Thyroid-stimulating Hormone Production Research Articles

Hypothalamic tanycytes as mediators of maternally programmed seasonal plasticity

In mammals, maternal photoperiodic programming (MPP) provides a means whereby juvenile development can be matched to forthcoming seasonal environmental conditions.1,2,3,4 This phenomenon is driven by in utero effects of maternal melatonin5,6,7 on the production of thyrotropin (TSH) in the fetal pars tuberalis (PT) and consequent TSH receptor-mediated effects on tanycytes lining the 3rd ventricle of the mediobasal hypothalamus (MBH).8,9,10 Here we use LASER capture microdissection and transcriptomic profiling to show that TSH-dependent MPP controls the attributes of the ependymal region of the MBH in juvenile animals. In Siberian hamster pups gestated and raised on a long photoperiod (LP) and thereby committed to a fast trajectory for growth and reproductive maturation, the ependymal region is enriched for tanycytes bearing sensory cilia and receptors implicated in metabolic sensing. Contrastingly, in pups gestated and raised on short photoperiod (SP) and therefore following an over-wintering developmental trajectory with delayed sexual maturation, the ependymal region has fewer sensory tanycytes. Post-weaning transfer of SP-gestated pups to an intermediate photoperiod (IP), which accelerates reproductive maturation, results in a pronounced shift toward a ciliated tanycytic profile and formation of tanycytic processes. We suggest that tanycytic plasticity constitutes a mechanism to tailor metabolic development for extended survival in variable overwintering environments.

Thyroid-stimulating hormone-thyroid hormone signaling contributes to circadian regulation through repressing clock2/npas2 in zebrafish

Thyroid-stimulating hormone (TSH) is important for the thyroid gland, development, growth, and metabolism. Defects in TSH production or the thyrotrope cells within the pituitary gland cause congenital hypothyroidism (CH), resulting in growth retardation and neurocognitive impairment. While human TSH is known to display rhythmicity, the molecular mechanisms underlying the circadian regulation of TSH and the effects of TSH-thyroid hormone (TH) signaling on the circadian clock remain elusive. Here we show that TSH, thyroxine (T4), triiodothyronine (T3), and tshba display rhythmicity in both larval and adult zebrafish and tshba is regulated directly by the circadian clock via both E′-box and D-box. Zebrafish tshba−/− mutants manifest congenital hypothyroidism, with the characteristics of low levels of T4 and T3 and growth retardation. Loss or overexpression of tshba alters the rhythmicity of locomotor activities and expression of core circadian clock genes and hypothalamic-pituitary-thyroid (HPT) axis-related genes. Furthermore, TSH-TH signaling regulates clock2/npas2 via the thyroid response element (TRE) in its promoter, and transcriptome analysis reveals extensive functions of Tshba in zebrafish. Together, our results demonstrate that zebrafish tshba is a direct target of the circadian clock and in turn plays critical roles in circadian regulation along with other functions.

Peculiarities of circadian regulation of the thyroid gland

Circadian rhythmicity is an autonomous period of organ cells’ functioning that is controlled by feedback mechanisms and specific genes. The thyroid gland, as a peripheral organ of the endocrine system, is subordinate to the adenohypophysis and pineal gland. Melatonin, as one of the main mediators of circadian influence, is well known for its antitumor and regulatory effects on a number of tissues, but its relationship with the hormone-producing activity of the thyroid gland has not been sufficiently studied. The purpose of the work was to analyze the current data on circadian regulation of the thyroid gland by examining evidence-based scientific publications from open databases over the past five years. Melatonin-producing pineal cells possess the homeotic genes Otx2 and Crx whose deactivation leads to a significant decrease in melatonin production by the pineal gland. In addition to pineal cells, melatonin can be synthesized by adenohypophysis-independent parafollicular cells. The effect of melatonin on thyrocytes is provided by binding to MT1 receptors and affecting the expression of thyroglobulin, RX-8, and TTF-1 (NKX2-1) genes. Under conditions of short photoperiod, melatonin inhibits the production of thyroid-stimulating hormone (TSH) β, which, in turn, acts on hypothalamic tanycytes by regulating the balance of deiodinase (Dio2/Dio3). This leads to a well-regulated seasonal control of the release of the thyroid hormone triiodothyronine. Conclusions. Circadian regulation of thyrocyte activity occurs under the influence of melatonin, which is secreted by pinealocytes and sometimes by parafollicular cells. TSH is secreted with a certain circadian periodicity under the influence of the activation of chronorhythmic genes. Hormone replacement therapy should be aimed not only at restoring the levels of pituitary hormones, but also at restoring the biological rhythm of TSH secretion. Melatonin affects the circadian work of thyrocytes, which is proven by determining the expression of the chronorhythm genes Bmal-1, Dio2, TTF-1. In thyroid pathology, there is a violation of circadian rhythms, a decrease in melatonin levels, and a decrease in the expression of Clock genes.

Bilateral Shifts in Deuterium Supply Similarly Change Physiology of the Pituitary-Thyroid Axis, but Differentially Influence Na+/I- Symporter Production.

Deuterium, a stable isotope of hydrogen, is abundant in organisms. It is known to produce various biological effects. However, its impact in thyroid hormone synthesis and secretion is poorly studied. The aim of this investigation was to evaluate the dynamics of thyroid hormones and pituitary thyroid-stimulating hormone secretion during bilateral shifts in deuterium supply and assess a possible role of the Na+/I- symporter (NIS), the main iodide transporter, in altered thyroid function. The experiment was performed on adult male Wistar rats, which consumed deuterium-depleted ([D] = 10 ppm) and deuterium-enriched ([D] = 500,000 ppm) water for 21 days. The assessment of total thyroxine and triiodothyronine and their free fractions, as well as thyroid-stimulating hormone in blood serum, revealed the rapid response of the thyroid gland to shifts in the deuterium/protium balance. The present investigation shows that the bilateral changes in the deuterium body content similarly modulate thyroid hormone production and functional activity of the pituitary gland, but the responses of the thyroid and pituitary glands differ. The response of the thyroid cells was to increase the synthesis of the hormones and the pituitary thyrotropes, in order to reduce the production of the thyroid-stimulating hormone. The evaluation of NIS serum levels found a gradual increase in the rats that consumed deuterium-enriched water and no differences in the group exposed to deuterium depletion. NIS levels in both groups did not correlate with thyroid hormones and pituitary thyroid-stimulating hormone production. The data obtained show that thyroid gland has a higher sensitivity to shifts in the deuterium body content than the hypothalamic-pituitary complex, which responded later but similarly in the case of deuteration or deuterium depletion. It indicates a different sensitivity of the endocrine glands to alterations in deuterium content. It suggests that thyroid hormone production rate may depend on deuterium blood/tissue and cytosol/organelle gradients, which possibly disturb the secretory process independently of the NIS.

Levothyroxine suppressive therapy in differentiated thyroid cancer treatment.

Levothyroxine therapy in management of diferentiated thyroid carcinoma (DTC) has been common practice for decades. Levothyroxine is being administered to patiens with DTC after total thyreoidectomy (with or without postopreative radioiodine treatment) not only to restore euthyroidism but to suppress the production of thyroid-stimulating hormone (TSH) as well because TSH is considered as a growth factor for thyroid follicular cells. However there has been a downside to this threatment recently. The main concerns are the known risks related to iatrogenic subclinical or even mild but clinicaly overt iatrogenic hyperthyroidism. Therefore individualized treatment approach aiming to balance between the risk of tumor recurence and the risks related to hypertyhroidism in view of pateints age, risk factors and comorbidities is essential. Close folow-up is therefore necessary with frequent dose adjustments according to target TSH values published in American Thyroid Association guidelines.

Recombinant or endogenous TSH for radioactive iodine therapy in thyroid cancer: state of knowledge and current controversies.

For patients undergoing radioiodine therapy of differentiated thyroid carcinoma (DTC), TSH stimulation prior to radioiodine therapy (RIT) can be achieved using thyroid hormone withdrawal (THW) or administration of recombinant human TSH (rhTSH). As THW can lead to nausea, headaches, vomiting, fatigue and dizziness secondary to transient acute hypothyroidism, rhTSH could be a good alternative. rhTSH has been administered in patients in order to stimulate TSH for RIT since 2005. According to the Martinique criteria formulated by the leading professional societies involved in care of patients with DTC, rhTSH can be applied in three settings: for remnant ablation, adjuvant treatment and treatment of known disease. Numerous studies have investigated the effects of rhTSH as a method of TSH stimulation on the thyroid cell, the systemic effects, biokinetics and clinical outcomes, however no consensus has been reached about many aspects of its potential use. rhTSH is able to stimulate sufficient TSH-levels (>30 mIU/L) and is hypothesized to decrease risks of tumor cell proliferation. As rhTSH-use avoids the transiently-impaired renal function associated with THW, radioiodine excretion is faster with the former, leading to to a lower iodine-131(I-131) uptake and a difference in fractional remnant uptake, effective half-life, mean residence time, and dose to the blood. Differences between rhTSH and THW were observed in radioiodine genotoxic effects and endothelial-dependent vasodilation and inflammation. For thyroid remnant ablation, THW and rhTSH lead to similar remnant ablation rates. For adjuvant therapy and treatment of known disease, insufficient trials have been conducted and future prospective studies are recommended.

Dynamics of thyroid diseases and thyroid-axis gland masses.

Thyroid disorders are common and often require lifelong hormone replacement. Treating thyroid disorders involves a fascinating and troublesome delay, in which it takes many weeks for serum thyroid‐stimulating hormone (TSH) concentration to normalize after thyroid hormones return to normal. This delay challenges attempts to stabilize thyroid hormones in millions of patients. Despite its importance, the physiological mechanism for the delay is unclear. Here, we present data on hormone delays from Israeli medical records spanning 46 million life‐years and develop a mathematical model for dynamic compensation in the thyroid axis, which explains the delays. The delays are due to a feedback mechanism in which peripheral thyroid hormones and TSH control the growth of the thyroid and pituitary glands; enlarged or atrophied glands take many weeks to recover upon treatment due to the slow turnover of the tissues. The model explains why thyroid disorders such as Hashimoto's thyroiditis and Graves' disease have both subclinical and clinical states and explains the complex inverse relation between TSH and thyroid hormones. The present model may guide approaches to dynamically adjust the treatment of thyroid disorders.

Epidemiology of Thyroid Cancer.

Epidemiology of Thyroid Cancer.

Diagnosis and Treatment of Primary Hypothyroidism in Primary Care

Decreased thyroid function occurs among 0,2–1% of men and 1,4–5% of women in the general population, and among people over 60 years among 2,5% of men and 6% of women. Hypothyroidism in 95% of cases is caused by thyroid disfunction (primary hypothyroidism), only 5% of cases are central hypothyroidism, associated with dysfunction of the pituitary gland (insufficient production of thyroid-stimulating hormone) and hypothalamus (impaired thyroliberin synthesis). Nonspecific clinical manifestations of hypothyroidism are the reason for examining the patient for thyroid hormone levels in primary care. Primary hypothyroidism screening is a common clinical situation in the general practitioner`s practice. According to Guideline 00514. Hypothyroidism of the Finnish Medical Research Society Duodecim Medical Publications Ltd, the use of which is approved by the Order of the Ministry of Health of Ukraine № 1422 of December 29, 2016, diagnosis of hypothyroidism and treatment of primary hypothyroidism are the tasks of primary care professionals. Decreased thyroid function may have subclinical and manifest forms, which are detected in the analysis of the results of thyroid hormones and clinical signs of the disease, require different treatment approaches. There are the differences in the use of levothyroxine replacement therapy in patients of different ages and depending on the causes of hypothyroidism. Patients under 55 years old are prescribed levothyroxine sodium in a daily dose of 1,6–1,8 μg/kg body weight. In patients over 55 years old, the daily requirement of levothyroxine sodium is calculated at 0,9 μg/kg body weight, taking into account existing cardiovascular disease. If patients are obese, the calculation is made on the «ideal» weight. The calculation of the dose and rules of levothyroxine sodium prescription in primary care are presented on the example of four clinical cases. The algorithm for control levothyroxine replacement therapy in patients with primary hypothyroidism is also presented.

GnRH and the photoperiodic control of seasonal reproduction: Delegating the task to kisspeptin and RFRP-3.

Synchronization of mammalian breeding activity to the annual change of photoperiod and environmental conditions is of the utmost importance for individual survival and species perpetuation. Subsequent to the early 1960s, when the central role of melatonin in this adaptive process was demonstrated, our comprehension of the mechanisms through which light regulates gonadal activity has increased considerably. The current model for the photoperiodic neuroendocrine system points to pivotal roles for the melatonin-sensitive pars tuberalis (PT) and its seasonally-regulated production of thyroid-stimulating hormone (TSH), as well as for TSH-sensitive hypothalamic tanycytes, radial glia-like cells located in the basal part of the third ventricle. Tanycytes respond to TSH through increased expression of thyroid hormone (TH) deiodinase 2 (Dio2), which leads to heightened production of intrahypothalamic triiodothyronine (T3) during longer days of spring and summer. There is strong evidence that this local, long-day driven, increase in T3 links melatonin input at the PT to gonadotropin-releasing hormone (GnRH) output, to align breeding with the seasons. The mechanism(s) through which T3 impinges upon GnRH remain(s) unclear. However, two distinct neuronal populations of the medio-basal hypothalamus, which express the (Arg)(Phe)-amide peptides kisspeptin and RFamide-related peptide-3, appear to be well-positioned to relay this seasonal T3 message towards GnRH neurons. Here, we summarize our current understanding of the cellular, molecular and neuroendocrine players, which keep track of photoperiod and ultimately govern GnRH output and seasonal breeding.

Thyroid Disorders.

Thyroid Disorders.

Increased maternal leptin levels may be an indicator of subclinical hypothyroidism in a newborn.

BackgroundSeveral factors may influence newborn thyroid-stimulating hormone (TSH) concentrations and cause subclinical hypothyroidism in a newborn. A sufficient level of leptin signalling is needed for the normal production of TSH and thyroid hormones by the thyroid gland. Our study aimed to investigate the correlation between maternal serum leptin concentration during the third trimester of pregnancy and newborn screening-TSH levels.MethodsThis prospective cross-sectional study was conducted in obstetrics and gynaecology clinics of a state hospital between June and August 2013. Maternal venous blood samples were collected from 270 healthy pregnant women in the third trimester just before delivery. Measurements of maternal fT3, fT4, TSH, anti-thyroid peroxidase (TPO), and anti-thyroglobulin (anti-Tg) antibodies from serum samples were performed by chemiluminescence immunoassay. Maternal serum leptin levels were determined by ELISA. Dried capillary blood spots were used to measure newborn TSH levels.ResultsSubjects were divided into two groups according to the neonatal TSH levels using a cut-point of 5.5 mIU/L. Median maternal serum leptin levels were significantly higher in newborns whose TSH levels were higher than >5.5 mIU/L [13.2 μg/L (1.3 - 46.5) vs 19.7 μg/L (2.4 - 48.5), p<0.05]. Serum leptin levels showed a negative correlation with maternal fT4 (r=0.32, p<0.05), fT3 (r=0.23, p<0.05), and a positive correlation with BMI (r=0.30, p<0.05).ConclusionsOur results suggest that high leptin levels in the third trimester of pregnancy influence maternal thyroid functions and might cause an increase in newborn TSH levels. Detection of high maternal serum leptin levels may be a reason for subclinical hypothyroidism.

Calcium/calmodulin-dependent kinases can regulate the TSH expression in the rat pituitary.

The endocrine secretion of TSH is a finely orchestrated process controlled by the thyrotropin-releasing hormone (TRH). Its homeostasis and signaling rely on many calcium-binding proteins belonging to the "EF-hand" protein family. The Ca2+/calmodulin (CaM) complex is associated with Ca2+/CaM-dependent kinases (Ca2+/CaMK). We have investigated Ca2+/CaMK expression and regulation in the rat pituitary. The expression of CaMKII and CaMKIV in rat anterior pituitary cells was shown by immunohistochemistry. Cultured anterior pituitary cells were stimulated by TRH in the presence and absence of KN93, the pharmacological inhibitor of CaMKII and CaMKIV. Western blotting was then used to measure the expression of these kinases and of the cAMP response element-binding protein (CREB). TSH production was measured by RIA after time-dependent stimulation with TRH. Cells were infected with a lentiviral construct coding for CaMKIV followed by measurement of CREB phosphorylation and TSH. Our study shows that two CaM kinases, CaMKII and CaMKII, are expressed in rat pituitary cells and their phosphorylation in response to TRH occurs at different time points, with CaMKIV being activated earlier than CaMKII. TRH induces CREB phosphorylation through the activity of both CaMKII and CaMKIV. The activation of CREB increases TSH gene expression. CaMKIV induces CREB phosphorylation while its dominant negative and KN93 exert the opposite effects. Our data indicate that the expression of Ca2+/CaMK in rat anterior pituitary are correlated to the role of CREB in the genetic regulation of TSH, and that TRH stimulation activates CaMKIV, which in turn phosphorylates CREB. This phosphorylation is linked to the production of thyrotropin.

The association between serum TSH concentration whithin the normal range and nutritional status in euthyroid pregnant women at the first trimester of gestation.

Background:Follow-up studies have shown an increased risk of thyroid dysfunction in individuals with normal serum thyroid-stimulating hormone (TSH) levels. Furthermore, the possible consequences of minor differences in thyroid function (without achieving poor thyroid function) in the risk of weight gain during pregnancy are questionable, too. The production of TSH is under the hypothalamus–pituitary control, and food is one of the most effective environmental agents that control hypothalamic–pituitary–thyroid axis activity. Regarding the few available studies, we assessed the association of minor variations of TSH concentrations and nutritional status in the first trimester of pregnancy.Materials and Methods:This cross-sectional descriptive and analytical study was performed on 150 primiparous healthy women. Demographic and family characteristics were collected using a researcher-administered questionnaire. Nutrients intake were extracted from a 72-h recall, and physical activity scores were determined by the pregnancy physical activity scale.Results:The prepregnancy body mass index (BMI) (β =0.022, P = 0.004) and participants' weight at 6–10 weeks of gestation (β =0.006, P = 0.024) were positively associated with TSH concentrations, while total physical activity score was negatively correlated (β = ‒0.006, P = 0.047). We did not find any significant association between TSH values and energy-adjusted nutrients intake (P > 0.05).Conclusion:We suggest that differences in TSH concentrations within normal range in the first trimester are correlated with gaining weight, physical activity level, and prepregnancy BMI. TSH concentration and consequently thyroid function may influence on gestational weight gain or vice versa.

Patterns of changes in immune and hormonal regulation in hand-arm vibration syndrome and sensorineural hearing loss

The purpose of the research was to identify changes in immune and hormonal regulation in patients with hand-arm vibration syndrome and sensorineural hearing loss to substantiate informative biomarkers. Materials and methods . Men with occupational injury induced by exposure to vibration and noise were examined. The first group included 26 people diagnosed with stage 1 and 2 hand-arm vibration syndrome. The second group consisted of 38 patients diagnosed with s ensorineural hearing loss . Serum levels of c ortisol, dehydroepiandrosterone sulfate, prolactin, free triiodothyronine (T 3 ), free thyroxine (T 4 ), thyroid-stimulating hormone (TSH), and interleukins IL-1β, IL-8, IL-10 were determined by enzyme-linked immunosorbent assay. Results. The results of the study revealed the peculiarities in the immune and hormonal regulation in hand-arm vibration syndrome and sensorineural hearing loss. More pronounced changes were observed in sensorineural hearing loss. A common pattern in patients with hand-arm vibration syndrome and sensorineural hearing loss was an increase in cortisol, prolactin and IL-8 and a decrease in free T 4 and IL-1β. Differences in the identified changes in the immune and hormonal status were characterized by increased TSH production in the first group, and increased free T 3 production and decreased IL-10 in the second group. In hand-arm vibration syndrome, high levels of cortisol were accompanied by a decrease in the IL-1β and IL-10 concentrations. In sensorineural hearing loss, an increase in the prolactin concentration was accompanied by increased production of IL-8. Conclusions . The identified features of immune and hormonal relations may be induced by the intensity of cortisol and prolactin production under the effects of various physical factors. Persistent high levels of cortisol and prolactin in the examined patients are important pathogenetically significant factors in the development of the disease. New laboratory indicators (IL-4, prolactin, free T 3 ) for additional diagnosis of occupational sensorineural hearing loss were identified.

Hormonal profile of pubertal age girls with chronic viral hepatitis

Chronic viral hepatitis (CVH) is more than 70% of the total number of children with chronic hepatitis, and in the population - 0.5%. Adolescents are the most vulnerable group of the population due to the physiological and psychological characteristics of this age. The liver coordinates both adaptive and reproductive processes in the body, and during puberty is the formation of pituitary-gonadal relationships. The aim: to study the features of hormonal homeostasis in adolescent girls with CVH. Materials and methods. We examined 300 girls aged 12-17 years, of which 120 patients with CVH (60 patients with hepatitis B and 60 - with hepatitis C) and 180 relatively healthy patients with physiological sexual development. The diagnosis of CVH was established on the basis of medical history, clinical, virological, biochemical, morphological and instrumental examination. Results. Analysis of the obtained data of the functional state of the liver in the examined patients with CVH revealed disorders of the morphofunctional state of the liver, manifested by cytolysis syndrome, cholestasis, hepatocellular insufficiency and mesenchymal-inflammatory syndrome. In patients with CVH there was a decrease in the production of luteinizing hormone (4.35 ± 0.09 vs. 5.13 ± 0.08 mIU / ml, p&lt;0.01); follicle-stimulating hormone (4.40 ± 0.15 vs. 5.40 ± 0.07 mIU / l, p&lt;0.01); prolactin (215.56 ± 4.76 vs. 282.93 ± 8.36 mIU / ml, p &lt;0.01); progesterone (2.09 ± 0.10 vs. 2.78 ± 0.08 nmol / l, p&lt;0.01) on the background of increasing the average level of estradiol (468.65 ± 21.32 vs. 437.45 ± 9.59 pmol / l, p&lt;0,01) and free testosterone (1,98 ± 0,08 vs. 1,16 ± 0,04 nmol / l, p &lt;0,01). Thyroid status was characterized by a relative decrease in the production of thyroid-stimulating hormone (1.74 ± 0.04 vs. 2.15 ± 0.05 μIU / ml (p&lt;0.01) and an increase in the secretion of free triiodothyronine (9.32 ± 0.09 vs. 5,46 ± 0.07 pmol / l, p&lt;0.01) and free thyroxine (23.35 ± 0.76 vs. 18.55 ± 0.20 pmol / l, p&lt;0.01). chronic infectious process, affects the morphofunctional state of the liver and leads to dysfunction of the hypothalamic-pituitary-ovarian and pituitary-thyroid systems, manifested by pathological changes in the secretion of gonadotropins, prolactin, thyroid-stimulating hormone, sex steroids and hormonal steroids.

Thyrocyte-specific deletion of insulin and IGF-1 receptors induces papillary thyroid carcinoma-like lesions through EGFR pathway activation.

Insulin and insulin-like growth factor (IGF)-1 signaling in the thyroid are thought to be permissive for the coordinated regulation by thyroid-stimulating hormone (TSH) of thyrocyte proliferation and hormone production. However, the integrated role of insulin receptor (IR) and IGF-1 receptor (IGF-1R) in thyroid development and function has not been explored. Here, we generated thyrocyte-specific IR and IGF-1R double knockout (DTIRKO) mice to precisely evaluate the coordinated functions of these receptors in the thyroid of neonates and adults. Neonatal DTIRKO mice displayed smaller thyroids, paralleling defective folliculogenesis associated with repression of the thyroid-specific transcription factor Foxe1. By contrast, at postnatal day 14, absence of IR and IGF-1R paradoxically induced thyrocyte proliferation, which was mediated by mTOR-dependent signaling pathways. Furthermore, we found elevated production of TSH during the development of follicular hyperplasia at 8 weeks of age. By 50 weeks, all DTIRKO mice developed papillary thyroid carcinoma (PTC)-like lesions that correlated with induction of the ErbB pathway. Taken together, these data define a critical role for IR and IGF-1R in neonatal thyroid folliculogenesis. They also reveal an important reciprocal relationship between IR/IGF-1R and TSH/ErbB signaling in the pathogenesis of thyroid follicular hyperplasia and, possibly, of papillary carcinoma.

The impact of thyroid hormone in seasonal breeding has a restricted transcriptional signature.

Thyroid hormone (TH) directs seasonal breeding through reciprocal regulation of TH deiodinase (Dio2/Dio3) gene expression in tanycytes in the ependymal zone of the medio-basal hypothalamus (MBH). Thyrotropin secretion by the pars tuberalis (PT) is a major photoperiod-dependent upstream regulator of Dio2/Dio3 gene expression. Long days enhance thyrotropin production, which increases Dio2 expression and suppresses Dio3 expression, thereby heightening TH signaling in the MBH. Short days appear to exert the converse effect. Here, we combined endocrine profiling and transcriptomics to understand how photoperiod and TH control the ovine reproductive status through effects on hypothalamic function. Almost 3000 genes showed altered hypothalamic expression between the breeding- and non-breeding seasons, showing gene ontology enrichment for cell signaling, epigenetics and neural plasticity. In contrast, acute switching from a short (SP) to a long photoperiod (LP) affected the expression of a much smaller core of 134 LP-responsive genes, including a canonical group previously linked to photoperiodic synchronization. Reproductive switch-off at the end of the winter breeding season was completely blocked by thyroidectomy (THX), despite a very modest effect on the hypothalamic transcriptome. Only 49 genes displayed altered expression between intact and THX ewes, including less than 10% of the LP-induced gene set. Neuroanatomical mapping showed that many LP-induced genes were expressed in the PT, independently of the TH status. In contrast, TH-sensitive seasonal genes were principally expressed in the ependymal zone. These data highlight the distinctions between seasonal remodeling effects, which appear to be largely independent of TH, and TH-dependent localised effects which are permissive for transition to the non-breeding state.

Dual control of pituitary thyroid stimulating hormone secretion by thyroxine and triiodothyronine in athyreotic patients.

Patient responses to levothyroxine (LT4) monotherapy vary considerably. We sought to differentiate contributions of FT4 and FT3 in controlling pituitary thyroid stimulating hormone (TSH) secretion. We retrospectively assessed the relationships between TSH and thyroid hormones in 319 patients with thyroid carcinoma through 2914 visits on various LT4 doses during follow-up for 5.5 years (median, IQR 4.2, 6.9). We also associated patient complaints with the relationships. Under varying dose requirements (median 1.84 µg/kg, IQR 1.62, 2.11), patients reached TSH targets below 0.4, 0.1 or 0.01 mIU/l at 73%, 54% and 27% of visits. While intercept, slope and fit of linearity of the relationships between lnTSH and FT4/FT3 varied between individuals, gender, age, LT4 dose and deiodinase activity influenced the relationships in the cohort (all p < 0.001). Deiodinase activity impaired by LT4 dose significantly affected the lnTSH-FT4 relationship. Dose increase and reduced conversion efficiency displaced FT3-TSH equilibria. In LT4-treated patients, FT4 and FT3 contributed on average 52% versus 38%, and by interaction 10% towards TSH suppression. Symptomatic presentations (11%) accompanied reduced FT3 concentrations (-0.23 pmol/l, p = 0.001) adjusted for gender, age and BMI, their relationships being shifted towards higher TSH values at comparable FT3/FT4 levels. Variation in deiodinase activity and resulting FT3 levels shape the TSH-FT4 relationship in LT4-treated athyreotic patients, suggesting cascade control of pituitary TSH production by the two hormones. Consequently, measurement of FT3 and calculation of conversion efficiency may identify patients with impaired biochemistry and a resulting lack of symptomatic control.

Novel Mutation (T273R) in Thyroid Hormone Receptor β Gene Provides Further Insight into Cryptic Negative Regulation by Thyroid Hormone

Production of thyroid hormone is precisely regulated in a negative feed-back mechanism that depends critically on thyroid hormone receptor β (TRβ). This mechanism decreases production of thyrotropin- releasing hormone (TRH) and thyrotropin (TSH) in the hypothalamus and pituitary gland in response to high levels of circulating thyroid hormones (TH). Despite the wealth of accumulated knowledge, it is still not clear how exactly this negative regulation is executed. The syndrome of resistance to thyroid hormone (RTH), in which the levels of TH are not properly sensed, represents naturally occurring situations in which molecular components of this regulation are displayed and may be uncovered. TRβ, which is central to this regulation, is in the majority of RTH cases mutated in a way that preserves some functions of the receptor. Approximately 150 different mutations in TRβ have been identified to date. Here, we hypothesized that additional pathogenic mutations in TRβ are likely to exist in human population and analysed clinical cases with suspected RTH. In keeping with our prediction, analysis of 17 patients from nine families led to identification of four presumed pathogenic mutations of TRβ, including a previously unknown mutation, T273R. This suggests that threonine 273 is likely to be critical for the normal function of TRβ, possibly due to its role in helix 12 mobility and interaction with coactivators, and thus supports the concept that TRβ-dependent trans-activating function is necessary for the inhibition of TRH and TSH expression in response to elevated levels of TH.