Hypothalamo-pituitary-thyroid Research Articles

OR14-04 Musashi-1 Is A Cell-type Specific Regulator Of Type 2 Deiodinase-mediated Thyroid Hormone Activation

Abstract Disclosure: P. Mohacsik: None. E. Halmos: None. Y. Ruska: None. C. Fekete: None. B. Gereben: None. Thyroid hormone (TH) exerts a profound effect on the regulation of energy homeostasis, metabolism, brain development and the determination of cell fate in various tissues. Type 2 deiodinase enzyme (D2) is the crucial regulator of TH activation by converting the prohormone thyroxine to T3 that can bind the TH receptor. This represents a fundamental step of cell-type specific TH action. D2 regulation is tightly controlled at various molecular levels to allow quick adaptation of TH action to specific challenges. Within the brain, D2 is expressed in hypothalamic tanycytes that play a crucial role in the regulation of the hypothalamo-pituitary-thyroid (HPT) axis and in astrocytes of extrahypothalamic brain regions. Under changing TH economy, D2 activity undergoes homeostatic alteration in astrocytes while remains largely unaffected in hypothalamic tanycytes. Our aim was to identify regulators that could underlie this phenomenon as a cell-type specific regulator of D2-dependent TH action. Musashi (Msi)-1 is a highly conserved RNA-binding protein that regulates cell cycle and play a crucial role during brain development. We found, that Msi-1 was co-expressed with D2 both in hypothalamic tanycytes and cortical astrocytes in mice and T3 treatment (24h T3 1µg/bwg, i.p.) increased Msi-1 protein level in both cell types indicating its TH-dependent regulation. Then we identified multiple potential Msi-1 binding sites in the extremely long 3’UTR both of the human, mouse, rat and chicken D2 mRNA and used RNA electromobility shift assay that revealed direct binding of Msi-1 to the 3’UTR of the D2 mRNA. Studies on the impact of Msi-1 level on D2 activity showed, that Msi-1 overexpression decreased D2 activity in HEK293 cells while this effect was abolished by the deletion of a 3 kb region of the 3’UTR of D2 containing the Msi-1 binding sites. Furthermore, Msi-1 knock down by shRNA in H4 glioma cells increased endogenous D2 activity. A mouse model, lacking Msi-1 protein exclusively in the brain and pituitary, showed increased D2 activity in the cortex accompanied with a slightly decreased serum fT4 and decreased liver dio1 expression. Increased cortical D2 activity was not a consequence of the mildly hypothyroid periphery since cortical expression of dio3, the T3-regulated T3-degrading enzyme remained unchanged along with enpp2, another T3-regulated gene. In contrast, D2 activity remained unchanged in hypothalamic tanycytes. Our results identify Msi-1 as a TH-dependent cell-type specific regulator of D2 activity in the mouse brain that acts via direct binding to the 3’UTR of the D2 mRNA. In summary, Msi-1 regulates D2 activity cell type specifically and may contribute to the homeostatic regulation of cortical D2 while at the same time allows TH-resistant D2 function in tanycytes that is required by proper HPT function. Presentation: Friday, June 16, 2023

Transcriptome Analysis During Follicle Development in Turkey Hens With Low and High Egg Production.

Low and high egg producing hens exhibit gene expression differences related to ovarian steroidogenesis. High egg producing hens display increased expression of genes involved in progesterone and estradiol production, in the granulosa layer of the largest follicle (F1G) and small white follicles (SWF), respectively, whereas low egg producing hens display increased expression of genes related to progesterone and androgen production in the granulosa (F5G) and theca interna layer (F5I) of the fifth largest follicle, respectively. Transcriptome analysis was performed on F1G, F5G, F5I, and SWF samples from low and high egg producing hens to identify novel regulators of ovarian steroidogenesis. In total, 12,221 differentially expressed genes (DEGs) were identified between low and high egg producing hens across the four cell types examined. Pathway analysis implied differential regulation of the hypothalamo-pituitary-thyroid (HPT) axis, particularly thyroid hormone transporters and thyroid hormone receptors, and of estradiol signaling in low and high egg producing hens. The HPT axis showed up-regulation in high egg producing hens in less mature follicles but up-regulation in low egg producing hens in more mature follicles. Estradiol signaling exclusively exhibited up-regulation in high egg producing hens. Treatment of SWF cells from low and high egg producing hens with thyroid hormone in vitro decreased estradiol production in cells from high egg producing hens to the levels seen in cells from low egg producing hens, whereas thyroid hormone treatment did not impact estradiol production in cells from low egg producing hens. Transcriptome analysis of the major cell types involved in steroidogenesis inferred the involvement of the HPT axis and estradiol signaling in the regulation of differential steroid hormone production seen among hens with different egg production levels.

Characterization of hypothalamo–pituitary–thyroid axis gene expression in the hypothalamus, pituitary gland, and ovarian follicles of turkey hens during the preovulatory surge and in hens with low and high egg production

Dysregulation of the preovulatory surge (PS) leads to lowered egg production. The hypothalamo–pituitary–thyroid (HPT) axis has been shown to influence plasma progesterone levels and follicle ovulation. The presence of thyroid hormone receptors (THR) in the reproductive axis suggests possible effects of thyroid hormone. To further understand the potential role of thyroid hormone on the PS, HPT axis plasma hormone concentrations and gene expression were characterized surrounding the PS in average egg producing hens (AEPH), low egg producing hens (LEPH), and high egg producing hens (HEPH) (n = 3 hens/group). Data were analyzed using the mixed models procedure of SAS, with significance indicated at P < 0.05. Average egg producing hens and HEPH displayed lower levels of triiodothyronine (T3) and higher levels of thyroxine (T4) inside of the PS, whereas LEPH showed inverse T3 and T4 levels relative to the PS. Expression of mRNA for hypothalamic thyrotropin-releasing hormone (TRH), pituitary thyrotropin (TSHB), and the main thyroid hormone metabolism enzyme (DIO2) were downregulated during the PS in AEPH and HEPH. Low egg producing hens displayed higher expression of mRNA for hypothalamic TRH as well as pituitary TSHB and DIO2 compared with HEPH. Average egg producing hens expression of THR mRNAs was upregulated during the PS in the hypothalamus but downregulated in the pituitary. High egg producing hens showed decreased expression of THR mRNAs in both the hypothalamus and pituitary when compared with LEPH. In ovarian follicles, THR mRNAs were more prevalent in the thecal layer of the follicle wall compared with the granulosa layer, and expression tended to decrease with follicle maturity. Minimal differences in follicular THR expression were seen between LEPH and HEPH, indicating that THR expression is unlikely to be responsible for steroid hormone production differences occurring between LEPH and HEPH. Generally, downregulation of the HPT axis was seen during the PS in AEPH and HEPH, whereas upregulation of the HPT axis was seen in LEPH. Further studies will be required to clarify the role of the HPT axis in the regulation of ovulation and egg production rates in turkey hens.

Transcriptome analysis of the hypothalamus and pituitary of turkey hens with low and high egg production

BackgroundHigh egg producing hens (HEPH) show increased hypothalamic and pituitary gene expression related to hypothalamo-pituitary-gonadal (HPG) axis stimulation as well as increased in vitro responsiveness to gonadotropin releasing hormone (GnRH) stimulation in the pituitary when compared to low egg producing hens (LEPH). Transcriptome analysis was performed on hypothalamus and pituitary samples from LEPH and HEPH to identify novel regulators of HPG axis function.ResultsIn the hypothalamus and pituitary, 4644 differentially expressed genes (DEGs) were identified between LEPH and HEPH, with 2021 genes up-regulated in LEPH and 2623 genes up-regulated in HEPH. In LEPH, up-regulated genes showed enrichment of the hypothalamo-pituitary-thyroid (HPT) axis. Beta-estradiol was identified as an upstream regulator regardless of tissue. When LEPH and HEPH samples were compared, beta-estradiol was activated in HEPH in 3 of the 4 comparisons, which correlated to the number of beta-estradiol target genes up-regulated in HEPH. In in vitro pituitary cell cultures from LEPH and HEPH, thyroid hormone pretreatment negatively impacted gonadotropin subunit mRNA levels in cells from both LEPH and HEPH, with the effect being more prominent in HEPH cells. Additionally, the effect of estradiol pretreatment on gonadotropin subunit mRNA levels in HEPH cells was negative, whereas estradiol pretreatment increased gonadotropin subunit mRNA levels in LEPH cells.ConclusionsUp-regulation of the HPT axis in LEPH and upstream beta-estradiol activation in HEPH may play a role in regulating HPG axis function, and ultimately ovulation rates. Thyroid hormone and estradiol pretreatment impacted gonadotropin mRNA levels following GnRH stimulation, with the inhibitory effects of thyroid hormone more detrimental in HEPH and estradiol stimulatory effects more prominent in LEPH. Responsiveness to thyroid hormone and estradiol may be due to desensitization to thyroid hormone and estradiol in LEPH and HEPH, respectively, due to up-regulation of the HPT axis in LEPH and of the HPG axis in HEPH. Further studies will be necessary to identify possible target gene desensitization mechanisms and elicit the regulatory role of the HPT axis and beta-estradiol on ovulation rates in turkey hens.

Alteration of levels of thyroid hormones in acute ischemic stroke and its correlation with severity and functional outcome

Introduction – With increasing life expectancy and changing trends in diseases, lifestyle diseases come forward and become a major concern. Ischemic stroke is an emerging public health issue leading to significant morbidity and mortality. To improvise positive outcome in acute ischemic stroke (AIS) and optimizing healthcare resources, accurate and timed prognostication of functional outcome is important. Various studies implied derangement of Hypothalamo-pituitary-thyroid (HPT) axis in AIS, thereby advocates neuroprotective properties to these hormones. This is, still, an open field for active research. Thyroid hormones can, therefore, be used as a surrogate tool for outcome predilection in AIS. This prospective observational cohort study aimed to investigate the alteration of levels of thyroid hormones in AIS and simultaneously correlate their levels in assessment of clinical severity and predicting the functional outcome. Materials and methods – We had collected data from 60 patients of, radiologically confirmed new cases of AIS who sought medical help within 72 hours of initiation of stroke symptom and had no previous history of thyroid disease. Blood samples for thyroid function test [TSH, FreeT3 (FT3), and FreeT4 (FT4)] were collected within 24 hours after admission and subsequently at 7th and 30th day of discharge .On admission neurological clinical severity was assessed by using National Institute of Health Stroke Scale (NIHSS). Functional outcome was assessed by Modified Rankin Scale (mRS) at 7th and 30th day of discharge. Result – Out of 60 AIS patients, 40 were having Non thyroidal illness Syndrome (NTIS). Low T3 was most common NTIS observed. Negative correlation was observed between FT3 levels and on admission NIHSS score and mRS score on follow up. Conclusion – This study thereby concludes that low T3 levels were associated with clinical severity and poor functional outcome in AIS. Keywords: stroke, thyroid profile, correlation, NIHSS, mRS, NTIS.

Opioids and Their Endocrine Effects: A Systematic Review and Meta-analysis

ContextThe increased use of opioids has resulted in an unprecedented opioid epidemic. Chronic opioid use causes hypogonadism, but its frequency, as well as the effects of opioids on other hypothalamo–pituitary–end organ hormone axes, remains unclear.ObjectiveThe aim of this systematic review and meta-analysis was to assess the effects of opioid use on pituitary function.MethodsEight electronic databases were searched for articles published up to May 8, 2018. Fixed or random effects meta-analysis was performed to estimate pooled proportions with 95% confidence intervals (CI). This study is reported following the PRISMA and MOOSE guidelines.Data synthesis52 studies (22 low risk of bias) were included describing 18 428 subjects, consisting of patients with chronic pain (n = 21 studies) or on maintenance treatment for opioid addiction (n = 9) and healthy volunteers (n = 4). The most frequently used opioid was methadone (n = 13 studies), followed by morphine (n = 12). Prevalence of hypogonadism was 63% (95% CI: 55%–70%, 15 studies, 3250 patients, 99.5% males). Prevalence of hypocortisolism relying on dynamic and nondynamic testing was 15% (95% CI: 6%–28%, 5 studies, 205 patients, 57.5% males) and including only studies using the insulin tolerance tests 24% (95% CI 16%–33%, 2 studies, n = 97 patients). In 5 out of 7 studies, hyperprolactinemia was present. No clear effects on the somatotropic and hypothalamo–pituitary–thyroid axes were described.ConclusionsHypogonadism occurs in more than half of male opioid users, and hypocortisolism in approximately one-fifth of all patients. Periodical evaluation of at least the gonadal and adrenal axes is therefore advisable.

Repetitive Transcranial Magnetic Stimulation (rTMS) Modulates Lipid Metabolism in Aging Adults.

Hyperlipidemia, one of the cardiovascular (CV) risk factors, is associated with an increase in the risk for dementia. Repetitive transcranial magnetic stimulation (rTMS) was applied over the right dorsolateral prefrontal cortex (DLPFC) to modulate serum lipid levels in older adults. Participants received 10 sessions of rTMS or sham stimulation intervention within 2 weeks. The serum lipid and thyroid hormone-related endocrine levels were assessed before and after the treatment. We found that rTMS significantly decreased serum lipid levels, including the total cholesterol (CHO) and triglyceride (TG); meanwhile, it also increased the thyroid-stimulating hormone (TSH) as well as thyroxine (T4) levels. This suggests that rTMS modulated the serum lipid metabolism by altering activity in the hypothalamo-pituitary-thyroid (HPT) axis. The trial was registered on the website of Chinese Clinical Trial Registry (http://www.chictr.org.cn).

Discovery of GnIH and Its Role in Hypothyroidism-Induced Delayed Puberty

It is known that hypothyroidism delays puberty in mammals. Interaction between the hypothalamo-pituitary-thyroid (HPT) and hypothalamo-pituitary-gonadal (HPG) axes may be important processes in delayed puberty. Gonadotropin-inhibitory hormone (GnIH) is a newly discovered hypothalamic neuropeptide that inhibits gonadotropin synthesis and release in quail. It now appears that GnIH is conserved across various mammals and primates, including humans, and inhibits reproduction. We have further demonstrated that GnIH is involved in pubertal delay induced by thyroid dysfunction in female mice. Hypothyroidism delays pubertal onset with the increase in hypothalamic GnIH expression and the decrease in circulating gonadotropin and estradiol levels. Thyroid status regulates GnIH expression by epigenetic modification of the GnIH promoter region. Furthermore, knockout of GnIH gene abolishes the effect of hypothyroidism on delayed pubertal onset. Accordingly, it is considered that GnIH is a mediator of pubertal disorder induced by thyroid dysfunction. This is a novel function of GnIH that interacts between the HPT-HPG axes in pubertal onset delay. This mini-review summarizes the structure, expression, and function of GnIH and highlights the action of GnIH in pubertal disorder induced by thyroid dysfunction.

Pituitary Adenylate Cyclase-Activating Polypeptide (PACAP) Regulates the Hypothalamo-Pituitary-Thyroid (HPT) Axis via Type 2 Deiodinase in Male Mice.

The hypothalamic activation of thyroid hormones by type 2 deiodinase (D2), catalyzing the conversion of thyroxine to T3, is critical for the proper function of the hypothalamo-pituitary-thyroid (HPT) axis. Regulation of D2 expression in tanycytes alters the activity of the HPT axis. However, signals that regulate D2 expression in tanycytes are poorly understood. The pituitary adenylate cyclase-activating polypeptide (PACAP) increases intracellular cAMP level, a second messenger known to stimulate the DIO2 gene; however, its importance in tanycytes is not completely characterized. Therefore, we tested whether this ubiquitously expressed neuropeptide regulates the HPT axis through stimulation of D2 in tanycytes. PACAP increased the activity of human DIO2 promoter in luciferase reporter assay that was abolished by mutation of cAMP-response element. Furthermore, PAC1R receptor immunoreactivity was identified in hypothalamic tanycytes, suggesting that these D2-expressing cells could be regulated by PACAP. Intracerebroventricular PACAP administration resulted in increased D2 activity in the mediobasal hypothalamus, suppressed Trh expression in the hypothalamic paraventricular nucleus, and decreased Tshb expression in the pituitary demonstrating that PACAP affects the D2-mediated control of the HPT axis. To understand the role of endogenous PACAP in the regulation of HPT axis, the effect of decreased PACAP expression was studied in heterozygous Adcyap1 (PACAP) knockout mice. These animals were hypothyroid that may be the consequence of altered hypothalamic T3 degradation during set-point formation of the HPT axis. In conclusion, PACAP is an endogenous regulator of the HPT axis by affecting T3-mediated negative feedback via cAMP-induced D2 expression of tanycytes.

Thyroid endocrine status of wild European eels (Anguilla anguilla) in the Loire (France). Relationships with organic contaminant body burdens

In teleost fish, thyroid function is involved in various critical physiological processes. Given the complexity of the hypothalamo–pituitary–thyroid (HPT) axis, a large number of genes and proteins can be the potential target of endocrine-disrupting compounds (EDCs). The aim of this study was to evaluate, in yellow and silver European eels (Anguilla anguilla), potential effects of EDCs on thyroid status by analyzing the associations between EDC body burdens and thyroid hormones (THs). In yellow individuals, greater free T3/T4 ratios (FT3/FT4) and lower plasma FT4 levels were associated with greater concentrations of polychlorinated biphenyls (PCBs) and polybrominated diphenyl ethers (PBDEs), as highlighted by significant correlations with many congeners. Few positive relationships with alkylphenols were noticed. In contrast, silver eels usually exhibited less significant correlations between THs and contaminant loads. Expression of a series of genes involved in the HPT axis was also investigated in the silver individuals. Concerning mRNA expression in silver females, some main correlations were noticed: thyroid-stimulating hormone (TSHβ) gene expression was significantly correlated to numerous PCBs, and hepatic mRNA levels of deiodinase 2 (Deio 2) were negatively correlated to 2-hydroxyfluorene (2-OHF) and 2-naphtol (2-OHNa). Thyroid receptor (TRα and TRβ) mRNA levels exhibited weak negative correlations with some PBDEs in silver females and males. Hepatic vitellogenin (Vtg) mRNA levels were detected in all silver males but at lower levels than in silver females. In males, Vtg mRNA levels were positively associated to FT4/TT4. In silver females, strong positive correlations were found between congeners of PCBs, PBDEs and PFAS suggesting potential estrogenic effects. Overall, the observed results indicate that several organic contaminants, mainly dl-, ndl-PCBs and PBDEs, could be associated with changes in thyroid homeostasis in these fish, via direct or indirect interactions with peripheral deiodination, metabolism of T4 and mechanisms involved in TSHβ, Deio 2 and Vtg gene transcription.

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.

Regulation of TRH neurons and energy homeostasis-related signals under stress.

Energy homeostasis relies on a concerted response of the nervous and endocrine systems to signals evoked by intake, storage, and expenditure of fuels. Glucocorticoids (GCs) and thyroid hormones are involved in meeting immediate energy demands, thus placing the hypothalamo-pituitary-thyroid (HPT) and hypothalamo-pituitary-adrenal axes at a central interface. This review describes the mode of regulation of hypophysiotropic TRHergic neurons and the evidence supporting the concept that they act as metabolic integrators. Emphasis has been be placed on i) the effects of GCs on the modulation of transcription of Trh in vivo and in vitro, ii) the physiological and molecular mechanisms by which acute or chronic situations of stress and energy demands affect the activity of TRHergic neurons and the HPT axis, and iii) the less explored role of non-hypophysiotropic hypothalamic TRH neurons. The partial evidence gathered so far is indicative of a contrasting involvement of distinct TRH cell types, manifested through variability in cellular phenotype and physiology, including rapid responses to energy demands for thermogenesis or physical activity and nutritional status that may be modified according to stress history.

Rats with altered behaviour following nerve injury show evidence of centrally altered thyroid regulation.

The co-morbidity of mood disturbance, in a proportion of patients, is now described across a wide range of chronic disease states. Similarly, a 'Low Thyroid Syndrome' is also reported in a proportion of individuals with chronic diseases. Here, we report on central changes in an animal model of inflammatory stress in which altered social behaviour, representing social disability, persists in a sub-group of rats following injury. We showed in an earlier study that rats with social disability following injury have significantly decreased peripheral thyroid hormones, with no increase in Thyroid Stimulating Hormone (TSH). Only rats identified by behavioural change showed changes in hypothalamic gene expression. In whole hypothalamus extracted RNA, relative expression of mRNA for Thyrotrophin-releasing hormone (TRH) was significantly down-regulated in disabled rats (p=0.039) and deiodinase 3 up-regulated (p=0.006) compared to controls. Specifically in the paraventricular nucleus (PVN), numbers of immunoreactive cells for deiodinase 3-like and thyroid hormone receptor beta-like proteins were decreased in the sub-group with disability compared to the control group (p=0.031 and p=0.011 respectively). In rats with behavioural change post-injury, down-regulation of TRH provides an explanation for the failure of the hypothalamo-pituitary-thyroid (HPT) axis to respond to the post-injury decrease in thyroxine. Decreased local expression of deiodinase 3 protein, resulting in a local increase in T3, offers an explanation for down regulation of TRH in the hypophysiotrophic TRH neurons. It is possible that, in a sub-group of animals identified behaviourally, a mechanism resulting in hypothalamic down-regulation of the HPT axis persists following inflammatory injury.

Chapter 9 - Central regulation of the hypothalamo–pituitary–thyroid (HPT) axis: focus on clinical aspects

The hypothalamus is the most prominent brain region involved in setpoint regulation of the thyroid axis. It generates the diurnal thyroid-stimulating hormone (TSH) rhythm, and it plays a central role in the adaptation of the thyroid axis to environmental factors such as caloric deprivation or infection. Many studies, including studies in human post-mortem tissue samples, have confirmed a key role for the thyrotropin-releasing hormone (TRH) neuron in the hypothalamic paraventricular nucleus (PVN) in thyroid axis regulation. In addition to their negative feedback action on TRH neurons in the hypothalamus, intrahypothalamic thyroid hormones can also modulate metabolism in adipose tissue and the liver via the autonomic nervous system. Congenital or acquired dysfunction of the hypothalamus or pituitary gland may result in central hypothyroidism (CeH). In the Netherlands, the prevalence of permanent congenital CeH as detected by neonatal screening is approximately 1 in 18000. In most neonates congenital CeH is accompanied by additional anterior pituitary hormone deficiencies, and many show clear morphological abnormalities such as a small anterior gland, a thin or absent pituitary stalk, or an ectopic posterior pituitary gland. Recently, a mutation in the immunoglobulin superfamily member 1 (IGSF1) gene was reported as a novel cause of X-linked, apparently isolated CeH occurring in neonates, children and adults. In adults, the most frequent cause of acquired CeH is a pituitary macroadenoma, usually accompanied by other pituitary hormone deficiencies. Central hyperthyroidism is a rare disorder, especially in children. In adults, it is mostly caused by a TSH-secreting pituitary adenoma.

The prevalence of impaired glucose regulation in psychiatric patients with sleep disorders and its relationship with altered hypothalamopituitary–adrenal and hypothalamopituitary–thyroid axis activity

Sleep restriction, an important symptom of psychiatric diseases, is associated with adverse effects on glucose regulation, but few studies have examined its association with impaired glucose regulation and altered hypothalamic activity. Our study was designed to evaluate the sleep duration, fasting glucose, tolerance glucose, and concentration of plasma insulin; to assess the function of both the hypothalamopituitary-thyroid (HPT) and hypothalamopituitary-adrenal (HPA) axis; and to investigate the relationship of altered hypothalamic function with glucose metabolism in psychiatric patients with a sleep disorders. From January 2010 to December 2011, 324 women (64.7%) and 177 men (35.32%) with a diagnosis of a sleep disorder participated in our cross-sectional study in the psychiatric outpatient department of the West China Hospital of Sichuan University. Results from 75-g glucose tolerance tests, insulin-releasing tests, morning (8:00 am) serum cortisol, and thyroid-stimulating hormone (TSH) (TT3, TT4, FT3, FT4) were collected, as well as body mass index and waist-hip ratio to assess the prevalence of impaired glucose regulation and function of the HPA and HPT axis. Sleep quality was assessed through self-reported questionnaires. There were 301 patients previously diagnosed with an anxiety disorder (78%), and 200 patients previously diagnosed with depression and other psychiatric diseases (22%). Crude prevalence rates were 15.0% for diabetes mellitus (DM), 11.6% for impaired glucose tolerance, 15.8% for impaired fasting glucose, and 11.6% for impaired glucose regulation (impaired glucose tolerance [IGT]+impaired fasting glucose [IFG]). Total prevalence of impaired glucose regulation in patients with a sleep disorder was 48.8%. Mean cortisol level was 463.5±178.8 nmol/L, and the cortisol concentration at 8:00 am was significantly associated with a higher prevalence of impaired glucose regulation and insulin resistance. TSH values above 2.5 mU/L accounted for over 58% and were significantly associated with insulin resistance. These results partially confirm that a high level of cortisol and an increased activity of the HPT axis are associated with impaired glucose regulation. Therefore, as a pathophysiologic event abnormal activity of the hypothalamic function of psychiatric patients with sleep disorders could be viewed as a potential risk factor for increasing incidence of DM.

Thyroid Adverse Effects of Psychotropic Drugs

Because many patients with mental illness take more than one psychotropic drug, an understanding of the effects of every class of these drugs is very important to manage any thyroid abnormalities that can happen with these patients. A systematic review of all the published literature was made via Medline. Keywords used for the search were "thyroid side effects" in association with one of the following: "antipsychotics," "antidepressants," "lithium," "anticonvulsants," "benzodiazepines," "anticholinergics," "antihistaminergics," "cholinesterase inhibitors," "stimulants," "methadone," and "naltrexone." Phenothiazines, which are antipsychotics, mainly alter iodine capture, complex and deactivate it, as well as decrease thyroid-stimulating hormone's (TSH's) response to thyroid-releasing hormone (TRH). Nonphenothiazines, typical antipsychotics, can induce the formation of thyroid autoantibodies and can elevate TSH levels. Atypical antipsychotics may decrease TRH-stimulated TSH. Tricyclic antidepressant drugs complex with iodine and thyroid peroxidase and deactivate them, induce deiodinase activity and interfere with the hypothalamo-pituitary-thyroid (HPT) axis by decreasing TSH response to TRH. The main effect with other antidepressant drugs is a decrease in circulating thyroid hormone levels. Lithium inhibits thyroid hormone release and increases TRH-stimulated TSH, inducing goiter, clinical and subclinical hypothyroidism, and hyperthyroidism. Carbamazepine mainly reversibly decreases serum thyroid hormone levels. Other psychotropic drugs such as valproic acid, benzodiazepines, opiates, anticholinergic and antihistaminergic drugs, and stimulants have minor interferences with thyroid functions. Patients receiving lithium, phenothiazines, and tricyclic antidepressants TCA should be closely monitored for the development of thyroid function abnormalities. Only patients at risk for developing thyroid function abnormalities should be monitored when they receive typical and/or atypical antipsychotic drugs, nontricyclic antidepressant drugs, and carbamazepine. No specific recommendations are proposed as toward thyroid function monitoring for patients receiving any other psychopharmacologic drug.

The HPA axis modulates the CNS melanocortin control of liver triacylglyceride metabolism

The central melanocortin system regulates lipid metabolism in peripheral tissues such as white adipose tissue. Alterations in the activity of sympathetic nerves connecting hypothalamic cells expressing melanocortin 3/4 receptors (MC3/4R) with white adipocytes have been shown to partly mediate these effects. Interestingly, hypothalamic neurons producing corticotropin-releasing hormone and thyrotropin-releasing hormone co-express MC4R. Therefore we hypothesized that regulation of hypothalamo-pituitary adrenal (HPA) and hypothalamo-pituitary thyroid (HPT) axes activity by the central melanocortin system could contribute to its control of peripheral lipid metabolism. To test this hypothesis, we chronically infused rats intracerebroventricularly (i.c.v.) either with an MC3/4R antagonist (SHU9119), an MC3/4R agonist (MTII) or saline. Rats had been previously adrenalectomized (ADX) and supplemented daily with 1mg/kg corticosterone (s.c.), thyroidectomized (TDX) and supplemented daily with 10μg/kgL-thyroxin (s.c.), or sham operated (SO). Blockade of MC3/4R signaling with SHU9119 increased food intake and body mass, irrespective of gland surgery. The increase in body mass was accompanied by higher epididymal white adipose tissue (eWAT) weight and higher mRNA content of lipogenic enzymes in eWAT. SHU9119 infusion increased triglyceride content in the liver of SO and TDX rats, but not in those of ADX rats. Concomitantly, mRNA expression of lipogenic enzymes in liver was increased in SO and TDX, but not in ADX rats. We conclude that the HPA and HPT axes do not play an essential role in mediating central melanocortinergic effects on white adipose tissue and liver lipid metabolism. However, while basal hepatic lipid metabolism does not depend on a functional HPA axis, the induction of hepatic lipogenesis due to central melanocortin system blockade does require a functional HPA axis.

Hypothyroidism in preterm infants following normal screening

Congenital hypothyroidism is screened for in the UK using blood spot thyroid-stimulating hormone (TSH) screening at 5-8 d of age. Although standards are set by the UK Newborn Screening Programme Centre, there are variations in TSH cut-offs used. The introduction of repeat screening of preterm babies at 36 weeks' gestational age in 2005 was controversial in its utility and timing. Two cases of preterm babies are presented, who had normal blood spot TSH values on the first test and who became screen positive when re-tested at term. The first with Trisomy 21 was born at 29 + 6 weeks with an initial blood spot TSH of 3.3 mU/L rising to 263 mU/L at term-corrected gestational age (plasma TSH 476.5 mU/L). The second was born at 24 + 6 weeks' gestational age and on day 7, the heel prick blood spot TSH was <2 mU/L, rising to 6.4 mU/L at 36 weeks corrected gestational age. After a barium enema, the plasma TSH increased to 66.6 mU/L with a free thyroxine of 7.6 pmol/L at day 101. Both cases were treated with thyroxine until death due to complications of prematurity. These cases illustrate the difficulties in screening for congenital hypothyroidism in preterm infants, due to the immaturity of the hypothalamo-pituitary-thyroid axis, and the effect of intercurrent illness and drugs on thyroid function. Despite a reassuring published review of 2200 preterm infants, these cases suggest that it may be unwise not to re-screen ex-preterm infants for congenital hypothyroidism at term.

Phytoestrogens and thyroid hormone levels in the cerebrospinal fluid of ewes fed red clover silage

In sheep, phytoestrogens are known to act at various levels on the hypothalamo–pituitary–gonadal axis, as well as the hypothalamo–pituitary–thyroid axis. The levels of genistein and daidzein and their metabolites, p-ethylphenol and equol, in the cerebrospinal fluid (CSF) were studied in ewes fed red clover silage. Moreover, to test the hypothesis that phytoestrogens may affect the access of thyroid hormones in the brain, the concentrations of both total (TT4) and free thyroxine (fT4) in the blood and CSF, were recorded. In the CSF, daidzein, equol and p-ethylphenol were present, but genistein absent. The total daidzein concentration increased from an undetectable level at 2h, to 0.11±0.05μM at 6h after feeding, representing 13.1% of the daidzein measured in the blood. Gradual increases in equol, from an undetectable level at 2h, to 0.24±0.13μM at 6h after feeding (5.1% of that in blood), and in p-ethylphenol, from 0.03±0.02μM at 2h to 1.7±0.74μM at 6h after feeding (0.1–5.8% of that in blood) were recorded. In sheep fed a phytoestrogen rich diet, the blood concentration of TT4 was lower (P<0.05), but the concentration and the percentage of free T4 (fT4) higher (P<0.01) than in the control sheep. In the CSF, the TT4 concentration was similar in both groups, but the concentration and percentage of fT4 was higher in sheep fed a phytoestrogen rich diet. It could be assumed that (i) in sheep, reproductive disorders, at the base of the hypothalamus, following phytoestrogen consumption are evoked by daidzein and equol, its metabolite, rather than genistein, and (ii) phytoestrogens affect the brain's ability to access T4 in the blood.

Thyroid Functions and Bipolar Affective Disorder

Accumulating evidence suggests that hypothalamo-pituitary-thyroid (HPT) axis dysfunction is relevant to the pathophysiology and clinical course of bipolar affective disorder. Hypothyroidism, either overt or more commonly subclinical, appears to the commonest abnormality found in bipolar disorder. The prevalence of thyroid dysfunction is also likely to be greater among patients with rapid cycling and other refractory forms of the disorder. Lithium-treatment has potent antithyroid effects and can induce hypothyroidism or exacerbate a preexisting hypothyroid state. Even minor perturbations of the HPT axis may affect the outcome of bipolar disorder, necessitating careful monitoring of thyroid functions of patients on treatment. Supplementation with high dose thyroxine can be considered in some patients with treatment-refractory bipolar disorder. Neurotransmitter, neuroimaging, and genetic studies have begun to provide clues, which could lead to an improved understanding of the thyroid-bipolar disorder connection, and more optimal ways of managing this potentially disabling condition.