Pituitary-thyroid Axis Research Articles

The Effect of Hydroalcohlic Vac Extract on Pituitary-Thyroid Axis Function in Adult Male Rats

The Effect of Hydroalcohlic Vac Extract on Pituitary-Thyroid Axis Function in Adult Male Rats

Thyrotoxic storm during sepsis: study of a rare complication, clinical and biological observations

We describe an uncommon severe clinical complication of sepsis – thyrotoxic storm (TS). Common biologic, pathogenic, clinical conditions that can determine sepsis can cause a TS. High circulating values of vascular cellular adhesive molecules-1 and various pro-inflammatory citochines are related with thyroid damage. During sepsis, moderate dysfunctions are not expression of actual disease, but severe damage in pituitary-thyroid hormonal axis. Thyroid stimulated hormon release, and consequent overproduction of thyroid hormones can cause TS. In critical patients, presence of hormonal dysfunctions determines more elevated clinical score of sepsis severity and higher risk of death than control groups (without thyroid disease) or survived patients.

Effects of 3,5-diiodo-L-thyronine on the liver of high fat diet fed rats

Experimental studies have highlighted that the administration of 3,5-diiodo-L-thyronine (T2) to rats fed diets rich in lipids induces a decrease of cholesterol and triglycerides plasma levels and body weight (BW) without inducing liver steatosis. On the basis of these observations we carried out some experimental <em>in vivo</em> studies to assess the effects of multiple high doses of T2 on the pituitary thyroid axis of rats fed diet rich in lipids. Fifteen male Wistar rats were divided into three groups of five animals each. The first group (N group) received standard diet, the second group was fed with a high fat diet (HFD group), while the third group (HFDT2 group) was additionally given T2 intraperitoneally at a dose level of 70 µg/100 g of BW three times a week up to four weeks. At the end of the treatment, blood sample from each animal was collected, centrifuged and the serum was stored at -20°C. The serum concentrations of thyroidstimulating hormone (TSH), triiodothyronine, thyroxine, adrenocorticotropic hormone, triglycerides, cholesterol, glucose, alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase were then determined. In addition, liver of rats was examined by histology in order to assess the presence and degree of steatosis. The administration of T2 to rats fed with a high fat diet suppressed TSH secretion (P=0.013) while no steatosis was observed in the liver of these animals. Our data show that multiple administrations of high doses of T2 to rats fed diets rich in lipid inhibit TSH secretion and prevent the onset of liver steatosis in these animals.

Analysis of the correlation between lipotoxicity and pituitary-thyroid axis hormone levels in men and male rats.

Lipotoxicity seriously harms human health, but it is unclear whether lipotoxicity is detrimental to the pituitary. We investigated the correlation between serum triglyceride and pituitary axis hormone levels in epidemiological and animal studies. In the epidemiological study, serum thyroid-stimulating hormone (TSH), follicle-stimulating hormone (FSH) and luteinizing hormone (LH) levels were greater in male patients with isolated hypertriglyceridemia than in controls, whereas adrenocorticotropin (ACTH) levels were lower in the patients with hypertriglyceridemia. Pituitary hormone levels correlated with triglyceride levels, even after adjustment for potential confounders. In the animal study, male rats were fed a high-fat or control diet for 28 weeks. As the duration of high-fat feeding increased, the serum and pituitary triglyceride concentrations increased. At early times, the high-fat diet elevated serum TSH and triiodothyronine. At later times, much higher serum TSH levels coupled with reduced thyroxine were observed in the high-fat group. Serum levels of pituitary-gonadal and pituitary-adrenal axis hormones were not affected by the diet. The mRNA and protein expression of Tshβ were greater in the high-fat group than in the control group, whereas expression of Fshβ, Lhβ and Acth had no difference between the groups. Overall, serum triglyceride levels were associated with pituitary-thyroid axis hormone levels.

The synthetic gestagen levonorgestrel directly affects gene expression in thyroid and pituitary glands of Xenopus laevis tadpoles

The synthetic gestagen levonorgestrel (LNG) was previously shown to perturb thyroid hormone-dependent metamorphosis in Xenopus laevis. However, so far the mechanisms underlying the anti-metamorphic effects of LNG remained unknown. Therefore, a series of in vivo and ex vivo experiments was performed to identify potential target sites of LNG action along the pituitary-thyroid axis of X. laevis tadpoles. Prometamorphic tadpoles were treated in vivo with LNG (0.01–10nM) for 72h and brain-pituitary and thyroid tissue was analyzed for marker gene expression. While no treatment-related changes were observed in brain-pituitary tissue, LNG treatment readily affected thyroidal gene expression in tadpoles including decreased slc5a5 and iyd mRNA expression and a strong induction of dio2 and dio3 expression. When using an ex vivo organ explant culture approach, direct effects of LNG on both pituitary and thyroid gland gene expression were detecTable Specifically, treatment of pituitary explants with 10nM LNG strongly stimulated dio2 expression and concurrently suppressed tshb expression. In thyroid glands, ex vivo LNG treatment induced dio2 and dio3 mRNA expression in a thyrotropin-independent manner. When thyroid explants were cultured in thyrotropin-containing media, LNG caused similar gene expression changes as seen after 72h in vivo treatment including a very strong repression of thyrotropin-induced slc5a5 expression. Concerning the anti-thyroidal activity of LNG as seen under in vivo conditions, our ex vivo data provide clear evidence that LNG directly affects expression of genes important for thyroidal iodide handling as well as genes involved in negative feedback regulation of pituitary tshb expression.

Circulating IL-6 and neopterin concentrations link cell-mediated immunity and tumor stage in patients with gastro-intestinal adenocarcinoma: relevance to the pituitary-adrenal axis and pituitary-thyroid axis

Abstract Although cortisol is a powerful modulator of the immune system and inhibits production of pro-inflammatory cytokines, adrenocorticotropic hormone (ACTH) levels do not correspond to the chronically elevated concentrations of cortisol in cancer patients. Thyroid stimulating hormone (TSH) has been shown to have an effect on immunological functions. Actually it is not known whether cortisol, TSH and IL-6 have an effect on tumor progression via modulation of cell mediated immunity in patients with gastrointestinal carcinoma. Sixty-seven gastrointestinal cancer patients and 42 cancer-free subjects with cholelithiasis as the control group, were included in the study. Serum ACTH, cortisol, TSH, thyroid hormones, IL-6, IL-10 and neopterin levels were measured. Diagnosis and pathological staging were confirmed by surgical intervention. Cortisol levels were correlated with IL-6 in cancer patients. In addition to elevated neopterin values, linear regression analysis revealed that serum neopterin was associated more strongly with the increase of cortisol rather than IL-6 levels in advanced stage carcinoma. Furthermore, neopterin also correlated with IL-6, IL-10, cortisol and TSH levels in advanced carcinoma cases. These data indicated that cortisol, IL-6 and neopterin values of cancer patients were influenced by the tumor presence and progression.

ENDOCRINE PROFILE OF THE MALE POPULATION IN RUSSIA DEPENDING ON THE GEOGRAPHIC LATITUDE OF OCCUPATION

The goal of research is to examine the characteristics of the hormones of the pituitary-gonadal and pituitary-thyroid gland systems in the peripheral blood of the male population living in different areas of Russia, taking into account the population groups. The study involved 136 men aged 22 to 50 years old, who are permanently resident in the North no less than three generations. Among them there are 80 local residents of Arkhangelsk (64° 32' N), 19 local residents of Vologda (59° 13' N) and 37 local residents of Nes, Nenets Autonomous Okrug (66° 36' N). According to the basis of nationality group of men living in Nes was divided into: Russian - 23 people and settled aboriginal population (Nenets, Komi) - 14 people. We have shown that functional activity of the pituitary-thyroid axis (thyrotropin, thyroxine, free triiodothyronine) in the male Caucasoid and settled aboriginal population of the polar region exceeds its level in the inhabitants of the circumpolar area (Arkhangelsk). At the same time, men living in the mid-latitude area (Vologda) had minimal activity of the pituitary-thyroid axis (triiodothyronine, free thyroxine), compared with polar and circumpolar areas. It was shown that the functional activity of the pituitary-gonadal axis in men living in Vologda (luteinizing hormone, follicle-stimulating hormone, inhibin B, free testosterone, dehydroepiandrosterone sulfate) and in Nes (follicle-stimulating hormone, inhibin B, testosterone, free testosterone, sex-hormone-binding globuline) was higher compared with the inhabitants of the city of Arkhangelsk. The levels of sperm antibodies were minimal in men living in Nes. At the same time, changing the traditional way of life from nomadic to a settled one leads to the negative tendencies such as the decrease of the synthesis reserves of steroid hormones in the settled aboriginal population that is shown by the decreased serum levels of progesterone and dehydroepiandrosterone sulfate.

Evaluation of activity of hypothalamo-pituitary-gonadal axis in postmenopausal women suffering from severe acute illness.

Background & objectives:Postmenopausal women constitute an ideal model for studying the extent of hypothalamo-pituitary gonadal (HPG) axis suppression in critical illness as the gonadotropins are normally high and non-cyclical in them. The objective was to assess the impact of acute severe illness in postmenopausal women on the HPG axis and the activities of the hypothalamo-pituitary-adrenal (HPA), the hypothalamo- pituitary-thyroid (HPT) axes; and levels of serum prolactin, by comparison between critically ill postmenopausal women and otherwise healthy postmenopausal women.Methods:Thirty five consecutive postmenopausal women older than 60 yr admitted to medical intensive care with a Simplified Acute Physiology Score II (SAPS II) more than 30 were included. On day five of their in-hospital stay, blood samples were collected for oestradiol, luteinizing hormone (LH), follicle stimulating hormone (FSH), cortisol, androstenedione, prolactin and thyroid profile. Thirty five apparently healthy postmenopausal women were selected as controls.Results:Levels of LH, FSH, thyrotropin, free thyroxin (fT4) and free tri-iodothyronine (fT3) were lower while oestradiol, cortisol and dehydroepiandrosterone were higher among patients in comparison to healthy controls. Prolactin levels were similar in patients and controls. Among sick patients both FSH and fT4 showed a negative correlation (P<0.05) with the SAPS II score.Interpretation & conclusions:In critically ill postmenopausal women, paradoxically elevated oestrogen levels despite gonadotropin suppression suggests a non-ovarian origin. Prolactin remained unaltered in patients despite their illness, possibly reflecting atrophy of lactotrophs in menopause.

The Activation Mechanism of Glycoprotein Hormone Receptors with Implications in the Cause and Therapy of Endocrine Diseases

Glycoprotein hormones (GPHs) are the main regulators of the pituitary-thyroid and pituitary-gonadal axes. Selective interaction between GPHs and their cognate G protein-coupled receptors ensure specificity in GPH signaling. The mechanisms of how these hormones activate glycoprotein hormone receptors (GPHRs) or how mutations and autoantibodies can alter receptor function were unclear. Based on the hypothesis that GPHRs contain an internal agonist, we systematically screened peptide libraries derived from the ectodomain for agonistic activity on the receptors. We show that a peptide (p10) derived from a conserved sequence in the C-terminal part of the extracellular N terminus can activate all GPHRs in vitro and in GPHR-expressing tissues. Inactivating mutations in this conserved region or in p10 can inhibit activation of the thyroid-stimulating hormone receptor by autoantibodies. Our data suggest an activation mechanism where, upon extracellular ligand binding, this intramolecular agonist isomerizes and induces structural changes in the 7-transmembrane helix domain, triggering G protein activation. This mechanism can explain the pathophysiology of activating autoantibodies and several mutations causing endocrine dysfunctions such as Graves disease and hypo- and hyperthyroidism. Our findings highlight an evolutionarily conserved activation mechanism of GPHRs and will further promote the development of specific ligands useful to treat Graves disease and other dysfunctions of GPHRs.

Role of co-regulators in metabolic and transcriptional actions of thyroid hormone.

Thyroid hormone (TH) controls a wide range of physiological processes through TH receptor (TR) isoforms. Classically, TRs are proposed to function as tri-iodothyronine (T3)-dependent transcription factors: on positively regulated target genes, unliganded TRs mediate transcriptional repression through recruitment of co-repressor complexes, while T3 binding leads to dismissal of co-repressors and recruitment of co-activators to activate transcription. Co-repressors and co-activators were proposed to play opposite roles in the regulation of negative T3 target genes and hypothalamic-pituitary-thyroid axis, but exact mechanisms of the negative regulation by TH have remained elusive. Important insights into the roles of co-repressors and co-activators in different physiological processes have been obtained using animal models with disrupted co-regulator function. At the same time, recent studies interrogating genome-wide TR binding have generated compelling new data regarding effects of T3, local chromatin structure, and specific response element configuration on TR recruitment and function leading to the proposal of new models of transcriptional regulation by TRs. This review discusses data obtained in various mouse models with manipulated function of nuclear receptor co-repressor (NCoR or NCOR1) and silencing mediator of retinoic acid receptor and thyroid hormone receptor (SMRT or NCOR2), and family of steroid receptor co-activators (SRCs also known as NCOAs) in the context of TH action, as well as insights into the function of co-regulators that may emerge from the genome-wide TR recruitment analysis.

Homeostatic Control of the Thyroid-Pituitary Axis: Perspectives for Diagnosis and Treatment.

The long-held concept of a proportional negative feedback control between the thyroid and pituitary glands requires reconsideration in the light of more recent studies. Homeostatic equilibria depend on dynamic inter-relationships between thyroid hormones and pituitary thyrotropin (TSH). They display a high degree of individuality, thyroid-state-related hierarchy, and adaptive conditionality. Molecular mechanisms involve multiple feedback loops on several levels of organization, different time scales, and varying conditions of their optimum operation, including a proposed feedforward motif. This supports the concept of a dampened response and multistep regulation, making the interactions between TSH, FT4, and FT3 situational and mathematically more complex. As a homeostatically integrated parameter, TSH becomes neither normatively fixed nor a precise marker of euthyroidism. This is exemplified by the therapeutic situation with l-thyroxine (l-T4) where TSH levels defined for optimum health may not apply equivalently during treatment. In particular, an FT3–FT4 dissociation, discernible FT3–TSH disjoint, and conversion inefficiency have been recognized in l-T4-treated athyreotic patients. In addition to regulating T4 production, TSH appears to play an essential role in maintaining T3 homeostasis by directly controlling deiodinase activity. While still allowing for tissue-specific variation, this questions the currently assumed independence of the local T3 supply. Rather it integrates peripheral and central elements into an overarching control system. On l-T4 treatment, altered equilibria have been shown to give rise to lower circulating FT3 concentrations in the presence of normal serum TSH. While data on T3 in tissues are largely lacking in humans, rodent models suggest that the disequilibria may reflect widespread T3 deficiencies at the tissue level in various organs. As a consequence, the use of TSH, valuable though it is in many situations, should be scaled back to a supporting role that is more representative of its conditional interplay with peripheral thyroid hormones. This reopens the debate on the measurement of free thyroid hormones and encourages the identification of suitable biomarkers. Homeostatic principles conjoin all thyroid parameters into an adaptive context, demanding a more flexible interpretation in the accurate diagnosis and treatment of thyroid dysfunction.

Histopathological and immunohistochemical characterization of spontaneous pituitary tumors in dwarfs derived from Wistar Hannover GALAS rats

Histopathological and immunohistochemical characteristics of spontaneous pituitary adenomas found in dwarfs derived from Wistar Hanover GALAS are being described for the first time. The adenomas were seen in 5 males aged 48 weeks or older and in 11 females aged 34 weeks or older. Immunohistochemically, 13 cases without post-mortem changes could be evaluated; 4 Thyroid stimulating hormone (TSH)-containing adenomas, 2 TSH- and prolactin (PRL)-containing adenomas, 1 PRL-containing adenoma and 6 all-negative adenomas that did not react to any of the examined anti-hormone antibodies. The most common type were TSH-containing pituitary adenomas (a total of 6 cases; 46%) which occurred exclusively in females; the tumors consisted mainly of basophilic or amphophilic cells with bizarre nuclei and neoplastic cells and were positive for TSH in varying degrees. The TSH-containing pituitary adenomas, a characteristic of this mutant rat, could be induced by genetically-controlled hypothyroidism in dwarf rats, with higher sensitivity to possible disturbance of the pituitary–thyroid axis in females.

Acute exposure to synthetic pyrethroids causes bioconcentration and disruption of the hypothalamus–pituitary–thyroid axis in zebrafish embryos

Synthetic pyrethroids (SPs) have the potential to disrupt the thyroid endocrine system in mammals; however, little is known of the effects of SPs and underlying mechanisms in fish. In the current study, embryonic zebrafish were exposed to various concentrations (1, 3 and 10μg/L) of bifenthrin (BF) or λ-cyhalothrin (λ-CH) until 72h post fertilization, and body condition, bioaccumulation, thyroid hormone levels and transcription of related genes along the hypothalamus–pituitary–thyroid (HPT) axis examined. Body weight was significantly decreased in the λ-CH exposure groups, but not the BF exposure groups. BF and λ-CH markedly accumulated in the larvae, with concentrations ranging from 90.7 to 596.8ng/g. In both exposure groups, alterations were observed in thyroxine (T4) and triiodothyronine (T3) levels. In addition, the majority of the HPT axis-related genes examined, including CRH, TSHβ, TTR, UGT1ab, Pax8, Dio2 and TRα, were significantly upregulated in the presence of BF. Compared to BF, λ-CH induced different transcriptional regulation patterns of the tested genes, in particular, significant stimulation of TTR, Pax8, Dio2 and TRα levels along with concomitant downregulation of Dio1. Molecular docking analyses revealed that at the atomic level, BF binds to thyroid hormone receptor (TRα) protein more potently than λ-CH, consequently affecting HPT axis signal transduction. In vitro and in silico experiments disclosed that during the early stages of zebrafish development, BF and λ-CH have the potential to disrupt thyroid endocrine system.

Ipilimumab-induced hypophysitis in melanoma patients: an Australian case series.

Ipilimumab (Yervoy; Bristol-Myers Squibb) is a novel fully humanised monoclonal antibody that blocks cytotoxic T-lymphocyte antigen 4, an immune checkpoint molecule, to augment anti-tumour T-cell responses. It is associated with significant immune-related side-effects including hypophysitis. We reviewed the clinical and biochemical characteristics of 10 patients with ipilimumab-induced hypophysitis (IH), and developed guidelines for the early detection and management of IH based on our experiences at three major teaching hospitals in Sydney. All patients were evaluated at the Crown Princess Mary Cancer Centre and Department of Endocrinology, Westmead Hospital, Department of Endocrinology, Royal Prince Alfred Hospital, the Melanoma Institute Australia and Macarthur Cancer Therapy Centre, Campbelltown Hospital from 2010 to 2014. Relevant data were extracted by review of medical records. Main outcome measures included clinical features, hormone profile and radiological findings associated with IH, and presence of pituitary recovery. Ten patients were identified with IH. In four patients who underwent monitoring of plasma cortisol, there was a fall in levels in the weeks prior to presentation. The pituitary-adrenal and pituitary-thyroid axes were affected in the majority of patients, with the need for physiological hormone replacement. Imaging abnormalities were identified in five of 10 patients, and resolved without high-dose glucocorticoid therapy. To date, all patients remain on levothyroxine and hydrocortisone replacement, where appropriate. There is significant morbidity associated with development of IH. We suggest guidelines to assist with early recognition and therapeutic intervention.

Recent advances in central congenital hypothyroidism.

Central congenital hypothyroidism (CCH) may occur in isolation, or more frequently in combination with additional pituitary hormone deficits with or without associated extrapituitary abnormalities. Although uncommon, it may be more prevalent than previously thought, affecting up to 1:16 000 neonates in the Netherlands. Since TSH is not elevated, CCH will evade diagnosis in primary, TSH-based, CH screening programs and delayed detection may result in neurodevelopmental delay due to untreated neonatal hypothyroidism. Alternatively, coexisting growth hormones or ACTH deficiency may pose additional risks, such as life threatening hypoglycaemia. Genetic ascertainment is possible in a minority of cases and reveals mutations in genes controlling the TSH biosynthetic pathway (TSHB, TRHR, IGSF1) in isolated TSH deficiency, or early (HESX1, LHX3, LHX4, SOX3, OTX2) or late (PROP1, POU1F1) pituitary transcription factors in combined hormone deficits. Since TSH cannot be used as an indicator of euthyroidism, adequacy of treatment can be difficult to monitor due to a paucity of alternative biomarkers. This review will summarize the normal physiology of pituitary development and the hypothalamic–pituitary–thyroid axis, then describe known genetic causes of isolated central hypothyroidism and combined pituitary hormone deficits associated with TSH deficiency. Difficulties in diagnosis and management of these conditions will then be discussed.

Polybrominated Diphenyl Ether Exposure and Thyroid Function Tests in North American Adults.

Background:Polybrominated diphenyl ethers (PBDEs) are flame-retardant chemicals that are added to many consumer products. Multiple animal studies have shown PBDEs to be thyroid hormone (TH) disruptors. Epidemiologic evidence of PBDE exposure associated with TH disruption has been inconclusive.Objectives:We used repeated measures to estimate associations between serum PBDE concentrations and THs in a North American adult cohort.Methods:From 2010 to 2011, we collected ≤ 3 serum samples at approximately 6-month intervals from 52 healthy adult office workers from Boston, Massachusetts, for analysis of PBDE congeners and THs.Results:The geometric mean sum concentrations of the most prevalent PBDE congeners (BDE-28, BDE-47, BDE-99, BDE-100, and BDE-153) were 22 ng/g lipid in winter 2010, 23 ng/g lipid in summer 2010, and 19 ng/g lipid in winter 2011. BDE-47 was the predominant congener. Based on a multivariable mixed regression model, we estimated that on average, a 1-ng/g serum increase in BDE-47 was associated with a 2.6-μg/dL decrease in total thyroxine (T4) (95% CI: –4.7, –0.35). Total T4 was inversely associated with each PBDE congener. Serum concentrations of PBDEs were not strongly associated with total triiodothyronine (T3), free T4, or thyroid-stimulating hormone (TSH).Conclusion:These results are consistent with those from animal studies showing that exposure to PBDEs is associated with a decrease in serum T4. Because the other TH concentrations did not appear to be associated with BDE exposures, our findings do not indicate effects on the pituitary–thyroid axis. Taken together, our findings suggest that PBDE exposure might decrease the binding of T4 to serum T4 binding proteins.Citation:Makey CM, McClean MD, Braverman LE, Pearce EN, He XM, Sjödin A, Weinberg JM, Webster TF. 2016. Polybrominated diphenyl ether exposure and thyroid function tests in North American adults. Environ Health Perspect 124:420–425; http://dx.doi.org/10.1289/ehp.1509755

Testosterone and estradiol treatments differently affect pituitary-thyroid axis and liver deiodinase 1 activity in orchidectomized middle-aged rats

We previously reported that orchidectomy (Orx) of middle-aged rats (15–16-month-old; MA) slightly affected pituitary-thyroid axis, but decreased liver deiodinase (Dio) type 1 and pituitary Dio2 enzyme activities. At present, we examined the effects of subsequent testosterone-propionate treatment (5mg/kg; Orx+T), and compared the effects of testosterone with the effects of estradiol-dipropionate (0.06mg/kg; Orx+E) treatment. Hormones were subcutaneously administered, daily, for three weeks, while Orx and sham-operated (SO) controls received only the vehicle. The applied dose of T did not alter serum TSH, T4 and T3 concentrations in Orx- MA, though it increased TSH when administrated to Orx young adults (2.5-month-old; Orx-YA). However, pituitaries of Orx–MA+T rats had higher relative intensity of immunofluorescence (RIF) for TSHβ; in their thyroids we found increased volume and height of follicular epithelium, decreased volume of the colloid and higher RIF for T4-bound to thyroglobulin (Tg-T4). Liver Dio1 activity was increased. E-treatment did not affect serum hormone levels, pituitary RIF for TSHβ, or liver Dio1 activity in Orx-MA rats. Thyroids had decreased relative volume and height of follicular epithelium, increased relative volume of the colloid, decreased volume of sodium-iodide symporter-immunopositive epithelium and lower RIF for Tg-T4. Detected changes were statistically significant. In conclusion, androgenization enhanced pituitary TSHβ RIF, thyroid activation and liver Dio1 enzyme activity in Orx-MA, without elevating serum TSH as in Orx-YA rats. Estrogenization induced pituitary enlargement with no effect on pituitary TSHβ RIF, serum TSH or liver Dio1 activity. E also induced alterations in thyroid histology that indicate mild suppression of its functioning, and contributed to thyroid blood vessel enlargement in Orx-MA rats.

Effects of long-term valproic acid treatment on hematological and biochemical parameters in adolescent psychiatric inpatients: a retrospective naturalistic study.

The objective of this study was to determine the long-term hematological and biochemical side effects of valproic acid (VPA) in psychiatric adolescent inpatients. A retrospective naturalistic study design was used. Participants were psychiatric inpatients treated with VPA, alone or in combination with other medications. Electronic medical files were reviewed for changes in hematological and biochemical parameters following a course of VPA treatment. One hundred and four adolescents aged 12-18 (mean 15.76±1.58) years fulfilled the study criteria. The mean blood level and duration of VPA treatment were 65.81±22.18 mcg/ml and 98.57±135.94 days, respectively. The mean levels of thyroid-stimulating hormones and triglyceride levels increased significantly from the first to the last measurement. Platelet count decreased significantly following VPA treatment. No correlation was observed between these parameters and age, duration of treatment, or VPA levels. No serious adverse events were reported. Long-term VPA treatment in adolescents with psychiatric disorders is associated with significant increases in triglyceride levels. Moreover, VPA-treated adolescent psychiatric inpatients may be at risk of developing pituitary-thyroid axis dysregulation and decreased platelet count. Therefore, baseline measurement of thyroid functions and metabolic and hematological parameters and monitoring throughout the treatment are recommended.

60 YEARS OF NEUROENDOCRINOLOGY: TRH, the first hypophysiotropic releasing hormone isolated: control of the pituitary-thyroid axis.

This review presents the findings that led to the discovery of TRH and the understanding of the central mechanisms which control hypothalamus-pituitary-thyroid axis (HPT) activity. The earliest studies on thyroid physiology are now dated a century ago when basal metabolic rate was associated with thyroid status. It took over 50 years to identify the key elements involved in the HPT axis. Thyroid hormones (TH: T4 and T3) were characterized first, followed by the semi-purification of TSH whose later characterization paralleled that of TRH. Studies on the effects of TH became possible with the availability of synthetic hormones. DNA recombinant techniques facilitated the identification of all the elements involved in the HPT axis, including their mode of regulation. Hypophysiotropic TRH neurons, which control the pituitary-thyroid axis, were identified among other hypothalamic neurons which express TRH. Three different deiodinases were recognized in various tissues, as well as their involvement in cell-specific modulation of T3 concentration. The role of tanycytes in setting TRH levels due to the activity of deiodinase type 2 and the TRH-degrading ectoenzyme was unraveled. TH-feedback effects occur at different levels, including TRH and TSH synthesis and release, deiodinase activity, pituitary TRH-receptor and TRH degradation. The activity of TRH neurons is regulated by nutritional status through neurons of the arcuate nucleus, which sense metabolic signals such as circulating leptin levels. Trh expression and the HPT axis are activated by energy demanding situations, such as cold and exercise, whereas it is inhibited by negative energy balance situations such as fasting, inflammation or chronic stress. New approaches are being used to understand the activity of TRHergic neurons within metabolic circuits.

Chronobiological hypothalamic–pituitary–thyroid axis status and antidepressant outcome in major depression

We previously demonstrated that the difference between 2300h and 0800h TSH response to protirelin (TRH) tests on the same day (ΔΔTSH test) is an improved measure in detecting hypothalamic-pituitary-thyroid (HPT) axis dysregulation in depression. This chronobiological index (1) is reduced in about three quarters of major depressed inpatients, and (2) is normalized after successful antidepressant treatment. In the present study, we examined whether early changes in HPT axis activity during the first 2 weeks of antidepressant treatment could be associated with subsequent outcome. The ΔΔTSH test was performed in 50 drug-free DSM-IV euthyroid major depressed inpatients and 50 hospitalized controls. After 2 weeks of antidepressant treatment the ΔΔTSH test was repeated in all inpatients. Antidepressant response was evaluated after 6 weeks of treatment. At baseline, ΔΔTSH values were significantly lower in patients compared to controls and 38 patients (76%) showed reduced ΔΔTSH values (i.e., <2.5mU/L). After 2 weeks of antidepressant treatment, 20 patients showed ΔΔTSH normalization (among them 18 were subsequent remitters), while 18 patients did not normalize their ΔΔTSH (among them 15 were non-remitters) (p<0.00001). Among the 12 patients who had normal ΔΔTSH values at baseline, 8 out 9 who had still normal values after 2 weeks of treatment were remitters, while the 3 with worsening HPT axis function (i.e., reduced ΔΔTSH value after 2 weeks of treatment) were non-remitters (p<0.02). A logistic regression analysis revealed that ΔΔTSH levels after 2 weeks of treatment could predict the probability of remission (odds ratio [OR]=2.11, 95% confidence interval [CI]=1.31-3.41). Our results suggest that after 2 weeks of antidepressant treatment: (1) chronobiological restoration of the HPT axis activity precedes clinical remission, and (2) alteration of the HPT axis is associated with treatment resistance.