric emergency wards of Nemazee and Dastgheib Hospitals, Shiraz, Southern Iran. Those patients taking steroids, beta-agonists or intravenously administered glucose before venipuncture, and patients with diabetes mellitus (DM) or thyroid diseases were excluded. Children with blood glucose ≥ 150 mg/dL during admission were regarded as cases. The controls were age- and- sex- matched, euglycemic children. Stress hormones including cortisol, insulin, growth hormone, and prolactin were measured, and thyroid function was tested with a radioimmunoassay (RIA) method in all cases and controls. The results showed that among 1,054 screened children, 39 cases (3.7 %) had stress hyperglycemia and 89 controls were included in the study. The occurrence of hyperglycemia was independent of sex, but it occurred mostly in children under 6 years old. Hyperglycemia occurred more frequently in patients with a positive family history of DM (odds ratio = 3.2, 95 % CI = 1.3-7.9, and P = 0.009). There were no significant differences between cases and controls regarding any hormones except higher cortisol, and lower total T3 and T4 in cases compared with controls. Neither of cases developed diabetes in the 24-month follow-up period. These findings led us to the conclusion that stress hyperglycemia is occasionally seen in critically ill patients. Among the stress hormones measured, only cortisol increased during hyperglycemia. It seems that hyperglycemia is not an important risk factor for future diabetes.

  11. Effects of Perchlorate on Thyroidal Uptake of Iodide with Corresponding Hormonal Changes

    DTIC Science & Technology

    2000-07-01

    AFRL-HE-WP-TR-2000-0076 UNITED STATES AIR FORCE RESEARCH LABORATORY EFFECTS OF PERCHLORATE ON THYROIDAL UPTAKE OF IODIDE WITH CORRESPONDING HORMONAL ...on Thyroidal Uptake of Iodide with Corresponding Hormonal Contract F41624-96-C-9010 Changes PE 62202F PR 1710 6. AUTHOR(S) TA 1710D K.O. Yu, L...in reduced thyroidal hormone synthesis. The objective of this project was to conduct a series of experiments to investigate the role of perchlorate on

  12. Interdependence of thyroglobulin processing and thyroid hormone export in the mouse thyroid gland.

    PubMed

    Weber, Jonas; McInnes, Joseph; Kizilirmak, Cise; Rehders, Maren; Qatato, Maria; Wirth, Eva K; Schweizer, Ulrich; Verrey, Francois; Heuer, Heike; Brix, Klaudia

    2017-03-05

    Thyroid hormone (TH) target cells need to adopt mechanisms to maintain sufficient levels of TH to ensure regular functions. This includes thyroid epithelial cells, which generate TH in addition to being TH-responsive. However, the cellular and molecular pathways underlying thyroid auto-regulation are insufficiently understood. In order to investigate whether thyroglobulin processing and TH export are sensed by thyrocytes, we inactivated thyroglobulin-processing cathepsins and TH-exporting monocarboxylate transporters (Mct) in the mouse. The states of thyroglobulin storage and its protease-mediated processing and degradation were related to the levels of TH transporter molecules by immunoblotting and immunofluorescence microscopy. Thyroid epithelial cells of cathepsin-deficient mice showed increased Mct8 protein levels at the basolateral plasma membrane domains when compared to wild type controls. While the protein amounts of the thyroglobulin-degrading cathepsin D remained largely unaffected by Mct8 or Mct10 single-deficiencies, a significant increase in the amounts of the thyroglobulin-processing cathepsins B and L was detectable in particular in Mct8/Mct10 double deficiency. In addition, it was observed that larger endo-lysosomes containing cathepsins B, D, and L were typical for Mct8- and/or Mct10-deficient mouse thyroid epithelial cells. These data support the notion of a crosstalk between TH transporters and thyroglobulin-processing proteases in thyroid epithelial cells. We conclude that a defect in exporting thyroxine from thyroid follicles feeds back positively on its cathepsin-mediated proteolytic liberation from the precursor thyroglobulin, thereby adding to the development of auto-thyrotoxic states in Mct8 and/or Mct10 deficiencies. The data suggest TH sensing molecules within thyrocytes that contribute to thyroid auto-regulation.

  13. Deiodination of thyroid hormones by the perfused rat liver

    PubMed Central

    Hillier, A. P.

    1972-01-01

    1. An investigation has been made into the deiodination of thyroid hormones by the perfused rat liver. The hormones were labelled with 125I in the phenolic ring and the rate of deiodination was estimated by measuring the release of radio-iodide into the perfusate. 2. At tracer concentrations, 0·98% of the liver thyroxine is deiodinated/5 min. The deiodination of tri-iodothyronine is considerably faster, 3·3%/5 min. 3. Deiodination is very sensitive to changes in temperature. 4. The reaction shows saturation kinetics typical of many enzymes, the reciprocal of the rate of deiodination being proportional to the reciprocal of the hormone concentration in the tissue. The maximum rate of deiodination of each hormone is about 1·5 μg/min for a whole liver preparation weighing 16 g. 5. Tri-iodothyronine inhibits thyroxine deiodination and vice versa, suggesting that a single enzyme is responsible for both reactions. 6. Propyl thiouracil (PTU) at high concentrations inhibits the deiodination of both hormones. 7. An abnormally high rate of deiodination is associated with the actual injection of hormone into the preparation. This suggests that only the free (unbound) hormone in the tissue is directly available to the deiodinating enzyme. 8. About half of the whole body deiodination of thyroxine is relatively insensitive to PTU. It is suggested that most of this type of deiodination is performed in the liver and that the process is one of inactivation. PMID:5033472

  14. Thyroid-Stimulating Hormone Receptor Antibodies in Pregnancy: Clinical Relevance

    PubMed Central

    Bucci, Ines; Giuliani, Cesidio; Napolitano, Giorgio

    2017-01-01

    Graves’ disease is the most common cause of thyrotoxicosis in women of childbearing age. Approximately 1% of pregnant women been treated before, or are being treated during pregnancy for Graves’ hyperthyroidism. In pregnancy, as in not pregnant state, thyroid-stimulating hormone (TSH) receptor (TSHR) antibodies (TRAbs) are the pathogenetic hallmark of Graves’ disease. TRAbs are heterogeneous for molecular and functional properties and are subdivided into activating (TSAbs), blocking (TBAbs), or neutral (N-TRAbs) depending on their effect on TSHR. The typical clinical features of Graves’ disease (goiter, hyperthyroidism, ophthalmopathy, dermopathy) occur when TSAbs predominate. Graves’ disease shows some peculiarities in pregnancy. The TRAbs disturb the maternal as well as the fetal thyroid function given their ability to cross the placental barrier. The pregnancy-related immunosuppression reduces the levels of TRAbs in most cases although they persist in women with active disease as well as in women who received definitive therapy (radioiodine or surgery) before pregnancy. Changes of functional properties from stimulating to blocking the TSHR could occur during gestation. Drug therapy is the treatment of choice for hyperthyroidism during gestation. Antithyroid drugs also cross the placenta and therefore decrease both the maternal and the fetal thyroid hormone production. The management of Graves’ disease in pregnancy should be aimed at maintaining euthyroidism in the mother as well as in the fetus. Maternal and fetal thyroid dysfunction (hyperthyroidism as well as hypothyroidism) are in fact associated with several morbidities. Monitoring of the maternal thyroid function, TRAbs measurement, and fetal surveillance are the mainstay for the management of Graves’ disease in pregnancy. This review summarizes the biochemical, immunological, and therapeutic aspects of Graves’ disease in pregnancy focusing on the role of the TRAbs in maternal and fetal

  15. Arsenic impacted the development, thyroid hormone and gene transcription of thyroid hormone receptors in bighead carp larvae (Hypophthalmichthys nobilis).

    PubMed

    Sun, Hong-Jie; Xiang, Ping; Tang, Ming-Hu; Sun, Li; Ma, Lena Q

    2016-02-13

    Arsenic (As) contamination in aquatic environment adversely impacts aquatic organisms. The present study assessed the toxicity of different As species and concentrations on bighead carp (Hypophthalmichthys nobilis) at early life stage, a major fish in Yangtze River, China. We measured the changes in embryo and larvae survival rate, larvae aberration, concentrations of thyroid hormone thyroxine, and transcription levels of thyroid hormone receptors (TRs) in fish larvae after exposing to arsenite (AsIII) or arsenate (AsV) at 0, 10, 30, 50, 100, or 150 μg L(-1) for 78 h. As concentrations ≤ 150 μg L(-1) had limited effect on embryo survival rate (6-8% inhibition), but larvae survival rate decreased to 53-57% and larvae aberration rate increased to 20-24% after As exposure. Moreover, thyroxine levels elevated by 23% and 50% at 100 μg L(-1) AsIII and 150 μg L(-1) AsV. Besides, AsIII and AsV decreased the transcriptional levels of TRα by 72 and 53%, and TRβ by 91 and 81% at 150 μg L(-1) As. Our data showed that AsIII and AsV had limited effect on carp embryo survival, but they were both toxic to carp larvae, with AsIII showing more effect than AsV. As concentrations <150μg L(-1) adversely influenced the development of bighead carp larvae and disturbed their thyroid hormone homeostasis.

  16. Non-genomic aldosterone action: from the cell membrane to human physiology.

    PubMed

    Lösel, Ralf; Feuring, Martin; Wehling, Martin

    2002-12-01

    According to the traditional model, steroid hormones bind to intracellular receptors and subsequently modulate transcription and protein synthesis, thus triggering genomic events finally responsible for delayed effects. In addition, very rapid effects of steroids mainly affecting intracellular signaling have been widely recognized which are clearly incompatible with the genomic model. These rapid, non-genomic steroid actions are likely to be transmitted via specific membrane receptors. Evidences for non-genomic steroid effects and distinct receptors involved are now presented for all steroid groups including vitamin D(3) and thyroid hormones. Mechanisms of action are being studied with regard to signal perception and transduction involved, and for various steroids including aldosterone a patchy sketch of a membrane receptor/second messenger cascade shows up being not essentially dissimilar to cascades involved in catecholamine or peptide hormone action. Aside non-classical membrane receptors with a high affinity for aldosterone, these effects involve phospholipase C, phosphoinositide turnover, intracellular pH and calcium, protein kinase C and tyrosine kinases. Increasing evidence is being accumulated for rapid physiological responses in humans, e.g. at the level of circulatory or metabolic effects, rendering clinical significance to these rapid actions.

  17. Attenuation of kindling-induced decreases in NT-3 mRNA by thyroid hormone depletion.

    PubMed

    Kim, S Y; Smith, M A; Post, R M; Rosen, J B

    1998-02-01

    The expression of neurotrophins is altered by amygdala kindled seizures. Because thyroid hormone can regulate the transcription of neurotrophins, we asked whether thyroid hormone regulates neurotrophin mRNA expression following amygdala kindling. Rats with electrodes implanted in the basolateral nucleus of the amygdala were either depleted of thyroid hormone or given excess thyroid hormone. The rats were then kindled daily until they had one generalized seizure. The brains were removed 4 h after the seizure and processed for in situ hybridization of nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF) and neurotrophin-3 (NT-3) mRNAs. In non-kindled rats, thyroid hormone depletion increased the levels of BDNF mRNA in the paraventricular nucleus of the hypothalamus and the pituitary gland. NGF and NT-3 mRNA expression was not altered. In addition, thyroid hormone manipulations had no effect on kindling or on kindling-induced BDNF and NGF mRNA. However, the kindling-induced decrease in NT-3 mRNA expression in the dentate gyrus granule cell layer was significantly attenuated by thyroid hormone depletion. These effects were reversed by thyroid hormone replacement. The results indicate that thyroid hormone plays a modulatory role in the seizure-induced changes of NT-3 mRNA expression found in the dentate gyrus.

  18. Maternal thyroid hormones early in pregnancy and fetal brain development.

    PubMed

    de Escobar, Gabriella Morreale; Obregón, María Jesús; del Rey, Francisco Escobar

    2004-06-01

    During the last few decades our understanding of the possible role of thyroid hormones during brain development has increased and contributed to resolve previously discordant hypotheses, although much remains to be clarified. Thyroid hormones of maternal origin are present in the fetal compartment, despite the very efficient uterine-placental 'barrier', necessary to avoid potentially toxic concentrations of free T4 and T3 from reaching fetal tissues before they are required for development. T3 remains low throughout pregnancy, whereas FT4 in fetal fluids increases rapidly to adult levels, and is determined by the maternal availability of T4. It is present in embryonic fluids 4 weeks after conception, with FT4 steadily increasing to biologically relevant values. T3, generated from T4 in the cerebral cortex, reaches adult values by mid-gestation and is partly bound to specific nuclear receptor isoforms. Iodothyronine deioidinases are important for the spatial and temporal regulation of T3 bioavailability, tailored to the differing and changing requirements of thyroid hormone-sensitive genes in different brain structures, but other regulatory mechanism(s) are likely to be involved. Maternal transfer constitutes a major fraction of fetal serum T4, even after onset of fetal thyroid secretion, and continues to have an important protective role in fetal neurodevelopment until birth. Prompt treatment of maternal hypothyroidism, identified by increased TSH, is being advocated to mitigate a negative effect on the woman and her child. However, even a moderate transient period of maternal hypothyroxinemia at the beginning of rat neurogenesis disrupts neuronal migration into cortical layers. These findings reinforce the epidemiological evidence that early maternal hypothyroxinemia-when neuronal migratory waves are starting-is potentially damaging for the child. Detection of an inappropiate first trimester FT4 surge that may not result in increased TSH, may be crucial for the

  19. Thyroid Stimulating Hormone and Cognition during Severe, Transient Hypothyroidism

    PubMed Central

    Schraml, Frank V.; Goslar, Pamela W.; Baxter, Leslie; Beason-Held, Lori L.

    2011-01-01

    OBJECTIVE The purpose of our pilot study was to explore the relationship between serum thyroid stimulating hormone (TSH) levels during overt hypothyroidism (OH) and hypothyroid-related neuropsychological symptoms. We hypothesized that TSH level may reflect the degree of ‘brain hypothyroidism’ such that an inverse correlation may exist between serum TSH and cognitive function in patients experiencing overt hypothyroidism (OH), and sought to explore this hypothesis. METHODS Eleven thyroidectomized patients underwent neuropsychological and thyroid function testing while overtly hypothyroid, and again following thyroid hormone replacement. Their test performance was compared with that of eleven healthy controls at a similarly separated two points in time, and the change over time for the patient group and the controls was likewise assessed and compared. The patients’ neuropsychological test scores were then correlated with their serum TSH levels while hypothyroid. RESULTS The patients’ performance while hypothyroid was worse than that of the controls in only one neurocognitive measure--Working Memory Index. The subjects improved similarly or to a greater degree than the controls, when the subjects were thyroid hormone replaced, on all but one neurocognitive measure--Thurstone Word Fluency. TSH level during hypothyroidism was inversely proportional to the patients’ performance on these same two measures, but no others. CONCLUSION Serum TSH level during hypothyroidism was inversely proportional to performance on the only two neurocognitive measures evidencing an adverse effect from hypothyroidism in our cohort. This suggests that serum TSH level may reflect the severity of ‘brain hypothyroidism’ during the overt stage of this condition. PMID:21712772

  20. Developmental thyroid hormone disruption: prevalence, environmental contaminants and neurodevelopmental consequences.

    PubMed

    Gilbert, Mary E; Rovet, Joanne; Chen, Zupei; Koibuchi, Noriyuki

    2012-08-01

    Thyroid hormones (TH) are critical for growth and development and particularly brain development. There are numerous environmental agents that lead to marginal reductions of circulating TH. Although it is clear that severe developmental hypothyroidism is profoundly detrimental to neurodevelopment, there is less information regarding the consequences of modest degrees of thyroid. The impact of low level TH disruptions induced by environmental contaminants has not been defined. This paper is a synopsis from four invited speakers who presented at the 13th International Neurotoxicology Association meeting held in Xi'an, China during the summer of 2011. An overview of the role of TH in brain development and a review of human and animal data on the neurological sequelae of disruption of the thyroid axis in the pre- and early post-natal periods were presented by Mary Gilbert and Joanne Rovet. Iodine deficiency, a common cause of TH insufficiency and mental retardation in many countries, including China, was addressed by Zupei Chen. In this presentation the current incidence of iodine deficiency and neurological outcome in China and the efficacy of recently implemented iodinization programs to eliminate this cause of mental retardation were reviewed. Joanne Rovet described the impact of TH disruption during pregnancy and under conditions of congenital hypothyroidism. Children born with normal thyroid function, but who experienced TH insufficiency in the womb, display subtle cognitive impairments and abnormalities in brain imaging. Despite early detection and treatment, deficiencies also exist in children born with thyroid disorders. Different patterns of cognitive effects result from prenatal versus postnatal TH insufficiency. Mary Gilbert reported on the effects of environmental contaminants with thyroid disrupting action on brain development in animals. Results of neurophysiological, behavioral, structural and molecular alterations that accompany modest perturbations of

  1. Thyroid hormones in chronic heat exposed men

    NASA Astrophysics Data System (ADS)

    Gertner, A.; Israeli, R.; Lev, A.; Cassuto, Y.

    1983-03-01

    Previous reports have indicated that thyroid gland activity, is depressed in the heat. Total thyroxine (T4) and triiodothyronine (T3) serum levels in 17 workers of the metal work shop at a plant near the Dead Sea and 8 workers in Beer Sheva, Israel were examined. The metal workshop of the plant near the Dead Sea is part of a large chemical plant. The one in Beer Sheva is part of a large construction company. Maintenance work, as well as metal work projects are performed in both workshops. During the work shifts, the workers of the Dead Sea plant were exposed to temperatures ranging from 30 36°C (May Oct.) and 14 21°C (Dec. Feb). In Beer Sheva the range was 25 32°C (June Sept.) and 10 17°C (Dec. Feb.). Total T4 was measured by competitive protein binding and total T3 by radioimmunoassay in blood drawn before work (0700) in July and January. In summer. T4 was higher and T3 was lower for both groups than in winter. The observed summer T3 decrease may result from depressed extrathyroidal conversion of T4 to T3. We conclude that the regulation of energy metabolism in hot climates may be related to extrathyroidal conversion of T4 to T3.

  2. Thyroid hormone and dehydroepiandrosterone permit gluconeogenic hormone responses in hepatocytes.

    PubMed

    Kneer, N; Lardy, H

    2000-03-01

    The importance of the sn-glycerol- 3-phosphate (G-3-P) electron transfer shuttle in hormonal regulation of gluconeogenesis was examined in hepatocytes from rats with decreased mitochondrial G-3-P dehydrogenase activity (thyroidectomized) or increased G-3-P dehydrogenase activity [triiodothyronine (T(3)) or dehydroepiandrosterone (DHEA) treated]. Rates of glucose formation from 10 mM lactate, 10 mM pyruvate, or 2.5 mM dihydroxyacetone were somewhat less in hypothyroid cells than in cells from normal rats but gluconeogenic responses to calcium addition and to norepinephrine (NE), glucagon (G), or vasopressin (VP) were similar to the responses observed in cells from normal rats. However, with 2. 5 mM glycerol or 2.5 mM sorbitol, substrates that must be oxidized in the cytosol before conversion to glucose, basal gluconeogenesis was not appreciably altered by hypothyroidism but responses to calcium and to the calcium-mobilizing hormones were abolished. Injecting thyroidectomized rats with T(3) 2 days before preparing the hepatocytes greatly enhanced gluconeogenesis from glyc erol and restored the response to Ca(2+) and gluconeogenic hormones. Feeding dehydroepiandrosterone for 6 days depressed gluconeogenesis from lactate or pyruvate but substantially increased glucose production from glycerol in euthyroid cells and restored responses to Ca(2+) in hypothyroid cells metabolizing glycerol. Euthyroid cells metabolizing glycerol or sorbitol use the G-3-P and malate/aspartate shuttles to oxidize excess NADH generated in the cytosol. The transaminase inhibitor aminooxyacetate (AOA) decreased gluconeogenesis from glycerol 40%, but had little effect on responses to Ca(2+) and NE. However, in hypothyroid cells, with minimal G-3-P dehydrogenase, AOA decreased gluconeogenesis from glycerol more than 90%. Thus, the basal rate of gluconeogenesis from glycerol in the euthyroid cells is only partly dependent on electron transport from cytosol to mitochondria via the malate

  3. Thyroid storm due to inappropriate administration of a compounded thyroid hormone preparation successfully treated with plasmapheresis.

    PubMed

    Jha, Sujeet; Waghdhare, Swati; Reddi, Rajashekar; Bhattacharya, Priyanka

    2012-12-01

    a life-saving treatment in patients who are exposed to amounts of thyroid hormone far in excess of that usually produced by the thyroid gland.

  4. Thyroid-stimulating hormone, anti-thyroid antibodies, and pregnancy outcomes.

    PubMed

    Plowden, Torie C; Schisterman, Enrique F; Sjaarda, Lindsey A; Perkins, Neil J; Silver, Robert; Radin, Rose; Kim, Keewan; Galai, Noya; DeCherney, Alan H; Mumford, Sunni L

    2017-09-14

    Overt thyroid dysfunction has been associated with adverse obstetric outcomes. However, less is known regarding subclinical hypothyroidism or thyroid autoimmunity and their relationship to pregnancy complications. The purpose of this study was to examine the association between prepregnancy anti-thyroid antibodies and subclinical hypothyroidism and preterm delivery, gestational diabetes mellitus, and preeclampsia. We conducted a secondary analysis of a prospective cohort of 18- to 40-year-old women with 1-2 previous pregnancy losses (n=1193) who participated in a multicenter randomized, placebo-controlled trial of low-dose aspirin. Prepregnancy levels of thyroid-stimulating hormone, free thyroxine, thyroglobulin antibody, and thyroid peroxidase antibody were measured. Relative risks and 95% confidence intervals were estimated with the use of generalized linear models with adjustment for age and body mass index. Among women with an ongoing pregnancy of >20 weeks estimated gestational age, there was no association between prepregnancy thyroid-stimulating hormone level (>2.5 vs ≤2.5 mIU/L) and preterm delivery (adjusted relative risk, 0.77; 95% confidence interval, 0.40-1.47), gestational diabetes mellitus (adjusted relative risk, 1.28; 95% confidence interval, 0.54-3.04), or preeclampsia (adjusted relative risk, 1.20; 95% confidence interval, 0.71-2.04). Similarly, among women with thyroid antibodies, there was no increase in the likelihood of preterm delivery (relative risk, 1.26; 95% confidence interval, 0.65-2.45), gestational diabetes mellitus (relative risk, 1.33; 95% confidence interval, 0.51-3.49), or preeclampsia (relative risk, 1.02; 95% confidence interval, 0.54-1.92), compared with women without these antibodies. Among women with 1-2 previous pregnancy losses, subclinical hypothyroidism and thyroid autoimmunity were not associated with an increased risk of preterm delivery, gestational diabetes mellitus, or preeclampsia. These data support current

  5. Stimulation of thyroid hormone secretion by thyrotropin in beluga whales, Delphinapterus leucas.

    PubMed

    St Aubin, D J

    1987-07-01

    Bovine thyroid stimulating hormone administered to three beluga whales, Delphinapterus leucas, was effective in producing an increase in circulating levels of triiodothyronine and thyroxine. A single dose of 10 I.U. of thyroid stimulating hormone resulted in a 145% increase in triiodothyronine and a 35% increase in thyroxine after nine hours in a whale tested within two hours after capture. The response was less pronounced in an animal tested with the same does on two occasions after four and eight weeks in captivity. In the third whale, 10 I.U. of thyroid stimulating hormone given on each of three consecutive days produced a marked increase in triiodothyronine and thyroxine. The elevation of thyroxine concentration persisted for at least two days after the last injection of thyroid stimulating hormone. A subsequent decrease in thyroxine to levels below baseline signalled the suppression of endogenous thyroid stimulating hormone. This preliminary study helps to establish a protocol for testing thyroid function in cetaceans.

  6. Stimulation of thyroid hormone secretion by thyrotropin in beluga whales, Delphinapterus leucas.

    PubMed Central

    St Aubin, D J

    1987-01-01

    Bovine thyroid stimulating hormone administered to three beluga whales, Delphinapterus leucas, was effective in producing an increase in circulating levels of triiodothyronine and thyroxine. A single dose of 10 I.U. of thyroid stimulating hormone resulted in a 145% increase in triiodothyronine and a 35% increase in thyroxine after nine hours in a whale tested within two hours after capture. The response was less pronounced in an animal tested with the same does on two occasions after four and eight weeks in captivity. In the third whale, 10 I.U. of thyroid stimulating hormone given on each of three consecutive days produced a marked increase in triiodothyronine and thyroxine. The elevation of thyroxine concentration persisted for at least two days after the last injection of thyroid stimulating hormone. A subsequent decrease in thyroxine to levels below baseline signalled the suppression of endogenous thyroid stimulating hormone. This preliminary study helps to establish a protocol for testing thyroid function in cetaceans. PMID:3651900

  7. Insulin sensitivity and counter-regulatory hormones in hypothyroidism and during thyroid hormone replacement therapy.

    PubMed

    Stanická, Sona; Vondra, Karel; Pelikánová, Terezie; Vlcek, Petr; Hill, Martin; Zamrazil, Václav

    2005-01-01

    We examined insulin sensitivity and secretion, together with the levels of selected glucoregulatory hormones, in 15 female patients with severe hypothyroidism (H) and during subsequent thyroid hormone replacement therapy (HRT) using the euglycaemic hyperinsulinaemic clamp technique. Insulin action, as evaluated by glucose disposal, the insulin sensitivity index, and fasting post-hepatic insulin delivery rate were established. The basal levels of insulin, C-peptide and counter-regulatory hormones were measured in basal condition. In H, glucose disposal (p<0.01), the insulin sensitivity index (p<0.01) and post-hepatic insulin delivery rate (p<0.05) were significantly lower than during HRT. No significant changes in the levels of fasting insulin and C-peptide were observed. The levels of counter-regulatory hormones in patients with H were significantly higher than during HRT (glucagon, p<0.05; epinephrine, p<0.01; cortisol, p<0.05; growth hormone, p<0.05). In H, an inverse correlation between insulin sensitivity and insulin secretion was observed (p<0.05). Cortisol was the most important factor affecting the variability of insulin sensitivity values, regardless of thyroid function (p=0.0012). In conclusion, H altered both insulin sensitivity and the levels of selected counter-regulatory hormones. The situation was restored by HRT, as manifested not only by normalisation of insulin sensitivity, secretion and levels of glucoregulatory hormones, but also by improvement of their relationships.

  8. Melatonin in the thyroid gland: regulation by thyroid-stimulating hormone and role in thyroglobulin gene expression.

    PubMed

    Garcia-Marin, R; Fernandez-Santos, J M; Morillo-Bernal, J; Gordillo-Martinez, F; Vazquez-Roman, V; Utrilla, J C; Carrillo-Vico, A; Guerrero, J M; Martin-Lacave, I

    2015-10-01

    Melatonin is an indoleamine with multiple functions in both plant and animal species. In addition to data in literature describing many other important roles for melatonin, such as antioxidant, circadian rhythm controlling, anti-aging, antiproliferative or immunomodulatory activities, our group recently reported that thyroid C-cells synthesize melatonin and suggested a paracrine role for this molecule in the regulation of thyroid activity. To discern the role played by melatonin at thyroid level and its involvement in the hypothalamic-pituitary-thyroid axis, in the present study we have analyzed the effect of thyrotropin in the regulation of the enzymatic machinery for melatonin biosynthesis in C cells as well as the effect of melatonin in the regulation of thyroid hormone biosynthesis in thyrocytes. Our results show that the key enzymes for melatonin biosynthesis (AANAT and ASMT) are regulated by thyroid-stimulating hormone. Furthermore, exogenous melatonin increases thyroglobulin expression at mRNA and protein levels on cultured thyrocytes and this effect is not strictly mediated by the upregulation of TTF1 or, noteworthy, PAX8 transcription factors. The present data show that thyroid C-cells synthesize melatonin under thyroid-stimulating hormone control and, consistently with previous data, support the hypothesis of a paracrine role for C-cell-synthesised melatonin within the thyroid gland. Additionally, in the present study we show evidence for the involvement of melatonin in thyroid function by directly-regulating thyroglobulin gene expression in follicular cells.

  9. Alterations in TSH and Thyroid Hormones following Mobile Phone Use

    PubMed Central

    Mortavazi, Seyed; Habib, Asadollah; Ganj-Karami, Amir; Samimi-Doost, Razieh; Pour-Abedi, Atefe; Babaie, Ali

    2009-01-01

    Objectives In recent years, the widespread use of mobile phones has lead to a public debate about possible detrimental effects on human health. In spite of years of research, there is still a great controversy regarding the possibility of induction of any significant physiological effects in humans by microwave radiations emitted by mobile phones. This study aims to investigate the effects of electromagnetic fields induced by the Global System for Mobile communications (GSM) mobile phones on the Thyroid Stimulating Hormone (TSH) and thyroid hormones in humans. Methods 77 healthy university students participated in this study. The levels of T3, T4 and TSH were measured by using appropriate enzyme-linked immunosorbent assay (ELISA) kits (Human, Germany). Results The average levels of T3, T4 and TSH in students who moderately used mobile phones were 1.25±0.27 ng/ml, 7.76±1.73 µg/dl and 4.25±2.12 µu/l respectively. The levels in the students who severely used mobile phones were 1.18±0.30, 7.75±1.14 and 3.75±2.05 respectively. In non-users, the levels were 1.15±0.27, 8.42±2.72 and 2.70±1.75, respectively. The difference among the levels of TSH in these 3 groups was statistically significant (P<0.05). Conclusion As far as the study is concerned, this is the first human study to assess the associations between mobile phone use and alterations in the levels of TSH and thyroid hormones. Based on the findings, a higher than normal TSH level, low mean T4 and normal T3 concentrations in mobile users were observed. It seems that minor degrees of thyroid dysfunction with a compensatory rise in TSH may occur following excessive use of mobile phones. It may be concluded that possible deleterious effects of mobile microwaves on hypothalamic-pituitary-thyroid axis affects the levels of these hormones. PMID:22216380

  10. Adverse effects of thyroid hormone preparations and antithyroid drugs.

    PubMed

    Bartalena, L; Bogazzi, F; Martino, E

    1996-07-01

    Thyroid hormone preparations, especially thyroxine, are widely used either at replacement doses to correct hypothyroidism or at suppressive doses to abolish thyrotropin (thyroid-stimulating hormone) secretion in patients with differentiated thyroid carcinoma after total thyroidectomy or with diffuse/ nodular nontoxic goitre. In order to suppress thyrotropin secretion, it is necessary to administer slightly supraphysiological doses of thyroxine. Possible adverse effects of this therapy include cardiovascular changes (shortening of systolic time intervals, increased frequency of atrial premature beats and, possibly, left ventricular hypertrophy) and bone changes (reduced bone density and bone mass), but the risk of these adverse effects can be minimised by carefully monitoring serum free thyroxine and free liothyronine (triiodothyronine) measurements and adjusting the dosage accordingly. Thionamides [thiamazole (methimazole), carbimazole, propylthiouracil] are the most widely used antithyroid drugs. They are given for long periods of time and cause adverse effects in 3 to 5% of patients. In most cases, adverse effects are minor and transient (e.g. skin rash, itching, mild leucopenia). The most dangerous effect is agranulocytosis, which occurs in 0.1 to 0.5% of patients. This life-threatening condition can now be effectively treated by granulocyte colony-stimulating factor administration. Other major adverse effects (aplastic anaemia, thrombocytopenia, lupus erythematosus-like syndrome, vasculitis) are exceedingly rare.

  11. Targeting the thyroid gland with thyroid-stimulating hormone (TSH)-nanoliposomes.

    PubMed

    Paolino, Donatella; Cosco, Donato; Gaspari, Marco; Celano, Marilena; Wolfram, Joy; Voce, Pasquale; Puxeddu, Efisio; Filetti, Sebastiano; Celia, Christian; Ferrari, Mauro; Russo, Diego; Fresta, Massimo

    2014-08-01

    Various tissue-specific antibodies have been attached to nanoparticles to obtain targeted delivery. In particular, nanodelivery systems with selectivity for breast, prostate and cancer tissue have been developed. Here, we have developed a nanodelivery system that targets the thyroid gland. Nanoliposomes have been conjugated to the thyroid-stimulating hormone (TSH), which binds to the TSH receptor (TSHr) on the surface of thyrocytes. The results indicate that the intracellular uptake of TSH-nanoliposomes is increased in cells expressing the TSHr. The accumulation of targeted nanoliposomes in the thyroid gland following intravenous injection was 3.5-fold higher in comparison to untargeted nanoliposomes. Furthermore, TSH-nanoliposomes encapsulated with gemcitabine showed improved anticancer efficacy in vitro and in a tumor model of follicular thyroid carcinoma. This drug delivery system could be used for the treatment of a broad spectrum of thyroid diseases to reduce side effects and improve therapeutic efficacy. Copyright © 2014 The Authors. Published by Elsevier Ltd.. All rights reserved.

  12. IN VITRO METABOLISM OF THYROID HORMONES BY RECOMBINANT HUMAN UDP-GLUCORONOSYLTRANSFERASES AND SULFOTRANSFERASES

    EPA Science Inventory

    Endocrine disruptors can decrease thyroid hormone levels via the induction of hepatic uridinediphosphate-glucoronosyltransferases (UGTs) and sulfotransferases (SULTs). Due to their ability to catalyze glucuronidation and sulfation of hormones and xenobiotics, UGTs and SULTs play ...

  13. IN VITRO METABOLISM OF THYROID HORMONES BY RECOMBINANT HUMAN UDP-GLUCORONOSYLTRANSFERASES AND SULFOTRANSFERASES

    EPA Science Inventory

    Endocrine disruptors can decrease thyroid hormone levels via the induction of hepatic uridinediphosphate-glucoronosyltransferases (UGTs) and sulfotransferases (SULTs). Due to their ability to catalyze glucuronidation and sulfation of hormones and xenobiotics, UGTs and SULTs play ...

  14. Thyroid hormones in the elderly sick: "T4 euthyroidism".

    PubMed Central

    Burrows, A W; Shakespear, R A; Hesch, R D; Cooper, E; Aickin, C M; Burke, C W

    1975-01-01

    Thyroid function and serum levels of triiodothyronine (T3) and thyroxine (T4) were investigated in 79 euthyroid geriatric patients. Of the 59 inpatients and 20 outpatients 35 (59%) and 2, respectively, had low T3 levels. In contrast, 7 (12%) and 6 (30%), respectively, had raised T4 levels. Two further patients were excluded from the study because of raised levels of thyroid-stimulating hormone. Thyroxine-binding globulin was greatly increased in both groups of patients, but low serum albumin levels were present in 31 (39%). Despite these changes free T3 and T4 indices closely followed total T3 and T4 levels. The difference between the two groups of patients did not correlate with body weight, diagnostic categories, age, drug treatment, or duration of stay in hospital. PMID:811313

  15. Thyroid hormones in the elderly sick: "T4 euthyroidism".

    PubMed

    Burrows, A W; Shakespear, R A; Hesch, R D; Cooper, E; Aickin, C M; Burke, C W

    1975-11-22

    Thyroid function and serum levels of triiodothyronine (T3) and thyroxine (T4) were investigated in 79 euthyroid geriatric patients. Of the 59 inpatients and 20 outpatients 35 (59%) and 2, respectively, had low T3 levels. In contrast, 7 (12%) and 6 (30%), respectively, had raised T4 levels. Two further patients were excluded from the study because of raised levels of thyroid-stimulating hormone. Thyroxine-binding globulin was greatly increased in both groups of patients, but low serum albumin levels were present in 31 (39%). Despite these changes free T3 and T4 indices closely followed total T3 and T4 levels. The difference between the two groups of patients did not correlate with body weight, diagnostic categories, age, drug treatment, or duration of stay in hospital.

  16. Medullary thyroid carcinoma with ectopic adrenocorticotropic hormone syndrome.

    PubMed

    Choi, Hong Seok; Kim, Min Joo; Moon, Chae Ho; Yoon, Jong Ho; Ku, Ha Ra; Kang, Geon Wook; Na, Im Il; Lee, Seung-Sook; Lee, Byung-Chul; Park, Young Joo; Kim, Hong Il; Ku, Yun Hyi

    2014-03-01

    Ectopic adrenocorticotropic hormone (ACTH) syndrome is caused most frequently by a bronchial carcinoid tumor or by small cell lung cancer. Medullary thyroid carcinoma (MTC) is a rare etiology of ectopic ACTH syndrome. We describe a case of Cushing syndrome due to ectopic ACTH production from MTC in a 48-year-old male. He was diagnosed with MTC 14 years ago and underwent total thyroidectomy, cervical lymph node dissection and a series of metastasectomies. MTC was confirmed by the pathological examination of the thyroid and metastatic mediastinal lymph node tissues. Two years after his last surgery, he developed Cushingoid features, such as moon face and central obesity, accompanied by uncontrolled hypertension and new-onset diabetes. The laboratory results were compatible with ectopic ACTH syndrome. A bilateral adrenalectomy improved the clinical and laboratory findings that were associated with Cushing syndrome. This is the first confirmed case of ectopic ACTH syndrome caused by MTC in Korea.

  17. 3,5-Diiodothyronine in vivo maintains euthyroidal expression of type 2 iodothyronine deiodinase, growth hormone, and thyroid hormone receptor beta1 in the killifish.

    PubMed

    García-G, C; López-Bojorquez, L; Nuñez, J; Valverde-R, C; Orozco, A

    2007-08-01

    Until recently, 3,5-diiodothyronine (3,5-T(2)) has been considered an inactive by-product of triiodothyronine (T(3)) deiodination. However, studies from several laboratories have shown that 3,5-T(2) has specific, nongenomic effects on mitochondrial oxidative capacity and respiration rate that are distinct from those due to T(3). Nevertheless, little is known about the putative genomic effects of 3,5-T(2). We have previously shown that hyperthyroidism induced by supraphysiological doses of 3,5-T(2) inhibits hepatic iodothyronine deiodinase type 2 (D2) activity and lowers mRNA levels in the killifish in the same manner as T(3) and T(4), suggesting a pretranslational effect of 3,5-T(2) (Garcia-G C, Jeziorski MC, Valverde-R C, Orozco A. Gen Comp Endocrinol 135: 201-209, 2004). The question remains as to whether 3,5-T(2) would have effects under conditions similar to those that are physiological for T(3). To this end, intact killifish were rendered hypothyroid by administering methimazole. Groups of hypothyroid animals simultaneously received 30 nM of either T(3), reverse T(3), or 3,5-T(2). Under these conditions, we expected that, if it were bioactive, 3,5-T(2) would mimic T(3) and thus reverse the compensatory upregulation of D2 and tyroid receptor beta1 and downregulation of growth hormone that characterize hypothyroidism. Our results demonstrate that 3,5-T(2) is indeed bioactive, reversing both hepatic D2 and growth hormone responses during a hypothyroidal state. Furthermore, we observed that 3,5-T(2) and T(3) recruit two distinct populations of transcription factors to typical palindromic and DR4 thyroid hormone response elements. Taken together, these results add further evidence to support the notion that 3,5-T(2) is a bioactive iodothyronine.

  18. Thyroid Hormones, T3 and T4, in the Brain

    PubMed Central

    Schroeder, Amy C.; Privalsky, Martin L.

    2014-01-01

    Thyroid hormones (THs) are essential for fetal and post-natal nervous system development and also play an important role in the maintenance of adult brain function. Of the two major THs, T4 (3,5,3′,5′-tetraiodo-l-thyronine) is classically viewed as an pro-hormone that must be converted to T3 (3,5,3′-tri-iodo-l-thyronine) via tissue-level deiodinases for biological activity. THs primarily mediate their effects by binding to thyroid hormone receptor (TR) isoforms, predominantly TRα1 and TRβ1, which are expressed in different tissues and exhibit distinctive roles in endocrinology. Notably, the ability to respond to T4 and to T3 differs for the two TR isoforms, with TRα1 generally more responsive to T4 than TRβ1. TRα1 is also the most abundantly expressed TR isoform in the brain, encompassing 70–80% of all TR expression in this tissue. Conversion of T4 into T3 via deiodinase 2 in astrocytes has been classically viewed as critical for generating local T3 for neurons. However, deiodinase-deficient mice do not exhibit obvious defectives in brain development or function. Considering that TRα1 is well-established as the predominant isoform in brain, and that TRα1 responds to both T3 and T4, we suggest T4 may play a more active role in brain physiology than has been previously accepted. PMID:24744751

  19. Thyroid hormones, t3 and t4, in the brain.

    PubMed

    Schroeder, Amy C; Privalsky, Martin L

    2014-01-01

    Thyroid hormones (THs) are essential for fetal and post-natal nervous system development and also play an important role in the maintenance of adult brain function. Of the two major THs, T4 (3,5,3',5'-tetraiodo-l-thyronine) is classically viewed as an pro-hormone that must be converted to T3 (3,5,3'-tri-iodo-l-thyronine) via tissue-level deiodinases for biological activity. THs primarily mediate their effects by binding to thyroid hormone receptor (TR) isoforms, predominantly TRα1 and TRβ1, which are expressed in different tissues and exhibit distinctive roles in endocrinology. Notably, the ability to respond to T4 and to T3 differs for the two TR isoforms, with TRα1 generally more responsive to T4 than TRβ1. TRα1 is also the most abundantly expressed TR isoform in the brain, encompassing 70-80% of all TR expression in this tissue. Conversion of T4 into T3 via deiodinase 2 in astrocytes has been classically viewed as critical for generating local T3 for neurons. However, deiodinase-deficient mice do not exhibit obvious defectives in brain development or function. Considering that TRα1 is well-established as the predominant isoform in brain, and that TRα1 responds to both T3 and T4, we suggest T4 may play a more active role in brain physiology than has been previously accepted.

  20. Thyroid organotypic rat and human cultures used to investigate drug effects on thyroid function, hormone synthesis and release pathways

    SciTech Connect

    Vickers, Alison E.M.; Heale, Jason; Sinclair, John R.; Morris, Stephen; Rowe, Josh M.; Fisher, Robyn L.

    2012-04-01

    Drug induced thyroid effects were evaluated in organotypic models utilizing either a rat thyroid lobe or human thyroid slices to compare rodent and human response. An inhibition of thyroid peroxidase (TPO) function led to a perturbation in the expression of key genes in thyroid hormone synthesis and release pathways. The clinically used thiourea drugs, methimazole (MMI) and 6-n-propyl-2-thioruacil (PTU), were used to evaluate thyroid drug response in these models. Inhibition of TPO occurred early as shown in rat thyroid lobes (2 h) and was sustained in both rat (24–48 h) and human (24 h) with ≥ 10 μM MMI. Thyroid from rats treated with single doses of MMI (30–1000 mg/kg) exhibited sustained TPO inhibition at 48 h. The MMI in vivo thyroid concentrations were comparable to the culture concentrations (∼ 15–84 μM), thus demonstrating a close correlation between in vivo and ex vivo thyroid effects. A compensatory response to TPO inhibition was demonstrated in the rat thyroid lobe with significant up-regulation of genes involved in the pathway of thyroid hormone synthesis (Tpo, Dio1, Slc5a5, Tg, Tshr) and the megalin release pathway (Lrp2) by 24 h with MMI (≥ 10 μM) and PTU (100 μM). Similarly, thyroid from the rat in vivo study exhibited an up-regulation of Dio1, Slc5a5, Lrp2, and Tshr. In human thyroid slices, there were few gene expression changes (Slc5a5, ∼ 2-fold) and only at higher MMI concentrations (≥ 1500 μM, 24 h). Extended exposure (48 h) resulted in up-regulation of Tpo, Dio1 and Lrp2, along with Slc5a5 and Tshr. In summary, TPO was inhibited by similar MMI concentrations in rat and human tissue, however an increased sensitivity to drug treatment in rat is indicated by the up-regulation of thyroid hormone synthesis and release gene pathways at concentrations found not to affect human tissue. -- Highlights: ► Novel model of rat thyroid or human thyroid slices to evaluate pathways of injury. ► TPO inhibition by MMI or PTU altered

  1. Bisphenol A influences oestrogen- and thyroid hormone-regulated thyroid hormone receptor expression in rat cerebellar cell culture.

    PubMed

    Somogyi, Virág; Horváth, Tamás L; Tóth, István; Bartha, Tibor; Frenyó, László Vilmos; Kiss, Dávid Sándor; Jócsák, Gergely; Kerti, Annamária; Naftolin, Frederick; Zsarnovszky, Attila

    2016-12-01

    Thyroid hormones (THs) and oestrogens are crucial in the regulation of cerebellar development. TH receptors (TRs) mediate these hormone effects and are regulated by both hormone families. We reported earlier that THs and oestradiol (E2) determine TR levels in cerebellar cell culture. Here we demonstrate the effects of low concentrations (10(-10) M) of the endocrine disruptor (ED) bisphenol A (BPA) on the hormonal (THs, E2) regulation of TRα,β in rat cerebellar cell culture. Primary cerebellar cell cultures, glia-containing and glia-destroyed, were treated with BPA or a combination of BPA and E2 and/or THs. Oestrogen receptor and TH receptor mRNA and protein levels were determined by real-time qPCR and Western blot techniques. The results show that BPA alone decreases, while BPA in combination with THs and/or E2 increases TR mRNA expression. In contrast, BPA alone increased receptor protein expressions, but did not further increase them in combination with THs and/or E2. The modulatory effects of BPA were mediated by the glia; however, the degree of changes also depended on the specific hormone ligand used. The results signify the importance of the regulatory mechanisms interposed between transcription and translation and raise the possibility that BPA could act to influence nuclear hormone receptor levels independently of ligand-receptor interaction.

  2. Influx of Thyroid Hormones into Rat Liver In Vivo

    PubMed Central

    Pardridge, William M.; Mietus, Lawrence J.

    1980-01-01

    The transport of [125I]thyroxine (T4) and [125I]triiodothyronine (T3) into liver was investigated with a tissue sampling-portal vein injection technique in the anesthetized rat. The method allows the investigation of the effects of plasma proteins in human serum on the unidirectional influx of T4 or T3 into liver cells. The percent extraction of unidirectional clearance of T3 and T4 was 77±2% and 43±2%, respectively, after portal injection of a bolus of Ringer's solution. Cell membrane transport of T4 or T3 was nonsaturable because 50-μM concentrations of unlabeled hormone had no effect on transport. The addition of bovine albumin in concentrations of 1, 5, or 10 g/100 ml bound >98% of T4 or T3 in vitro, but had no significant effect on T3 or T4 transport in vivo. Conversely, 10% rabbit antisera specific for T3 or T4, completely abolished the intracellular distribution of thyroid hormone into liver. In the presence of rat serum, which contains albumin and thyroid hormone binding pre-albumin (TBPA), 18 and 81% of total plasma T4 and T3, respectively, were available for transport in vivo. The fraction of hormone available for transport in the presence of normal human serum, which contains albumin, TBPA, and thyroid hormone binding globulin (TBG) was 11% for T4 and 72% for T3. The fraction of hormone transported into liver after injection of serum obtained from pregnant or birth control pilltreated volunteers was 4% for T4 (but this was not significantly different from zero) and 54% for T3. These data suggest: (a) The mechanism by which T4 and T3 traverse the liver cell membrane is probably free diffusion. (b) Albumin-bound T4 or T3 is freely cleared by liver, ∼50% of TBG-bound T3 is transported, but little, if any, of TBPA-bound T4 or TBG-bound T4 is cleared by liver cells. (c) Although the albumin-bound fraction of T4 greatly exceeds the free (dialyzable) moiety, the two fractions are both inversely related to the existing TBA or TBG level; therefore, in vitro

  3. Improved response of growth hormone to growth hormone-releasing hormone and reversible chronic thyroiditis after hydrocortisone replacement in isolated adrenocorticotropic hormone deficiency.

    PubMed

    Inagaki, Miho; Sato, Haruhiro; Miyamoto, Yoshiyasu; Hirukawa, Takashi; Sawaya, Asako; Miyakogawa, Takayo; Tatsumi, Ryoko; Kakuta, Takatoshi

    2009-07-20

    We report a 44-year-old Japanese man who showed a reversible blunted response of growth hormone (GH) to GH-releasing hormone (GRH) stimulation test and reversible chronic thyroiditis accompanied by isolated ACTH deficiency. He was admitted to our hospital because of severe general malaise, hypotension, and hypoglycemia. He showed repeated attacks of hypoglycemia, and his serum sodium level gradually decreased. Finally, he was referred to the endocrinology division, where his adrenocorticotropic hormone (ACTH) and cortisol values were found to be low, and his GH level was slightly elevated. An increased value of thyroid stimulating hormone (TSH) and decreased values of free triidothyronine and free thyroxine were observed along with anti-thyroglobulin antibody, suggesting chronic thyroiditis. Pituitary stimulation tests revealed a blunted response of ACTH and cortisol to corticotropin-releasing hormone, and a blunted response of GH to GRH. Hydrocortisone replacement was then started, and this improved the patient's general condition. His hypothyroid state gradually ameliorated and his titer of anti-thyroglobulin antibody decreased to the normal range. Pituitary function was re-evaluated with GRH stimulation test under a maintenance dose of 20 mg/day hydrocortisone and showed a normal response of GH to GRH. It is suggested that re-evaluation of pituitary and thyroid function is useful for diagnosing isolated ACTH deficiency after starting a maintenance dose of hydrocortisone in order to avoid unnecessary replacement of thyroid hormone.

  4. Thyroid hormone regulation of hepatic lipid and carbohydrate metabolism.

    PubMed

    Sinha, Rohit A; Singh, Brijesh K; Yen, Paul M

    2014-10-01

    Thyroid hormone (TH) has important roles in regulating hepatic lipid, cholesterol, and glucose metabolism. Recent findings suggest that clinical conditions such as non-alcoholic fatty liver disease and type 2 diabetes mellitus, which are associated with dysregulated hepatic metabolism, may involve altered intracellular TH action. In addition, TH has key roles in lipophagy in lipid metabolism, mitochondrial quality control, and the regulation of metabolic genes. In this review, we discuss recent findings regarding the functions of TH in hepatic metabolism, the relationship between TH and metabolic disorders, and the potential therapeutic use of thyromimetics to treat metabolic dysfunction in the liver. Copyright © 2014 Elsevier Ltd. All rights reserved.

  5. Thyroid-pituitary interaction: Feedback regulation of thyrotropin secretion by thyroid hormones

    SciTech Connect

    Larsen, P.R.; Bleich, H.L.; Moore, M.J.

    1982-01-07

    Thyroid-hormone regulation of TSH production involves a response to plasma concentrations of T4 and T3. A substantial fraction of intracellular T3 in the pituitary derives from the conversion of T4 to T3, and recent studies indicate that this process is physiologically regulated. Changes in pituitary conversion of T4 to T3 are often the opposite of those that occur in the liver and kidney under similar circumstances. The presence of this pathway for T3 production indicates that the pituitary can respond independently to changes in plasma levels of T4 and T3; in contrast, many tissues appear to be sensitive mainly to the plasma T3 concentration. Recent studies suggest that conversion of T4 to T3 in the cerebral cortex and cerebellum is also important in providing intracellular T3 to these particular tissues. Given these results, it is not suprising that a complete definition of thyroid status requires more than the measurement of the serum concentrations of thyroid hormones. For some tissues, among them the brain and pituitary, the intracellular T3 concentrations may only partly reflect those in the serum. Recognition that the intracellular T3 concentration in each tissue may be subject to local regulation and an understanding of the importance of this process to the regulation of TSH production shoul permit a better appreciation of the limitations of radioimmunoassay serum thyroid hormone and TSH levels. These concepts also provide a physiologic rationale for the use of thyroxine for replacement in hypothyroid patients or for TSH suppression.

  6. Screening for thyroid disease in a primary care unit with a thyroid stimulating hormone assay with a low detection limit.

    PubMed Central

    Eggertsen, R.; Petersen, K.; Lundberg, P. A.; Nyström, E.; Lindstedt, G.

    1988-01-01

    In a study at a primary care centre in a predominantly rural area of Sweden the records of all patients with established thyroid disease were scrutinised and 2000 consecutive adult patients screened with an immunoenzymometric thyroid stimulating hormone assay. The aims of the study were fourfold: firstly, to assess the total burden of thyroid disease in primary care centres in Sweden; secondly, to assess the efficacy of clinical diagnosis of the disease in unselected populations of patients; thirdly, to assess the efficacy of clinical evaluation of treatment with thyroxine; and, lastly, to see whether a single analysis of the serum thyroid stimulating hormone concentration by recent methods would be enough to identify an abnormality of thyroid function. Of the roughly 17,400 adults in the study community, 111 women and 10 men were being treated for thyroid disease. Screening detected 68 patients (3.5%) not receiving thyroxine who had a serum thyroid stimulating hormone concentration of 0.20 mU/l or less, all of whom were followed up clinically. Fifty of these patients were also studied biochemically during follow up. Only nine of the 68 patients had thyroid disease (three with thyrotoxicosis requiring treatment), no evidence of the disease being found in the remainder. Sixteen patients had spontaneous hypothyroidism requiring treatment, and neither these nor three patients with thyrotoxicosis had been detected at the preceding clinical examination. Of 35 patients in whom thyroid disease was suspected clinically at screening, none had laboratory evidence of thyroid dysfunction. In this series 1.3% of all women in the study community (2.6% of all 50-59 year olds) and 0.1% of the men were being treated for thyroid disease at the primary care centre, roughly 1.0% of adults subjected to screening were found to have thyroid disease requiring treatment, and most patients with a thyroid stimulating hormone concentration of 0.20 mU/l or less did not have thyroid dysfunction

  7. Human amniotic fluid contaminants alter thyroid hormone signalling and early brain development in Xenopus embryos

    NASA Astrophysics Data System (ADS)

    Fini, Jean-Baptiste; Mughal, Bilal B.; Le Mével, Sébastien; Leemans, Michelle; Lettmann, Mélodie; Spirhanzlova, Petra; Affaticati, Pierre; Jenett, Arnim; Demeneix, Barbara A.

    2017-03-01

    Thyroid hormones are essential for normal brain development in vertebrates. In humans, abnormal maternal thyroid hormone levels during early pregnancy are associated with decreased offspring IQ and modified brain structure. As numerous environmental chemicals disrupt thyroid hormone signalling, we questioned whether exposure to ubiquitous chemicals affects thyroid hormone responses during early neurogenesis. We established a mixture of 15 common chemicals at concentrations reported in human amniotic fluid. An in vivo larval reporter (GFP) assay served to determine integrated thyroid hormone transcriptional responses. Dose-dependent effects of short-term (72 h) exposure to single chemicals and the mixture were found. qPCR on dissected brains showed significant changes in thyroid hormone-related genes including receptors, deiodinases and neural differentiation markers. Further, exposure to mixture also modified neural proliferation as well as neuron and oligodendrocyte size. Finally, exposed tadpoles showed behavioural responses with dose-dependent reductions in mobility. In conclusion, exposure to a mixture of ubiquitous chemicals at concentrations found in human amniotic fluid affect thyroid hormone-dependent transcription, gene expression, brain development and behaviour in early embryogenesis. As thyroid hormone signalling is strongly conserved across vertebrates the results suggest that ubiquitous chemical mixtures could be exerting adverse effects on foetal human brain development.

  8. Prenatal and Neonatal Thyroid Stimulating Hormone Levels and Autism Spectrum Disorders

    ERIC Educational Resources Information Center

    Yau, Vincent M.; Lutsky, Marta; Yoshida, Cathleen K.; Lasley, Bill; Kharrazi, Martin; Windham, Gayle; Gee, Nancy; Croen, Lisa A.

    2015-01-01

    Thyroid hormones are critical for normal brain development. This study examined autism spectrum disorders (ASD) and thyroid stimulating hormone (TSH) levels measured in mid-pregnancy maternal serum and infant blood after birth. Three groups of children born in Orange County, CA in 2000-2001 were identified: ASD (n = 78), developmental delay…

  9. 21 CFR 201.316 - Drugs with thyroid hormone activity for human use; required warning.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... 21 Food and Drugs 4 2012-04-01 2012-04-01 false Drugs with thyroid hormone activity for human use... AND HUMAN SERVICES (CONTINUED) DRUGS: GENERAL LABELING Specific Labeling Requirements for Specific Drug Products § 201.316 Drugs with thyroid hormone activity for human use; required warning. (a) Drugs...

  10. Human amniotic fluid contaminants alter thyroid hormone signalling and early brain development in Xenopus embryos.

    PubMed

    Fini, Jean-Baptiste; Mughal, Bilal B; Le Mével, Sébastien; Leemans, Michelle; Lettmann, Mélodie; Spirhanzlova, Petra; Affaticati, Pierre; Jenett, Arnim; Demeneix, Barbara A

    2017-03-07

    Thyroid hormones are essential for normal brain development in vertebrates. In humans, abnormal maternal thyroid hormone levels during early pregnancy are associated with decreased offspring IQ and modified brain structure. As numerous environmental chemicals disrupt thyroid hormone signalling, we questioned whether exposure to ubiquitous chemicals affects thyroid hormone responses during early neurogenesis. We established a mixture of 15 common chemicals at concentrations reported in human amniotic fluid. An in vivo larval reporter (GFP) assay served to determine integrated thyroid hormone transcriptional responses. Dose-dependent effects of short-term (72 h) exposure to single chemicals and the mixture were found. qPCR on dissected brains showed significant changes in thyroid hormone-related genes including receptors, deiodinases and neural differentiation markers. Further, exposure to mixture also modified neural proliferation as well as neuron and oligodendrocyte size. Finally, exposed tadpoles showed behavioural responses with dose-dependent reductions in mobility. In conclusion, exposure to a mixture of ubiquitous chemicals at concentrations found in human amniotic fluid affect thyroid hormone-dependent transcription, gene expression, brain development and behaviour in early embryogenesis. As thyroid hormone signalling is strongly conserved across vertebrates the results suggest that ubiquitous chemical mixtures could be exerting adverse effects on foetal human brain development.

  11. Human amniotic fluid contaminants alter thyroid hormone signalling and early brain development in Xenopus embryos

    PubMed Central

    Fini, Jean-Baptiste; Mughal, Bilal B.; Le Mével, Sébastien; Leemans, Michelle; Lettmann, Mélodie; Spirhanzlova, Petra; Affaticati, Pierre; Jenett, Arnim; Demeneix, Barbara A.

    2017-01-01

    Thyroid hormones are essential for normal brain development in vertebrates. In humans, abnormal maternal thyroid hormone levels during early pregnancy are associated with decreased offspring IQ and modified brain structure. As numerous environmental chemicals disrupt thyroid hormone signalling, we questioned whether exposure to ubiquitous chemicals affects thyroid hormone responses during early neurogenesis. We established a mixture of 15 common chemicals at concentrations reported in human amniotic fluid. An in vivo larval reporter (GFP) assay served to determine integrated thyroid hormone transcriptional responses. Dose-dependent effects of short-term (72 h) exposure to single chemicals and the mixture were found. qPCR on dissected brains showed significant changes in thyroid hormone-related genes including receptors, deiodinases and neural differentiation markers. Further, exposure to mixture also modified neural proliferation as well as neuron and oligodendrocyte size. Finally, exposed tadpoles showed behavioural responses with dose-dependent reductions in mobility. In conclusion, exposure to a mixture of ubiquitous chemicals at concentrations found in human amniotic fluid affect thyroid hormone-dependent transcription, gene expression, brain development and behaviour in early embryogenesis. As thyroid hormone signalling is strongly conserved across vertebrates the results suggest that ubiquitous chemical mixtures could be exerting adverse effects on foetal human brain development. PMID:28266608

  12. Prenatal and Neonatal Thyroid Stimulating Hormone Levels and Autism Spectrum Disorders

    ERIC Educational Resources Information Center

    Yau, Vincent M.; Lutsky, Marta; Yoshida, Cathleen K.; Lasley, Bill; Kharrazi, Martin; Windham, Gayle; Gee, Nancy; Croen, Lisa A.

    2015-01-01

    Thyroid hormones are critical for normal brain development. This study examined autism spectrum disorders (ASD) and thyroid stimulating hormone (TSH) levels measured in mid-pregnancy maternal serum and infant blood after birth. Three groups of children born in Orange County, CA in 2000-2001 were identified: ASD (n = 78), developmental delay…

  13. Alterations in thyroid hormone economy in patients with hydatidiform mole

    PubMed Central

    Galton, Valerie Anne; Ingbar, Sidney H.; Jimenez-Fonseca, Jesus; Hershman, Jerome M.

    1971-01-01

    Studies of several aspects of thyroid hormone economy have been conducted in 11 patients before and after removal of a molar pregnancy. Before evacuation of the mole, all patients demonstrated moderately to greatly elevated values for thyroidal 131I uptake, absolute iodine uptake, and serum protein-bound-131I. Values for serum PBI and serum thyroxine (T4) concentration were consistently and often greatly increased, averaging more than twice those found in normal pregnancy and three times those in normal controls. On the other hand, the maximum binding capacity of the T4-binding globulin (TBG) was variably affected, and ranged between the values found in normal controls and those found in normal pregnancy. Values for the absolute concentration of free T4 in serum were, on the average, only moderately elevated, since the proportion of free T4 was moderately low, although not as low as in normal pregnancy. Sera of patients with molar pregnancy contained high levels of thyroid stimulating activity, as assessed in the McKenzie mouse bioassay system. The stimulator displayed a more prolonged duration of action than that of TSH and did not reveal a major immunological cross-reactivity with either human or bovine TSH, differing in the latter respect from the chorionic thyrotropin of normal human placenta. Abnormalities in iodine metabolism were rapidly ameliorated after removal of the molar pregnancy, and this was associated with the disappearance from serum of the thyroid stimulator. Despite the foregoing evidence of thyroid hyperfunction and hypersecretion of T4, patients with molar pregnancy were neither goitrous nor overtly thyrotoxic. They did display, however, high values of the urinary pigment/creatinine ratio, a possible indication of the presence of a hypermetabolic state. It is concluded that in patients with molar pregnancy, thyroid function and T4 secretion are stimulated, often greatly so, by an unusual thyroid stimulator which is demonstrable in the blood and

  14. Polybrominated Diphenyl Ether (DE-71)Interferes with Thyroid Hormone Action Independent Of Effects On Circulating Levels of Thyroid Hormone in Male Rats

    EPA Science Inventory

    Polybrominated diphenyl ethers (PBDEs) are routinely found in human tissues including cord blood and breast milk. PBDEs may interfere with thyroid hormone (TH) during development, which could produce neurobehavioral deficits. An assumption in experimental and epidemiological stud...

  15. Polybrominated Diphenyl Ether (DE-71)Interferes with Thyroid Hormone Action Independent Of Effects On Circulating Levels of Thyroid Hormone in Male Rats

    EPA Science Inventory

    Polybrominated diphenyl ethers (PBDEs) are routinely found in human tissues including cord blood and breast milk. PBDEs may interfere with thyroid hormone (TH) during development, which could produce neurobehavioral deficits. An assumption in experimental and epidemiological stud...

  16. A novel thyroid stimulating hormone beta-subunit isoform in human pituitary, peripheral blood leukocytes, and thyroid.

    PubMed

    Schaefer, Jeremy S; Klein, John R

    2009-07-01

    Thyroid stimulating hormone (TSH) is produced by the anterior pituitary and is used to regulate thyroid hormone output, which in turn controls metabolic activity. Currently, the pituitary is believed to be the only source of TSH used by the thyroid. Recent studies in mice from our laboratory have identified a TSHbeta isoform that is expressed in the pituitary, in peripheral blood leukocytes (PBL), and in the thyroid. To determine whether a human TSHbeta splice variant exists that is analogous to the mouse TSHbeta splice variant, and whether the pattern of expression of the splice variant is similar to that observed in mice, PCR amplification of RNAs from pituitary, thyroid, PBL, and bone marrow was done by reverse-transcriptase PCR and quantitative realtime PCR. Human pituitary expressed a TSHbeta isoform that is analogous to the mouse TSHbeta splice variant, consisting of a 27 nucleotide portion of intron 2 and all of exon 3, coding for 71.2% of the native human TSHbeta polypeptide. Of particular interest, the TSHbeta splice variant was expressed at significantly higher levels than the native form or TSHbeta in PBL and the thyroid. The TSHalpha gene also was expressed in the pituitary, thyroid, and PBL, but not the BM, suggesting that the TSHbeta polypeptide in the thyroid and PBL may exist as a dimer with TSHalpha. These findings identify an unknown splice variant of human TSHbeta. They also have implications for immune-endocrine interactions in the thyroid and for understanding autoimmune thyroid disease from a new perspective.

  17. JNK pathway decreases thyroid hormones via TRH receptor: a novel mechanism for disturbance of thyroid hormone homeostasis by PCB153.

    PubMed

    Liu, Changjiang; Ha, Mei; Cui, Yushan; Wang, Chengmin; Yan, Maosheng; Fu, Wenjuan; Quan, Chao; Zhou, Jun; Yang, Kedi

    2012-12-08

    PCBs, widespread and well-characterized endocrine disruptors, cause the disruption of thyroid hormone (TH) homeostasis in humans and animals. In order to verify the hypotheses that MAPK pathways would play roles in disturbance of TH levels caused by PCBs, and that TH-associated receptors could function in certain MAPK pathway, Sprague-Dawley rats were dosed with PCB153 intraperitoneally (i.p.) at 0, 4, 16 and 32mg/kg for 5 consecutive days, and Nthy-ori 3-1 cells were treated with PCB153 (0, 1, 5, 10μM) for 30min. Results showed that after the treatment with PCB153, serum total thyroxine (TT4), free thyroxine (FT4), total triiodothyronine (TT3) and thyrotropin releasing hormone (TRH) were decreased, whereas free triiodothyronine (FT3) and serum thyroid stimulating hormone (TSH) were not altered. In vivo and in vitro studies indicated that JNK pathway was activated after PCB153 exposure. Moreover, TRH receptor (TRHr) level was suppressed after the activation of JNK pathway and was elevated after the inhibition of JNK pathway, but TSH receptor (TSHr) level was not affected by the status of JNK pathway though it was reduced after PCB153 treatment. The activated signs of ERK and P38 pathways were not observed in this study. Taken together, observed effects suggested that JNK pathway could decrease TH levels via TRHr, and that would be one novel mechanism of PCB153-mediated disruption of THs.

  18. Thyroid hormone signaling in energy homeostasis and energy metabolism.

    PubMed

    McAninch, Elizabeth A; Bianco, Antonio C

    2014-04-01

    The thyroid hormone (TH) plays a significant role in diverse processes related to growth, development, differentiation, and metabolism. TH signaling modulates energy expenditure through both central and peripheral pathways. At the cellular level, the TH exerts its effects after concerted mechanisms facilitate binding to the TH receptor. In the hypothalamus, signals from a range of metabolic pathways, including appetite, temperature, afferent stimuli via the autonomic nervous system, availability of energy substrates, hormones, and other biologically active molecules, converge to maintain plasma TH at the appropriate level to preserve energy homeostasis. At the tissue level, TH actions on metabolism are controlled by transmembrane transporters, deiodinases, and TH receptors. In the modern environment, humans are susceptible to an energy surplus, which has resulted in an obesity epidemic and, thus, understanding the contribution of the TH to cellular and organism metabolism is increasingly relevant.

  19. Deiodinase-mediated thyroid hormone inactivation minimizes thyroid hormone signaling in the early development of fetal skeleton

    PubMed Central

    Capelo, Luciane P.; Beber, Eduardo H.; Huang, Stephen A.; Zorn, Telma M.T.; Bianco, Antonio C.; Gouveia, Cecília H.A.

    2015-01-01

    Thyroid hormone (TH) plays a key role on post-natal bone development and metabolism, while its relevance during fetal bone development is uncertain. To study this, pregnant mice were made hypothyroid and fetuses harvested at embryonic days (E) 12.5, 14.5, 16.5 and 18.5. Despite a marked reduction in fetal tissue concentration of both T4 and T3, bone development, as assessed at the distal epiphyseal growth plate of the femur and vertebra, was largely preserved up to E16.5. Only at E18.5, the hypothyroid fetuses exhibited a reduction in femoral type I and type X collagen and osteocalcin mRNA levels, in the length and area of the proliferative and hypertrophic zones, in the number of chondrocytes per proliferative column, and in the number of hypertrophic chondrocytes, in addition to a slight delay in endochondral and intramembranous ossification. This suggests that up to E16.5, thyroid hormone signaling in bone is kept to a minimum. In fact, measuring the expression level of the activating and inactivating iodothyronine deiodinases (D2 and D3) helped understand how this is achieved. D3 mRNA was readily detected as early as E14.5 and its expression decreased markedly (~ 10-fold) at E18.5, and even more at 14 days after birth (P14). In contrast, D2 mRNA expression increased significantly by E18.5 and markedly (~2.5-fold) by P14. The reciprocal expression levels of D2 and D3 genes during early bone development along with the absence of a hypothyroidism-induced bone phenotype at this time suggest that coordinated reciprocal deiodinase expression keeps thyroid hormone signaling in bone to very low levels at this early stage of bone development. PMID:18682303

  20. Deiodinase-mediated thyroid hormone inactivation minimizes thyroid hormone signaling in the early development of fetal skeleton.

    PubMed

    Capelo, Luciane P; Beber, Eduardo H; Huang, Stephen A; Zorn, Telma M T; Bianco, Antonio C; Gouveia, Cecília H A

    2008-11-01

    Thyroid hormone (TH) plays a key role on post-natal bone development and metabolism, while its relevance during fetal bone development is uncertain. To study this, pregnant mice were made hypothyroid and fetuses harvested at embryonic days (E) 12.5, 14.5, 16.5 and 18.5. Despite a marked reduction in fetal tissue concentration of both T4 and T3, bone development, as assessed at the distal epiphyseal growth plate of the femur and vertebra, was largely preserved up to E16.5. Only at E18.5, the hypothyroid fetuses exhibited a reduction in femoral type I and type X collagen and osteocalcin mRNA levels, in the length and area of the proliferative and hypertrophic zones, in the number of chondrocytes per proliferative column, and in the number of hypertrophic chondrocytes, in addition to a slight delay in endochondral and intramembranous ossification. This suggests that up to E16.5, thyroid hormone signaling in bone is kept to a minimum. In fact, measuring the expression level of the activating and inactivating iodothyronine deiodinases (D2 and D3) helped understand how this is achieved. D3 mRNA was readily detected as early as E14.5 and its expression decreased markedly ( approximately 10-fold) at E18.5, and even more at 14 days after birth (P14). In contrast, D2 mRNA expression increased significantly by E18.5 and markedly ( approximately 2.5-fold) by P14. The reciprocal expression levels of D2 and D3 genes during early bone development along with the absence of a hypothyroidism-induced bone phenotype at this time suggest that coordinated reciprocal deiodinase expression keeps thyroid hormone signaling in bone to very low levels at this early stage of bone development.

  1. Rabbits immunized with thyroid-stimulating hormone produce autoantiidiotypic thyroid-stimulating antibodies.

    PubMed

    Beall, G N; Rapoport, B; Chopra, I J; Kruger, S R

    1985-05-01

    We immunized rabbits with thyroid-stimulating hormone (TSH) to investigate the hypothesis that such immunization could result in production of thyroid-stimulating autoantiidiotypic antibodies to anti-TSH. Thyroid-stimulating immunoglobulin (TSI) appeared in the serum of several rabbits after immunization. At 160 d, TSI equivalent to 6-18 microU TSH/1.5 mg IgG was present in two of six human (h)TSH-, two of six hTSH beta chain-, and two of the four surviving bovine (b)TSH-immunized animals. Control (human serum albumin-immunized rabbits) serum TSI was 4.3 +/- 0.4 (mean +/- SD) at this time. Antiidiotypic antibodies that could bind to monoclonal anti-hTSH were found in the sera of the bTSH-immunized rabbits. The peak TSI activity occurred 3 mo after a TSH booster immunization and declined gradually during subsequent weeks. Evidence that antiidiotypic antibodies to anti-TSH can cause thyroid stimulation strengthens the notion that such antibodies may be the cause of Graves' hyperthyroidism.

  2. Thyroid Storm Caused by a Chinese Herb Contaminated with Thyroid Hormones

    PubMed Central

    St-Onge, Maude; Vandenberghe, Hilde; Thompson, Margaret

    2015-01-01

    Patient: Male, 70 Final Diagnosis: Thyroid storm Symptoms: Atrial fibrillation • confusion • hyperthermia • tachycardia Medication: — Clinical Procedure: Intubation • cardioversion Specialty: Critical Care Medicine Objective: Adverse events of drug therapy Background: We report a case of thyroid storm caused by consuming a Chinese herb contaminated with thyroid hormones. Case Report: A 70-year-old man presented to an emergency department after 2 days of nausea, vomiting, and weakness. Three days previously, he had started taking Cordyceps powder and “Flower Man Sang Hung” as recommended by his Chinese physician. Following admission, the patient deteriorated and was eventually diagnosed with thyroid storm complicated by rapid atrial fibrillation requiring cardioversion, intubation, and intensive care admission. The analysis of the Chinese herb “Flower Man Sang Hung” was positive for levothyroxine. The patient was extubated 11 days after admission and discharged to a rehabilitation centre after 17 days of hospitalization. The Chinese medicine physician was informed of the events. Conclusions: Herbal products can be the source of illness, medication interactions, and contamination. Awareness should be raised among Chinese medicine physicians, allopathic physicians, and their patients. Clinicians should also have a low threshold of suspicion to seek laboratory analysis of suspect substances when the cause of the clinical presentation is unclear. PMID:25644333

  3. Predictors of Thyroid Hormone Initiation in Older Adults: Results From the Cardiovascular Health Study

    PubMed Central

    Somwaru, Lily L.; Arnold, Alice M.

    2011-01-01

    Background. Despite widespread use, there are no data on initiation of thyroid hormone use in older people. We report the prevalence of thyroid hormone use and predictors of thyroid hormone initiation in a population of older men and women. Methods. Thyroid hormone medication data were collected annually from 1989 to 2006 in community-dwelling individuals aged 65 years and older enrolled in the Cardiovascular Health Study (N = 5,888). Associations of age, sex, race, body mass index, education, and coronary heart disease with initiation were evaluated using discrete-time survival analysis. Results. In 1989–1990, 8.9% (95% confidence interval 8.1%–9.7%) of participants were taking a thyroid hormone preparation, increasing to 20.0% (95% confidence interval 8.2%–21.8%) over 16 years. The average initiation rate was 1% per year. The initiation rate was nonlinear with age, and those aged 85 years and older initiated thyroid hormone more than twice as frequently as those aged 65–69 years (hazard ratio = 2.34; 95% confidence interval 1.43–3.85). White women were more likely to initiate thyroid hormone than any other race and sex group. Higher body mass index was independently associated with higher risk for initiation (p = .002) as was greater education (p = .02) and prevalent coronary heart disease (p = .03). Conclusions. Thyroid hormone use is common in older people. The indications and benefits of thyroid hormone use in older individuals with the highest rate of thyroid hormone initiation—the oldest old, overweight and obese individuals, and those with coronary heart disease—should be investigated. PMID:21628677

  4. Iodothyronine deiodinases and thyroid hormone receptors regulation during flatfish (Solea senegalensis) metamorphosis.

    PubMed

    Isorna, Esther; Obregon, Maria Jesus; Calvo, Rosa Maria; Vázquez, Rosa; Pendón, Carlos; Falcón, Jack; Muñoz-Cueto, José Antonio

    2009-05-15

    Thyroid hormone-induced metamorphosis seems to represent an ancestral feature of chrordates (urochordates, cephalochordates and vertebrates), but also of nonchordate animals. Although thyroid hormones and thyroid hormone receptor profiles during metamorphosis have been analyzed in different vertebrate taxa, including fish, developmental expression and activity of type 2 (dio2, D2) and type 3 (dio3, D3) iodothyronine deiodinases, two key enzymes in anuran metamorphosis, remain unknown in any fish species. The aim of this work was to investigate the development of thyroid hormone system during the metamorphosis of a flatfish species, the Senegalese sole, focusing on the deiodinases developmental profile. We have cloned sole D2 and D3 and analyzed several parameters of thyroid hormones system in pre-, early-, middle-, and late-metamorphic larvae. Both deiodinases contain in their catalytic centers an UGA triplet encoding for a selenocystein (Sec) residue as expected. Left eye migration and rotation in body position were associated with a significant increase in both thyroid hormones and thyroid hormone receptors at the middle-late metamorphic stages. Although dio2 expression slightly increased during metamorphosis, D2 activity augmentation was much more significant. Sole dio3 expression declined only slightly, whereas the D3 activity clearly decreased at mid-late metamorphic period. This developmental profile of deiodinases sustained the rise of thyroid hormones levels observed during sole metamorphosis. No clear cut daily rhythms were observed in the parameters analyzed although it seemed that thyroid hormone system was more active during daytime, in particular at late metamorphic stages. These developmental changes point out the importance not only of thyroid hormones and their receptors but also of dio2 and dio3 in mediating flatfish metamorphosis, as it has been described in amphibians.

  5. Thyroid hormones upregulate apolipoprotein E gene expression in astrocytes

    SciTech Connect

    Roman, Corina; Fuior, Elena V.; Trusca, Violeta G.; Kardassis, Dimitris; Simionescu, Maya; Gafencu, Anca V.

    2015-12-04

    Apolipoprotein E (apoE), a protein mainly involved in lipid metabolism, is associated with several neurodegenerative disorders including Alzheimer's disease. Despite numerous attempts to elucidate apoE gene regulation in the brain, the exact mechanism is still uncovered. The mechanism of apoE gene regulation in the brain involves the proximal promoter and multienhancers ME.1 and ME.2, which evolved by gene duplication. Herein we questioned whether thyroid hormones and their nuclear receptors have a role in apoE gene regulation in astrocytes. Our data showed that thyroid hormones increase apoE gene expression in HTB14 astrocytes in a dose-dependent manner. This effect can be intermediated by the thyroid receptor β (TRβ) which is expressed in these cells. In the presence of triiodothyronine (T3) and 9-cis retinoic acid, in astrocytes transfected to overexpress TRβ and retinoid X receptor α (RXRα), apoE promoter was indirectly activated through the interaction with ME.2. To determine the location of TRβ/RXRα binding site on ME.2, we performed DNA pull down assays and found that TRβ/RXRα complex bound to the region 341–488 of ME.2. This result was confirmed by transient transfection experiments in which a series of 5′- and 3′-deletion mutants of ME.2 were used. These data support the existence of a biologically active TRβ binding site starting at 409 in ME.2. In conclusion, our data revealed that ligand-activated TRβ/RXRα heterodimers bind with high efficiency on tissue-specific distal regulatory element ME.2 and thus modulate apoE gene expression in the brain. - Highlights: • T3 induce a dose-dependent increase of apoE expression in astrocytes. • Thyroid hormones activate apoE promoter in a cell specific manner. • Ligand activated TRβ/RXRα bind on the distal regulatory element ME.2 to modulate apoE. • The binding site of TRβ/RXRα heterodimer is located at 409 bp on ME.2.

  6. Thyroid hormones changes in infants and children with metabolic acidosis.

    PubMed

    Tahirović, H F

    1991-10-01

    The influence of the acidotic state on the thyroxine (T4) peripheral metabolism was studied in two different forms of metabolic acidosis, ie infantile diarrhea and diabetic ketoacidosis. The serum concentrations of T4, free T4 (FT4), triiodothyronine (T3), reverse T3 (rT3), thyrotropin (TSH) and thyroxine-binding globulin (TBG) were measured and compared to healthy control groups. Lower T4 and T3 and higher rT3 serum concentrations were found in both tested groups of patients in relation to the control groups. In infants with severe metabolic acidosis FT4 values were lower than those observed in the control group. In addition, serum TBG levels were lower in diabetic patients as compared to control subjects. Despite the reduced serum T3 and T4 concentrations in both groups of patients, TSH concentrations, were within the normal range. Therefore, we concluded that acidosis caused either by diarrhea (not so far described) or by diabetes mellitus (well documented up to now) affects the thyroid hormones metabolism in a similar way, at least as far as the thyroid hormones blood levels are concerned.

  7. Novel insights into thyroid hormones from the study of common genetic variation.

    PubMed

    Dayan, Colin M; Panicker, Vijay

    2009-04-01

    Effects of thyroid hormones in individual tissues are determined by many factors beyond their serum levels, including local deiodination and expression and activity of thyroid hormone transporters. These effects are difficult to examine by traditional techniques, but a novel approach that exploits the existence of common genetic variants has yielded new and surprising insights. Convincing evidence indicates a role of type 1 iodothyronine deiodinase (D1) in determining the serum T(4):T(3) ratio and a role of phosphodiesterase 8B in determining TSH levels. In addition, studies of type 2 iodothyronine deiodinase (D2) variants have shown that thyroid hormones contribute to osteoarthritis and these variants influence Intelligence quotient alterations associated with iodine deficiency. Preliminary evidence suggests associations between TSH-receptor variants and fasting glucose level, D1 variants and insulin-like growth factor I production, and D2 variants and hypertension, psychological well-being and response to T(3) or T(4) treatment. Intriguingly, most of these associations are independent of serum thyroid hormone levels, which highlights the importance of local regulation of thyroid hormones in tissues. Future research might reveal novel roles for thyroid hormones in obesity, cardiovascular disease, osteoporosis and depression and could have implications for interpretation of thyroid function tests and individualization of thyroid hormone replacement therapy.

  8. Forgotten drugs: long-term prescriptions of thyroid hormones – a cross-sectional study

    PubMed Central

    Viniol, Annika; Bösner, Stefan; Baum, Erika; Donner-Banzhoff, Norbert

    2013-01-01

    Background Thyroid hormones are among the most prescribed drugs in Germany. Although iodine supply has been improving in the last decade, annual prescriptions for thyroid hormones are rising. The aim of this study was to provide prevalence of thyroid hormone prescribing and to explore reasons for thyroid hormone prescription in primary care settings. Study design A cross-sectional study. Methods Data collection took place in six general practitioner (GP) practices in Hesse, Germany. We used the records of six GP practices to estimate prevalence of thyroid hormone prescribing. All patients who received a prescription of the active ingredient levotyroxine during the preceding 3 months were mailed a study invitation. A proportion of the identified patients were interviewed. In addition, demographical data and all medical findings related to thyroid disease were recorded. Results On average, 9.2% (SD 4.6) of all patients from participating practices were taking thyroid hormones. The majority were female (82.5%). In 47.7% of the study participants, the GP’s diagnosis, according to their records, was nonexistent. In 13.6% of cases, the documentation of the diagnostic information was incomplete. While 25% of interviewed patients with high educational background initiated further diagnostic investigation, only 4.4% of the patients with lower education did so. Conclusion In the majority of patients treated with thyroid hormones, doctors had not documented the precise indication for prescription. PMID:23641158

  9. Thyroid hormones upregulate apolipoprotein E gene expression in astrocytes.

    PubMed

    Roman, Corina; Fuior, Elena V; Trusca, Violeta G; Kardassis, Dimitris; Simionescu, Maya; Gafencu, Anca V

    Apolipoprotein E (apoE), a protein mainly involved in lipid metabolism, is associated with several neurodegenerative disorders including Alzheimer's disease. Despite numerous attempts to elucidate apoE gene regulation in the brain, the exact mechanism is still uncovered. The mechanism of apoE gene regulation in the brain involves the proximal promoter and multienhancers ME.1 and ME.2, which evolved by gene duplication. Herein we questioned whether thyroid hormones and their nuclear receptors have a role in apoE gene regulation in astrocytes. Our data showed that thyroid hormones increase apoE gene expression in HTB14 astrocytes in a dose-dependent manner. This effect can be intermediated by the thyroid receptor β (TRβ) which is expressed in these cells. In the presence of triiodothyronine (T3) and 9-cis retinoic acid, in astrocytes transfected to overexpress TRβ and retinoid X receptor α (RXRα), apoE promoter was indirectly activated through the interaction with ME.2. To determine the location of TRβ/RXRα binding site on ME.2, we performed DNA pull down assays and found that TRβ/RXRα complex bound to the region 341-488 of ME.2. This result was confirmed by transient transfection experiments in which a series of 5'- and 3'-deletion mutants of ME.2 were used. These data support the existence of a biologically active TRβ binding site starting at 409 in ME.2. In conclusion, our data revealed that ligand-activated TRβ/RXRα heterodimers bind with high efficiency on tissue-specific distal regulatory element ME.2 and thus modulate apoE gene expression in the brain.

  10. Thyroid hormones and functional outcomes after ischemic stroke.

    PubMed

    O'Keefe, Lena M; Conway, Sarah E; Czap, Alexandra; Malchoff, Carl D; Benashski, Sharon; Fortunato, Gilbert; Staff, Ilene; McCullough, Louise D

    2015-01-01

    Stroke is the fifth leading cause of death and the primary cause of long-term adult disability in the United States. Increasing evidence suggests that low T3 levels immediately following acute ischemic stroke are associated with greater stroke severity, higher mortality rates, and poorer functional outcomes. Prognosis is also poor in critically ill hospitalized patients who have non-thyroidal illness syndrome (NTIS), where T3 levels are low, but TSH is normal. However, data regarding the association between TSH levels and functional outcomes are contradictory. Thus, this study investigated the role of TSH on stroke outcomes, concomitantly with T3 and T4. In this work, blood was collected from patients with radiologically confirmed acute ischemic stroke at 24±6 hours post-symptom onset and serum levels of TSH, free T3, and free T4 were measured. Stroke outcomes were measured at discharge, 3 and 12 months using the modified Rankin scale and modified Barthel Index as markers of disability. Though we found that lower levels of free T3 were associated with worse prognosis at hospital discharge, and at 3 and 12 months post-stroke, none of these outcomes held after multivariate analysis. Thus, it is likely that thyroid hormones are associated with other factors that impact stroke outcomes, such as sex, age and stroke etiology. This study found that lower levels of free T3 were associated with poorer outcomes at hospital discharge, and at 3 and 12 months post stroke, however, these associations diminished after correction for other known predictors of stroke outcome. Thyroid hormones have a complex relationship with ischemic stroke and stroke recovery, which merits further larger investigations.

  11. Neuroendocrine actions of organohalogens: thyroid hormones, arginine vasopressin, and neuroplasticity.

    PubMed

    Kodavanti, Prasada Rao S; Curras-Collazo, Margarita C

    2010-10-01

    Organohalogen compounds are global environmental pollutants. They are highly persistent, bioaccumulative, and cause adverse effects in humans and wildlife. Because of the widespread use of these organohalogens in household items and consumer products, indoor contamination may be a significant source of human exposure, especially for children. One significant concern with regard to health effects associated with exposure to organohalogens is endocrine disruption. This review focuses on PCBs and PBDEs as old and new organohalogens, respectively, and their effects on two neuroendocrine systems; thyroid hormones and the arginine vasopressin system (AVP). Regarding neuroendocrine effects of organohalogens, there is considerable information on the thyroid system as a target and evidence is now accumulating that the AVP system and associated functions are also susceptible to disruption. AVP-mediated functions such as osmoregulation, cardiovascular function as well as social behavior, sexual function and learning/memory are discussed. For both thyroid and AVP systems, the timing of exposure seems to play a major role in the outcome of adverse effects. The mechanism of organohalogen action is well understood for the thyroid system. In comparison, this aspect is understudied in the AVP system but some similarities in neural processes, shown to be targeted by these pollutants, serve as promising possibilities for study. One challenge in understanding modes of action within neuroendocrine systems is their complexity stemming, in part, from interdependent levels of organization. Further, because of the interplay between neuroendocrine and neural functions and behavior, further investigation into organohalogen-mediated effects is warranted and may yield insights with wider scope. Indeed, the current literature provides scattered evidence regarding the role of organohalogen-induced neuroendocrine disruption in the neuroplasticity related to both learning functions and brain

  12. Gene Expression as a Biomarker of Effect of Thyroid Hormone Action in Developing Brain: Relation to Serum Hormones.

    EPA Science Inventory

    Disruption of thyroid hormone (TH) homeostasis is a known effect of environmental contaminants. Although animal models of developmental TH deficiency can predict the impact of severe insults to the thyroid system, the effects of moderate TH insufficiencies have proved more diffic...

  13. Gene Expression as a Biomarker of Effect of Thyroid Hormone Action in Developing Brain: Relation to Serum Hormones.

    EPA Science Inventory

    Disruption of thyroid hormone (TH) homeostasis is a known effect of environmental contaminants. Although animal models of developmental TH deficiency can predict the impact of severe insults to the thyroid system, the effects of moderate TH insufficiencies have proved more diffic...

  14. Molecules important for thyroid hormone synthesis and action - known facts and future perspectives.

    PubMed

    Brix, Klaudia; Führer, Dagmar; Biebermann, Heike

    2011-08-03

    Thyroid hormones are of crucial importance for the functioning of nearly every organ. Remarkably, disturbances of thyroid hormone synthesis and function are among the most common endocrine disorders affecting approximately one third of the working German population. Over the last ten years our understanding of biosynthesis and functioning of these hormones has increased tremendously. This includes the identification of proteins involved in thyroid hormone biosynthesis like Thox2 and Dehal where mutations in these genes are responsible for certain degrees of hypothyroidism. One of the most important findings was the identification of a specific transporter for triiodothyronine (T3), the monocarboxylate transporter 8 (MCT8) responsible for directed transport of T3 into target cells and for export of thyroid hormones out of thyroid epithelial cells. Genetic disturbances of MCT8 in patients result in a biochemical constellation of high T3 levels in combination with low or normal TSH and thyroxine levels leading to a new syndrome of severe X-linked mental retardation. Importantly mice lacking MCT8 presented only with a mild phenotype, indicating that compensatory mechanisms exist in mice. Moreover, it has become clear that not only genomic actions of T3 exist. T3 is also capable to activate adhesion receptors and it signals via activation of PI3K and MAPK pathways. Most recently, thyroid hormone derivatives were identified, the thyronamines which are decarboxylated thyroid hormones initiating physiological actions like lowering body temperature and heart rate, thereby acting in opposite direction to the classical thyroid hormones. So far it is believed that thyronamines function via the activation of a G-protein coupled receptor, TAAR1. The objective of this review is to summarise the recent findings in thyroid hormone synthesis and action and to discuss their implications for diagnosis of thyroid disease and for treatment of patients.

  15. Novel chimeric thyroid-stimulating hormone-receptor bioassay for thyroid-stimulating immunoglobulins

    PubMed Central

    Lytton, S D; Li, Y; Olivo, P D; Kohn, L D; Kahaly, G J

    2010-01-01

    Thyroid-stimulating immunoglobulins (TSI) are a functional biomarker of Graves' disease (GD). To develop a novel TSI bioassay, a cell line (MC4-CHO-Luc) was bio-engineered to constitutively express a chimeric TSH receptor (TSHR) and constructed with a cyclic adenosine monophosphate (cAMP)-dependent luciferase reporter gene that enables TSI quantification. Data presented as percentage of specimen-to-reference ratio (SRR%) were obtained from 271 patients with various autoimmune and thyroid diseases and 180 controls. Sensitivity of 96% and specificity of 99% for untreated GD were attained by receiver operating characteristic analysis, area under the curve 0·989, 95% confidence interval 0·969–0·999, P = 0·0001. Precision testing of manufactured reagents of high, medium, low and negative SRR% gave a percentage of coefficient-of-variation of 11·5%, 12·8%, 14·5% and 15·7%, respectively. There was no observed interference by haemoglobin, lipids and bilirubin and no non-specific stimulation by various hormones at and above physiological concentrations. TSI levels from GD patients without (SRR% 406 ± 134, mean ± standard deviation) or under anti-thyroid treatment (173 ± 147) were higher (P < 0·0001) compared with TSI levels of patients with Hashimoto's thyroiditis (51 ± 37), autoimmune diseases without GD (24 ± 10), thyroid nodules (30 ± 26) and controls (35 ± 18). The bioassay showed greater sensitivity when compared with anti-TSHR binding assays. In conclusion, the TSI-Mc4 bioassay measures the functional biomarker accurately in GD with a standardized protocol and could improve substantially the diagnosis of autoimmune diseases involving TSHR autoantibodies. PMID:21070207

  16. Prevalence and clinical relevance of thyroid stimulating hormone receptor-blocking antibodies in autoimmune thyroid disease.

    PubMed

    Diana, T; Krause, J; Olivo, P D; König, J; Kanitz, M; Decallonne, B; Kahaly, G J

    2017-09-01

    The prevalence and clinical relevance of thyroid stimulating hormone (TSH) receptor (TSHR) blocking antibodies (TBAb) in patients with autoimmune thyroid disease (AITD) was investigated. Serum TBAb were measured with a reporter gene bioassay using Chinese hamster ovary cells. Blocking activity was defined as percentage inhibition of luciferase expression relative to induction with bovine TSH alone (cut-off 40% inhibition). All samples were measured for TSHR stimulatory antibody (TSAb) and TSHR binding inhibiting immunoglobulins (TBII). A total of 1079 unselected, consecutive patients with AITD and 302 healthy controls were included. All unselected controls were negative for TBAb and TSAb. In contrast, the prevalence of TBAb-positive patients with Hashimoto's thyroiditis and Graves' disease was 67 of 722 (9·3%) and 15 of 357 (4·2%). Of the 82 TBAb-positive patients, thirty-nine (48%), 33 (40%) and 10 (12%) were hypothyroid, euthyroid and hyperthyroid, respectively. Ten patients were both TBAb- and TSAb-positive (four hypothyroid, two euthyroid and four hyperthyroid). Thyroid-associated orbitopathy was present in four of 82 (4·9%) TBAb-positive patients, with dual TSHR antibody positivity being observed in three. TBAb correlated positively with TBII (r = 0·67, P < 0·001) and negatively with TSAb (r = -0·86, P < 0·05). The percentage of TBII-positive patients was higher the higher the level of inhibition in the TBAb assay. Of the TBAb-positive samples with  > 70% inhibition, 87% were TBII-positive. Functional TSHR antibodies impact thyroid status. TBAb determination is helpful in the evaluation and management of patients with AITD. The TBAb assay is a relevant and important tool to identify potentially reversible hypothyroidism. © 2017 British Society for Immunology.

  17. Chemistry and Biology in the Biosynthesis and Action of Thyroid Hormones.

    PubMed

    Mondal, Santanu; Raja, Karuppusamy; Schweizer, Ulrich; Mugesh, Govindasamy

    2016-06-27

    Thyroid hormones (THs) are secreted by the thyroid gland. They control lipid, carbohydrate, and protein metabolism, heart rate, neural development, as well as cardiovascular, renal, and brain functions. The thyroid gland mainly produces l-thyroxine (T4) as a prohormone, and 5'-deiodination of T4 by iodothyronine deiodinases generates the nuclear receptor binding hormone T3. In this Review, we discuss the basic aspects of the chemistry and biology as well as recent advances in the biosynthesis of THs in the thyroid gland, plasma transport, and internalization of THs in their target organs, in addition to the deiodination and various other enzyme-mediated metabolic pathways of THs. We also discuss thyroid hormone receptors and their mechanism of action to regulate gene expression, as well as various thyroid-related disorders and the available treatments. © 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  18. Identification of thyroid hormone response elements in vivo using mice expressing a tagged thyroid hormone receptor α1.

    PubMed

    Dudazy-Gralla, Susi; Nordström, Kristina; Hofmann, Peter Josef; Meseh, Dina Abdul; Schomburg, Lutz; Vennström, Björn; Mittag, Jens

    2013-03-13

    TRα1 (thyroid hormone receptor α1) is well recognized for its importance in brain development. However, due to the difficulties in predicting TREs (thyroid hormone response elements) in silico and the lack of suitable antibodies against TRα1 for ChIP (chromatin immunoprecipitation), only a few direct TRα1 target genes have been identified in the brain. Here we demonstrate that mice expressing a TRα1-GFP (green fluorescent protein) fusion protein from the endogenous TRα locus provide a valuable animal model to identify TRα1 target genes. To this end, we analysed DNA-TRα1 interactions in vivo using ChIP with an anti-GFP antibody. We validated our system using established TREs from neurogranin and hairless, and by verifying additional TREs from known TRα1 target genes in brain and heart. Moreover, our model system enabled the identification of novel TRα1 target genes such as RNF166 (ring finger protein 166). Our results demonstrate that transgenic mice expressing a tagged nuclear receptor constitute a feasible approach to study receptor-DNA interactions in vivo, circumventing the need for specific antibodies. Models like the TRα1-GFP mice may thus pave the way for genome-wide mapping of nuclear receptor-binding sites, and advance the identification of novel target genes in vivo.

  19. Identification of thyroid hormone response elements in vivo using mice expressing a tagged thyroid hormone receptor α1

    PubMed Central

    Dudazy-Gralla, Susi; Nordström, Kristina; Hofmann, Peter Josef; Meseh, Dina Abdul; Schomburg, Lutz; Vennström, Björn; Mittag, Jens

    2013-01-01

    TRα1 (thyroid hormone receptor α1) is well recognized for its importance in brain development. However, due to the difficulties in predicting TREs (thyroid hormone response elements) in silico and the lack of suitable antibodies against TRα1 for ChIP (chromatin immunoprecipitation), only a few direct TRα1 target genes have been identified in the brain. Here we demonstrate that mice expressing a TRα1–GFP (green fluorescent protein) fusion protein from the endogenous TRα locus provide a valuable animal model to identify TRα1 target genes. To this end, we analysed DNA–TRα1 interactions in vivo using ChIP with an anti-GFP antibody. We validated our system using established TREs from neurogranin and hairless, and by verifying additional TREs from known TRα1 target genes in brain and heart. Moreover, our model system enabled the identification of novel TRα1 target genes such as RNF166 (ring finger protein 166). Our results demonstrate that transgenic mice expressing a tagged nuclear receptor constitute a feasible approach to study receptor–DNA interactions in vivo, circumventing the need for specific antibodies. Models like the TRα1–GFP mice may thus pave the way for genome-wide mapping of nuclear receptor-binding sites, and advance the identification of novel target genes in vivo. PMID:23398480

  20. Recessive resistance to thyroid hormone in mice lacking thyroid hormone receptor beta: evidence for tissue-specific modulation of receptor function.

    PubMed Central

    Forrest, D; Hanebuth, E; Smeyne, R J; Everds, N; Stewart, C L; Wehner, J M; Curran, T

    1996-01-01

    The diverse functions of thyroid hormone (T3) are presumed to be mediated by two genes encoding the related receptors, TRalpha and TRbeta. However, the in vivo functions of TRalpha and TRbeta are undefined. Here, we report that targeted inactivation of the mouse TRbeta gene results in goitre and elevated levels of thyroid hormone. Also, thyroid-stimulating hormone (TSH), which is released by pituitary thyrotropes and which is normally suppressed by increased levels of thyroid hormone, was present at elevated levels in homozygous mutant (Thrb-/-) mice. These findings suggest a unique role for TRbeta that cannot be substituted by TRalpha in the T3-dependent feedback regulation of TSH transcription. Thrb-/- mice provide a recessive model for the human syndrome of resistance to thyroid hormone (RTH) that exhibits a similar endocrine disorder but which is typically caused by dominant TRbeta mutants that are transcriptional inhibitors. It is unknown whether TRalpha, TRbeta or other receptors are targets for inhibition in dominant RTH; however, the analysis of Thrb-/- mice suggests that antagonism of TRbeta-mediated pathways underlies the disorder of the pituitary-thyroid axis. Interestingly, in the brain, the absence of TRbeta may not mimic the defects often associated with dominant RTH, since no overt behavioural or neuroanatomical abnormalities were detected in Thrb-/- mice. These data define in vivo functions for TRbeta and indicate that specificity in T3 signalling is conferred by distinct receptor genes. Images PMID:8670802

  1. Characterization of a thyroid hormone receptor expressed in human kidney and other tissues

    SciTech Connect

    Nakai, A.; Seino, S.; Sakurai, A.; Szilak, I.; Bell, G.I.; DeGroot, L.J.

    1988-04-01

    A cDNA encoding a specific form of thyroid hormone receptor expressed in human liver, kidney, placenta, and brain was isolated from a human kidney library. Identical clones were found in human placenta and HepG2 cDNA libraries. The cDNA encodes a 490-amino acid protein. When expressed and translated in vitro, the protein products binds triiodothyronine with K/sub a/ of 2.3 /times/ 10/sup 9/ M/sup /minus/1/. This protein, designated human thyroid hormone receptor type ..cap alpha..2 (hTR..cap alpha..2), has the same domain structure as other members of the v-erbA-related superfamily of receptor genes. It is similar to thyroid hormone receptor type ..cap alpha.. described in chicken and rat and less similar to human thyroid hormone receptor type ..beta.. (formerly referred to as c-erbA..beta..) from placenta. However, it is distinguished from these receptors by an extension of the C-terminal hormone binding domain making it 80 amino acids longer than rat thyroid hormone receptor type ..cap alpha..1. Different sizes of mRNA found in liver and kidney suggest that there may be tissue-specific processing of the primary transcript of this gene. Identification of human thyroid hormone receptor type ..cap alpha..2 indicates that two or more forms of thyroid hormone receptor exist in human tissues and may explain the normal variation in thyroid hormone responsiveness of various organs and the selective tissue abnormalities found in the thyroid hormone resistance syndromes.

  2. Resistance to Thyroid Hormone Complicated with Type 2 Diabetes and Cardiomyopathy in a Patient with a TRβ Mutation

    PubMed Central

    Wakasaki, Hisao; Matsumoto, Miyuki; Tamaki, Shinya; Miyata, Kaori; Yamamoto, Shohei; Minaga, Takamasa; Hayashi, Yoshitaka; Komukai, Kenichi; Imanishi, Toshio; Yamaoka, Hiroyuki; Matsuno, Shohei; Nishi, Masahiro; Akamizu, Takashi

    2016-01-01

    Resistance to thyroid hormone (RTH) is a genetic disorder characterized by reduced tissue responsiveness to thyroid hormone. We herein describe a 60-year old man who presented with the clinical features of cardiomyopathy, diabetes mellitus and elevated thyroid hormones with unsuppressed thyroid stimulating hormone. A genetic analysis of thyroid hormone receptor (TR) revealed a missense mutation (A268D) in the TRβ gene. Clinical manifestations of RTH may be variable due to different tissue distributions of TR subtypes and different actions of mutant receptors. The current case demonstrates that patients with a TRβ mutation may have impaired his glucose metabolism and a reduced cardiac function, although patients appear clinically euthyroid. PMID:27853072

  3. The importance of thyroid hormone transporters for brain development and function.

    PubMed

    Heuer, Heike

    2007-06-01

    Thyroid hormone is essential for proper brain development and function. As a prerequisite for its action, transporters must exist to mediate its cellular entry. As impaired uptake of thyroid hormone into the CNS causes severe neurological symptoms, it is of utmost importance to identify these carriers. The monocarboxylate transporter 8 (MCT8) was recently characterized as a very specific thyroid hormone transporter. Inactivating mutations in the MCT8 gene are associated with a severe syndrome of psychomotor retardation and abnormal thyroid hormone parameters. To elucidate the underlying pathogenic mechanisms, MCT8-deficient mice that replicate the human thyroid phenotype, despite the absence of overt neurological symptoms, have been generated. Here, we summarize recent findings obtained by analyzing these animals and discuss their potential impact for the treatment of affected patients.

  4. Epidermal growth factor (EGF) inhibits stimulated thyroid hormone secretion in the mouse

    SciTech Connect

    Ahren, B.

    1987-07-01

    It is known that epidermal growth factor (EGF) inhibits iodide uptake in the thyroid follicular cells and lowers plasma levels of thyroid hormones upon infusion into sheep and ewes. In this study, the effects of EGF on basal and stimulated thyroid hormone secretion were investigated in the mouse. Mice were pretreated with /sup 125/I and thyroxine; the subsequent release of /sup 125/I is an estimation of thyroid hormone secretion. It was found that basal radioiodine secretion was not altered by intravenous injection of EGF (5 micrograms/animal). However, the radioiodine secretion stimulated by both TSH (120 microU/animal) and vasoactive intestinal peptide (VIP; 5 micrograms/animal) were inhibited by EGF (5 micrograms/animal). At a lower dose level (0.5 microgram/animal), EGF had no influence on stimulated radioiodine secretion. In conclusion, EGF inhibits stimulated thyroid hormone secretion in the mouse.

  5. Identification of Thyroid Hormones and Functional Characterization of Thyroid Hormone Receptor in the Pacific Oyster Crassostrea gigas Provide Insight into Evolution of the Thyroid Hormone System

    PubMed Central

    Huang, Wen; Xu, Fei; Qu, Tao; Zhang, Rui; Li, Li; Que, Huayong; Zhang, Guofan

    2015-01-01

    Thyroid hormones (THs) play important roles in development, metamorphosis, and metabolism in vertebrates. During the past century, TH functions were regarded as a synapomorphy of vertebrates. More recently, accumulating evidence has gradually convinced us that TH functions also occur in invertebrate chordates. To date, however, TH-related studies in non-chordate invertebrates have been limited. In this study, THs were qualitatively detected by two reliable methods (HPLC and LC/MS) in a well-studied molluscan species, the Pacific oyster Crassostrea gigas. Quantitative measurement of THs during the development of C. gigas showed high TH contents during embryogenesis and that oyster embryos may synthesize THs endogenously. As a first step in elucidating the TH signaling cascade, an ortholog of vertebrate TH receptor (TR), the most critical gene mediating TH effects, was cloned in C. gigas. The sequence of CgTR has conserved DNA-binding and ligand-binding domains that normally characterize these receptors. Experimental results demonstrated that CgTR can repress gene expression through binding to promoters of target genes and can interact with oyster retinoid X receptor. Moreover, CgTR mRNA expression was activated by T4 and the transcriptional activity of CgTR promoter was repressed by unliganded CgTR protein. An atypical thyroid hormone response element (CgDR5) was found in the promoter of CgTR, which was verified by electrophoretic mobility shift assay (EMSA). These results indicated that some of the CgTR function is conserved. However, the EMSA assay showed that DNA binding specificity of CgTR was different from that of the vertebrate TR and experiments with two dual-luciferase reporter systems indicated that l-thyroxine, 3,3′,5-triiodothyronine, and triiodothyroacetic acid failed to activate the transcriptional activity of CgTR. This is the first study to functionally characterize TR in mollusks. The presence of THs and the functions of CgTR in mollusks

  6. Identification of Thyroid Hormones and Functional Characterization of Thyroid Hormone Receptor in the Pacific Oyster Crassostrea gigas Provide Insight into Evolution of the Thyroid Hormone System.

    PubMed

    Huang, Wen; Xu, Fei; Qu, Tao; Zhang, Rui; Li, Li; Que, Huayong; Zhang, Guofan

    2015-01-01

    Thyroid hormones (THs) play important roles in development, metamorphosis, and metabolism in vertebrates. During the past century, TH functions were regarded as a synapomorphy of vertebrates. More recently, accumulating evidence has gradually convinced us that TH functions also occur in invertebrate chordates. To date, however, TH-related studies in non-chordate invertebrates have been limited. In this study, THs were qualitatively detected by two reliable methods (HPLC and LC/MS) in a well-studied molluscan species, the Pacific oyster Crassostrea gigas. Quantitative measurement of THs during the development of C. gigas showed high TH contents during embryogenesis and that oyster embryos may synthesize THs endogenously. As a first step in elucidating the TH signaling cascade, an ortholog of vertebrate TH receptor (TR), the most critical gene mediating TH effects, was cloned in C. gigas. The sequence of CgTR has conserved DNA-binding and ligand-binding domains that normally characterize these receptors. Experimental results demonstrated that CgTR can repress gene expression through binding to promoters of target genes and can interact with oyster retinoid X receptor. Moreover, CgTR mRNA expression was activated by T4 and the transcriptional activity of CgTR promoter was repressed by unliganded CgTR protein. An atypical thyroid hormone response element (CgDR5) was found in the promoter of CgTR, which was verified by electrophoretic mobility shift assay (EMSA). These results indicated that some of the CgTR function is conserved. However, the EMSA assay showed that DNA binding specificity of CgTR was different from that of the vertebrate TR and experiments with two dual-luciferase reporter systems indicated that l-thyroxine, 3,3',5-triiodothyronine, and triiodothyroacetic acid failed to activate the transcriptional activity of CgTR. This is the first study to functionally characterize TR in mollusks. The presence of THs and the functions of CgTR in mollusks contribute

  7. Thyroid hormone concentrations differ between donkeys and horses.

    PubMed

    Mendoza, F J; Perez-Ecija, R A; Toribio, R E; Estepa, J C

    2013-03-01

    Reference intervals for thyroid hormones (TH) concentrations have not been previously established for donkeys, leading to potential misdiagnosis of thyroid disease. To determine the normal values of TH in healthy adult donkeys and compare them to TH values from healthy adult horses. Thirty-eight healthy Andalusian donkeys and 19 healthy Andalusian horses from 2 different farms were used. Donkeys were divided into 3 age groups: <5, 5-10 and >11 years and into 2 gender groups. Serum concentrations of fT3, tT3, rT3, fT4 and tT4 were quantified by radioimmunoassay. All blood samples were collected the same day in the morning. None of the animals had received any treatment for 30 days prior to sampling or had any history of disease. Both farms were in close proximity and under similar management. Differences between groups were determined using a one-way ANOVA analysis followed by Fisher's LSD test. P<0.05 was considered significant. Serum TH concentrations were higher in donkeys than in horses (P<0.01). Donkeys <5 years had higher serum rT3, fT4 and tT4 concentrations than donkeys >5 years (P<0.05). Furthermore, older donkeys (>11 years) had lower serum fT3 and tT3 concentrations than younger donkeys' groups (<5 and 5-10 years, P<0.05). TH concentrations were not different between genders (fT3: P = 0.06; tT3: P = 0.08; rT3: P = 0.15; fT4: P = 0.89; and tT4: P = 0.19). Thyroid hormone concentrations are different between healthy adult donkeys and horses. Establishing species-specific TH reference ranges is important when evaluating clinicopathologic data in equids in order to avoid the misdiagnosis of thyroid gland dysfunction. Further studies to elucidate the physiological mechanisms leading to these differences are warranted. © 2012 EVJ Ltd.

  8. Serum copper as a novel biomarker for resistance to thyroid hormone.

    PubMed

    Mittag, Jens; Behrends, Thomas; Nordström, Kristina; Anselmo, Joao; Vennström, Björn; Schomburg, Lutz

    2012-04-01

    Thyroid hormone action is mediated by the thyroid hormone receptors TRα1 and TRβ. Defects in TRβ lead to RTH (resistance to thyroid hormone) β, a syndrome characterized by high levels of thyroid hormone and non-suppressed TSH (thyroid-stimulating hormone). However, a correct diagnosis of RTHβ patients is difficult as the clinical picture varies. A biochemical serum marker indicative of defects in TRβ signalling is needed and could simplify the diagnosis of RTHβ, in particular the differentiation to TSH-secreting pituitary adenomas, which present with clinically similar symptoms. In the present paper we show that serum copper levels are regulated by thyroid hormone, which stimulates the synthesis and the export of the hepatic copper-transport protein ceruloplasmin into the serum. This is accompanied by a concerted reduction in the mRNA levels of other copper-containing proteins such as metallothioneins 1 and 2 or superoxide dismutase 1. The induction of serum copper is abolished in genetically hyperthyroid mice lacking TRβ and human RTHβ patients, demonstrating an important role of TRβ for this process. Together with a previously reported TRα1 specific regulation of serum selenium, we show that the ratio of serum copper and selenium, which is largely independent of thyroid hormone levels, volume changes or sample degradation, can constitute a valuable novel biomarker for RTHβ. Moreover, it could also provide a suitable large-scale screening parameter to identify RTHα patients, which have not been identified to date.

  9. Association of thyroid-stimulating hormone with insulin resistance and androgen parameters in women with PCOS.

    PubMed

    Dittrich, Ralf; Kajaia, Natia; Cupisti, Susanne; Hoffmann, Inge; Beckmann, Matthias W; Mueller, Andreas

    2009-09-01

    There is a relationship between thyroid function and insulin sensitivity and alterations in lipids and metabolic parameters. Little information is available regarding this relationship in women with polycystic ovary syndrome. However all those pathologies are also described as often affecting women with polycystic ovary syndrome. The association between thyroid-stimulating hormone <2.5 mIU/l and > or =2.5 mIU/l with insulin resistance and endocrine parameters in 103 women with polycystic ovary syndrome was studied. Clinical, metabolic and endocrine parameters were obtained and an oral glucose tolerance test was performed with calculation of insulin resistance indices. Women with thyroid-stimulating hormone > or =2.5 mIU/l had a significantly higher body mass index (P = 0.003), higher fasting insulin concentrations (P = 0.02) and altered insulin resistance indices (P = 0.007), higher total testosterone (P = 0.009) and free androgen indices (P = 0.001) and decreased sex hormone-binding globulin concentrations (P = 0.01) in comparison with women with thyroid-stimulating hormone <2.5 mIU/l. Generally, all of these parameters correlated significantly (P < 0.05) with thyroid-stimulating hormone only in women with thyroid-stimulating hormone > or =2.5 mIU/l. Women with polycystic ovary syndrome and with thyroid-stimulating hormone > or =2.5 mIU/l had significantly altered endocrine and metabolic changes.

  10. The role of thyroid hormone signaling in the prevention of digestive system cancers.

    PubMed

    Brown, Adam R; Simmen, Rosalia C M; Simmen, Frank A

    2013-08-06

    Thyroid hormones play a critical role in the growth and development of the alimentary tract in vertebrates. Their effects are mediated by nuclear receptors as well as the cell surface receptor integrin αVβ3. Systemic thyroid hormone levels are controlled via activation and deactivation by iodothyronine deiodinases in the liver and other tissues. Given that thyroid hormone signaling has been characterized as a major effector of digestive system growth and homeostasis, numerous investigations have examined its role in the occurrence and progression of cancers in various tissues of this organ system. The present review summarizes current findings regarding the effects of thyroid hormone signaling on cancers of the esophagus, stomach, liver, pancreas, and colon. Particular attention is given to the roles of different thyroid hormone receptor isoforms, the novel integrin αVβ3 receptor, and thyroid hormone-related nutrients as possible protective agents and therapeutic targets. Future investigations geared towards a better understanding of thyroid hormone signaling in digestive system cancers may provide preventive or therapeutic strategies to diminish risk, improve outcome and avert recurrence in afflicted individuals.

  11. Thyroid hormone concentrations in captive and free-ranging West Indian manatees (Trichechus manatus).

    PubMed

    Ortiz, R M; MacKenzie, D S; Worthy, G A

    2000-12-01

    Because thyroid hormones play a critical role in the regulation of metabolism, the low metabolic rates reported for manatees suggest that thyroid hormone concentrations in these animals may also be reduced. However, thyroid hormone concentrations have yet to be examined in manatees. The effects of captivity, diet and water salinity on plasma total triiodothyronine (tT(3)), total thyroxine (tT(4)) and free thyroxine (fT(4)) concentrations were assessed in adult West Indian manatees (Trichechus manatus). Free-ranging manatees exhibited significantly greater tT(4) and fT(4) concentrations than captive adults, regardless of diet, indicating that some aspect of a captive existence results in reduced T(4) concentrations. To determine whether this reduction might be related to feeding, captive adults fed on a mixed vegetable diet were switched to a strictly sea grass diet, resulting in decreased food consumption and a decrease in body mass. However, tT(4) and fT(4) concentrations were significantly elevated over initial values for 19 days. This may indicate that during periods of reduced food consumption manatees activate thyroid-hormone-promoted lipolysis to meet water and energetic requirements. Alterations in water salinity for captive animals did not induce significant changes in thyroid hormone concentrations. In spite of lower metabolic rates, thyroid hormone concentrations in captive manatees were comparable with those for other terrestrial and marine mammals, suggesting that the low metabolic rate in manatees is not attributable to reduced circulating thyroid hormone concentrations.

  12. Effects of substitution and high-dose thyroid hormone therapy on deiodination, sulfoconjugation, and tissue thyroid hormone levels in prolonged critically ill rabbits.

    PubMed

    Debaveye, Yves; Ellger, Björn; Mebis, Liese; Visser, Theo J; Darras, Veerle M; Van den Berghe, Greet

    2008-08-01

    To delineate the metabolic fate of thyroid hormone in prolonged critically ill rabbits, we investigated the impact of two dose regimes of thyroid hormone on plasma 3,3'-diiodothyronine (T(2)) and T(4)S, deiodinase type 1 (D1) and D3 activity, and tissue iodothyronine levels in liver and kidney, as compared with saline and TRH. D2-expressing tissues were ignored. The regimens comprised either substitution dose or a 3- to 5- fold higher dose of T(4) and T(3), either alone or combined, targeted to achieve plasma thyroid hormone levels obtained by TRH. Compared with healthy animals, saline-treated ill rabbits revealed lower plasma T(3) (P=0.006), hepatic T(3) (P=0.02), and hepatic D1 activity (P=0.01). Substitution-dosed thyroid hormone therapy did not affect these changes except a further decline in plasma (P=0.0006) and tissue T(4) (P=0.04). High-dosed thyroid hormone therapy elevated plasma and tissue iodothyronine levels and hepatic D1 activity, as did TRH. Changes in iodothyronine tissue levels mimicked changes in plasma. Tissue T(3) and tissue T(3)/reverse T(3) ratio correlated with deiodinase activities. Neither substitution- nor high-dose treatment altered plasma T(2). Plasma T(4)S was increased only by T(4) in high dose. We conclude that in prolonged critically ill rabbits, low plasma T(3) levels were associated with low liver and kidney T(3) levels. Restoration of plasma and liver and kidney tissue iodothyronine levels was not achieved by thyroid hormone in substitution dose but instead required severalfold this dose. This indicates thyroid hormone hypermetabolism, which in this model of critical illness is not entirely explained by deiodination or by sulfoconjugation.

  13. Thyroid surgery in untreated severe hyperthyroidism: perioperative kinetics of free thyroid hormones in the glandular venous effluent and peripheral blood.

    PubMed

    Hermann, M; Richter, B; Roka, R; Freissmuth, M

    1994-02-01

    It is generally believed that thyroid surgery in Graves' disease requires a euthyroid state to avoid thyrotoxic reactions. We carried out a prospective study on 23 patients who had severe hyperthyroidism with free thyroid hormone concentrations (fT3 or fT4) exceeding the upper normal boundary by 300% or more and who were not pretreated with thyrostatic agents. We determined hormone levels during operation in the thyroid venous effluent before and after surgical trauma and monitored their postoperative elimination kinetics. The concentration of fT3 and fT4 in the venous effluent of the hyperactive gland did not exceed the peripheral levels. Surgery did not induce any intraoperative or postoperative increase in fT4 or fT3, whereas thyroglobulin concentrations rose sharply. Both fT4 and fT3 followed biphasic elimination kinetics, and a significant decline of circulating free hormone concentrations was measurable within the first postoperative hour. Contrary to widely held assumptions, the surgical trauma does not stimulate the release of thyroid hormones. Hence this mechanism cannot account for the postoperative development of thyroid storm. Our observations imply that immediate operation should generally be considered for the emergency treatment of an imminent thyroid storm.

  14. The targeted inactivation of TRβ gene in thyroid follicular cells suggests a new mechanism of regulation of thyroid hormone production.

    PubMed

    Selmi-Ruby, Samia; Bouazza, Lamia; Obregon, Maria-Jesus; Conscience, Aude; Flamant, Frédéric; Samarut, Jacques; Borson-Chazot, Françoise; Rousset, Bernard

    2014-02-01

    Thyroid epithelial cells, or thyrocytes, express functional thyroid hormone receptors but no precise role has yet been assigned to either TRα or TRβ in the thyroid gland. In this study, we analyzed the impact of inactivating the TRβ gene in the thyroid of mice. First, we generated a mouse line named Thyr-Cre, expressing the Cre recombinase under the control of the thyroglobulin gene promoter, which led to a complete recombination of floxed genes in thyrocytes. Thyr-Cre mice were then crossed with TRβ floxed mice (TRβ(flox/flox)) to obtain a thyrocyte-selective deletion of TRβ. Thyr-TRβ(-/-) mice were characterized by a decrease in the size and functional activity of the thyroid gland. These alterations were associated with a decrease in plasma TSH concentration. Surprisingly, Thyr-TRβ(-/-) displayed elevated serum T(4) and rT(3) concentrations with no significant change in serum T(3) levels. Their intrathyroidal free T(4) and rT(3) contents were also elevated, whereas the ratio of serum T(4) to thyroid free T(4) was decreased by comparison with wild-type littermates. Also, within the thyroid, deiodinases D1 and D2 were reduced as well as the expression levels of genes encoding monocarboxylate transporters (Mct8 and Mct10). Such a decrease in intrathyroidal deiodination of T(4) and in the expression of genes encoding thyroid hormone transporters may contribute to the primary overproduction of T(4) observed in Thyr-TRβ(-/-) mice. In conclusion, these data show that the control of thyroid hormone production involves not only TRβ-dependent mechanisms acting at the level of hypothalamus and pituitary but also TRβ-dependent mechanisms acting at the thyroid level.

  15. Thyroid hormone acting via TRβ induces expression of browning genes in mouse bone marrow adipose tissue.

    PubMed

    Lindsey, Richard C; Mohan, Subburaman

    2017-04-01

    Mutant hypothyroid mouse models have recently shown that thyroid hormone is critical for skeletal development during an important prepubertal growth period. Additionally, thyroid hormone negatively regulates total body fat, consistent with the well-established effects of thyroid hormone on energy and fat metabolism. Since bone marrow mesenchymal stromal cells differentiate into both adipocytes and osteoblasts and a relationship between bone marrow adipogenesis and osteogenesis has been predicted, we hypothesized thyroid hormone deficiency during the postnatal growth period increases marrow adiposity in mice. Marrow adiposity in TH-deficient (Tshr (-/-)) mice treated with T3/T4, TH receptor β-specific agonist GC-1, or vehicle control was evaluated via dual-energy X-ray absorptiometry and osmium micro-computed tomography. To further examine the mechanism for thyroid hormone regulation of marrow adiposity, we used real-time RT-PCR to measure the effects of thyroid hormone on adipocyte differentiation markers in primary mouse bone marrow mesenchymal stromal cells and two mouse cell lines in vitro and in Tshr (-/-) mice in vivo. Marrow adiposity increased >20% (P < 0.01) in Tshr (-/-) mice at 3 weeks of age, and treatment with T3/T4 when serum thyroid hormone normally increases (day 5-14) rescued this phenotype. Furthermore, GC-1 rescued this phenotype equally well, suggesting this thyroid hormone effect is in part mediated via TRβ signaling. Treatment of bone marrow mesenchymal stromal or ST2 cells with T3 or GC-1 significantly increased expression of several brown/beige fat markers. Moreover, injection of T3/T4 increased browning-specific markers in white fat of Tshr (-/-) mice. These data suggest that thyroid hormone regulation of marrow adiposity is mediated at least in part via activation of TRβ signaling.

  16. Differentiated thyroid cancer in patients with resistance to thyroid hormone syndrome. A novel case and a review of the literature

    PubMed Central

    Vinagre, João; Borges, Fátima; Costa, António; Alvelos, Maria Inês; Mazeto, Glaúcia; Sobrinho-Simões, Manuel; Soares, Paula

    2014-01-01

    Resistance to thyroid hormone (RTH) represents a syndrome in which patients present elevated circulating thyroid hormones in the presence of non-suppressed TSH. We report a novel case where a patient with RTH presented a differentiated thyroid cancer. A19 year-old female had been referred due to thyroid disease that disclosed features characteristic of a RTH. During the follow up it was detected a follicular tumor that led to the recommendation for thyroid surgical ablation, where an incidental papillary thyroid microcarcinoma (mPTC) was found. The increase of thyroglobulin (TG) levels following thyroid removal referred the patient for radioiodine treatment. Post-treatment, it was detected jugular adenopathies and the patient was subjected to cervical lymph node drainage where metastases of the mPTC were found. RTH syndrome was confirmed by the detection of a THRB germline mutation. A BRAF mutation was also found in the mPTC but not detected in the follicular adenoma or normal adjacent tissue. The young age of the patient, the rarity of BRAF mutations in childhood and the high dissemination of the malignancy, lead us to the speculation that increased TSH stimulation in a RTH background and oncogenic activation of BRAF could have served as (co) drivers and might have triggered an advanced stage of the neoplastic disease. These findings together with a review of published cases add novel information to the management of RTH patients with differentiated thyroid cancer. PMID:25988151

  17. Differentiated thyroid cancer in patients with resistance to thyroid hormone syndrome. A novel case and a review of the literature.

    PubMed

    Vinagre, João; Borges, Fátima; Costa, António; Alvelos, Maria Inês; Mazeto, Glaúcia; Sobrinho-Simões, Manuel; Soares, Paula

    2014-01-01

    Resistance to thyroid hormone (RTH) represents a syndrome in which patients present elevated circulating thyroid hormones in the presence of non-suppressed TSH. We report a novel case where a patient with RTH presented a differentiated thyroid cancer. A19 year-old female had been referred due to thyroid disease that disclosed features characteristic of a RTH. During the follow up it was detected a follicular tumor that led to the recommendation for thyroid surgical ablation, where an incidental papillary thyroid microcarcinoma (mPTC) was found. The increase of thyroglobulin (TG) levels following thyroid removal referred the patient for radioiodine treatment. Post-treatment, it was detected jugular adenopathies and the patient was subjected to cervical lymph node drainage where metastases of the mPTC were found. RTH syndrome was confirmed by the detection of a THRB germline mutation. A BRAF mutation was also found in the mPTC but not detected in the follicular adenoma or normal adjacent tissue. The young age of the patient, the rarity of BRAF mutations in childhood and the high dissemination of the malignancy, lead us to the speculation that increased TSH stimulation in a RTH background and oncogenic activation of BRAF could have served as (co) drivers and might have triggered an advanced stage of the neoplastic disease. These findings together with a review of published cases add novel information to the management of RTH patients with differentiated thyroid cancer.

  18. Postpartum Thyroiditis

    MedlinePlus

    ... high thyroid hormone levels in the blood) and hypothyroidism (low thyroid hormone levels in the blood). In postpartum thyroiditis, thyrotoxicosis occurs first followed by hypothyroidism. What causes postpartum thyroiditis? The exact cause is ...

  19. Postpartum Thyroiditis

    MedlinePlus

    ... high thyroid hormone levels in the blood) and hypothyroidism (low thyroid hormone levels in the blood). In postpartum thyroiditis, thyrotoxicosis occurs first followed by hypothyroidism. What causes postpartum thyroiditis? The exact cause is ...

  20. Effects of amiodarone and thyroid dysfunction on myocardial calcium, serum calcium and thyroid hormones in the rat.

    PubMed Central

    Gammage, M. D.; Franklyn, J. A.; Logan, S. D.

    1987-01-01

    1 Myocardial calcium content was found to be elevated and serum calcium reduced in hypothyroid rats. 2 Treatment of rats with amiodarone at either 30 mg kg-1 or 150 mg kg-1 daily did not result in any significant changes in myocardial or serum calcium. 3 The administration of amiodarone to hypothyroid rats attenuated the changes in serum but not myocardial calcium, suggesting that amiodarone may exert a thyroid hormone-like effect in the hypothyroid state. 4 The administration of amiodarone to thyroid hormone-treated rats resulted in attenuation of the effects on serum calcium and calculated intracellular calcium; this was consistent with an antagonistic interaction between amiodarone and thyroid hormones. 5 Administration of amiodarone resulted in significant changes in circulating thyroid hormone levels in the rat; triiodothyronine was reduced and basal thyrotrophin elevated compared to euthyroid controls. Serum thyroxine was not changed; this is in contrast to the effects in man. 6 Amiodarone does not exert its anti-arrhythmic action via changes in total myocardial calcium content in the euthyroid rat; nonetheless the described interactions between the drug and thyroid hormones may be involved in its mechanism of action. PMID:3676598

  1. [Biological markers reflecting peripheral effects of thyroid hormones in autonomous thyroid adenoma].

    PubMed

    Földes, J; Németh, J; Bános, C; Tarján, G; Büki, B

    1991-09-08

    In some patients with functioning thyroid autonomous nodules preclinical hyperthyroidism is detected. It is important to know, whether in this intermediate clinical state beside the suppression of pituitary TSH secretion other target organs are also affected by serum free-thyroxine and free-triiodothyronine levels still within the normal range. Determining some sensitive, but not specific biologic markers reflecting the impact of thyroid hormones at the peripheral tissue level, it was demonstrated that in the group of preclinical hyperthyroidism the mean level of plasma fibronectin exceeded that of the controls (mean +/- S. D.: 583.5 +/- 163.9 vs. 424.2 +/- 84.1 micrograms/ml, p less than 0.001), serum procollagen-III-peptide concentration was already significantly raised, though its value was still within the normal range (mean +/- S. D.: 0.73 +/- 0.17 vs. 0.57 +/- 0.16 U/ml, p less than 0.05), conversely, mean sex-hormone binding globulin level was the same as in euthyroid controls (mean +/- S. D. 47.4 +/- 18.2 vs. 48.3 +/- 16.3 nmol/l). The value of all three parameters was significantly elevated in patients with toxic nodular goiter. Based on the results of this study "tissue"-thyrotoxicosis is suspected in some patients with preclinical hyperthyroidism, which may have therapeutical implications.

  2. Notes on the history of cellular uptake and deiodination of thyroid hormone.

    PubMed

    Hennemann, Georg

    2005-08-01

    In this mini review on the history of the research devoted to thyroid hormone metabolism two pathways are discussed, i.e. uptake and subsequent deiodination in cells and tissues. In the 1950's the investigations of these processes were greatly stimulated when 131I became available for research purposes. The true nature of both mechanisms surfaced in the 1970's when it became apparent that transport of thyroid hormones into cells was a regulated carrier mediated process, while deiodination appeared to be catalyzed by different types of enzymes. Kinetic data indicated that these processes were of great importance in the ultimate regulation of thyroid hormone bio-availability.

  3. Thyroid hormone transport in and out of cells.

    PubMed

    Visser, W Edward; Friesema, Edith C H; Jansen, Jurgen; Visser, Theo J

    2008-03-01

    Thyroid hormone (TH) is essential for the proper development of numerous tissues, notably the brain. TH acts mostly intracellularly, which requires transport by TH transporters across the plasma membrane. Although several transporter families have been identified, only monocarboxylate transporter (MCT)8, MCT10 and organic anion-transporting polypeptide (OATP)1C1 demonstrate a high degree of specificity towards TH. Recently, the biological importance of MCT8 has been elucidated. Mutations in MCT8 are associated with elevated serum T(3) levels and severe psychomotor retardation, indicating a pivotal role for MCT8 in brain development. MCT8 knockout mice lack neurological damage, but mimic TH abnormalities of MCT8 patients. The exact pathophysiological mechanisms in MCT8 patients remain to be elucidated fully. Future research will probably identify novel TH transporters and disorders based on TH transporter defects.

  4. Multigenic control of thyroid hormone functions in the nervous system

    PubMed Central

    Nunez, Jacques; Celi, Francesco S.; Ng, Lily; Forrest, Douglas

    2008-01-01

    Summary Thyroid hormone (TH) has a remarkable range of actions in the development and function of the nervous system. A multigenic picture is emerging of the mechanisms that specify these diverse functions in target tissues. Distinct responses are mediated by α and β isoforms of TH receptor which act as ligand-regulated transcription factors. Receptor activity can be regulated at several levels including that of uptake of TH ligand and the activation or inactivation of ligand by deiodinase enzymes in target tissues. Processes under the control of TH range from learning and anxiety-like behaviour to sensory function. At the cellular level, TH controls events as diverse as axonal outgrowth, hippocampal synaptic activity and the patterning of opsin photopigments necessary for colour vision. Overall, TH coordinates this variety of events in both central and sensory systems to promote the function of the nervous system as a complete entity. PMID:18448240

  5. Energy balance regulation by thyroid hormones at central level.

    PubMed

    López, Miguel; Alvarez, Clara V; Nogueiras, Rubén; Diéguez, Carlos

    2013-07-01

    Classically, medical textbooks taught that most effects of thyroid hormones (THs) on energy homeostasis are directly exerted in peripheral tissues. However, current evidence is changing (and challenging) our perspective about the role of THs from a 'peripheral' to a 'central' vision, implying that they affect food intake, energy expenditure, and metabolism by acting, to a large extent, at the central level. Interestingly, effects of THs are interrelated with global energy sensors in the central nervous system (CNS), such as uncoupling protein 2 (UCP2), AMP-activated protein kinase (AMPK; the 'AMPK-BAT axis'), and mechanistic target of rapamycin (mTOR). Here, we review what is currently known about THs and their regulation of energy balance and metabolism in both peripheral and central tissues.

  6. The syndromes of reduced sensitivity to thyroid hormone

    PubMed Central

    Dumitrescu, Alexandra M.; Refetoff, Samuel

    2012-01-01

    Background Six known steps are required for the circulating thyroid hormone (TH) to exert its action on target tissues. For three of these steps, human mutations and distinct phenotypes have been identified. Scope of Review The clinical, laboratory, genetic and molecular characteristics of these three defects of TH action are the subject of this review. The first defect, recognized 45 years ago, produces resistance to TH and carries the acronym, RTH. In the majority of cases it is caused by TH receptor β gene mutations. It has been found in over 3,000 individuals belonging to approximately 1,000 families. Two relatively novel syndromes presenting reduced sensitivity to TH involve membrane transport and metabolism of TH. One of them, caused by mutations in the TH cell-membrane transporter MCT8, produces severe psychomotor defects. It has been identified in more than 170 males from 90 families. A defect of the intracellular metabolism of TH in 10 individuals from 8 families is caused by mutations in the SECISBP2 gene required for the synthesis of selenoproteins, including TH deiodinases. Major Conclusions Defects at different steps along the pathway leading to TH action at cellular level can manifest as reduced sensitivity to TH. General Significance Knowledge of the molecular mechanisms involved in TH action allows the recognition of the phenotypes caused by defects of TH action. Once previously known defects have been ruled out, new molecular defects could be sought, thus opening the avenue for novel insights in thyroid physiology. PMID:22986150

  7. Impact of Endocrine Disruptors on the Thyroid Hormone System.

    PubMed

    Gutleb, Arno C; Cambier, Sébastien; Serchi, Tommaso

    2016-01-01

    The thyroid hormone (TH) system plays a central role in central physiological processes of many species, including mammals and humans, ranging from growth and cell differentiation, energy metabolism, thermoregulation and phasing of hibernation or annual movements of migratory species, metamorphosis from larvae to adult forms, brain development, reproduction, or the cardiovascular system. Several chemicals are known to be TH-disrupting compounds (THDCs) and have been shown to interact with virtually all elements of TH homeostasis such as feedback mechanisms with the hypothalamus-pituitary axis, TH synthesis, TH storage and release from the thyroid gland, transport protein binding and TH distribution in tissues and organs, cellular TH uptake, intracellular TH metabolism, and TH receptor binding. Therefore, chemicals interfering with the TH homeostasis have the potential to interact with many of these important processes, and especially early-life stage exposure results in permanent alterations of tissue organization and homeostatic regulation of adaptive processes. This is not only of theoretical importance as the reported plasma concentrations of THDCs in human plasma fall well within the range of reported in vitro effect concentrations, and this is of even higher importance as the developing fetus and young children are in a sensitive developmental stage. © 2016 S. Karger AG, Basel.

  8. Thyroid hormones regulate selenoprotein expression and selenium status in mice.

    PubMed

    Mittag, Jens; Behrends, Thomas; Hoefig, Carolin S; Vennström, Björn; Schomburg, Lutz

    2010-09-22

    Impaired expression of selenium-containing proteins leads to perturbed thyroid hormone (TH) levels, indicating the central importance of selenium for TH homeostasis. Moreover, critically ill patients with declining serum selenium develop a syndrome of low circulating TH and a central downregulation of the hypothalamus-pituitary-thyroid axis. This prompted us to test the reciprocal effect, i.e., if TH status would also regulate selenoprotein expression and selenium levels. To investigate the TH dependency of selenium metabolism, we analyzed mice expressing a mutant TH receptor α1 (TRα1+m) that confers a receptor-mediated hypothyroidism. Serum selenium was reduced in these animals, which was a direct consequence of the mutant TRα1 and not related to their metabolic alterations. Accordingly, hyperthyroidism, genetically caused by the inactivation of TRβ or by oral TH treatment of adult mice, increased serum selenium levels in TRα1+m and controls, thus demonstrating a novel and specific role for TRα1 in selenium metabolism. Furthermore, TH affected the mRNA levels for several enzymes involved in selenoprotein biosynthesis as well as serum selenoprotein P concentrations and the expression of other antioxidative selenoproteins. Taken together, our results show that TH positively affects the serum selenium status and regulates the expression of several selenoproteins. This demonstrates that selenium and TH metabolism are interconnected through a feed-forward regulation, which can in part explain the rapid parallel downregulation of both systems in critical illness.

  9. Thyroid hormones regulate skeletal muscle regeneration after acute injury.

    PubMed

    Leal, Anna Lúcia R C; Albuquerque, João Paulo C; Matos, Marina S; Fortunato, Rodrigo S; Carvalho, Denise P; Rosenthal, Doris; da Costa, Vânia Maria Corrêa

    2015-02-01

    We evaluated the effects of hypo- and hyperthyroid statuses during the initial phase of skeletal muscle regeneration in rats. To induce hypo- or hyperthyroidism, adult male Wistar rats were treated with methimazole (0.03%) or T4 (10 μg/100 g), respectively, for 10 days. Three days before sacrifice, a crush injury was produced in the solear muscles of one half of the animals, while the other half remained intact. T3, T4, TSH, and leptin serum levels were not affected by the injury. Serum T3 and T4 levels were significantly increased in hyperthyroid and hyper-injury animals. Hypothyroidism was confirmed by the significant increase in serum TSH levels in hypothyroid and hypo-injury animals. Injury increased cell infiltration and macrophage accumulation especially in hyperthyroid animals. Both type 2 and type 3 deiodinases were induced by lesion, and the opposite occurred with the type 1 isoform, at least in the control and hyperthyroid groups. Injury increased both MyoD and myogenin expression in all the studied groups, but only MyoD expression was increased by thyroidal status only at the protein level. We conclude that thyroid hormones modulate skeletal muscle regeneration possibly by regulating the inflammatory process, as well as MyoD and myogenin expression in the injured tissue.

  10. Thyroid Hormone Availability and Action during Brain Development in Rodents.

    PubMed

    Bárez-López, Soledad; Guadaño-Ferraz, Ana

    2017-01-01

    Thyroid hormones (THs) play an essential role in the development of all vertebrates; in particular adequate TH content is crucial for proper neurodevelopment. TH availability and action in the brain are precisely regulated by several mechanisms, including the secretion of THs by the thyroid gland, the transport of THs to the brain and neural cells, THs activation and inactivation by the metabolic enzymes deiodinases and, in the fetus, transplacental passage of maternal THs. Although these mechanisms have been extensively studied in rats, in the last decade, models of genetically modified mice have been more frequently used to understand the role of the main proteins involved in TH signaling in health and disease. Despite this, there is little knowledge about the mechanisms underlying THs availability in the mouse brain. This mini-review article gathers information from findings in rats, and the latest findings in mice regarding the ontogeny of TH action and the sources of THs to the brain, with special focus on neurodevelopmental stages. Unraveling TH economy and action in the mouse brain may help to better understand the physiology and pathophysiology of TH signaling in brain and may contribute to addressing the neurological alterations due to hypo and hyperthyroidism and TH resistance syndromes.

  11. Exhaustive exercise and vitamins C and E modulate thyroid hormone levels at low and high altitudes.

    PubMed

    Al-Hashem, Fahaid; Alkhateeb, Mahmoud; Al-Ani, Bahjat; Sakr, Hussein; Khalil, Mohammad

    2012-01-01

    Thyroid hormones play an important role in cell growth and differentiation and regulation of oxygen consumption and thermogenesis. The effect of altitude and vitamin supplementation on thyroid hormone levels in animals or humans performing acute exhaustive exercise have not been investigated before. Therefore, we thought to test whether exhaustive exercise-induced stress with antioxidant supplementation was capable of modulating the level of thyroid hormones at different altitudes. Serum levels of T4 (Thyroxin), T3 (Triiodothyronine), and TSH (Thyroid Stimulating Hormone) were measured in rats (N=36) born and bred in low altitude (600 m above sea level) and high altitude (2200 m above sea level) following forced swimming with or without vitamins C and E (25 mg/kg) pre-treatments. Thyroid levels were significantly decreased in resting rats at high altitude compared to low altitude, and swimming exercise moderately increased T3 and TSH at both high and low altitudes, whereas T4 was markedly increased (62 %) at low altitude compared to a moderate high altitude increase (28 %). Co-administration of vitamins C and E augmented the observed forced swimming-induced thyroid release. However, the conversion of T4 to T3 was reduced in both altitude areas following swimming exercise and vitamin pre-treatment had no effect. We conclude that acute stress induced thyroidal hormones in rats, which was augmented by antioxidant drugs in both high and low altitude areas. These findings may play an important role in the human pathophysiology of thyroid gland at different altitudes.

  12. Association of thyroid hormones with obesity and metabolic syndrome in Japanese children.

    PubMed

    Minami, Yukako; Takaya, Ryuzo; Takitani, Kimitaka; Ishiro, Manabu; Okasora, Keisuke; Niegawa, Tomomi; Tamai, Hiroshi

    2015-09-01

    Obesity is associated with health consequences, and thyroid dysfunction may be an adaption to the increased energy expenditure in obesity. With the rising prevalence of obesity in childhood, the prevalence of metabolic syndrome may also increase. In the current study, we have shown gender differences in the association of thyroid hormones with obesity, and attempted to elucidate the relationship between thyroid hormones and anthropometric parameters and biochemical data in obese Japanese children. We analyzed anthropometric measurements, blood pressure, body composition, thyroid hormones, and lipid profiles in 283 obese children. The association between thyroid hormones and several parameters differed by gender. The free T3 to free T4 ratio (fT3/fT4) in boys was negatively associated with the quantitative insulin sensitivity check index, whereas in girls, thyroid-stimulating hormone levels were positively correlated with levels of glucose, diastolic blood pressure, and non-high density lipoprotein-cholesterol, and fT3/fT4 was positively correlated with uric acid levels. FT3/fT4 in boys with metabolic syndrome was relatively higher than in those without metabolic syndrome. The cause of gender differences is unknown. Therefore, further studies with larger sample sizes and a long-term follow-up period are needed to address the influence of thyroid hormones on various parameters.

  13. Association of thyroid hormones with obesity and metabolic syndrome in Japanese children

    PubMed Central

    Minami, Yukako; Takaya, Ryuzo; Takitani, Kimitaka; Ishiro, Manabu; Okasora, Keisuke; Niegawa, Tomomi; Tamai, Hiroshi

    2015-01-01

    Obesity is associated with health consequences, and thyroid dysfunction may be an adaption to the increased energy expenditure in obesity. With the rising prevalence of obesity in childhood, the prevalence of metabolic syndrome may also increase. In the current study, we have shown gender differences in the association of thyroid hormones with obesity, and attempted to elucidate the relationship between thyroid hormones and anthropometric parameters and biochemical data in obese Japanese children. We analyzed anthropometric measurements, blood pressure, body composition, thyroid hormones, and lipid profiles in 283 obese children. The association between thyroid hormones and several parameters differed by gender. The free T3 to free T4 ratio (fT3/fT4) in boys was negatively associated with the quantitative insulin sensitivity check index, whereas in girls, thyroid-stimulating hormone levels were positively correlated with levels of glucose, diastolic blood pressure, and non-high density lipoprotein-cholesterol, and fT3/fT4 was positively correlated with uric acid levels. FT3/fT4 in boys with metabolic syndrome was relatively higher than in those without metabolic syndrome. The cause of gender differences is unknown. Therefore, further studies with larger sample sizes and a long-term follow-up period are needed to address the influence of thyroid hormones on various parameters. PMID:26388669

  14. Cholinergic and VIPergic effects on thyroid hormone secretion in the mouse

    SciTech Connect

    Ahren, B.

    1985-07-01

    The thyroid gland is known to harbor cholinergic and VIPergic nerves. In the present study, the influences of cholinergic stimulation by carbachol, cholinergic blockade by methylatropine and stimulation with various VIP sequences on basal, TSH-induced and VIP-induced thyroid hormone secretion were investigated in vivo in mice. The mice were pretreated with /sup 125/I and thyroxine; the subsequent release of /sup 125/I is an estimation of thyroid hormone secretion. It was found that basal radioiodine secretion was inhibited by both carbachol and methylatropine. Furthermore, TSH-induced radioiodine secretion was inhibited already by a low dose of carbachol. Moreover, a high dose of carbachol could inhibit VIP-induced radioiodine secretion. Methylatropine did not influence TSH- or VIP-stimulated radioiodine secretion, but counteracted the inhibitory action of carbachol on TSH- and VIP-induced radioiodine release. In addition, contrary to VIP, six various synthesized VIP fragments had no effect on basal or stimulated radioiodine release. It is concluded that basal thyroid hormone secretion is inhibited by both cholinergic activation and blockade. Furthermore, TSH-induced thyroid hormone secretion is more sensitive to inhibition with cholinergic stimulation than is VIP-induced thyroid hormone secretion. In addition, the VIP stimulation of thyroid hormone secretion seems to require the full VIP sequence.

  15. Role of thyroid hormone in postnatal circulatory and metabolic adjustments.

    PubMed Central

    Breall, J A; Rudolph, A M; Heymann, M A

    1984-01-01

    To assess the role of the early postnatal surge in plasma thyroid hormone concentrations on cardiovascular and metabolic adaptations, we measured cardiac output, total oxygen consumption, and plasma triiodothyronine (T3) concentrations in three groups of lambs in the first 6 h after delivery. 15 fetal lambs were prepared at gestational ages of 128-129 d by placing catheters in the brachiocephalic artery, descending aorta, distal inferior vena cava, left atrium, and pulmonary artery so that measurements could be made soon after delivery. They were divided into three groups: Group I comprised five control animals; Group II consisted of five fetuses in which thyroidectomy was performed at surgery at 129 d gestation; and Group III consisted of five animals in which thyroidectomy was performed at term gestation during delivery by caesarian section, prior to severing the umbilical cord. The lambs in Group I exhibited a rapid postnatal rise in T3 concentrations, similar to that described previously, reaching a peak value of about 5 ng/ml. Although the postnatal surge in T3 concentration was arrested in Group II and III animals, Group II had no detectable plasma T3, while the Group III animals had T3 concentrations of about 0.8 ng/ml, which were within the range previously reported for term lamb fetuses. The lambs in group II showed 40-50% lower left ventricular outputs (190 vs. 297 ml/kg per min), systemic blood flows (155 vs. 286 ml/kg per min), and oxygen consumptions (9.8 vs. 20.2 ml/kg per min) as compared with Group I animals over the entire 6-h period. The lambs in Group II also had significantly lower heart rates (131 vs. 192 beats/min) and mean systemic arterial pressures (56 vs. 72 torr). However, there were no significant differences for any of these measurements between the Group III and Group I lambs. The reduction in cardiac output in the Group II animals were reflected in a significantly lower blood flow to the peripheral circulation, but there were no

  16. MODEST THYROID HORMONE INSUFFICIENCY DURING DEVELOPMENT INDUCES A CELLULAR MALFORMATION IN THE CORPUS CALLOSUM: A MODEL OF CORTICAL DYSPLASIA.

    EPA Science Inventory

    There is a growing body of evidence that subtle decreases in maternal thyroid hormone during gestation can impact fetal brain development. The present study examined the impact of graded levels of thyroid hormone insufficiency on brain development in rodents. Maternal thyroid ho...

  17. MODEST THYROID HORMONE INSUFFICIENCY DURING DEVELOPMENT INDUCES A CELLULAR MALFORMATION IN THE CORPUS CALLOSUM: A MODEL OF CORTICAL DYSPLASIA.

    EPA Science Inventory

    There is a growing body of evidence that subtle decreases in maternal thyroid hormone during gestation can impact fetal brain development. The present study examined the impact of graded levels of thyroid hormone insufficiency on brain development in rodents. Maternal thyroid ho...

  18. The effects of iodine deficiency on thyroid hormone deiodination.

    PubMed

    Obregon, Maria-Jesus; Escobar del Rey, Francisco; Morreale de Escobar, Gabriella

    2005-08-01

    hormones of maternal origin are available to the embryo early in development and continue contributing to fetal thyroid hormone status, even after onset of fetal thyroid secretion. In the case of congenital hypothyroidism and normal maternal T(4), the transfer of the latter, together with increased D2 activity, protects the fetal brain from T(3) deficiency, even when it may be insufficient to maintain euthyroidism in other fetal tissues. Practically all of the T(3) found in the fetal brain is derived locally from T(4), and not from circulating T(3). In the case of severe iodine deficiency, both the embryo and the mother are T(4)-deficient; therefore, the fetal brain is exposed to T(3)-deficiency, both before and after onset of fetal thyroid function. This leads to irreversible alterations and damage to the central nervous system (i.e. abnormal corticogenesis). Moreover, because intrathyroidal autoregulatory mechanisms are not yet operative in the fetus, both T(4) and T(3) continue to be very low until birth, and the fetus is not only hypothyroxinemic, similar to its mother, but also clinically and biochemically hypothyroid.

  19. Thyroid hormones directly activate the expression of the human and mouse uncoupling protein-3 genes through a thyroid response element in the proximal promoter region

    PubMed Central

    2004-01-01

    The transcription of the human UCP3 (uncoupling protein-3) gene in skeletal muscle is tightly regulated by metabolic signals related to fatty acid availability. However, changes in thyroid status also modulate UCP3 gene expression, albeit by unknown mechanisms. We created transgenic mice bearing the entire human UCP3 gene to investigate the effect of thyroid hormones on human UCP3 gene expression. Treatment of human UCP3 transgenic mice with thyroid hormones induced the expression of the human gene in skeletal muscle. In addition, transient transfection experiments demonstrate that thyroid hormones activate the transcription of the human UCP3 gene promoter when MyoD and the TR (thyroid hormone receptor) were co-transfected. The action of thyroid hormones on UCP3 gene transcription is mediated by the binding of the TR to a proximal region in the UCP3 gene promoter that contains a direct repeat structure. An intact DNA sequence of this site is required for thyroid hormone responsiveness and TR binding. Chromatin immunoprecipitation assays revealed that the TR binds this element in vivo. The murine Ucp3 gene promoter was also dependent on MyoD and responsive to thyroid hormone in transient transfection assays. However, it was much less sensitive to thyroid hormone than the human UCP3 promoter. In summary, UCP3 gene transcription is activated by thyroid hormone treatment in vivo, and this activation is mediated by a TRE (thyroid hormone response element) in the proximal promoter region. Such regulation suggests a link between UCP3 gene expression and the effects of thyroid hormone on mitochondrial function in skeletal muscle. PMID:15496137

  20. Iodotyrosine deiodinase, a novel target of environmental halogenated chemicals for disruption of the thyroid hormone system in mammals.

    PubMed

    Shimizu, Ryo

    2014-01-01

    Many synthetic chemicals have been identified as environmental contaminants with activity to disrupt normal function of the thyroid hormone system. Thyroid hormones play important roles in growth, development, differentiation, and basal metabolic homeostasis, as well as in brain development in human fetus and children, and thyroid dysfunction can have very serious consequences, including mental retardation. Environmental chemicals may affect thyroid hormone action in multiple ways, including reduced thyroid hormone synthesis owing to direct toxicity at the thyroid gland, interaction with thyroid hormone receptors and transporters such as transthyretin, and disturbance of thyroid hormone metabolism (e.g., glucuronidation, sulfation and deiodination). In addition, iodotyrosine deiodinase, which is involved in iodide salvage by catalyzing deiodination of iodinated by-products of thyroid hormone production, was recently identified as a possible new target for disruption of thyroid hormone homeostasis by environmental halogenated chemicals. This topic, after briefly summarizing findings on the thyroid hormone-disrupting action of environmental chemicals in mammals, focuses on the effects of environmental halogenated chemicals on iodotyrosine deiodinase activity.

  1. Frogs model man: In vivo thyroid hormone signaling during development.

    PubMed

    Sachs, Laurent M; Buchholz, Daniel R

    2017-01-01

    Thyroid hormone (TH) signaling comprises TH transport across cell membranes, metabolism by deiodinases, and molecular mechanisms of gene regulation. Proper TH signaling is essential for normal perinatal development, most notably for neurogenesis and fetal growth. Knowledge of perinatal TH endocrinology needs improvement to provide better treatments for premature infants and endocrine diseases during gestation and to counteract effects of endocrine disrupting chemicals. Studies in amphibians have provided major insights to understand in vivo mechanisms of TH signaling. The frog model boasts dramatic TH-dependent changes directly observable in free-living tadpoles with precise and easy experimental control of the TH response at developmental stages comparable to fetal stages in mammals. The hormones, their receptors, molecular mechanisms, and developmental roles of TH signaling are conserved to a high degree in humans and amphibians, such that with respect to developmental TH signaling "frogs are just little people that hop." The frog model is exceptionally illustrative of fundamental molecular mechanisms of in vivo TH action involving TH receptors, transcriptional cofactors, and chromatin remodeling. This review highlights the current need, recent successes, and future prospects using amphibians as a model to elucidate molecular mechanisms and functional roles of TH signaling during post-embryonic development.

  2. Novel Insights on Thyroid-Stimulating Hormone Receptor Signal Transduction

    PubMed Central

    Neumann, Susanne; Grüters, Annette; Krude, Heiko

    2013-01-01

    The TSH receptor (TSHR) is a member of the glycoprotein hormone receptors, a subfamily of family A G protein-coupled receptors. The TSHR is of great importance for the growth and function of the thyroid gland. The TSHR and its endogenous ligand TSH are pivotal proteins with respect to a variety of physiological functions and malfunctions. The molecular events of TSHR regulation can be summarized as a process of signal transduction, including signal reception, conversion, and amplification. The steps during signal transduction from the extra- to the intracellular sites of the cell are not yet comprehensively understood. However, essential new insights have been achieved in recent years on the interrelated mechanisms at the extracellular region, the transmembrane domain, and intracellular components. This review contains a critical summary of available knowledge of the molecular mechanisms of signal transduction at the TSHR, for example, the key amino acids involved in hormone binding or in the structural conformational changes that lead to G protein activation or signaling regulation. Aspects of TSHR oligomerization, signaling promiscuity, signaling selectivity, phenotypes of genetic variations, and potential extrathyroidal receptor activity are also considered, because these are relevant to an understanding of the overall function of the TSHR, including physiological, pathophysiological, and pharmacological perspectives. Directions for future research are discussed. PMID:23645907

  3. Hatching the Cleidoic Egg: The Role of Thyroid Hormones

    PubMed Central

    De Groef, Bert; Grommen, Sylvia V.H.; Darras, Veerle M.

    2013-01-01

    A major life stage transition in birds and other oviparous sauropsids is the hatching of the cleidoic egg. Not unlike amphibian metamorphosis, hatching in these species can be regarded as a transition from a relatively well-protected “aqueous” environment to a more hazardous and terrestrial life outside the egg, a transition in which thyroid hormones (THs) (often in concert with glucocorticoids) play an important role. In precocial birds such as the chicken, the perihatch period is characterized by peak values of THs. THs are implicated in the control of muscle development, lung maturation and the switch from chorioallantoic to pulmonary respiration, yolk sac retraction, gut development and induction of hepatic genes to accommodate the change in dietary energy source, initiation of thermoregulation, and the final stages of brain maturation as well as early post-hatch imprinting behavior. There is evidence that, at least for some of these processes, THs may have similar roles in non-avian sauropsids. In altricial birds such as passerines on the other hand, THs do not rise significantly until well after hatching and peak values coincide with the development of endothermy. It is not known how hatching-associated processes are regulated by hormones in these animals or how this developmental mode evolved from TH-dependent precocial hatching. PMID:23755041

  4. Comparison of the in vitro effects of TCDD, PCB 126 and PCB 153 on thyroid-restricted gene expression and thyroid hormone secretion by the chicken thyroid gland.

    PubMed

    Katarzyńska, Dorota; Hrabia, Anna; Kowalik, Kinga; Sechman, Andrzej

    2015-03-01

    The aim of this study was to compare the in vitro effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), 3,3',4,4',5-pentachlorobiphenyl (PCB 126; a coplanar PCB congener) and 2,2'4,4',5,5'-hexachlorobiphenyl (PCB153; non-coplanar PCB) on mRNA expression of thyroid-restricted genes, i.e. sodium iodide symporter (NIS), thyroid peroxidase (TPO) and thyroglobulin (TG), and thyroid hormone secretion from the thyroid gland of the laying chicken. Relative expression levels of NIS, TG and TPO genes and thyroxine (T4) and triiodothyronine (T3) secretion from the thyroidal explants were quantified by the real-time qPCR and RIA methods, respectively. In comparison with the control group, TCDD and PCB 126 significantly increased mRNA expression of TPO and TG genes. TCDD did not affect NIS mRNA levels, but PCB 126 decreased its expression. No effect of PCB 153 on the expression of these genes was observed. TCDD and PCB 126 significantly decreased T4 and T3 secretion. There was no significant effect of PCB 153 on these hormone secretions. In conclusion, the results obtained show that in comparison with non-coplanar PCB 153, TCDD and coplanar PCB 126 can directly affect thyroid hormone synthesis and secretion, and in consequence, they may disrupt the endocrine function of the thyroid gland of the laying chicken.

  5. THYROID HORMONE INSUFFICIENCY DURING BRAIN DEVELOPMENT REDUCES PARVALBUMIN IMMUNOREACTIVITY AND INHIBITORY FUNCTION IN THE HIPPOCAMPUS.

    EPA Science Inventory

    The EPA must evaluate the risk of exposure of the developing brain to chemicals with the potential to disrupt thyroid hormone homeostasis. The existing literature identifies morphological and neurochemical indices of severe neonatal hypothyroidism in the early postnatal period i...

  6. Computational Modeling of Thyroid Hormone Regulated Neurodevelopment for Chemical Prioritization (SOT)

    EPA Science Inventory

    Thyroid hormones (TH) are critical for normal brain development. Environmental chemicals may disrupt TH homeostasis through a variety of physiological systems including membrane transporters, serum transporters, synthesis and catabolic enzymes, and nuclear receptors. Current comp...

  7. THYROID HORMONE INSUFFICIENCY DURING BRAIN DEVELOPMENT REDUCES PARVALBUMIN IMMUNOREACTIVITY AND INHIBITORY FUNCTION IN THE HIPPOCAMPUS.

    EPA Science Inventory

    The EPA must evaluate the risk of exposure of the developing brain to chemicals with the potential to disrupt thyroid hormone homeostasis. The existing literature identifies morphological and neurochemical indices of severe neonatal hypothyroidism in the early postnatal period i...

  8. DEVELOPMENTAL THYROID HORMONE INSUFFICIENCY ALTERS THE AMPLITUDE OF THE ACOUSTIC STARTLE RESPONSE IN RATS

    EPA Science Inventory

    Purpose: The thyroid hormone (TH) system is one of the targets of endocrine disrupting chemicals. Since TH is essential for proper brain development, disruption by exposure to chemicals during development can result in adverse neurological outcomes. Previous studies revealed th...

  9. Computational Modeling of Thyroid Hormone Regulated Neurodevelopment for Chemical Prioritization (SOT)

    EPA Science Inventory

    Thyroid hormones (TH) are critical for normal brain development. Environmental chemicals may disrupt TH homeostasis through a variety of physiological systems including membrane transporters, serum transporters, synthesis and catabolic enzymes, and nuclear receptors. Current comp...

  10. RISK ASSESSMENT OF THYROID HORMONE DISRUPTION AND MIXTURES IN MARINE BIOTA

    EPA Science Inventory

    Varieties of chemicals alter thyroid hormones (THs) in vertabrates. The importance of THs during neurodevelopment, suggest that these chemicals would likely be developmental neurotoxicants. A number of epidemiological studies have demonstrated associations between exposure to p...

  11. Developmental Thyroid Hormone Insufficiency Impairs Visual Contrast Sensitivity in Adult Male Offspring.

    EPA Science Inventory

    Severe thyroid hormone (TH) insufficiency during early development results in alterations in brain structure and function. Many environmental agents produce subtle alterations in TH status, but the dose-response relationships for such effects are unclear. We have previously demon...

  12. DEVELOPMENTAL THYROID HORMONE INSUFFICIENCY ALTERS THE AMPLITUDE OF THE ACOUSTIC STARTLE RESPONSE IN RATS

    EPA Science Inventory

    Purpose: The thyroid hormone (TH) system is one of the targets of endocrine disrupting chemicals. Since TH is essential for proper brain development, disruption by exposure to chemicals during development can result in adverse neurological outcomes. Previous studies revealed th...

  13. MEASUREMENT OF THYROID HORMONES IN THE RAT SERA CONTAINING PERFLUOROOCTANESULFONATE (PFOS)

    EPA Science Inventory

    Perfluorooctanesulfonate (PFOS), a persistent and bioaccumulative acid, is widely distributed in humans and wildlife. Prior studies with PFOS (rats and monkeys) have observed decreased total and free thyroid hormones (TH) in serum without a rise in thyrotropin (TSH). Measuremen...

  14. Impact of Low-Level Thyroid Hormone Disruption Induced by Propylthiouracil on Brain Development and Function.*

    EPA Science Inventory

    The critical role of thyroid hormone (TH) in brain development is well established, severe deficiencies leading to significant neurological dysfunction. Much less information is available on more modest perturbations of TH on brain function. The present study induced varying degr...

  15. Developmental Thyroid Hormone Insufficiency Impairs Visual Contrast Sensitivity in Adult Male Offspring.

    EPA Science Inventory

    Severe thyroid hormone (TH) insufficiency during early development results in alterations in brain structure and function. Many environmental agents produce subtle alterations in TH status, but the dose-response relationships for such effects are unclear. We have previously demon...

  16. RISK ASSESSMENT OF THYROID HORMONE DISRUPTION AND MIXTURES IN MARINE BIOTA

    EPA Science Inventory

    Varieties of chemicals alter thyroid hormones (THs) in vertabrates. The importance of THs during neurodevelopment, suggest that these chemicals would likely be developmental neurotoxicants. A number of epidemiological studies have demonstrated associations between exposure to p...

  17. Impact of Low-Level Thyroid Hormone Disruption Induced by Propylthiouracil on Brain Development and Function.*

    EPA Science Inventory

    The critical role of thyroid hormone (TH) in brain development is well established, severe deficiencies leading to significant neurological dysfunction. Much less information is available on more modest perturbations of TH on brain function. The present study induced varying degr...

  18. Effects of a Model Inducer, Phenobarbital, on Thyroid Hormone Glucuronidation in Rat Hepatocytes

    EPA Science Inventory

    In vivo, hepatic enzyme inducers such as phenobarbital (PB) decrease circulating thyroid hormone (TH) concentrations. This decrease in circulating TH occurs in part through extrathyroidal mechanisms. Specifically, through the induction of hepatic xenobiotic metabolizing enzymes...

  19. Characterization of Thyroid Hormone Transporter Protein Expression during Tissue-specific Metamorphic Events in Xenopus tropicalis

    EPA Science Inventory

    Thyroid hormone (TH) induces the dramatic morphological and physiological changes that together comprise amphibian metamorphosis. TH-responsive tissues vary widely with developmental timing of TH-induced changes. How larval tadpole tissues are able to employ distinct metamorphi...

  20. Characterization of Thyroid Hormone Transporter Protein Expression during Tissue-specific Metamorphic Events in Xenopus tropicalis

    EPA Science Inventory

    Thyroid hormone (TH) induces the dramatic morphological and physiological changes that together comprise amphibian metamorphosis. TH-responsive tissues vary widely with developmental timing of TH-induced changes. How larval tadpole tissues are able to employ distinct metamorphi...

  1. Neonatal screening for congenital hypothyroidism by measurement of plasma thyroxine and thyroid stimulating hormone concentrations.

    PubMed Central

    Griffiths, K D; Virdi, N K; Rayner, P H; Green, A

    1985-01-01

    Neonatal screening for congenital hypothyroidism was introduced in the City of Birmingham in 1980 by measuring concentrations of both thyroid stimulating hormone and thyroxine in plasma. Over two years 30 108 babies were tested. Thirty one babies were recalled because of thyroid stimulating hormone concentrations greater than 40 mU/l, of whom 12 were treated with replacement thyroxine. Six babies were found to have low thyroxine concentrations because of reduced thyroxine binding globulin and five raised thyroxine values because of increased thyroxine binding globulin. As a result of this study screening was continued with measurement of thyroid stimulating hormone only as the primary test for congenital hypothyroidism, the thyroxine value being measured only when the concentration of thyroid stimulating hormone exceeded 20 mU/l. PMID:3926078

  2. MEASUREMENT OF THYROID HORMONES IN THE RAT SERA CONTAINING PERFLUOROOCTANESULFONATE (PFOS)

    EPA Science Inventory

    Perfluorooctanesulfonate (PFOS), a persistent and bioaccumulative acid, is widely distributed in humans and wildlife. Prior studies with PFOS (rats and monkeys) have observed decreased total and free thyroid hormones (TH) in serum without a rise in thyrotropin (TSH). Measuremen...

  3. Effects of a Model Inducer, Phenobarbital, on Thyroid Hormone Glucuronidation in Rat Hepatocytes

    EPA Science Inventory

    In vivo, hepatic enzyme inducers such as phenobarbital (PB) decrease circulating thyroid hormone (TH) concentrations. This decrease in circulating TH occurs in part through extrathyroidal mechanisms. Specifically, through the induction of hepatic xenobiotic metabolizing enzymes...

  4. Mechanism-based testing strategy using in vitro approaches for identification of thyroid hormone disrupting chemicals

    EPA Science Inventory

    The thyroid hormone (TH) system is involved in several important physiological processes, including regulation of energy metabolism, growth and differentiation, development and maintenance of brain function, thermo-regulation, osmo-regulation, and axis of regulation of other endo...

  5. Thyroid hormone influences muscle mechanics in carp (Cyprinus carpio) independently from SERCA activity.

    PubMed

    James, Rob S; Little, Alexander G; Tallis, Jason; Seebacher, Frank

    2016-09-15

    Thyroid hormone is a key regulator of metabolism, and in zebrafish, hypothyroidism decreases sustained and burst swimming performance. These effects are accompanied by decreases in both metabolic scope and the activity of sarco-endoplasmic reticulum ATPase (SERCA) in zebrafish. Our aim was to determine whether thyroid hormone affects skeletal muscle contractile function directly and whether these effects are mediated by influencing SERCA activity. We show that hypothyroidism reduces sustained locomotor performance but not sprint performance in carp (Cyprinus carpio). We accept our hypothesis that hypothyroidism reduces force production in isolated skeletal muscle, when compared with the thyroid hormone T2, but we reject the hypothesis that this effect is mediated by influencing SERCA activity. Blocking SERCA activity with thapsigargin reduced muscle fatigue resistance, but hypothyroidism had no effect on fatigue. Hence, thyroid hormone plays a role in determining isolated skeletal muscle mechanics, but its effects are more likely to be mediated by mechanisms other than affecting SERCA activity.

  6. Mechanism-based testing strategy using in vitro approaches for identification of thyroid hormone disrupting chemicals

    EPA Science Inventory

    The thyroid hormone (TH) system is involved in several important physiological processes, including regulation of energy metabolism, growth and differentiation, development and maintenance of brain function, thermo-regulation, osmo-regulation, and axis of regulation of other endo...

  7. Effect of thyroid hormone replacement therapy on ovarian volume and androgen hormones in patients with untreated primary hypothyroidism.

    PubMed

    Muderris, Iptisam Ipek; Boztosun, Abdullah; Oner, Gokalp; Bayram, Fahri

    2011-01-01

    Primary hypothyroidism may be associated with ovarian enlargement and/ or cyst formation. We evaluated the effect of thyroid hormone replacement therapy on hormonal changes, ovarian volume and sonographic appearance. Open, prospective study of women admitted to university gynecology clinic. The study included 26 patients with untreated hypothyroidism who had polycystic (n=10) or normal-appearing (n=16) ovaries and 20 euthyroidic controls. Basal serum total testosterone, free testosterone, androstenedione, dehydroepiandosterone-sulfate, prolactin, estradiol, luteinizing hormone, follicle-stimulating hormone, free T3, free T4 and thyroid-stimulating horone, together with ovarian volumes, were determined and repeated after euthyroidism was achieved. Ovarian volumes of patients with hypothyroidism were significantly greater compared with controls, and their magnitudes diminished significantly during thyroid hormone replacement therapy. Hypothyroidic patients with polycystic ovaries had significantly higher serum free testosterone and dehydroepiandosterone-sulfate, but lower androstenodione levels compared with those who had normal-appearing ovaries. Serum total testosterone concentrations were significantly higher in hypothyroidic patients without polycystic ovaries, and thyroid hormone replacement therapy achieved a significant reduction in total as well as free testosterone. Severe longstanding hypothyroidism leads to increased ovarian volume and/or cyst formation. A decrease in ovarian volume, resolution of ovarian cysts and reversal of the polycystic ovary syndrome-like appearance, together with improvement in serum hormone levels, occurred after euthyroidism was achieved.

  8. Tissue-specific thyroid hormone regulation of gene transcripts encoding iodothyronine deiodinases and thyroid hormone receptors in striped parrotfish (Scarus iseri).

    PubMed

    Johnson, Kaitlin M; Lema, Sean C

    2011-07-01

    In fish as in other vertebrates, the diverse functions of thyroid hormones are mediated at the peripheral tissue level through iodothyronine deiodinase (dio) enzymes and thyroid hormone receptor (tr) proteins. In this study, we examined thyroid hormone regulation of mRNAs encoding the three deiodinases dio1, dio2 and dio3 - as well as three thyroid hormone receptors trαA, trαB and trβ - in initial phase striped parrotfish (Scarus iseri). Parrotfish were treated with dissolved phase T(3) (20 nM) or methimazole (3 mM) for 3 days. Treatment with exogenous T(3) elevated circulating T(3), while the methimazole treatment depressed plasma T(4). Experimentally-induced hyperthyroidism increased the relative abundance of transcripts encoding trαA and trβ in the liver and brain, but did not affect trαB mRNA levels in either tissue. In both sexes, methimazole-treated fish exhibited elevated dio2 transcripts in the liver and brain, suggesting enhanced outer-ring deiodination activity in these tissues. Accordingly, systemic hyperthyroidism elevated relative dio3 transcript levels in these same tissues. In the gonad, however, patterns of transcript regulation were distinctly different with elevated T(3) increasing mRNAs encoding dio2 in testicular and ovarian tissues and dio3, trαA and trαB in the testes only. Thyroid hormone status did not affect dio1 transcript abundance in the liver, brain or gonads. Taken as a whole, these results demonstrate that thyroidal status influences relative transcript abundance for dio2 and dio3 in the liver, provide new evidence for similar patterns of dio2 and dio3 mRNA regulation in the brain, and make evident that fish exhibit tr subtype-specific transcript abundance changes to altered thyroid status.

  9. Analysis of thyroid hormones in gland and serum using liquid chromatography-tandem mass spectrometry

    EPA Science Inventory

    Thyroid hormones (THs), which are critical for growth and development in all vertebrates, can be impacted through chemical perturbation of the hypothalamic-pituitary-thyroid (HPT)-axis. Amphibian and mammalian models are being used to address this research priority within US EPA...

  10. [The disturbances of the thyroid hormone homeostasis caused by chemical substances occurring in natural environment].

    PubMed

    Kiałka, Marta; Doroszewska, Katarzyna; Mrozińska, Sandra; Milewicz, Tomasz; Stochmal, Ewa; Krzysiek, Józef

    2014-01-01

    The thyroid is an endocrine gland synthesizing, storaging and secreting thyroxine (T4) and triiodothyronine (T3). Currently, there are more and more reports and evidences that various chemical contaminants present in the environment, mainly polychlorinated biphenyls, interfere with stages of regulation, synthesis, secretion, transport of thyroid hormones. That can have a significant negative impact on the human body's endocrine homeostasis.

  11. HPLC-ICP/MS Analysis of Thyroid Hormone and Related Iodinated Compounds in Tissues and Media

    EPA Science Inventory

    Quantifying thyroid hormone (TH) and the synthetic precursors and metabolic products of TH is important for developing models of the hypothalamic-pituitary-thyroid (HPT) axis as well as for understanding the effects of xenobiotics on HPT axis function. In this study, the developm...

  12. Gene Expression in Developing Brain is Altered by Modest Reductions in Circulating Levels of Thyroid Hormone.

    EPA Science Inventory

    Disruption of thyroid hormone (TH) homeostasis is a known effect of environmental contaminants. Although animal models of developmental TH deficiency can predict the impact of severe insults to the thyroid system, the effects of moderate TH insufficiencies have not been adequatel...

  13. Analysis of thyroid hormones in gland and serum using liquid chromatography-tandem mass spectrometry

    EPA Science Inventory

    Thyroid hormones (THs), which are critical for growth and development in all vertebrates, can be impacted through chemical perturbation of the hypothalamic-pituitary-thyroid (HPT)-axis. Amphibian and mammalian models are being used to address this research priority within US EPA...

  14. Gene Expression in Developing Brain is Altered by Modest Reductions in Circulating Levels of Thyroid Hormone.

    EPA Science Inventory

    Disruption of thyroid hormone (TH) homeostasis is a known effect of environmental contaminants. Although animal models of developmental TH deficiency can predict the impact of severe insults to the thyroid system, the effects of moderate TH insufficiencies have not been adequatel...

  15. HPLC-ICP/MS Analysis of Thyroid Hormone and Related Iodinated Compounds in Tissues and Media

    EPA Science Inventory

    Quantifying thyroid hormone (TH) and the synthetic precursors and metabolic products of TH is important for developing models of the hypothalamic-pituitary-thyroid (HPT) axis as well as for understanding the effects of xenobiotics on HPT axis function. In this study, the developm...

  16. Thyroid gland removal - discharge

    MedlinePlus

    ... will make your scar show less. Thyroid Hormone Replacement You may need to take thyroid hormone medicine ... natural thyroid hormone. You may not need hormone replacement if only part of your thyroid was removed. ...

  17. Evolving research in nongenomic actions of aldosterone.

    PubMed

    Williams, Jonathan S

    2013-06-01

    Aldosterone is now recognized as an increasingly important contributor to cardiometabolic pathology via inflammatory and fibrosis-related pathways in addition to its classically described role in sodium and volume regulation. Consequently, much effort has been directed towards characterizing the molecular pathways involved in aldosterone-mediated fibrosis and inflammation. What was once viewed as straightforward steroid hormone biology is now appreciated as a highly complex and tightly regulated series of pathways and interactions. These recognitions have fuelled a multidisciplinary effort to identify precisely how aldosterone mediates intracellular activation of both genomic (latent) and nongenomic (rapid) mechanisms of influence. This review will explore recent novel pathways regulating aldosterone action, focusing on the nongenomic pathways. Several recent discoveries have redefined our understanding of aldosterone interactions at the cellular level. This includes activation of the mineralocorticoid receptor at the plasma membrane instead of via classical nuclear hormone receptor interaction, and identification of novel cofactor scaffolding proteins that modify aldosterone influence at the cellular level. In addition, aldosterone activation of secondary messenger system cascades can occur directly and independent of mineralocorticoid receptor interaction. Substantial progress in detailing the molecular biology of aldosterone regulation and action should facilitate study of how it exerts detrimental effects in cardiometabolic diseases. However, to date, the clinical impact of these discoveries has not been validated. Translational efforts are now required to determine if novel therapeutic targets can be developed.

  18. Activation and inactivation of thyroid hormone by deiodinases: local action with general consequences.

    PubMed

    Gereben, B; Zeöld, A; Dentice, M; Salvatore, D; Bianco, A C

    2008-02-01

    The thyroid hormone plays a fundamental role in the development, growth, and metabolic homeostasis in all vertebrates by affecting the expression of different sets of genes. A group of thioredoxin fold-containing selenoproteins known as deiodinases control thyroid hormone action by activating or inactivating the precursor molecule thyroxine that is secreted by the thyroid gland. These pathways ensure regulation of the availability of the biologically active molecule T3, which occurs in a time-and tissue-specific fashion. In addition, because cells and plasma are in equilibrium and deiodination affects central thyroid hormone regulation, these local deiodinase-mediated events can also affect systemic thyroid hormone economy, such as in the case of non-thyroidal illness. Heightened interest in the field has been generated following the discovery that the deiodinases can be a component in both the Sonic hedgehog signaling pathway and the TGR-5 signaling cascade, a G-protein-coupled receptor for bile acids. These new mechanisms involved in deiodinase regulation indicate that local thyroid hormone activation and inactivation play a much broader role than previously thought.

  19. Perfluoroalkyl substances exposure and thyroid hormones in humans: epidemiological observations and implications

    PubMed Central

    Lee, Jung Eun

    2017-01-01

    Thyroid hormones play crucial roles in normal neurodevelopment of fetus and child. Many chemicals can affect control and homeostasis of thyroid hormones, and eventually lead to various adverse health effects including neurodevelopmental disorders. Perfluoroalkyl substances (PFASs) are among the thyroid disrupting chemicals that can be encountered among general human population. Due to their unique physicochemical characteristics, PFASs have been used as surfactants and surface coating materials in many applications. Therefore, PFASs have been frequently detected in humans and environment worldwide. In cross-sectional studies using nationally representative general human populations of United States, several PFASs have shown significant associations with thyroid hormones. Moreover, among pregnant women and their infants, not only major PFASs such as perfluorooctane sulfonic acid and perfluorooctanoic acid, but also those with shorter or longer carbon chains showed significant associations with thyroid hormones. Often demographic characteristics such as sex, age, and disease status appear to influence the associations between PFASs exposure and thyroid hormones. In general, major PFASs showed hypothyroidism effects among pregnant women and infants. As 8 carbon based PFASs have been phased out, those with shorter or longer carbon chains have been used in growing amount as replacement. However, only limited information is available for their occurrences and toxicity among humans. Further investigations on these substituting PFASs are required. In addition, efforts are warranted to identify sources of and mitigate exposure to these thyroid disrupting chemicals especially during pregnancy and early stages of life. PMID:28443254

  20. Perfluoroalkyl substances exposure and thyroid hormones in humans: epidemiological observations and implications.

    PubMed

    Lee, Jung Eun; Choi, Kyungho

    2017-03-01

    Thyroid hormones play crucial roles in normal neurodevelopment of fetus and child. Many chemicals can affect control and homeostasis of thyroid hormones, and eventually lead to various adverse health effects including neurodevelopmental disorders. Perfluoroalkyl substances (PFASs) are among the thyroid disrupting chemicals that can be encountered among general human population. Due to their unique physicochemical characteristics, PFASs have been used as surfactants and surface coating materials in many applications. Therefore, PFASs have been frequently detected in humans and environment worldwide. In cross-sectional studies using nationally representative general human populations of United States, several PFASs have shown significant associations with thyroid hormones. Moreover, among pregnant women and their infants, not only major PFASs such as perfluorooctane sulfonic acid and perfluorooctanoic acid, but also those with shorter or longer carbon chains showed significant associations with thyroid hormones. Often demographic characteristics such as sex, age, and disease status appear to influence the associations between PFASs exposure and thyroid hormones. In general, major PFASs showed hypothyroidism effects among pregnant women and infants. As 8 carbon based PFASs have been phased out, those with shorter or longer carbon chains have been used in growing amount as replacement. However, only limited information is available for their occurrences and toxicity among humans. Further investigations on these substituting PFASs are required. In addition, efforts are warranted to identify sources of and mitigate exposure to these thyroid disrupting chemicals especially during pregnancy and early stages of life.

  1. Type 3 deiodinase, a thyroid-hormone inactivating enzyme, controls survival and maturation of cone photoreceptors

    PubMed Central

    Ng, Lily; Lyubarsky, Arkady; Nikonov, Sergei S.; Ma, Michelle; Srinivas, Maya; Kefas, Benjamin; St.Germain, Donald L.; Hernandez, Arturo; Pugh, Edward N.; Forrest, Douglas

    2010-01-01

    Maturation of the mammalian nervous system requires adequate provision of thyroid hormone and mechanisms that enhance tissue responses to the hormone. Here, we report that the development of cones, the photoreceptors for daylight and color vision, requires protection from thyroid hormone by type 3 deiodinase, a thyroid hormone-inactivating enzyme. Type 3 deiodinase, encoded by Dio3, is expressed in the immature mouse retina. In Dio3−/− mice, ~80% of cones are lost through neonatal cell death. Cones that express opsin photopigments for response to both short (S) and medium-long (M) wavelength light are lost. Rod photoreceptors, which mediate dim light vision, remain largely intact. Excessive thyroid hormone in wild type pups also eliminates cones. Cone loss is mediated by cone-specific thyroid hormone receptor β2 (TRβ2) as deletion of TRβ2 rescues cones in Dio3−/− mice. However, rescued cones respond to short but not longer wavelength light because TRβ2 under moderate hormonal stimulation normally induces M opsin and controls the patterning of M and S opsins over the retina. The results suggest that type 3 deiodinase limits hormonal exposure of the cone to levels that safeguard both cone survival and the patterning of opsins that is required for cone function. PMID:20203194

  2. Paradigm Shift in Thyroid Hormone Mechanism of Action | Center for Cancer Research

    Cancer.gov

    Thyroid hormone (TH) is one of the primary endocrine regulators of human metabolism and homeostasis. Acting through three forms of the thyroid hormone receptor (THR; alpha-1, beta-1, and beta-2), TH regulates target gene expression in nearly every cell in the body, modulating fundamental processes, such as basal metabolic rate, long bone growth, and neural maturation. TH is also essential for proper development and differentiation of all cells of the human body.

  3. Synthesis and evaluation of methylsulfonylnitrobenzamides (MSNBAs) as inhibitors of the thyroid hormone receptor-coactivator interaction

    PubMed Central

    Hwang, Jong Yeon; Attia, Ramy R.; Carrillo, Angela K.; Connelly, Michele C.; Guy, R. Kiplin

    2013-01-01

    We previously identified the methylsulfonylnitrobenzoates (MSNBs) that block the interaction of the thyroid hormone receptor with its obligate transcriptional coactivators and prevent thyroid hormone signaling. As part of our lead optimization work we demonstrated that sulfonylnitrophenylthiazoles (SNPTs), which replace the ester linkage of MSNBs with a thiazole, also inhibited coactivator binding to TR. Here we report that replacement of the ester with an amide (methylsulfonylnitrobenzamides, MSNBA) also provides active TR antagonists. PMID:23414840

  4. Identification of a new hormone-binding site on the surface of thyroid hormone receptor.

    PubMed

    Souza, P C T; Puhl, A C; Martínez, L; Aparício, R; Nascimento, A S; Figueira, A C M; Nguyen, P; Webb, P; Skaf, M S; Polikarpov, I

    2014-04-01

    Thyroid hormone receptors (TRs) are members of the nuclear receptor superfamily of ligand-activated transcription factors involved in cell differentiation, growth, and homeostasis. Although X-ray structures of many nuclear receptor ligand-binding domains (LBDs) reveal that the ligand binds within the hydrophobic core of the ligand-binding pocket, a few studies suggest the possibility of ligands binding to other sites. Here, we report a new x-ray crystallographic structure of TR-LBD that shows a second binding site for T3 and T4 located between H9, H10, and H11 of the TRα LBD surface. Statistical multiple sequence analysis, site-directed mutagenesis, and cell transactivation assays indicate that residues of the second binding site could be important for the TR function. We also conducted molecular dynamics simulations to investigate ligand mobility and ligand-protein interaction for T3 and T4 bound to this new TR surface-binding site. Extensive molecular dynamics simulations designed to compute ligand-protein dissociation constant indicate that the binding affinities to this surface site are of the order of the plasma and intracellular concentrations of the thyroid hormones, suggesting that ligands may bind to this new binding site under physiological conditions. Therefore, the second binding site could be useful as a new target site for drug design and could modulate selectively TR functions.

  5. Stimulatory effects of thyroid hormone on brain angiogenesis in vivo and in vitro.

    PubMed

    Zhang, Liqun; Cooper-Kuhn, Christiana Marie; Nannmark, Ulf; Blomgren, Klas; Kuhn, Hans Georg

    2010-02-01

    Thyroid hormone is critical for the proper development of the central nervous system. However, the specific role of thyroid hormone on brain angiogenesis remains poorly understood. Treatment of rats from birth to postnatal day 21 (P21) with propylthiouracil (PTU), a reversible blocker of triiodothyronine (T3) synthesis, resulted in decreased brain angiogenesis, as indicated by reduced complexity and density of microvessels. However, when PTU was withdrawn at P22, these parameters were fully recovered by P90. These changes were paralleled by an altered expression of vascular endothelial growth factor A (Vegfa) and basic fibroblast growth factor (Fgf2). Physiologic concentrations of T3 and thyroxine (T4) stimulated proliferation and tubulogenesis of rat brain-derived endothelial (RBE4) cells in vitro. Protein and mRNA levels of VEGF-A and FGF-2 increased after T3 stimulation of RBE4 cells. The thyroid hormone receptor blocker NH-3 abolished T3-induced Fgf2 and Vegfa upregulation, indicating a receptor-mediated effect. Thyroid hormone inhibited the apoptosis in RBE4 cells and altered mRNA levels of apoptosis-related genes, namely Bcl2 and Bad. The present results show that thyroid hormone has a substantial impact on vasculature development in the brain. Pathologically altered vascularization could, therefore, be a contributing factor to the neurologic deficits induced by thyroid hormone deficiency.

  6. Beyond low plasma T3: local thyroid hormone metabolism during inflammation and infection.

    PubMed

    Boelen, Anita; Kwakkel, Joan; Fliers, Eric

    2011-10-01

    Decreased serum thyroid hormone concentrations in severely ill patients were first reported in the 1970s, but the functional meaning of the observed changes in thyroid hormone levels, together known as nonthyroidal illness syndrome (NTIS), remains enigmatic. Although the common view was that NTIS results in overall down-regulation of metabolism in order to save energy, recent work has shown a more complex picture. NTIS comprises marked variation in transcriptional and translational activity of genes involved in thyroid hormone metabolism, ranging from inhibition to activation, dependent on the organ or tissue studied. Illness-induced changes in each of these organs appear to be very different during acute or chronic inflammation, adding an additional level of complexity. Organ- and timing-specific changes in the activity of thyroid hormone deiodinating enzymes (deiodinase types 1, 2, and 3) highlight deiodinases as proactive players in the response to illness, whereas the granulocyte is a novel and potentially important cell type involved in NTIS during bacterial infection. Although acute NTIS can be seen as an adaptive response to support the immune response, NTIS may turn disadvantageous when critical illness enters a chronic phase necessitating prolonged life support. For instance, changes in thyroid hormone metabolism in muscle during critical illness may be relevant for the pathogenesis of myopathy associated with prolonged ventilator dependence. This review focuses on NTIS as a timing-related and organ-specific response to illness, occurring independently from the decrease in serum thyroid hormone levels and potentially relevant for disease progression.

  7. Resistance to thyroid hormone is associated with raised energy expenditure, muscle mitochondrial uncoupling, and hyperphagia

    PubMed Central

    Mitchell, Catherine S.; Savage, David B.; Dufour, Sylvie; Schoenmakers, Nadia; Murgatroyd, Peter; Befroy, Douglas; Halsall, David; Northcott, Samantha; Raymond-Barker, Philippa; Curran, Suzanne; Henning, Elana; Keogh, Julia; Owen, Penny; Lazarus, John; Rothman, Douglas L.; Farooqi, I. Sadaf; Shulman, Gerald I.; Chatterjee, Krishna; Petersen, Kitt Falk

    2010-01-01

    Resistance to thyroid hormone (RTH), a dominantly inherited disorder usually associated with mutations in thyroid hormone receptor β (THRB), is characterized by elevated levels of circulating thyroid hormones (including thyroxine), failure of feedback suppression of thyrotropin, and variable tissue refractoriness to thyroid hormone action. Raised energy expenditure and hyperphagia are recognized features of hyperthyroidism, but the effects of comparable hyperthyroxinemia in RTH patients are unknown. Here, we show that resting energy expenditure (REE) was substantially increased in adults and children with THRB mutations. Energy intake in RTH subjects was increased by 40%, with marked hyperphagia particularly evident in children. Rates of muscle TCA cycle flux were increased by 75% in adults with RTH, whereas rates of ATP synthesis were unchanged, as determined by 13C/31P magnetic resonance spectroscopy. Mitochondrial coupling index between ATP synthesis and mitochondrial rates of oxidation (as estimated by the ratio of ATP synthesis to TCA cycle flux) was significantly decreased in RTH patients. These data demonstrate that basal mitochondrial substrate oxidation is increased and energy production in the form of ATP synthesis is decreased in the muscle of RTH patients and that resting oxidative phosphorylation is uncoupled in this disorder. Furthermore, these observations suggest that mitochondrial uncoupling in skeletal muscle is a major contributor to increased REE in patients with RTH, due to tissue selective retention of thyroid hormone receptor α sensitivity to elevated thyroid hormone levels. PMID:20237409

  8. Dose-Response Analysis of Developmental Iodide Deficiency: Reductions in Thyroid Hormones and Impaired Hippocampal Synaptic Transmission

    EPA Science Inventory

    Iodide is an essential nutrient for thyroid hormone synthesis and severe iodide deficiency (ID) during early development is associated with neurological impairments. Several environmental contaminants can perturb the thyroid axis and this perturbation may be more acute under cond...

  9. Predictive Modeling of a Mixture of Thyroid Hormone Disrupting Chemicals that Affect Production and Clearance of Thyroxine

    EPA Science Inventory

    Thyroid hormone (TH) disrupting compounds interfere with both thyroidal and extrathyroidal mechanisms to decrease circulating thyroxine (T4). This research tested the hypothesis that serum T4 concentrations of rodents exposed to a mixture of both TH synthesis inhibitors (pesticid...

  10. Dose-Response Analysis of Developmental Iodide Deficiency: Reductions in Thyroid Hormones and Impaired Hippocampal Synaptic Transmission

    EPA Science Inventory

    Iodide is an essential nutrient for thyroid hormone synthesis and severe iodide deficiency (ID) during early development is associated with neurological impairments. Several environmental contaminants can perturb the thyroid axis and this perturbation may be more acute under cond...

  11. Predictive Modeling of a Mixture of Thyroid Hormone Disrupting Chemicals that Affect Production and Clearance of Thyroxine

    EPA Science Inventory

    Thyroid hormone (TH) disrupting compounds interfere with both thyroidal and extrathyroidal mechanisms to decrease circulating thyroxine (T4). This research tested the hypothesis that serum T4 concentrations of rodents exposed to a mixture of both TH synthesis inhibitors (pesticid...

  12. Food intake regulation of circulating thyroid hormones in domestic fowl.

    PubMed

    Klandorf, H; Harvey, S

    1985-11-01

    The relationship between food intake and thyroid function has been investigated in immature domestic fowl. Starvation delayed, but did not suppress, the triiodothyronine (T3) response to intravenously administered thyrotropin-releasing hormone (10 micrograms/kg). This probably resulted from a suppression of monodeiodinase activity, since the conversion of thyroxine (T4) to T3 in thyroidectomised birds following an intramuscular injection of T4 (10 micrograms/kg) was markedly reduced by starvation. Starvation, for 24 or 48 hr, lowered the circulating T3 level but increased the T4 concentration. When fasted birds were refed the T4 concentration was initially enhanced but subsequently declined as the T3 concentration progressively increased. The accompanying decline in the T4:T3 ratio in fasted-refed birds indicated that the rise in the T3 level resulted from the peripheral monodeiodination of T4. The increase in T3 concentration could be induced solely by carbohydrate; the intraperitoneal administration of glucose (2.0 g/kg) to fasted birds resulting in a slight, transient rise in the T3 concentration and a fall in the T4:T3 ratio. The generation of T3 was also energy dependent, in that the magnitude of the T3 response of fasted birds to refeeding was proportional to the amount of food consumed and to the metabolisable energy (ME) content of the diet. Moreover, when exogenous T4 (100 micrograms/kg) was intramuscularly administered to thyroidectomised birds fed a diet with a high ME content, the conversion of T4 to T4 was greater than that in birds fed a diet of lower ME content. These results demonstrate that nutritional stimuli are involved in the regulation of thyroid function in birds, particularly in the peripheral generation of T3.

  13. Effects of acute microinjections of thyroid hormone to the preoptic region of hypothyroid adult male rats on sleep, motor activity and body temperature.

    PubMed

    Moffett, Steven X; Giannopoulos, Phillip F; James, Thomas D; Martin, Joseph V

    2013-06-21

    Thyroid hormones induce short-latency nongenomic effects in adult brain tissue, suggesting that their acute administration would affect brain activity in intact animals. The influence on EEG-defined sleep of acute restoration of l-3,3'5-triiodothyronine (T3) to a sleep-regulatory brain region, the preoptic region, was examined in hypothyroid rats. Sleep parameters were monitored for 48 h weekly: for 24 h immediately following a control microinjection and for an additional 24h after a second microinjection including a T3 dose to the preoptic region or lateral ventricle. Male albino rats were implanted with EEG and EMG electrodes, abdominal temperature/activity transponders and unilateral lateral ventricle cannulae or bilateral preoptic region cannulae, and were given 0.02% n-propythiouracil (PTU) in their drinking water for 4 weeks. For histologically-confirmed bilateral preoptic region cannula placements (N=7), effects of T3 (especially a 3 μg dose) were apparent within 10h of injection as decreases in REM, NREM and total sleep and increases in waking and activity. Minimal effects of lateral ventricle T3 microinjection were demonstrated (N=5). Significant effects due to the time of day on the experimental measures were seen in both lateral ventricle and preoptic region groups, but these effects did not interact with the effect of administered hormone dose. These effects of T3 microinjection to the preoptic region were demonstrated after acute injections and within hours of injection rather than after chronic administration over days.

  14. Economic Evaluation of Recombinant Human Thyroid Stimulating Hormone Stimulation vs. Thyroid Hormone Withdrawal Prior to Radioiodine Ablation for Thyroid Cancer: The Korean Perspective

    PubMed Central

    Sohn, Seo Young; Jang, Hye Won; Cho, Yoon Young; Kim, Sun Wook

    2015-01-01

    Background Previous studies have suggested that recombinant human thyroid stimulating hormone (rhTSH) stimulation is an acceptable alternative to thyroid hormone withdrawal (THW) when radioiodine remnant ablation is planned for thyroid cancer treatment, based on superior short-term quality of life with non-inferior remnant ablation efficacy. This study evaluated the cost-effectiveness of radioiodine remnant ablation using rhTSH, compared with the traditional preparation method which renders patients hypothyroid by THW, in Korean perspective. Methods This economic evaluation considered the costs and benefits to the Korean public healthcare system. Clinical experts were surveyed regarding the current practice of radioiodine ablation in Korea and their responses helped inform assumptions used in a cost effectiveness model. Markov modelling with 17 weekly cycles was used to assess the incremental costs per quality-adjusted life year (QALY) associated with rhTSH. Clinical inputs were based on a multi-center, randomized controlled trial comparing remnant ablation success after rhTSH preparation with THW. The additional costs associated with rhTSH were considered relative to the clinical benefits and cost offsets. Results The additional benefits of rhTSH (0.036 QALY) are achieved with an additional cost of Korean won ₩961,105, equating to cost per QALY of ₩26,697,361. Sensitivity analyses had only a modest impact upon cost-effectiveness, with one-way sensitivity results of approximately ₩33,000,000/QALY. Conclusion The use of rhTSH is a cost-effective alternative to endogenous hypothyroid stimulation prior to radioiodine ablation for patients who have undergone thyroidectomy in Korea. PMID:26394733

  15. Effects of sub-lethal heroin administration on thyroid stimulating hormone (TSH), thyroid hormones (T3, T4) and thyroid gland of Mus norvegicus.

    PubMed

    Bhoir, Kaminidevi K; Suryawanshi, S A; Pandey, A K

    2009-11-01

    Serum TSH level of control Mus norvegicus fluctuated between 498.20 +/- 21.92 and 506.80 +/- 22.35 ng ml(-1), thyroxine (T4) between 68.17 +/- 3.46 and 69.03 +/- 4.12 microg dl(-1) and triiodothyronine (T3) between 4.76 +/- 0.52 and 5.00 +/- 0.66 microg dl(-1). Sub-lethal heroin administration induced a significant decline in the levels of all the three hormones at 24 hr and 15 days post-administration. Decline in the levels of these hormones registered the lowest values (p<0.001) by day 30 of the treatment. Thyroid gland of control rat consisted of spherical, round follicles lined with low cuboidal and columnar epithelial cells and lumina filled with eosinophilic colloid. Ultrastructurally, the thyroid follicular cells showed the presence of round nuclei, polymorphic mitochondria, Golgi complex as well as lysosomes located on the apical side of the nucleus and cytoplasm with different sizes of lipid droplets and smooth along with rough endoplasmic reticulum. Basal lamina of the follicular cells was often in association with the endothelium of the capillaries. Sub-lethal heroin administration for 30 days elicited degenerative changes in the follicular epithelial cells as evident by the vacuolization of cytoplasm, pycnotic nuclei and reduced colloidal content. Ultrastructurally, the thyroid follicular cells showed indented nuclei with heavy deposition of chromatin material on the inner membrane of nucleus and dilated rough endoplasmic reticulum. Along with RBC infiltration, vesiculated mitochondria owing to the loss of cristae were also seen. Diffused electron-dense material was seen at the periphery of the cell body. Heroin treatment caused cellular necrosis as revealed by the fragmentation of cytoplasmic materials in follicular epithelial cells of the gland.

  16. Degradation of Thyroid Hormones by Phagocytosing Human Leukocytes

    PubMed Central

    Klebanoff, Seymour J.; Green, William L.

    1973-01-01

    Thyroxine (T4) and triiodothyronine (T9) are rapidly degraded by a purified preparation of myeloperoxidase (MPO) and H2O2 with the formation of iodide and material which remains at the origin on paper chromatography. Deiodination by MPO and H2O2 occurs more readily at pH 7.0 than at pH 5.0 in contrast to iodination by this system which is known to occur more readily at pH 5.0 than at pH 7.0. Degradation is inhibited by azide, cyanide, ascorbic acid, and propylthiouracil. Methimazole stimulates deiodination by MPO and H2O2 but inhibits this reaction when MPO is replaced by lactoperoxidase or horseradish peroxidase. Intact human leukocytes, in the resting state, degrade T4 and T3 slowly: degradation, however, is increased markedly during phagocytosis of preopsonized particles. Serum inhibits this reaction. T3 can be detected as a minor product of T4 degradation. Proteolytic digestion of the reaction products increases the recovery of monoiodotyrosine. The fixation of iodine in the cytoplasm of leukocytes which contain ingested bacteria was detected radioautographically. Chronic granulomatous disease leukocytes, which are deficient in H2O2 formation, degrade T4 and T3 poorly during phagocytosis. MPO-deficient leukocytes degrade the thyroid hormones at a slower rate than do normal leukocytes although considerable degradation is still observed. Azide, cyanide, ascorbic acid, and propylthiouracil which inhibit certain peroxidasecatalyzed reactions inhibit degradation by normal leukocytes; however, inhibition is incomplete. Formation of iodinated origin material is inhibited to a greater degree by azide, cyanide, and propylthiouracil than is deiodination. Methimazole inhibits the formation of iodinated origin material by both normal and MPO-deficient leukocytes. However, deiodination by normal leukocytes is stimulated and that of MPO-deficient leukocytes is unaffected by methimazole. Hypoxia inhibits the degradation of T4 and T3 by untreated normal or MPO

  17. [Efficacy of quinagolide in the treatment of a patient with hypophyseal resistance to thyroid hormones].

    PubMed

    De Luis, D A; Lahera, M; Botella, J I; Valero, M A; Varela, C

    2001-05-01

    The pituitary resistance to thyroid hormones (PRTH) is not very frequent and well-known entity, their treatment it continues being topic of controversy. In this work we have evaluated the quinagolida effectiveness in the treatment of it unites patient with (PRTH). The relationship among thyroid stimulating hormone (TSH) and free triiodothyronine (FT3) it was used as marker of the thyroid resistance and of the response to the treatment. The concentrations of TSH and FT3 were normalized after adding quinagolida to methimazole. These results suggest that the quinagolida could be an useful drug in the treatment of this pathology, next to the classic treatments.

  18. Mitochondrial F0F1-ATP synthase is a molecular target of 3-iodothyronamine, an endogenous metabolite of thyroid hormone

    PubMed Central

    Cumero, S; Fogolari, F; Domenis, R; Zucchi, R; Mavelli, I; Contessi, S

    2012-01-01

    BACKGROUND AND PURPOSE 3-iodothyronamine (T1AM) is a metabolite of thyroid hormone acting as a signalling molecule via non-genomic effectors and can reach intracellular targets. Because of the importance of mitochondrial F0F1-ATP synthase as a drug target, here we evaluated interactions of T1AM with this enzyme. EXPERIMENTAL APPROACH Kinetic analyses were performed on F0F1-ATP synthase in sub-mitochondrial particles and soluble F1-ATPase. Activity assays and immunodetection of the inhibitor protein IF1 were used and combined with molecular docking analyses. Effects of T1AM on H9c2 cardiomyocytes were measured by in situ respirometric analysis. KEY RESULTS T1AM was a non-competitive inhibitor of F0F1-ATP synthase whose binding was mutually exclusive with that of the inhibitors IF1 and aurovertin B. Both kinetic and docking analyses were consistent with two different binding sites for T1AM. At low nanomolar concentrations, T1AM bound to a high-affinity region most likely located within the IF1 binding site, causing IF1 release. At higher concentrations, T1AM bound to a low affinity-region probably located within the aurovertin binding cavity and inhibited enzyme activity. Low nanomolar concentrations of T1AM increased ADP-stimulated mitochondrial respiration in cardiomyocytes, indicating activation of F0F1-ATP synthase consistent with displacement of endogenous IF1,, reinforcing the in vitro results. CONCLUSIONS AND IMPLICATIONS Effects of T1AM on F0F1-ATP synthase were twofold: IF1 displacement and enzyme inhibition. By targeting F0F1-ATP synthase within mitochondria, T1AM might affect cell bioenergetics with a positive effect on mitochondrial energy production at low, endogenous, concentrations. T1AM putative binding locations overlapping with IF1 and aurovertin binding sites are described. PMID:22452346

  19. Hyperresponse to Thyrotropin-Releasing Hormone Accompanying Small Decreases in Serum Thyroid Hormone Concentrations

    PubMed Central

    Vagenakis, Apostolos G.; Rapoport, Basil; Azizi, Fereidoun; Portnay, Gary I.; Braverman, Lewis E.; Ingbar, Sidney H.

    1974-01-01

    To determine whether pituitary thyrotropin (TSH) responsiveness to thyrotropin-releasing hormone (TRH) is enhanced by small decreases in serum thyroxine (T4) and triiodothyronine (T3), 12 euthyroid volunteers were given 190 mg iodide po daily for 10 days to inhibit T4 and T3 release from the thyroid. Basal serum T4, T3, and TSH concentrations and the serum T4 and TSH responses to 400 μg TRH i.v. were assessed before and at the end of iodide administration. Iodide induced small but highly significant decreases in basal serum T4 (8.0±1.6 vs. 6.6±1.7 μg/100 ml; mean ± SD) and T3 (128±15 vs. 110±22 ng/100 ml) and increases in basal serum TSH (1.3±0.9 vs. 2.1±1.0 μU/ml). During iodide administration, the TSH response to TRH was significantly increased at each of seven time points up to 120 min. The maximum increment in serum TSH after TRH increased from a control mean of 8.8±4.1 to a mean of 13.0±2.8 μU/ml during iodide administration. As evidence of the inhibitory effect of iodide on hormonal release, the increment in serum T3 at 120 min after TRH was significantly lessened during iodide administration (61±42 vs. 33±24 ng/100 ml). These findings demonstrate that small acute decreases in serum T4 and T3 concentrations, resulting in values well within the normal range, are associated both with slight increases in basal TSH concentrations and pronounced increases in the TSH response to TRH. These results demonstrate that a marked sensitivity of TSH secretion and responsiveness to TRH is applicable to decreasing, as well as increasing, concentrations of thyroid hormones. PMID:4214837

  20. Guidelines for the Treatment of Hypothyroidism: Prepared by the American Thyroid Association Task Force on Thyroid Hormone Replacement

    PubMed Central

    Bianco, Antonio C.; Bauer, Andrew J.; Burman, Kenneth D.; Cappola, Anne R.; Celi, Francesco S.; Cooper, David S.; Kim, Brian W.; Peeters, Robin P.; Rosenthal, M. Sara; Sawka, Anna M.

    2014-01-01

    Background: A number of recent advances in our understanding of thyroid physiology may shed light on why some patients feel unwell while taking levothyroxine monotherapy. The purpose of this task force was to review the goals of levothyroxine therapy, the optimal prescription of conventional levothyroxine therapy, the sources of dissatisfaction with levothyroxine therapy, the evidence on treatment alternatives, and the relevant knowledge gaps. We wished to determine whether there are sufficient new data generated by well-designed studies to provide reason to pursue such therapies and change the current standard of care. This document is intended to inform clinical decision-making on thyroid hormone replacement therapy; it is not a replacement for individualized clinical judgment. Methods: Task force members identified 24 questions relevant to the treatment of hypothyroidism. The clinical literature relating to each question was then reviewed. Clinical reviews were supplemented, when relevant, with related mechanistic and bench research literature reviews, performed by our team of translational scientists. Ethics reviews were provided, when relevant, by a bioethicist. The responses to questions were formatted, when possible, in the form of a formal clinical recommendation statement. When responses were not suitable for a formal clinical recommendation, a summary response statement without a formal clinical recommendation was developed. For clinical recommendations, the supporting evidence was appraised, and the strength of each clinical recommendation was assessed, using the American College of Physicians system. The final document was organized so that each topic is introduced with a question, followed by a formal clinical recommendation. Stakeholder input was received at a national meeting, with some subsequent refinement of the clinical questions addressed in the document. Consensus was achieved for all recommendations by the task force. Results: We reviewed the

  1. The Effect of Central Injection of Ghrelin and Bombesin on Mean Plasma Thyroid Hormones Concentration

    PubMed Central

    Mahmoudi, Fariba; Mohsennezhad, Fatemeh; Khazali, Homayoun; Ehtesham, Haleh

    2011-01-01

    Ghrelin increases food intakes and body weight. Bombesin decreases food intakes and inhibits the stimulatory effect of Ghrelin on food intakes. Thyroid hormones have a crucial role in the regulation of body weight and yet the effect of bombesin on thyroid axis activity is not fully clear. Therefore, the goal of this study was to determine the effect of different doses of Ghrelin or bombesin on mean plasma thyroid-stimulating hormone (TSH), Triiodothyronine (T3) and Thyroxin (T4) concentration and also, the effect of interaction between Ghrelin and bombesin on thyroid axis activity. Forty-nine rats in seven groups received saline or different doses of Ghrelin (4, 10 or 15 nmol) and bombesin ( 2.5, 5 or 10 nmol) and forty-two rats in six groups received simultaneous injection of Ghrelin (10 or 15 nmol) and different doses of bombesin (2.5, 5 or 10 nmol) via lateral cerebral ventricle. Blood samples were collected via decapitation 20 min after the injection and plasma was assayed for plasma TSH, T3 and T4 concentration by Radioimmunoassay (RIA). Ghrelin significantly decreased the concentration of mean plasma thyroid hormones compared to saline. Bombesin did not significantly increase thyroid hormones concentration compared to saline but bombesin blocked the inhibitory effect of Ghrelin on thyroid axis activity. Bombesin may be the antagonist of Ghrelin action. PMID:24250396

  2. A clinical and therapeutic approach to thyrotoxicosis with thyroid-stimulating hormone suppression only.

    PubMed

    Papi, Giampaolo; Papi, Giovanni; Pearce, Elizabeth N; Braverman, Lewis E; Betterle, Corrado; Roti, Elio

    2005-04-01

    Subclinical hyperthyroidism is defined as normal serum free thyroxine (T4) and triiodothyronine (T3) concentrations and persistently suppressed thyroid stimulating hormone (TSH) concentrations. The most common cause of subclinical hyperthyroidism is the use of suppressive doses of L-thyroxine for treatment of hypothyroidism or, less commonly, diffuse nontoxic goiter or thyroid carcinoma (exogenous subclinical hyperthyroidism). Endogenous subclinical hyperthyroidism may be caused by a variety of thyroid disorders that result in overproduction and release of thyroid hormones from the gland with normal/high 24-hour thyroid radioiodine uptake or by inflammation in the thyroid resulting in release of excess thyroid hormones and low 24-hour thyroid radioiodine uptake. Several groups have investigated whether persistent endogenous or exogenous subclinical hyperthyroidism, like overt hyperthyroidism, causes symptoms, adverse effects on the cardiovascular and the skeletal systems, and increased mortality, whether endogenous subclinical hyperthyroidism evolves to overt thyrotoxicosis, and whether or not it should be treated. The present report reviews the most important and recent studies of subclinical hyperthyroidism and attempts to draw conclusions based upon the literature and the authors' experience.

  3. Targeting the thyroid-stimulating hormone receptor with small molecule ligands and antibodies

    PubMed Central

    Davies, Terry F; Latif, Rauf

    2015-01-01

    Introduction The thyroid-stimulating hormone receptor (TSHR) is the essential molecule for thyroid growth and thyroid hormone production. Since it is also a key autoantigen in Graves’ disease and is involved in thyroid cancer pathophysiology, the targeting of the TSHR offers a logical model for disease control. Areas covered We review the structure and function of the TSHR and the progress in both small molecule ligands and TSHR antibodies for their therapeutic potential. Expert opinion Stabilization of a preferential conformation for the TSHR by allosteric ligands and TSHR antibodies with selective modulation of the signaling pathways is now possible. These tools may be the next generation of therapeutics for controlling the pathophysiological consequences mediated by the effects of the TSHR in the thyroid and other extrathyroidal tissues. PMID:25768836

  4. Catechin induced modulation in the activities of thyroid hormone synthesizing enzymes leading to hypothyroidism.

    PubMed

    Chandra, Amar K; De, Neela

    2013-02-01

    Catechins, the flavonoids found in abundance in green tea, have many beneficial health effects such as antioxidative, anticarcinogenic, anti-inflammatory, antiallergic, and hypotensive properties. However, flavonoids have antithyroid/goitrogenic effect, although less information is available about the effect of pure catechin on thyroid physiology. The present investigation has been undertaken to explore the effect of catechin administration on thyroid physiology in rat model. For the in vivo experiment catechin was injected intraperitoneally (i.p.) at doses of 10, 20 and 30 mg/kg body to male albino rats for 15 and 30 days, respectively, and thyroid activities were evaluated with respect to determination of serum levels of thyroid hormones, thyroid peroxidase, 5'-deiodinase I (5'-DI), and Na(+), K(+)-ATPase activities that are involved in the synthesis of thyroid hormone. Catechin decreased the activities of thyroid peroxidase and thyroidal 5'-deiodinase I, while Na(+), K(+)-ATPase activity significantly increased in dose-dependent manner; substantial decrease in serum T3 and T4 levels coupled with significant elevation of serum TSH were also noted. Histological examinations of the thyroid gland revealed marked hypertrophy and/or hyperplasia of the thyroid follicles with depleted colloid content. In in vitro study, short-term exposure of rat thyroid tissue to catechin at the concentrations of 0.10, 0.20, and 0.30 mg/ml leads to decrease in the activities of thyroid peroxidase and 5'-deiodinase I, while the activity of thyroidal Na(+), K(+)-ATPase remains unaltered even at high concentration of catechin treatment. The present study reinforces the concept that catechin, tea flavonoids possess potent antithyroid activity as evidenced from in vivo and in vitro studies.

  5. Effect of obesity and starvation on thyroid hormone, growth hormone, and cortisol secretion.

    PubMed

    Douyon, Liselle; Schteingart, David E

    2002-03-01

    Obesity and starvation have opposing affects on normal physiology and are associated with adaptive changes in hormone secretion. The effects of obesity and starvation on thyroid hormone, GH, and cortisol secretion are summarized in Table 1. Although hypothyroidism is associated with some weight gain, surveys of obese individuals show that less than 10% are hypothyroid. Discrepancies have been reported in some studies, but in untreated obesity, total and free T4, total and free T3, TSH levels, and the TSH response to TRH are normal. Some reports suggest an increase in total T3 and decrease in rT3 induced by overfeeding. Treatment of obesity with hypocaloric diets causes changes in thyroid function that resemble sick euthyroid syndrome. Changes consist of a decrease in total T4 and total and free T3 with a corresponding increase in rT3. untreated obesity is also associated with low GH levels; however, levels of IGF-1 are normal. GH-binding protein levels are increased and the GH response to GHRH is decreased. These changes are reversed by drastic weight reduction. Cortisol levels are abnormal in people with abdominal obesity who exhibit an increase in urinary free cortisol but exhibit normal or decreased serum cortisol and normal ACTH levels. These changes are explained by an increase in cortisol clearance. There is also an increased response to CRH. Treatment of obesity with very low calorie diets causes a decrease in serum cortisol explained by a decrease in cortisol-binding proteins. The increase in cortisol secretion seen in patients with abdominal obesity may contribute to the metabolic syndrome (insulin resistance, glucose intolerance, dyslipidemia, and hypertension). States of chronic starvation such as seen in anorexia nervosa are also associated with changes in thyroid hormone, GH, and cortisol secretion. There is a decrease in total and free T4 and T3, and an increase in rT3 similar to findings in sick euthyroid syndrome. The TSH response to TRH is

  6. Effects of thyroid hormone on the GH signal transduction pathway.

    PubMed

    Ocaranza, Paula; Lammoglia, Juan Javier; Iñiguez, Germán; Román, Rossana; Cassorla, Fernando

    2014-02-01

    The importance of thyroid hormone on growth and development in children is well recognized. In addition, linear growth is highly dependent on the response of peripheral tissues to growth hormone, a process known as GH sensitivity, but little is known about the possible effects of T4 on this process. We determined the effect of stimulation with recombinant human GH (rhGH; 200 ng/mL) alone or in combination with two different concentrations of T4 (250 nM and 500 nM for 24 h) on JAK2 and STAT5 activation in skin fibroblast cultures obtained from prepubertal boys with normal height. JAK2 and STAT5 were activated under co-incubation with T4 (at both concentrations) and rhGH in the non-nuclear fraction of the fibroblasts. In addition, after 24h of co-incubation with rhGH and T4 (500 nM), we observed an increase in phospho-STAT5 in the nuclear fraction, when compared to GH and T4 stimulation alone. This effect was not observed when the fibroblasts were co-incubated with GH and the lower concentration of T4 (250 nM). Combined stimulation with GH and T4 at a concentration of 500 nM increases synergistically nuclear phospho-STAT5 in skin fibroblasts, which may amplify tissue sensitivity to GH. These findings may help to explain the effect of T4 administration on growth velocity in some children with idiopathic short stature. Copyright © 2014 Elsevier Ltd. All rights reserved.

  7. The MCT8 thyroid hormone transporter and Allan-Herndon-Dudley syndrome.

    PubMed

    Schwartz, Charles E; Stevenson, Roger E

    2007-06-01

    Thyroid hormone is essential for the proper development and function of the brain. The active form of thyroid hormone is T(3), which binds to nuclear receptors. Recently, a transporter specific for T(3), MCT8 (monocarboxylate transporter 8) was identified. MCT8 is highly expressed in liver and brain. The gene is located in Xq13 and mutations in MCT8 are responsible for an X-linked condition, Allan-Herndon-Dudley syndrome (AHDS). This syndrome is characterized by congenital hypotonia that progresses to spasticity with severe psychomotor delays. Affected males also present with muscle hypoplasia, generalized muscle weakness, and limited speech. Importantly, these patients have elevated serum levels of free T(3), low to below normal serum levels of free T(4), and levels of thyroid stimulating hormone that are within the normal range. This constellation of measurements of thyroid function enables quick screening for AHDS in males presenting with cognitive impairment, congenital hypotonia, and generalized muscle weakness.

  8. The MCT8 thyroid hormone transporter and Allan--Herndon--Dudley syndrome

    PubMed Central

    Schwartz, Charles E.; Stevenson, Roger E.

    2007-01-01

    Thyroid hormone is essential for the proper development and function of the brain. The active form of thyroid hormone is T3, which binds to nuclear receptors. Recently, a transporter specific for T3, MCT8 (monocarboxylate transporter 8) was identified. MCT8 is highly expressed in liver and brain. The gene is located in Xq13 and mutations in MCT8 are responsible for an X-linked condition, Allan--Herndon--Dudley syndrome (AHDS). This syndrome is characterized by congenital hypotonia that progresses to spasticity with severe psychomotor delays. Affected males also present with muscle hypoplasia, generalized muscle weakness, and limited speech. Importantly, these patients have elevated serum levels of free T3, low to below normal serum levels of free T4, and levels of thyroid stimulating hormone that are within the normal range. This constellation of measurements of thyroid function enables quick screening for AHDS in males presenting with mental retardation, congenital hypotonia, and generalized muscle weakness. PMID:17574010

  9. Relation of Thyroid Hormone Levels with Fluid-Resistant Shock among Preterm Septicemic Neonates.

    PubMed

    Dutta, Sourabh; Singh, Sarvendra; Bhattacharya, Anish; Venkataseshan, Sundaram; Kumar, Praveen

    2017-02-15

    To compare thyroid hormone levels between septicemic preterm neonates with and without shock. Preterm septicemic infants with shock constituted Group A (n=36) and those without shock constituted Group B, with groups matched (1:1) for gestation and postnatal age. Those with maternal thyroid disorders, thyrotropic medication and life expectancy <12 hours were excluded. We compared serum tri-iodothyronine (T3), thyroxine (T4) and thyroid-stimulating hormone (TSH) between the groups by univariate and multivariate (adjusting for SNAPPE-II) analysis. Median (IQR) TSH was significantly lower in Group A [1.39 (0.83,3.48)] vs Group B [5.1 (2.32,7.19)] mmol/dL (P<0.001). Serum T3 and T4 were also lower in Group A (P<0.001). On multivariate analysis, none of these measures were independently associated with septic shock. Thyroid hormone levels do not independently predict presence of shock among septic preterms.

  10. Increased expression of thyroid hormone receptor isoforms in end-stage human congestive heart failure.

    PubMed

    d'Amati, G; di Gioia, C R; Mentuccia, D; Pistilli, D; Proietti-Pannunzi, L; Miraldi, F; Gallo, P; Celi, F S

    2001-05-01

    Thyroid hormone plays an important role on myocardial development and function. The local effects of thyroid hormone are mediated by the receptor isoforms ultimately driving the expression of cardiac-specific genes. Although overt and subclinical thyroid dysfunction causes well-known changes in the cardiovascular system, little is known about local thyroid hormone action in normal and failing human myocardium. With a newly developed multiplex competitive RT-PCR method, we evaluated the expression of thyroid hormone receptor (TR) isoforms alpha-1, alpha-2, and beta-1 in normal human hearts and in end-stage congestive heart failure. A statistically significant difference in the expression of all three TR isoforms was observed among samples from normal subjects, ischemic heart disease (IHD), and dilated cardiomyopathy (DCM). In DCM, compared with normal, the studied TR isoforms were significantly increased. In IHD, the increased expression was found significant only for alpha-1 and alpha-2 isoforms. No differences were observed between the pathologic groups. In conclusion, a coordinated increment in the expression of the TR isoforms was observed in both DCM and IHD by multiplex competitive RT-PCR. The observed changes could represent a compensatory mechanism to myocardial failure or to locally altered thyroid hormone action.

  11. Impaired Hair Growth and Wound Healing in Mice Lacking Thyroid Hormone Receptors

    PubMed Central

    Martínez-Fernández, Mónica; Ruiz-Llorente, Lidia; Paramio, Jesus M.; Aranda, Ana

    2014-01-01

    Both clinical and experimental observations show that the skin is affected by the thyroidal status. In hypothyroid patients the epidermis is thin and alopecia is common, indicating that thyroidal status might influence not only skin proliferation but also hair growth. We demonstrate here that the thyroid hormone receptors (TRs) mediate these effects of the thyroid hormones on the skin. Mice lacking TRα1 and TRβ (the main thyroid hormone binding isoforms) display impaired hair cycling associated to a decrease in follicular hair cell proliferation. This was also observed in hypothyroid mice, indicating the important role of the hormone-bound receptors in hair growth. In contrast, the individual deletion of either TRα1 or TRβ did not impair hair cycling, revealing an overlapping or compensatory role of the receptors in follicular cell proliferation. In support of the role of the receptors in hair growth, TRα1/TRβ-deficient mice developed alopecia after serial depilation. These mice also presented a wound-healing defect, with retarded re-epithelialization and wound gaping, associated to impaired keratinocyte proliferation. These results reinforce the idea that the thyroid hormone nuclear receptors play an important role on skin homeostasis and suggest that they could be targets for the treatment of cutaneous pathologies. PMID:25254665

  12. Impaired hair growth and wound healing in mice lacking thyroid hormone receptors.

    PubMed

    Contreras-Jurado, Constanza; García-Serrano, Laura; Martínez-Fernández, Mónica; Ruiz-Llorente, Lidia; Paramio, Jesus M; Aranda, Ana

    2014-01-01

    Both clinical and experimental observations show that the skin is affected by the thyroidal status. In hypothyroid patients the epidermis is thin and alopecia is common, indicating that thyroidal status might influence not only skin proliferation but also hair growth. We demonstrate here that the thyroid hormone receptors (TRs) mediate these effects of the thyroid hormones on the skin. Mice lacking TRα1 and TRβ (the main thyroid hormone binding isoforms) display impaired hair cycling associated to a decrease in follicular hair cell proliferation. This was also observed in hypothyroid mice, indicating the important role of the hormone-bound receptors in hair growth. In contrast, the individual deletion of either TRα1 or TRβ did not impair hair cycling, revealing an overlapping or compensatory role of the receptors in follicular cell proliferation. In support of the role of the receptors in hair growth, TRα1/TRβ-deficient mice developed alopecia after serial depilation. These mice also presented a wound-healing defect, with retarded re-epithelialization and wound gaping, associated to impaired keratinocyte proliferation. These results reinforce the idea that the thyroid hormone nuclear receptors play an important role on skin homeostasis and suggest that they could be targets for the treatment of cutaneous pathologies.

  13. Periostin silencing suppresses the aggressive phenotype of thyroid carcinoma cells by suppressing the Akt/thyroid stimulating hormone receptor axis.

    PubMed

    Wang, Min; Gui, Chunyi; Qiu, Shenglong; Tang, Jingdong; Peng, Zhihai

    2017-09-30

    Clinical evidence indicates that high periostin expression correlates with aggressive phenotype in thyroid carcinoma. However, the biological roles of periostin in thyroid carcinoma development and progression are still unclear. In this study, we explored the effects of periostin silencing on thyroid carcinoma cell growth, invasion, and tumorigenesis. We also studied the impact of periostin on the activation of phosphoinositide 3-kinase (PI3-K)/Akt signaling, which is involved in the pathogenesis of thyroid carcinoma. It was found that downregulation of periostin significantly inhibited the proliferation, colony formation, and invasion in both FTC-133 and BCPAP thyroid carcinoma cells. In vivo tumorigenic studies confirmed that periostin depletion retarded the growth of subcutaneous FTC-133 xenograft tumors, which was coupled with a significant decline in the percentage of Ki-67-positive proliferating cells. Western blot analysis demonstrated that periostin downregulation caused a marked inhibition of thyroid stimulating hormone receptor (TSHR) expression and Akt phosphorylation in FTC-133 and BCPAP cells. Co-expression of constitutively active Akt (CA-Akt) significantly reversed periostin-mediated downregulation of TSHR. Most importantly, overexpression of TSHR or CA-Akt rescued FTC-133 cells from periostin-induced growth and invasion suppression. Collectively, periostin regulates thyroid carcinoma growth and progression via the Akt/TSHR axis and represents a promising therapeutic target for this malignancy.

  14. Genetics and phenomics of thyroid hormone transport by MCT8.

    PubMed

    Friesema, Edith C H; Visser, W Edward; Visser, Theo J

    2010-06-30

    Thyroid hormone (TH) is crucial for the development of different organs, in particular the brain, as disturbances in TH supply cause severe neurological abnormalities. TH transporters are necessary for the intracellular availability of TH to have access to the deiodinases and nuclear receptors inside the cell. The clinical importance of TH transporters is dramatically shown in patients with mutations in MCT8, suffering from severe X-linked psychomotor retardation in combination with disturbed TH levels, especially high serum T(3) levels, now referred as Allan-Herndon-Dudley Syndrome (AHDS). Worldwide >45 families have now been identified with MCT8 mutations. Most MCT8 mutations result in a complete loss of TH transport function when tested in vitro, but some mutations show significant residual activity and are associated with a somewhat milder clinical phenotype. It is difficult to identify MCT8 patients only on the basis of the clinical characteristics of X-linked mental retardation. Therefore, the criterion for MCT8 mutation screening in these patients is the profile of increased T(3) and low-normal to low FT(4) serum levels.

  15. Structure and Function of Thyroid Hormone Plasma Membrane Transporters

    PubMed Central

    Schweizer, Ulrich; Johannes, Jörg; Bayer, Dorothea; Braun, Doreen

    2014-01-01

    Thyroid hormones (TH) cross the plasma membrane with the help of transporter proteins. As charged amino acid derivatives, TH cannot simply diffuse across a lipid bilayer membrane, despite their notorious hydrophobicity. The identification of monocarboxylate transporter 8 (MCT8, SLC16A2) as a specific and very active TH transporter paved the way to the finding that mutations in the MCT8 gene cause a syndrome of psychomotor retardation in humans. The purpose of this review is to introduce the current model of transmembrane transport and highlight the diversity of TH transmembrane transporters. The interactions of TH with plasma transfer proteins, T3 receptors, and deiodinase are summarized. It is shown that proteins may bind TH owing to their hydrophobic character in hydrophobic cavities and/or by specific polar interaction with the phenolic hydroxyl, the aminopropionic acid moiety, and by weak polar interactions with the iodine atoms. These findings are compared with our understanding of how TH transporters interact with substrate. The presumed effects of mutations in MCT8 on protein folding and transport function are explained in light of the available homology model. PMID:25538896

  16. Imprinting of maternal thyroid hormones in the offspring.

    PubMed

    Opazo, María Cecilia; Haensgen, Henny; Bohmwald, Karen; Venegas, Luis F; Boudin, Helene; Elorza, Alvaro A; Simon, Felipe; Fardella, Carlos; Bueno, Susan M; Kalergis, Alexis M; Riedel, Claudia A

    2017-03-08

    Thyroid hormones (THs) during pregnancy contribute significantly to cellular differentiation and development in several tissues of the offspring, principally the central nervous system (CNS). TH deficiencies, such as hypothyroidism or hypothyroxinemia, are highly frequent during pregnancy worldwide and known to be detrimental for the development of the fetus. The function of CNS in the offspring gestated under TH deficiency will be irreversible impaired, causing low intellectual quotient, attention deficit, and mental retardation. On the other hand, little is known about the effects of TH deficiency in the offspring immune system, being the prevalent notion that the effects are reversible and only for a while will affect the number of B and T cells. Recent studies have shown that maternal hypothyroidism can altered the function of immune system in the offspring, rendering the female offspring more susceptible to suffer autoimmune-inflammatory diseases, such as experimental autoimmune encephalomyelitis (EAE) and to be more resistant to a bacterial infection. In this article we discuss these recent findings, as well as the possible mechanisms underlying these effects and the potential implications for human health.

  17. Thyroid hormone responsive QTL and the evolution of paedomorphic salamanders

    PubMed Central

    Voss, S R; Kump, D K; Walker, J A; Shaffer, H B; Voss, G J

    2012-01-01

    The transformation of ancestral phenotypes into novel traits is poorly understood for many examples of evolutionary novelty. Ancestrally, salamanders have a biphasic life cycle with an aquatic larval stage, a brief and pronounced metamorphosis, followed by a terrestrial adult stage. Repeatedly during evolution, metamorphic timing has been delayed to exploit growth-permissive environments, resulting in paedomorphic salamanders that retain larval traits as adults. We used thyroid hormone (TH) to rescue metamorphic phenotypes in paedomorphic salamanders and then identified quantitative trait loci (QTL) for life history traits that are associated with amphibian life cycle evolution: metamorphic timing and adult body size. We demonstrate that paedomorphic tiger salamanders (Ambystoma tigrinum complex) carry alleles at three moderate effect QTL (met1–3) that vary in responsiveness to TH and additively affect metamorphic timing. Salamanders that delay metamorphosis attain significantly larger body sizes as adults and met2 explains a significant portion of this variation. Thus, substitution of alleles at TH-responsive loci suggests an adaptive pleiotropic basis for two key life-history traits in amphibians: body size and metamorphic timing. Our study demonstrates a likely pathway for the evolution of novel paedomorphic species from metamorphic ancestors via selection of TH-response alleles that delay metamorphic timing and increase adult body size. PMID:22850698

  18. Influence of thyroid hormone disruption on the incidence of shingles.

    PubMed

    Ajavon, A; Killian, D; Odom, R; Figliozzi, R W; Chen, F; Balish, M; Parmar, J; Freeman, R; Snitzer, J; Hsia, S V

    2015-12-01

    The reactivation of dormant alpha-human herpesvirus (αHHV) has been attributed to various causes often referred to as stressors. However, no clinical study investigating the relationship between stressors and reactivation exists in humans at this time. Herpes simplex virus type-1 (HSV-1), an important αHHV, was shown to have its gene expression and replication regulated by thyroid hormone (TH) using molecular biology approaches. Varicella zoster virus (VZV) is categorized in αHHV superfamily and shares similar homology with HSV-1. We hypothesize that a history of TH imbalance may be associated with the incidence of shingles (VZV reactivation). This current pilot study, based on a hospital medical claims database, was conducted as a retrospective case-controlled investigation to determine if a putative link between TH imbalance and incidence of shingles is present. An odds ratio of 2·95 with a χ 2 value of 51·74 was calculated for the total population diagnosed with TH disruption and shingles. Further analyses indicated that African American males exhibited a much higher chance of simultaneous diagnoses. These results show that a TH imbalance history may affect VZV reactivation at different incidence rates in different races and age groups.

  19. Structure and function of thyroid hormone plasma membrane transporters.

    PubMed

    Schweizer, Ulrich; Johannes, Jörg; Bayer, Dorothea; Braun, Doreen

    2014-09-01

    Thyroid hormones (TH) cross the plasma membrane with the help of transporter proteins. As charged amino acid derivatives, TH cannot simply diffuse across a lipid bilayer membrane, despite their notorious hydrophobicity. The identification of monocarboxylate transporter 8 (MCT8, SLC16A2) as a specific and very active TH transporter paved the way to the finding that mutations in the MCT8 gene cause a syndrome of psychomotor retardation in humans. The purpose of this review is to introduce the current model of transmembrane transport and highlight the diversity of TH transmembrane transporters. The interactions of TH with plasma transfer proteins, T3 receptors, and deiodinase are summarized. It is shown that proteins may bind TH owing to their hydrophobic character in hydrophobic cavities and/or by specific polar interaction with the phenolic hydroxyl, the aminopropionic acid moiety, and by weak polar interactions with the iodine atoms. These findings are compared with our understanding of how TH transporters interact with substrate. The presumed effects of mutations in MCT8 on protein folding and transport function are explained in light of the available homology model.

  20. Thyroid hormone mediates otolith growth and development during flatfish metamorphosis.

    PubMed

    Schreiber, A M; Wang, X; Tan, Y; Sievers, Q; Sievers, B; Lee, M; Burrall, K

    2010-11-01

    Flatfish begin life as bilaterally symmetrical larvae that swim up-right, then abruptly metamorphose into asymmetrically shaped juveniles with lateralized swimming postures. Flatfish metamorphosis is mediated entirely by thyroid hormone (TH). Changes in flatfish swim posture are thought to be regulated via vestibular remodeling, although the influence of TH on teleost inner ear development remains unclear. This study addresses the role of TH on the development of the three otolith end-organs (sacculus, utricle, and lagena) during southern flounder (Paralichthys lethostigma) metamorphosis. Compared with pre-metamorphosis, growth rates of the sacculus and utricle otoliths increase dramatically during metamorphosis in a manner that is uncoupled from general somatic growth. Treatment of P. lethostigma larvae with methimazol (a pharmacological inhibitor of endogenous TH production) inhibits growth of the sacculus and utricle, whereas treatment with TH dramatically accelerates their growth. In contrast with the sacculus and utricle otoliths that begin to form and mineralize during embryogenesis, a non-mineralized lagena otolith is first visible 10-12 days after hatching. The lagena grows during pre- and pro-metamorphosis, then abruptly mineralizes during metamorphic climax. Mineralization of the lagena, but not growth, can be induced with TH treatment, whereas treatment with methimazol completely inhibits lagena mineralization without inhibiting its growth. These findings suggest that during southern flounder metamorphosis TH exerts differential effects on growth and development among the three types of otolith.

  1. Thyroid hormone responsive QTL and the evolution of paedomorphic salamanders.

    PubMed

    Voss, S R; Kump, D K; Walker, J A; Shaffer, H B; Voss, G J

    2012-11-01

    The transformation of ancestral phenotypes into novel traits is poorly understood for many examples of evolutionary novelty. Ancestrally, salamanders have a biphasic life cycle with an aquatic larval stage, a brief and pronounced metamorphosis, followed by a terrestrial adult stage. Repeatedly during evolution, metamorphic timing has been delayed to exploit growth-permissive environments, resulting in paedomorphic salamanders that retain larval traits as adults. We used thyroid hormone (TH) to rescue metamorphic phenotypes in paedomorphic salamanders and then identified quantitative trait loci (QTL) for life history traits that are associated with amphibian life cycle evolution: metamorphic timing and adult body size. We demonstrate that paedomorphic tiger salamanders (Ambystoma tigrinum complex) carry alleles at three moderate effect QTL (met1-3) that vary in responsiveness to TH and additively affect metamorphic timing. Salamanders that delay metamorphosis attain significantly larger body sizes as adults and met2 explains a significant portion of this variation. Thus, substitution of alleles at TH-responsive loci suggests an adaptive pleiotropic basis for two key life-history traits in amphibians: body size and metamorphic timing. Our study demonstrates a likely pathway for the evolution of novel paedomorphic species from metamorphic ancestors via selection of TH-response alleles that delay metamorphic timing and increase adult body size.

  2. Thyroid Hormone T3 Counteracts STZ Induced Diabetes in Mouse

    PubMed Central

    Madaro, Luca; Ranieri, Danilo; Lupoi, Lorenzo; Stigliano, Antonio; Torrisi, Maria Rosaria; Bouchè, Marina; Toscano, Vincenzo; Misiti, Silvia

    2011-01-01

    This study intended to demonstrate that the thyroid hormone T3 counteracts the onset of a Streptozotocin (STZ) induced diabetes in wild type mice. To test our hypothesis diabetes has been induced in Balb/c male mice by multiple low dose Streptozotocin injection; and a group of mice was contemporaneously injected with T3. After 48 h mice were tested for glucose tolerance test, insulin serum levels and then sacrified. Whole pancreata were utilized for morphological and biochemical analyses, while protein extracts and RNA were utilized for expression analyses of specific molecules. The results showed that islets from T3 treated mice were comparable to age- and sex-matched control, untreated mice in number, shape, dimension, consistency, ultrastructure, insulin and glucagon levels, Tunel positivity and caspases activation, while all the cited parameters and molecules were altered by STZ alone. The T3-induced pro survival effect was associated with a strong increase in phosphorylated Akt. Moreover, T3 administration prevented the STZ-dependent alterations in glucose blood level, both during fasting and after glucose challenge, as well as in insulin serum level. In conclusion we demonstrated that T3 could act as a protective factor against STZ induced diabetes. PMID:21637761

  3. Thyroid stimulating hormone increases hepatic gluconeogenesis via CRTC2.

    PubMed

    Li, Yujie; Wang, Laicheng; Zhou, Lingyan; Song, Yongfeng; Ma, Shizhan; Yu, Chunxiao; Zhao, Jiajun; Xu, Chao; Gao, Ling

    2017-02-15

    Epidemiological evidence indicates that thyroid stimulating hormone (TSH) is positively correlated with abnormal glucose levels. We previously reported that TSH has direct effects on gluconeogenesis. However, the underlying molecular mechanism remains unclear. In this study, we observed increased fasting blood glucose and glucose production in a mouse model of subclinical hypothyroidism (only elevated TSH levels). TSH acts via the classical cAMP/PKA pathway and CRTC2 regulates glucose homeostasis. Thus, we explore whether CRTC2 is involved in the process of TSH-induced gluconeogenesis. We show that TSH increases CRTC2 expression via the TSHR/cAMP/PKA pathway, which in turn upregulates hepatic gluconeogenic genes. Furthermore, TSH stimulates CRTC2 dephosphorylation and upregulates p-CREB (Ser133) in HepG2 cells. Silencing CRTC2 and CREB decreases the effect of TSH on PEPCK-luciferase, the rate-limiting enzyme of gluconeogenesis. Finally, the deletion of TSHR reduces the levels of the CRTC2:CREB complex in mouse livers. This study demonstrates that TSH activates CRTC2 via the TSHR/cAMP/PKA pathway, leading to the formation of a CRTC2:CREB complex and increases hepatic gluconeogenesis.

  4. Basic mechanisms of augmentation of antidepressant effects with thyroid hormone.

    PubMed

    Lifschytz, Tsuri; Segman, Ronen; Shalom, Galit; Lerer, Bernard; Gur, Eitan; Golzer, Tanya; Newman, Michael E

    2006-02-01

    The thyroid hormone triiodothyronine (T3) has been used both to augment and accelerate the clinical effects of antidepressants, particularly the tricyclics. More recent work indicates that it may have similar actions with regard to the SSRIs. Two main mechanisms have been put forward to explain its antidepressant actions, (a) an action at the nuclear level involving stimulation of gene transcription, (b) an action at the cell membrane level involving potentiation of neurotransmission. In particular, there is considerable evidence for potentiation by T3 of the actions of the neurotransmitter 5-HT or serotonin. This evidence, which is mainly based on in vivo microdialysis studies, is reviewed, and evidence based on human and animal neuroendocrine studies considered. The effects of T3, alone and together with the SSRI fluoxetine, on mRNA levels for the 5-HT1A and 5-HT1B autoreceptors, which mediate serotonergic neurotransmission by feedback actions at the levels of cell firing(somatodendritic 5-HT1A autoreceptors) and neurotransmitter release (nerve terminal 5-HT1B autoreceptors) were also determined. Administration of a combination of fluoxetine and T3 induced reductions in the transcription of these autoreceptors, which may explain the clinical potentiating effects of this combination, and thus link the nuclear and neurotransmitter hypotheses of T3 action.

  5. Influence of Thyroid Hormone Disruption on the Incidence of Shingles

    PubMed Central

    Ajavon, Amakoe; Killian, Dennis; Odom, Randy; Figliozzi, Robert W.; Chen, Feng; Balish, Matthew; Parmar, Jayesh; Freeman, Robert; Snitzer, Jack; Hsia, S. Victor

    2015-01-01

    SUMMARY The reactivation of dormant alpha-Human Herpes Virus (αHHV) has been attributed to various causes often referred to as stressors. However, no clinical study investigating the relationship between stressors and reactivation exists in humans at this time. Herpes Simplex Virus Type-1 (HSV-1), an important αHHV, was shown to have its gene expression and replication regulated by Thyroid hormone (TH) using molecular biology approaches. Varicella Zoster Virus (VZV) is categorized in αHHV superfamily and shares similar homology with HSV-1. We hypothesize that a history of TH imbalance may be associated with the incidence of shingles (VZV reactivation). This current pilot study, based on a hospital medical claim database, was conducted as a retrospective case-controlled investigation to determine if a putative link between TH imbalance and incidence of shingles is present. An OR of 2.95 with a Chi-square of 51.74 was calculated for the total population diagnosed with TH disruption and shingles. Further analyses indicated that African American males exhibited much higher chance of simultaneous diagnoses. These results showed that a TH imbalance history may affect VZV reactivation at different incidence rates in different races and age groups. PMID:26189668

  6. Analysis of thyroid hormones in raw and treated waste water.

    PubMed

    Svanfelt, Jesper; Eriksson, Johan; Kronberg, Leif

    2010-10-15

    An analytical method for the quantification of thyroid hormones (3,5,3',5'-tetraiodo-L-thyronine, 3,3',5-triiodo-L-thyronine, 3,3',5'-triiodothyronine, 3,5-diiodothyronine, 3,3'-diiodothyronine) in different water matrices has been developed. The method, consisting of solid phase extraction (SPE) and liquid chromatography-tandem mass spectrometry (LC-MS/MS), was validated for tap and surface water as well as raw and treated waste water. The limits of quantifications (LOQs) were lowest in tap water, where they ranged from 1.1 to 13.3 ng L(-1), and highest in raw wastewater (10.5-84.9 ng L(-1)). Of the target analytes 3,5,3',5'-tetraiodo-L-thyronine (T(4)) could be quantified in the influent and effluent of a waste water treatment plant (WWTP) in Finland. The study showed that despite a relatively high removal rate during treatment (66%), part of the incoming T(4) will reach the aquatic environment and, due to the high endocrine activity of this compound, further studies are needed in order to assess its environmental fate and impact on natural ecosystems.

  7. Thyroid Hormones and Moderate Exposure to Perchlorate during Pregnancy in Women in Southern California.

    PubMed

    Steinmaus, Craig; Pearl, Michelle; Kharrazi, Martin; Blount, Benjamin C; Miller, Mark D; Pearce, Elizabeth N; Valentin-Blasini, Liza; DeLorenze, Gerald; Hoofnagle, Andrew N; Liaw, Jane

    2016-06-01

    Findings from national surveys suggest that everyone in the United States is exposed to perchlorate. At high doses, perchlorate, thiocyanate, and nitrate inhibit iodide uptake into the thyroid and decrease thyroid hormone production. Small changes in thyroid hormones during pregnancy, including changes within normal reference ranges, have been linked to cognitive function declines in the offspring. We evaluated the potential effects of low environmental exposures to perchlorate on thyroid function. Serum thyroid hormones and anti-thyroid antibodies and urinary perchlorate, thiocyanate, nitrate, and iodide concentrations were measured in 1,880 pregnant women from San Diego County, California, during 2000-2003, a period when much of the area's water supply was contaminated from an industrial plant with perchlorate at levels near the 2007 California regulatory standard of 6 μg/L. Linear regression was used to evaluate associations between urinary perchlorate and serum thyroid hormone concentrations in models adjusted for urinary creatinine and thiocyanate, maternal age and education, ethnicity, and gestational age at serum collection. The median urinary perchlorate concentration was 6.5 μg/L, about two times higher than in the general U.S. Adjusted associations were identified between increasing log10 perchlorate and decreasing total thyroxine (T4) [regression coefficient (β) = -0.70; 95% CI: -1.06, -0.34], decreasing free thyroxine (fT4) (β = -0.053; 95% CI: -0.092, -0.013), and increasing log10 thyroid-stimulating hormone (β = 0.071; 95% CI: 0.008, 0.133). These results suggest that environmental perchlorate exposures may affect thyroid hormone production during pregnancy. This could have implications for public health given widespread perchlorate exposure and the importance of thyroid hormone in fetal neurodevelopment. Steinmaus C, Pearl M, Kharrazi M, Blount BC, Miller MD, Pearce EN, Valentin-Blasini L, DeLorenze G, Hoofnagle AN, Liaw J. 2016. Thyroid

  8. Thyroid Hormones and Moderate Exposure to Perchlorate during Pregnancy in Women in Southern California

    PubMed Central

    Steinmaus, Craig; Pearl, Michelle; Kharrazi, Martin; Blount, Benjamin C.; Miller, Mark D.; Pearce, Elizabeth N.; Valentin-Blasini, Liza; DeLorenze, Gerald; Hoofnagle, Andrew N.; Liaw, Jane

    2015-01-01

    Background: Findings from national surveys suggest that everyone in the United States is exposed to perchlorate. At high doses, perchlorate, thiocyanate, and nitrate inhibit iodide uptake into the thyroid and decrease thyroid hormone production. Small changes in thyroid hormones during pregnancy, including changes within normal reference ranges, have been linked to cognitive function declines in the offspring. Objectives: We evaluated the potential effects of low environmental exposures to perchlorate on thyroid function. Methods: Serum thyroid hormones and anti-thyroid antibodies and urinary perchlorate, thiocyanate, nitrate, and iodide concentrations were measured in 1,880 pregnant women from San Diego County, California, during 2000–2003, a period when much of the area’s water supply was contaminated from an industrial plant with perchlorate at levels near the 2007 California regulatory standard of 6 μg/L. Linear regression was used to evaluate associations between urinary perchlorate and serum thyroid hormone concentrations in models adjusted for urinary creatinine and thiocyanate, maternal age and education, ethnicity, and gestational age at serum collection. Results: The median urinary perchlorate concentration was 6.5 μg/L, about two times higher than in the general U.S. population. Adjusted associations were identified between increasing log10 perchlorate and decreasing total thyroxine (T4) [regression coefficient (β) = –0.70; 95% CI: –1.06, –0.34], decreasing free thyroxine (fT4) (β = –0.053; 95% CI: –0.092, –0.013), and increasing log10 thyroid-stimulating hormone (β = 0.071; 95% CI: 0.008, 0.133). Conclusions: These results suggest that environmental perchlorate exposures may affect thyroid hormone production during pregnancy. This could have implications for public health given widespread perchlorate exposure and the importance of thyroid hormone in fetal neurodevelopment. Citation: Steinmaus C, Pearl M, Kharrazi M, Blount BC

  9. Thyroid hormone modulation of the hypothalamic growth hormone (GH)-releasing factor-pituitary GH axis in the rat.

    PubMed Central

    Miki, N; Ono, M; Hizuka, N; Aoki, T; Demura, H

    1992-01-01

    Both thyroid hormone and hypothalamic growth hormone (GH)-releasing factor (GRF) facilitate pituitary somatotroph function. However, the pathophysiological role of thyroid hormone in GRF secretion is less well understood. Thyrotoxicosis, induced by administration of thyroxine (T4) in rats, inhibited both pituitary GH levels and immunoreactive GRF secretion from incubated hypothalamus. At the highest dose of T4 given for 12 d, GRF secretion and pituitary GH decreased by 50 and 39%, respectively. Hypothyroidism induced by thyroidectomy (Tx) enhanced GRF secretion approximately twofold while depleting pituitary GH by greater than 99%. Both of these hypothalamic and pituitary effects were reversed by replacement of T4 but not human GH for 7 or 14 d. Human GH was as potent as T4 in restoring decreased body weight gains or serum insulin-like growth factor-1 levels in Tx rats. These results indicate that at both physiological and pathological concentrations in serum, thyroid hormone acts as an inhibitory modulator of GRF secretion, probably not involving a feedback mechanism through GH. A biphasic effect of thyroid hormone on pituitary GH levels appears to derive from the difference in primary target tissues of hyper- and hypothyroidism, the hypothalamus and the pituitary, respectively. PMID:1634603

  10. Methodology of the thyroid gland disease decision-making using profiling in steroid hormone pathway.

    PubMed

    Kim, Young Sun; Yoon, Chang No

    2007-02-19

    To find out the genetic factors of outbreak of thyroid gland disease, we developed the thyroid gland decision-making system, which processes the metabolic profile in steroid hormone map using a statistical method. Metabolic profile is a measured data of lots of mixed materials that includes not only known metabolites, but also unknown ones, which is estimated to have an influence on the thyroid gland disease. Therefore, to develop thyroid gland disease decision-making system, analyzing metabolic profile containing multi-materials would be useful for diagnosing thyroid gland disease. Because experimental values used for system construction are area values for the retention time, the observations are preprocessed through variable transition and t-test to use the area values concurrently and the highly correlated materials are estimated by principal component analysis. The thyroid gland decision-making system developed through the logistic regression is an excellent system demonstrating 98.7% accuracy in the classification table.

  11. Aminoaciduria, but normal thyroid hormone levels and signalling, in mice lacking the amino acid and thyroid hormone transporter Slc7a8.

    PubMed

    Braun, Doreen; Wirth, Eva K; Wohlgemuth, Franziska; Reix, Nathalie; Klein, Marc O; Grüters, Annette; Köhrle, Josef; Schweizer, Ulrich

    2011-10-15

    LAT2 (system L amino acid transporter 2) is composed of the subunits Slc7a8/Lat2 and Slc3a2/4F2hc. This transporter is highly expressed along the basolateral membranes of absorptive epithelia in kidney and small intestine, but is also abundant in the brain. Lat2 is an energy-independent exchanger of neutral amino acids, and was shown to transport thyroid hormones. We report in the present paper that targeted inactivation of Slc7a8 leads to increased urinary loss of small neutral amino acids. Development and growth of Slc7a8(-/-) mice appears normal, suggesting functional compensation of neutral amino acid transport by alternative transporters in kidney, intestine and placenta. Movement co-ordination is slightly impaired in mutant mice, although cerebellar development and structure remained inconspicuous. Circulating thyroid hormones, thyrotropin and thyroid hormone-responsive genes remained unchanged in Slc7a8(-/-) mice, possibly because of functional compensation by the thyroid hormone transporter Mct8 (monocarboxylate transporter 8), which is co-expressed in many cell types. The reason for the mild neurological phenotype remains unresolved.

  12. Modulation of Calcitonin, Parathyroid Hormone, and Thyroid Hormone Secretion by Electrical Stimulation of Sympathetic and Parasympathetic Nerves in Anesthetized Rats.

    PubMed

    Hotta, Harumi; Onda, Akiko; Suzuki, Harue; Milliken, Philip; Sridhar, Arun

    2017-01-01

    The thyroid and parathyroid glands are dually innervated by sympathetic (cervical sympathetic trunk [CST]) and parasympathetic (superior laryngeal nerve [SLN]) nerve fibers. We examined the effects of electrical stimulation of efferent or afferent nerve fibers innervating the thyroid and parathyroid glands on the secretion of immunoreactive calcitonin (iCT), parathyroid hormone (iPTH), 3,3',5-triiodothyronine (iT3), and thyroxine (iT4) from the thyroid and parathyroid glands. In anesthetized and artificially ventilated rats, thyroid venous blood was collected. The rate of hormone secretion from the glands was calculated from plasma hormone levels, measured by ELISA, and the flow rate of thyroid venous plasma. SLNs or CSTs were stimulated bilaterally with rectangular pulses with a 0.5-ms width. To define the role of unmyelinated nerve fibers (typically efferent), the cut peripheral segments were stimulated at various frequencies (up to 40 Hz) with a supramaximal intensity to excite all nerve fibers. The secretion of iCT, iT3, and iT4 increased during SLN stimulation and decreased during CST stimulation. iPTH secretion increased during CST stimulation, but was not affected by SLN stimulation. To examine the effects of selective stimulation of myelinated nerve fibers (typically afferent) in the SLN, intact SLNs were stimulated with a subthreshold intensity for unmyelinated nerve fibers. iCT, iT3, and iT4 secretion increased during stimulation of intact SLNs at 40 Hz. These results suggest that excitation of myelinated afferents induced by low intensity and high frequency stimulation of intact SLNs promotes secretion of CT and thyroid hormones from the thyroid gland, potentially via reflex activation of parasympathetic efferent nerve fibers in the SLN.

  13. Modulation of Calcitonin, Parathyroid Hormone, and Thyroid Hormone Secretion by Electrical Stimulation of Sympathetic and Parasympathetic Nerves in Anesthetized Rats

    PubMed Central

    Hotta, Harumi; Onda, Akiko; Suzuki, Harue; Milliken, Philip; Sridhar, Arun

    2017-01-01

    The thyroid and parathyroid glands are dually innervated by sympathetic (cervical sympathetic trunk [CST]) and parasympathetic (superior laryngeal nerve [SLN]) nerve fibers. We examined the effects of electrical stimulation of efferent or afferent nerve fibers innervating the thyroid and parathyroid glands on the secretion of immunoreactive calcitonin (iCT), parathyroid hormone (iPTH), 3,3′,5-triiodothyronine (iT3), and thyroxine (iT4) from the thyroid and parathyroid glands. In anesthetized and artificially ventilated rats, thyroid venous blood was collected. The rate of hormone secretion from the glands was calculated from plasma hormone levels, measured by ELISA, and the flow rate of thyroid venous plasma. SLNs or CSTs were stimulated bilaterally with rectangular pulses with a 0.5-ms width. To define the role of unmyelinated nerve fibers (typically efferent), the cut peripheral segments were stimulated at various frequencies (up to 40 Hz) with a supramaximal intensity to excite all nerve fibers. The secretion of iCT, iT3, and iT4 increased during SLN stimulation and decreased during CST stimulation. iPTH secretion increased during CST stimulation, but was not affected by SLN stimulation. To examine the effects of selective stimulation of myelinated nerve fibers (typically afferent) in the SLN, intact SLNs were stimulated with a subthreshold intensity for unmyelinated nerve fibers. iCT, iT3, and iT4 secretion increased during stimulation of intact SLNs at 40 Hz. These results suggest that excitation of myelinated afferents induced by low intensity and high frequency stimulation of intact SLNs promotes secretion of CT and thyroid hormones from the thyroid gland, potentially via reflex activation of parasympathetic efferent nerve fibers in the SLN. PMID:28713236

  14. Developmental and cell-specific expression of thyroid hormone transporters in the mouse cochlea.

    PubMed

    Sharlin, David S; Visser, Theo J; Forrest, Douglas

    2011-12-01

    Thyroid hormone is essential for the development of the cochlea and auditory function. Cochlear response tissues, which express thyroid hormone receptor β (encoded by Thrb), include the greater epithelial ridge and sensory epithelium residing inside the bony labyrinth. However, these response tissues lack direct blood flow, implying that mechanisms exist to shuttle hormone from the circulation to target tissues. Therefore, we investigated expression of candidate thyroid hormone transporters L-type amino acid transporter 1 (Lat1), monocarboxylate transporter (Mct)8, Mct10, and organic anion transporting polypeptide 1c1 (Oatp1c1) in mouse cochlear development by in situ hybridization and immunofluorescence analysis. L-type amino acid transporter 1 localized to cochlear blood vessels and transiently to sensory hair cells. Mct8 localized to the greater epithelial ridge, tympanic border cells underlying the sensory epithelium, spiral ligament fibrocytes, and spiral ganglion neurons, partly overlapping with the Thrb expression pattern. Mct10 was detected in a highly restricted pattern in the outer sulcus epithelium and weakly in tympanic border cells and hair cells. Organic anion transporting polypeptide 1c1 localized primarily to fibrocytes in vascularized tissues of the spiral limbus and spiral ligament and to tympanic border cells. Investigation of hypothyroid Tshr(-/-) mice showed that transporter expression was delayed consistent with retardation of cochlear tissue maturation but not with compensatory responses to hypothyroidism. The results demonstrate specific expression of thyroid hormone transporters in the cochlea and suggest that a network of thyroid hormone transport underlies cochlear development.

  15. Multiple Novel Signals Mediate Thyroid Hormone Receptor Nuclear Import and Export*

    PubMed Central

    Mavinakere, Manohara S.; Powers, Jeremy M.; Subramanian, Kelly S.; Roggero, Vincent R.; Allison, Lizabeth A.

    2012-01-01

    Thyroid hormone receptor (TR) is a member of the nuclear receptor superfamily that shuttles between the cytosol and nucleus. The fine balance between nuclear import and export of TR has emerged as a critical control point for modulating thyroid hormone-responsive gene expression; however, sequence motifs of TR that mediate shuttling are not fully defined. Here, we characterized multiple signals that direct TR shuttling. Along with the known nuclear localization signal in the hinge domain, we identified a novel nuclear localization signal in the A/B domain of thyroid hormone receptor α1 that is absent in thyroid hormone receptor β1 and inactive in the oncoprotein v-ErbA. Our prior studies showed that thyroid hormone receptor α1 exits the nucleus through two pathways, one dependent on the export factor CRM1 and the other CRM1-independent. Here, we identified three novel CRM1-independent nuclear export signal (NES) motifs in the ligand-binding domain as follows: a highly conserved NES in helix 12 (NES-H12) and two additional NES sequences spanning helix 3 and helix 6, respectively. Mutations predicted to disrupt the α-helical structure resulted in a significant decrease in NES-H12 activity. The high degree of conservation of helix 12 suggests that this region may function as a key NES in other nuclear receptors. Furthermore, our mutagenesis studies on NES-H12 suggest that altered shuttling of thyroid hormone receptor β1 may be a contributing factor in resistance to thyroid hormone syndrome. Taken together, our findings provide a detailed mechanistic understanding of the multiple signals that work together to regulate TR shuttling and transcriptional activity, and they provide important insights into nuclear receptor function in general. PMID:22815488

  16. A new point mutation (C446R) in the thyroid hormone receptor-{beta} gene of a family with resistance to thyroid hormone

    SciTech Connect

    Weiss, R.E.; Chyna, B.; Hayashi, Yoshitaka; Sunthornthepvarakul, T.; Refetoff, S.; Duell, P.B.

    1994-05-01

    Resistance to thyroid hormone (RTH) is a condition of impaired end-organ responsiveness to thyroid hormone characterized by goiter and elevated thyroid hormone levels with an appropriately normal TSH. RTH has been associated with mutations in the thyroid hormone receptor-{beta} (TR{beta}) gene. The authors report studies carried out in 21 members of a family (F119), 12 of whom exhibited the RTH phenotype. A point mutation was detected in the T{sub 3}-binding domain of the TR{beta} gene. It resulted in replacement of the normal cysteine-446 with an arginine (C446R) that has not been previously reported. The clinical characteristics of this family are similar to those reported in other families with RTH, namely goiter, tachycardia, and learning disabilities. Thyroid function tests are also typical of other subjects with RTH. The mean values ({+-}SD) in untreated affected subjects compared to those in unaffected family members were: free T{sub 4} index, 250 {+-} 21 vs. 108 {+-} 13; total T{sub 3}, 4.3 {+-} 0.4 vs. 2.4 {+-} 0.4 nmol/L; and TSH, 4.5 {+-} 1.1 vs. 2.4 {+-} 1.1 mU/L. DNA samples from 18 family members were screened for the TR{beta} mutation, which results in the loss of a BsmI restriction site, and each of the 11 subjects with abnormal thyroid function tests were heterozygous for the mutant allele. The mutant TR{beta} expressed in Cos-I cells did not bind T{sub 3} (K{sub a} of C446R/wild-type, <0.05). T{sub 3} at a concentration up to 100 nmol/L failed to enhance the transactivation of a reporter gene, and the mutant receptor inhibited the T{sub 3}-mediated transcriptional activation of the wild-type TR{beta}. 17 refs., 3 figs., 1 tab.

  17. A new point mutation (C446R) in the thyroid hormone receptor-beta gene of a family with resistance to thyroid hormone.

    PubMed

    Weiss, R E; Chyna, B; Duell, P B; Hayashi, Y; Sunthornthepvarakul, T; Refetoff, S

    1994-05-01

    Resistance to thyroid hormone (RTH) is a condition of impaired end-organ responsiveness to thyroid hormone characterized by goiter and elevated thyroid hormone levels with an inappropriately normal TSH. RTH has been associated with mutations in the thyroid hormone receptor-beta (TR beta) gene. We report studies carried out in 21 members of a family (F119), 12 of whom exhibited the RTH phenotype. A point mutation was detected in the T3-binding domain of the TR beta gene. It resulted in replacement of the normal cysteine-446 with an arginine (C446R) that has not been previously reported. The clinical characteristics of this family are similar to those reported in other families with RTH, namely goiter, tachycardia, and learning disabilities. Thyroid function tests are also typical of other subjects with RTH. The mean values (+/- SD) in untreated affected subjects compared to those in unaffected family members were: free T4 index, 250 +/- 21 vs. 108 +/- 13; total T3, 4.3 +/- 0.4 vs. 2.4 +/- 0.4 nmol/L; and TSH, 4.5 +/- 1.1 vs. 2.4 +/- 1.1 mU/L. DNA samples from 18 family members were screened for the TR beta mutation, which results in the loss of a BsmI restriction site, and each of the 11 subjects with abnormal thyroid function tests were heterozygous for the mutant allele. The mutant TR beta expressed in Cos-I cells did not bind T3 (Ka of C446R/wild-type, < 0.05). T3 at a concentration up to 100 nmol/L failed to enhance the transactivation of a reporter gene, and the mutant receptor inhibited the T3-mediated transcriptional activation of the wild-type TR beta.

  18. Laboratory diagnosis of multiple pituitary hormone deficiencies: issues with testing of the growth and thyroid axes.

    PubMed

    Nakamoto, Jon

    2009-01-01

    Clinical manifestations of hypopituitarism are variable and depend on the severity of hormone deficiency, creating a diagnostic challenge for diagnosis of the non-classical patient who may have a less severe growth hormone (GH) deficiency and only a suggestion of possible hypothyroidism. Laboratory tests contribute to the diagnostic process, but the tests for growth and thyroid dysfunction, two of the most common manifestations of multiple pituitary hormone deficiency, are some of the most problematic from a methodological perspective. Patients in the "grey zone" of diagnosis, for whom there is no distinct dividing line or gold standard diagnostic test, are the focus of this article. Issues relating to the use of laboratory tests involving GH, insulin-like growth factor-I, and free thyroxine in the diagnosis of GH and thyroid deficiency are reviewed. Assay harmonization initiatives are required before clinical research studies are performed to establish diagnostic thresholds for GH and thyroid hormone deficiencies.

  19. Optimized FPGA Implementation of the Thyroid Hormone Secretion Mechanism Using CAD Tools.

    PubMed

    Alghazo, Jaafar M

    2017-02-01

    The goal of this paper is to implement the secretion mechanism of the Thyroid Hormone (TH) based on bio-mathematical differential eqs. (DE) on an FPGA chip. Hardware Descriptive Language (HDL) is used to develop a behavioral model of the mechanism derived from the DE. The Thyroid Hormone secretion mechanism is simulated with the interaction of the related stimulating and inhibiting hormones. Synthesis of the simulation is done with the aid of CAD tools and downloaded on a Field Programmable Gate Arrays (FPGAs) Chip. The chip output shows identical behavior to that of the designed algorithm through simulation. It is concluded that the chip mimics the Thyroid Hormone secretion mechanism. The chip, operating in real-time, is computer-independent stand-alone system.

  20. Syndromes of reduced sensitivity to thyroid hormone: genetic defects in hormone receptors, cell transporters and deiodination.

    PubMed

    Refetoff, Samuel; Dumitrescu, Alexandra M

    2007-06-01

    At least six major steps are required for secreted thyroid hormone (TH) to exert its action on target tissues. Mutations interfering with three of these steps have been so far identified. The first recognized defect, which causes resistance to TH, involves the TH receptor beta gene and has been given the acronym RTH. Occurring in approximately 1 per 40,000 newborns, more than 1000 affected subjects, from 339 families, have been identified. The gene defect remains unknown in 15% of subjects with RTH. Two novel syndromes causing reduced sensitivity to TH were recently identified. One, producing severe psychomotor defects in > 100 males from 26 families, is caused by mutations in the cell-membrane transporter of TH, MCT8; the second, affecting the intracellular metabolism of TH in four individuals from two families, is caused by mutations in the SECISBP2 gene, which is required for the synthesis of selenoproteins, including TH deiodinases.

  1. The case of thyroid hormones: how to learn physiology by solving a detective case.

    PubMed

    Lellis-Santos, Camilo; Giannocco, Gisele; Nunes, Maria Tereza

    2011-06-01

    Thyroid diseases are prevalent among endocrine disorders, and careful evaluation of patients' symptoms is a very important part in their diagnosis. Developing new pedagogical strategies, such as problem-based learning (PBL), is extremely important to stimulate and encourage medical and biomedical students to learn thyroid physiology and identify the