Thyroid Hormone Secretion Research Articles

The Effects of Perchlorate on Thyroidal Gene Expression are Different from the Effects of Iodide Deficiency

Perchlorate (ClO4 −), which is a ubiquitous and persistent ion, competitively interferes with iodide (I) accumulation in the thyroid, producing I deficiency (ID), which may result in reduced thyroid hormone synthesis and secretion. Human studies suggest that ClO4 − presents little risk in healthy individuals; however, the precautionary principle demands that the sensitive populations of ID adults and mothers require extra consideration. In an attempt to determine whether the effects on gene expression were similar, the thyroidal effects of ClO4 − (10 mg/kg) treatment for 14 d in drinking water were compared with those produced by 8 wk of ID in rats. The thyroids were collected (n = 3 each group) and total mRNA was analyzed using the Affymetrix Rat Genome 230 2.0 GeneChip. Changes in gene expression were compared with appropriate control groups. The twofold gene changes due to ID were compared with alterations due to ClO4 − treatment. One hundred and eighty-nine transcripts were changed by the ID diet and 722 transcripts were altered by the ClO4 − treatment. Thirty-four percent of the transcripts changed by the I-deficient diet were also altered by ClO4 − and generally in the same direction. Three specific transporter genes, AQP1, NIS, and SLC22A3, were changed by both treatments, indicating that the membrane-specific changes were similar. Iodide deficiency primarily produced alterations in retinol and calcium signaling pathways and ClO4 − primarily produced changes related to the accumulation of extracellular matrix proteins. This study provides evidence that ClO4 −, at least at this dose level, changes more genes and alters different genes compared to ID.

Graves' Disease: Diagnostic and Therapeutic Challenges (Multimedia Activity)

Graves' disease is the most common cause of hyperthyroidism in the United States. Graves' disease occurs more often in women with a female:male ratio of 5:1 and a population prevalence of 1% to 2%. A genetic determinant to the susceptibility to Graves' disease is suspected because of familial clustering of the disease, a high sibling recurrence risk, the familial occurrence of thyroid autoantibodies, and the 30% concordance in disease status between identical twins. Graves' disease is an autoimmune thyroid disorder characterized by the infiltration of immune effector cells and thyroid antigen-specific T cells into the thyroid and thyroid-stimulating hormone receptor expressing tissues, with the production of autoantibodies to well-defined thyroidal antigens, such as thyroid peroxidase, thyroglobulin, and the thyroid-stimulating hormone receptor. The thyroid-stimulating hormone receptor is central to the regulation of thyroid growth and function. Stimulatory autoantibodies in Graves' disease activate the thyroid-stimulating hormone receptor leading to thyroid hyperplasia and unregulated thyroid hormone production and secretion. Below-normal levels of baseline serum thyroid-stimulating hormone receptor, normal to elevated serum levels of T4, elevated serum levels of T3 and thyroid-stimulating hormone receptor autoantibodies, and a diffusely enlarged, heterogeneous, hypervascular (increased Doppler flow) thyroid gland confirm diagnosis of Graves' disease (available at: http://supplements.amjmed.com/2010/hyperthyroid/faculty.php). This Resource Center is also available through the website of The American Journal of Medicine (www.amjmed.com). Click on the “Thyroid/Graves' Disease” link in the “Resource Centers” section, found on the right side of the Journal homepage.

Histomorphometric characterization of thyroid follicles' areas on experimental hyperthyroidism and acupuncture treatment

Hyperthyroidism is caused by excess synthesis and secretion of thyroid hormone by the thyroid, which increases the metabolic rate. The experimental model of hyperthyroidism is conducted by an administration of an high dose of levothyroxine for two weeks. The aim of this study is to contribute to the histomorphometric characterization of thyroid follicles' areas on experimental hyperthyroidism.20 Wistar male rats were used, randomly distributed in four groups: control group, kept with no manipulation (Ctrl); group II, which received an administration of 250 mg/kg of levothyroxine by gavage 3 times a week (HT); group III received levothyroxine and acupuncture treatment (HT+AC); group IV, submitted only to the acupuncture treatment. After two weeks, all the animals were sacrificed and fragments from thyroid were collected and analyzed using ImageJ®. The points used for puncture were: ST09, ST36, HC4, RM23.When compared with the control group, we observed more frequently large follicles on group IV than in control group. The animals of group II and III have more often smaller follicles than those observed in control group.The results, although without statistical significance, suggest that acupuncture may have some effect on thyroid function.

Small molecule TSHR agonists and antagonists

TSH activates the TSH receptor (TSHR) thereby stimulating the function of thyroid follicular cells (thyrocytes) leading to biosynthesis and secretion of thyroid hormones. Because TSHR is involved in several thyroid pathologies, there is a strong rationale for the design of small molecule “drug-like” ligands. Recombinant human TSH (rhTSH, Thyrogen ®) has been used in the follow-up of patients with thyroid cancer to increase the sensitivity for detection of recurrence or metastasis. rhTSH is difficult to produce and must be administered by injection. A small molecule TSHR agonist could produce the same beneficial effects as rhTSH but with greater ease of oral administration. We developed a small molecule ligand that is a full agonist at TSHR. Importantly for its clinical potential, this agonist elevated serum thyroxine and stimulated thyroidal radioiodide uptake in mice after its absorption from the gastrointestinal tract following oral administration. Graves’ disease (GD) is caused by persistent, unregulated stimulation of thyrocytes by thyroid-stimulating antibodies (TSAbs) that activate TSHR. We identified the first small molecule TSHR antagonists that inhibited TSH- and TSAb-stimulated signalling in primary cultures of human thyrocytes. Our results provide proof-of-principle for effectiveness of small molecule agonists and antagonists for TSHR. We suggest that these small molecule ligands are lead compounds for the development of higher potency ligands that can be used as probes of TSHR biology with therapeutic potential.

Distinct Roles of Deiodinases on the Phenotype of Mct8 Defect: A Comparison of Eight Different Mouse Genotypes

Mice deficient in the thyroid hormone (TH) transporter Mct8 (Mct8KO) have increased 5'-deiodination and impaired TH secretion and excretion. These and other unknown mechanisms result in the low-serum T(4), high T(3), and low rT(3) levels characteristic of Mct8 defects. We investigated to what extent each of the 5'-deiodinases (D1, D2) contributes to the serum TH abnormalities of the Mct8KO by generating mice with all combinations of Mct8 and D1 and/or D2 deficiencies and comparing the resulting eight genotypes. Adding D1 deficiency to that of Mct8 corrected the serum TH abnormalities of Mct8KO mice, normalized brain T(3) content, and reduced the impaired expression of TH-responsive genes. In contrast, Mct8D2KO mice maintained the serum TH abnormalities of Mct8KO mice. However, the serum TSH level increased 27-fold, suggesting a severely impaired hypothalamo-pituitary-thyroid axis. The brain of Mct8D2KO manifested a pattern of more severe impairment of TH action than Mct8KO alone. In triple Mct8D1D2KO mice, the markedly increased serum TH levels produced milder brain defect than that of Mct8D2KO at the expense of more severe liver thyrotoxicosis. Additionally, we observed that mice deficient in D2 had an unexplained marked reduction in the thyroid growth response to TSH. Our studies on these eight genotypes provide a unique insight into the complex interplay of the deiodinases in the Mct8 defect and suggest that D1 contributes to the increased serum T(3) in Mct8 deficiency, whereas D2 mainly functions locally, converting T(4) to T(3) to compensate for distinct cellular TH depletion in Mct8KO mice.

Effects of Long-Term Intraperitoneal Injection of Thyrotropin-Releasing Hormone (TRH) on Aging- and Obesity-Related Changes in Body Weight, Lipid Metabolism, and Thyroid Functions

Adult adipose mice, high fat diet-fed (HFD) mice, anterior hypothalamus-lesioned obese mice and genetically obese mice, were injected daily with thyrotropin releasing hormone (TRH). The treatment provoked a mobilization of triglycerides in the peripheral blood, a decrease of leptin and a loss of body weight. The weight loss did not depend on TSH-mediated stimulation of thyroid hormone secretion with consequent metabolic hyperthyroidism. The levels of blood cholesterol were not affected or even suppressed. Even at a very high dosage TRH did not affect the obesity of genetically obese mice. The ubiquitous tripeptide TRH may thus constitute a key element in the hormone-controlled regulation of body weight and fat stores in the adult and aging body.

Effects of Long-Term Intraperitoneal Injection of Thyrotropin-Releasing Hormone (TRH) on Aging- and Obesity-Related Changes in Body Weight, Lipid Metabolism, and Thyroid Functions

Adult adipose mice, high fat diet-fed (HFD) mice, anterior hypothalamus-lesioned obese mice and genetically obese mice, were injected daily with thyrotropin releasing hormone (TRH). The treatment provoked a mobilization of triglycerides in the peripheral blood, a decrease of leptin and a loss of body weight. The weight loss did not depend on TSH-mediated stimulation of thyroid hormone secretion with consequent metabolic hyperthyroidism. The levels of blood cholesterol were not affected or even suppressed. Even at a very high dosage TRH did not affect the obesity of genetically obese mice. The ubiquitous tripeptide TRH may thus constitute a key element in the hormone-controlled regulation of body weight and fat stores in the adult and aging body. Keywords: Thyrotropin releasing hormone, lipids, thyroid function, leptin, body weight, food intake, aging, triglycerides, hyperthyroidism, thymolytic-immunosuppressive effects, intraperitoneal (ip) route, anterior hypothalamic area (AHA), adiposity, halothane, narcosis, thyroxine (T4), triiodothyronine (T3), Free Fatty Acid (FFA), obesity, cholesterol levels, adipose, adipocytes, neuropeptide-Y (NPY), hypothalamic arcuate nucleus (ARC), paraventricular nuclei (PVN), homeostasis, phenotype, hypothalamic obesity, protein kinase, cylglycerol, Langerhans islets of the pancreas, amylase, pineal-hypothalamic-hypophysis axis, energy-adapting biochemical processes, thermoregulation, melatonin, hormonal cyclicity, homoeostasis, adipocyte-derived hormones

Thyroid hormones and fetal neurological development

The development of fetal thyroid function is dependent on the embryogenesis, differentiation, and maturation of the thyroid gland. This is coupled with evolution of the hypothalamic-pituitary-thyroid axis and thyroid hormone metabolism, resulting in the regulation of thyroid hormone action, production, and secretion. Throughout gestation there is a steady supply of maternal thyroxine (T(4)) which has been observed in embryonic circulation as early as 4 weeks post-implantation. This is essential for normal early fetal neurogenesis. Triiodothyronine concentrations remain very low during gestation due to metabolism via placental and fetal deiodinase type 3. T(4) concentrations are highly regulated to maintain low concentrations, essential for protecting the fetus and reaching key neurological sites such as the cerebral cortex at specific developmental stages. There are many known cell membrane thyroid hormone transporters in fetal brain that play an essential role in regulating thyroid hormone concentrations in key structures. They also provide the route for intracellular thyroid hormone interaction with associated thyroid hormone receptors, which activate their action. There is a growing body of experimental evidence from rats and humans to suggest that even mild maternal hypothyroxinemia may lead to abnormalities in fetal neurological development. Our review will focus on the ontogeny of thyroid hormone in fetal development, with a focus on cell membrane transporters and TR action in the brain.

Physiological importance and control of non-shivering facultative thermogenesis

This review examines general and evolutionary aspects of temperature homeostasis, focusing on mammalian facultative or adaptive thermogenesis and its control by the sympathetic nervous system and hormones. Thyroid hormone acquired a new role with the advent of homeothermy enhancing facultative thermogenesis by interacting synergistically with the sympathetic nervous system, and directly increasing basal metabolic rate (obligatory thermogenesis). Facultative thermogenesis is triggered by cold. The major site of facultative thermogenesis in mammals is brown adipose tissue, endowed with abundant mitochondria rich in a protein called uncoupling protein-1. This protein can uncouple phosphorylation in a controlled manner, releasing the energy of the proton-motive force as heat. Its synthesis and function are regulated synergistically by the sympathetic nervous system and thyroid hormone and modulated by other hormones directly, or indirectly, modulating sympathetic activity as well as thyroid hormone secretion and activation in brown adipose tissue. Alternate, evolutionary older forms of facultative thermogenesis activated in transgenic mice with disabled brown adipose tissue thermogenesis reveal this latter as the culmination of energy-efficient facultative thermogenesis.

Localisation of the neuropeptide PACAP and its receptors in the rat parathyroid and thyroid glands

PACAP (pituitary adenylate cyclase activating polypeptide) is widely distributed neuropeptide acting via three subtypes of receptors, PAC 1, VPAC 1 and VPAC 2. Here we examined the localisation and nature of PACAP-immunoreactive nerves in the rat thyroid and parathyroid glands and defined the distribution of PAC 1, VPAC 1 and VPAC 2 receptor mRNA’s. In the parathyroid gland a large number of nerve fibres displaying PACAP-immunoreactivity were distributed beneath the capsule, around blood vessels and close to glandular cells. Most of the PACAP-nerves were sensory, since they co-stored CGRP (calcitonin-gene-related peptide) and were sensitive to capsaicin-treatment. mRNA’s for PAC 1 and VPAC 2 receptors occurred in the parathyroid gland, mainly located in the glandular cells. In the thyroid gland PACAP-immunoreactive nerve fibres were associated with blood vessels, thyroid follicles and parafollicular C-cells. A high degree of co-existence between PACAP and VIP (vasoactive intestinal polypeptide) was observed in the intrathyroid nerve fibres and cell bodies of the thyroid ganglion indicating a common origin for the two peptides. A minor population of PACAP-immunoreactive nerve fibres with relation to blood vessels co-stored NPY (neuropeptide Y), whereas only a few fibres co-stored CGRP. PAC 1 and VPAC 1 receptor mRNA’s occurred in follicular cells and blood vessels, whereas the expression of the VPAC 2 receptor was low. The findings suggest that PACAP plays a role in the regulation of parathyroid and thyroid blood flow and hormone secretion.

Evaluation and clinical application of changes in thyroid hormone and TSH levels in critically ill full-term newborns

The term "euthyroid sick syndrome" (ESS) has been used to describe a pattern of thyroid hormone changes during the course of critical illness in adult patients without thyroid disease, often associated with reduced thyroid hormone secretion. To describe the thyroid hormone profile in full-term newborns critically ill compared with thyroid hormone profile of healthy infants, and determine if alterations could be related to the severity of the disease and outcome. A cross-sectional, observational, and prospective study of full-term infants admitted to the neonatal intensive care unit (NICU) of the Hospital de Pediatría J.P. Garrahan between July 2007 and April 2008. Serum T3, T4, and thyroid stimulating hormone (TSH) levels were measured at admission and severity of the disease was evaluated through SNAP, lactic acid, respiratory assistance and number of organs affected. Sick newborns showed significantly lower T3 and T4 levels compared with healthy infants [T3: -0.97 μg/dL (95% CI -0.89, -1.13) and T4: -4.37 μg/dL (95% CI -2.95, -5.78)]. Only 29 out of 94 (31%) infants presented a normal profile; 37 (39%) infants showed isolated low T3 levels, 20 (21%) infants had low T3 and T4 levels and eight (9%) infants had low TSH, T3, and T4. Of this latter group, five of eight (62%) children died suggesting a significantly higher risk of death for patients with low T3 associated with low T4 and TSH [Risk ratio (RR) 10.75 95% CI 3.93, 29]. Full-term sick newborns frequently have lower thyroid hormone levels than healthy ones. These observed thyroid hormones changes might be related to the underlying disease and could be used as a prognostic marker of the severity and fatal outcome of the patient.

A Physiological Systems Model for Iodine for Use in Radiation Protection

This paper summarizes the biokinetic database for iodine in the human body and proposes a biokinetic model for systemic iodine for use in dose assessments for internally deposited radioiodine. The model consolidates and extends existing physiological systems models describing three subsystems of the iodine cycle in the body: circulating inorganic iodide, thyroidal iodine (trapping and organic binding of iodide and synthesis, storage and secretion of thyroid hormones), and extrathyroidal organic iodine. Thyroidal uptake of inorganic iodide is described as a function of stable iodine intake (Y, µg day(-1)) and thyroidal secretion of hormonal iodine (S, µg day(-1)). Baseline parameter values are developed for reference adults with typical iodine intake. Compared with the current systemic biokinetic model of the International Commission on Radiological Protection (ICRP) for occupational intake of radioiodine, the proposed model predicts higher absorbed doses to the thyroid per unit uptake to blood for very short-lived iodine isotopes, similar absorbed doses to thyroid for iodine isotopes with half-life of at least a few hours, and substantially higher estimates of absorbed dose to stomach wall, salivary gland and kidneys for most iodine isotopes. Absorbed dose estimates for intravenous administration of radioiodine-labeled thyroid hormones based on the proposed model differ substantially in some cases from current ICRP values.

Pulse modulated 900 MHz radiation induces hypothyroidism and apoptosis in thyroid cells: A light, electron microscopy and immunohistochemical study

Purpose: In the present study we investigated the possible histopathological effects of pulse modulated Radiofrequency (RF) fields on the thyroid gland using light microscopy, electron microscopy and immunohistochemical methods.Materials and methods: Two months old male Wistar rats were exposed to a 900 MHz pulse-modulated RF radiation at a specific absorption rate (SAR) of 1.35 Watt/kg for 20 min/day for three weeks. The RF signals were pulse modulated by rectangular pulses with a repetition frequency of 217 Hz and a duty cycle of 1:8 (pulse width 0.576 ms). To assess thyroid endocrine disruption and estimate the degree of the pathology of the gland, we analysed structural alterations in follicular and colloidal diameters and areas, colloid content of the follicles, and height of the follicular epithelium. Apoptosis was confirmed by Transmission Electron Microscopy and assessing the activites of an initiator (caspase-9) and an effector (caspase-3) caspases that are important markers of cells undergoing apoptosis.Results: Morphological analyses revealed hypothyrophy of the gland in the 900 MHz RF exposure group. The results indicated that thyroid hormone secretion was inhibited by the RF radiation. In addition, we also observed formation of apoptotic bodies and increased caspase-3 and caspase-9 activities in thyroid cells of the rats that were exposed to modulated RF fields.Conclusion: The overall findings indicated that whole body exposure to pulse-modulated RF radiation that is similar to that emitted by global system for mobile communications (GSM) mobile phones can cause pathological changes in the thyroid gland by altering the gland structure and enhancing caspase-dependent pathways of apoptosis.

Impact of Monocarboxylate Transporter-8 Deficiency on the Hypothalamus-Pituitary-Thyroid Axis in Mice

In patients, inactivating mutations in the gene encoding the thyroid hormone-transporting monocarboxylate transporter 8 (Mct8) are associated with severe mental and neurological deficits and disturbed thyroid hormone levels. The latter phenotype characterized by high T3 and low T4 serum concentrations is replicated in Mct8 knockout (ko) mice, indicating that MCT8 deficiency interferes with thyroid hormone production and/or metabolism. Our studies of Mct8 ko mice indeed revealed increased thyroidal T3 and T4 concentrations without overt signs of a hyperactive thyroid gland. However, upon TSH stimulation Mct8 ko mice showed decreased T4 and increased T3 secretion compared with wild-type littermates. Moreover, similar changes in the thyroid hormone secretion pattern were observed in Mct8/Trhr1 double-ko mice, which are characterized by normal serum T3 levels and normal hepatic and renal D1 expression in the presence of very low T4 serum concentrations. These data strongly indicate that absence of Mct8 in the thyroid gland affects thyroid hormone efflux by shifting the ratio of the secreted hormones toward T3. To test this hypothesis, we generated Mct8/Pax8 double-mutant mice, which in addition to Mct8 lack a functional thyroid gland and are therefore completely athyroid. Following the injection of these animals with either T4 or T3, serum analysis revealed T3 concentrations similar to those observed in Pax8 ko mice under thyroid hormone replacement, indicating that indeed increased thyroidal T3 secretion in Mct8 ko mice represents an important pathogenic mechanism leading to the high serum T3 levels.

Mice deficient in MCT8 reveal a mechanism regulating thyroid hormone secretion

The mechanism of thyroid hormone (TH) secretion from the thyroid gland into blood is unknown. Humans and mice deficient in monocarboxylate transporter 8 (MCT8) have low serum thyroxine (T4) levels that cannot be fully explained by increased deiodination. Here, we have shown that Mct8 is localized at the basolateral membrane of thyrocytes and that the serum TH concentration is reduced in Mct8-KO mice early after being taken off a treatment that almost completely depleted the thyroid gland of TH. Thyroid glands in Mct8-KO mice contained more non-thyroglobulin-associated T4 and triiodothyronine than did those in wild-type mice, independent of deiodination. In addition, depletion of thyroidal TH content was slower during iodine deficiency. After administration of 125I, the rate of both its secretion from the thyroid gland and its appearance in the serum as trichloroacetic acid-precipitable radioactivity was greatly reduced in Mct8-KO mice. Similarly, the secretion of T4 induced by injection of thyrotropin was reduced in Mct8-KO in which endogenous TSH and T4 were suppressed by administration of triiodothyronine. To our knowledge, this study is the first to demonstrate that Mct8 is involved in the secretion of TH from the thyroid gland and contributes, in part, to the low serum T4 level observed in MCT8-deficient patients.

SIRT1 Regulates Thyroid-Stimulating Hormone Release by Enhancing PIP5Kγ Activity through Deacetylation of Specific Lysine Residues in Mammals

BackgroundSIRT1, a NAD-dependent deacetylase, has diverse roles in a variety of organs such as regulation of endocrine function and metabolism. However, it remains to be addressed how it regulates hormone release there.Methodology/Principal FindingsHere, we report that SIRT1 is abundantly expressed in pituitary thyrotropes and regulates thyroid hormone secretion. Manipulation of SIRT1 level revealed that SIRT1 positively regulated the exocytosis of TSH-containing granules. Using LC/MS-based interactomics, phosphatidylinositol-4-phosphate 5-kinase (PIP5K)γ was identified as a SIRT1 binding partner and deacetylation substrate. SIRT1 deacetylated two specific lysine residues (K265/K268) in PIP5Kγ and enhanced PIP5Kγ enzyme activity. SIRT1-mediated TSH secretion was abolished by PIP5Kγ knockdown. SIRT1 knockdown decreased the levels of deacetylated PIP5Kγ, PI(4,5)P2, and reduced the secretion of TSH from pituitary cells. These results were also observed in SIRT1-knockout mice.Conclusions/SignificanceOur findings indicated that the control of TSH release by the SIRT1-PIP5Kγ pathway is important for regulating the metabolism of the whole body.

Evaluation and Management of Hypothyroxinemia and Hypocortisolemia in Preterm Neonates: Current Concepts and Contentious Issues

Pediatricians, neonatologists and pediatric endocrinologists are often challenged with determining the significance of atypical thyroid and adrenocortical function studies in preterm, low birth-weight (gestational age <37 weeks; birth-weight <2500 g), very low birth-weight (gestational age <30 weeks; birth-weight <1500 g) or extremely low birth-weight (gestational age <27 weeks; birth-weight <1000 g) neonates. The neonatal period is defined as the first 30 days after birth. Often, these neonates are critically ill and being treated with several medications that further confound their evaluation and therapeutic management. Physicians who care for these patients are regularly faced with the questions: What are normal values of thyroid hormones and cortisol in preterm neonates? What is the significance of hypothyroxinemia or hypocortisolemia in these subjects? When is hormone-replacement therapy warranted? In this review, the physiology of thyroid and adrenocortical hormone secretion in the fetus and neonate is discussed and reference data for serum concentrations of thyroid and adrenocortical hormones in preterm and full-term neonates is presented. The evaluation and hormonal management of neonates with hypothyroxinemia and hypocortisolemia are outlined and critically analyzed.

The interactions of season, leptin and melatonin levels with thyroid hormone secretion, using an in vitro approach

Leptin's actions on the hypothalamic–pituitary–thyroid axis occur both centrally and peripherally. In addition, the thyroid activity may also be stimulated by melatonin. The mechanisms through which leptin, melatonin (MT) and the thyroid hormones co-operate in the regulation of the seasonal physiology in sheep, however, remains unclear. The aim of the study was to evaluate the interactions of season, leptin and melatonin levels with thyroid hormone secretion in sheep, using an in vitro approach. Thyroid glands from 18 ewes were collected during long-day (LD, n = 9) and short-day (SD, n = 9) photoperiods. The glands were dissected into approximately 30 mg samples. Each sample was equilibrated in RPMI 1640 (Roswell Park Memorial Institute 1640) + F12 (Nutrient Mixture F-12) medium (1/1) for 90 min, followed by an additional 3 h incubation. At the end of the equilibration period, all tissue samples were treated with a medium containing either 0 or 50 ng/ml leptin, with or without MT (40 ng/ml) and a medium containing MT (40 ng/ml) only. Secretions of thyroxine (T4) and triiodothyronine (T3) were higher ( P < 0.05) in the control group during the short-day (SD) period, compared to the long-day (LD) period. Melatonin tented to reduce the T4 secretion during the LD and SD periods. However, leptin stimulated ( P < 0.001) T4 secretion in both seasons. Leptin, MT, and both leptin and MT increased the secretion of T3 during LD period ( P < 0.001). Results demonstrated leptin to have a stimulatory effect on T3 and T4 secretion in sheep, however the effect of melatonin is dependent on the season.

Thyroid function in children with growth hormone (GH) deficiency during the initial phase of GH replacement therapy - clinical implications

BackgroundNormal thyroid hormone secretion or appropriate L-thyroxine (L-T4) substitution is necessary for the optimal effect of the growth hormone (GH) administration on growth rate. The decrease of free thyroxine (FT4) levels at recombinant human GH (rhGH) therapy onset has been reported in several studies. The aim of the present study was to evaluate the effect of rhGH administration on thyrotropin (TSH) and FT4 serum concentrations in children with GH deficiency (GHD) during the 1st year of therapy, as well as to assess potential indications to thyroid hormone supplementation in them.Patients and methodsThe analysis involved data of 75 children (59 boys, 16 girls) with disorders of GH secretion (GHD, neurosecretory dysfunction - NSD) and partial GH inactivity (inactGH), who were treated with rhGH for - at least - one year. In all the children, body height and height velocity (HV) were assessed before and after 1 year of therapy, while TSH, FT4, IGF-I and IGFBP-3 before treatment and after 3-6 months and 1 year of treatment. In the patients, who revealed hypothyroidism (HypoT), an appropriate L-T4 substitution was introduced immediately. The incidence of HypoT, occurring during the initial phase of rhGH therapy, was assessed, as well as its influence on the therapy effectiveness.ResultsBefore rhGH substitution, there were no significant differences in either auxological indices or TSH and FT4 secretion, or IGF-I concentration and its bioavailability among the groups of patients. During the initial 3-6 months of rhGH administration, a significant decrease of FT4 serum concentration, together with a significant increase of IGF-I SDS and IGF-I/IGFBP-3 molar ratio was observed in all the studied groups. In 17 children, HypoT was diagnosed and L-T4 substitution was administered. Despite similar IGF-I secretion increase, the improvement of HV presented significantly lower in children with HypoT than in those who remained euthyroid all the time.ConclusionsThe incidence of HypoT during the initial phase of GH treatment in children with GHD and the negative effect of even transient thyroid hormone deficiency on the growth rate should be taken into account.

Are endogenously lower serum thyroid hormones new predictors for thyroid malignancy in addition to higher serum thyrotropin?

It is well known that TSH plays a major role in the secretion of thyroid hormones, maintenance of thyroid specific gene expression, and gland growth. In this study, we aimed to evaluate association between tests of thyroid functions (fT3, fT4, TSH) and differentiated thyroid carcinoma. 441 patients operated for nodular goiter between 2005 and 2008 were analyzed. Thyroid functions were studied in the period of 1-30 days prior to surgery. In postoperative histopathological examination, differentiated thyroid carcinoma and benign thyroid disease were detected in 166 (37.6%) and 275 (62.4%) patients, respectively. Patients with thyroid malignancy had significantly lower serum fT3 (P = 0.001), lower fT4 (P = 0.022), and higher TSH levels (P < 0.001) compared to patients with benign disease, although all analytes were within the normal range. We subdivided by quartile serum fT3, fT4, and TSH in normal limits into three groups. The odds ratio (ORs) for the risk of thyroid cancer with a serum TSH between 0.63 and 1.67 μIU/ml and 1.68-4.00 μIU/ml, compared with a serum TSH between 0.40 and 0.62 μIU/ml were calculated as 2.60 (95% CIs 1.49-4.54) and 6.50 (95% CIs 3.51-12.03), respectively. There was also a greater risk of thyroid cancer in patients with fT3 levels of 1.57-3.00 pg/ml, compared with patients with fT3 levels of 3.89-4.71 pg/ml (OR 2.95, 95% CIs 1.68-5.20). For fT4, OR for the risk of thyroid cancer between 0.85 and 1.17 ng/dl compared with 1.48-1.78 ng/dl was 2.14 (95% CIs 1.22-3.74). In conclusion, lower fT3, fT4, and higher TSH concentrations within normal limits were related with increased thyroid cancer independent from sex and nodule type. Particularly, the association between lower fT3, fT4 levels and a diagnosis of thyroid cancer is a novel finding.