Hypothalamic-pituitary-thyroid Axis Function Research Articles

A biologically based computational model for the hypothalamic-pituitary-thyroid (HPT) axis in Xenopus laevis larvae

A biologically based computational model was developed to describe the hypothalamic-pituitary-thyroid (HPT) axis in developing Xenopus laevis larvae. The goal of this effort was to develop a tool that can be used to better understand mechanisms of thyroid hormone-mediated metamorphosis in X. laevis and predict organismal outcomes when those mechanisms are perturbed by chemical toxicants. In this report, we describe efforts to simulate the normal biology of control organisms. The structure of the model borrows from established models of HPT axis function in mammals. Additional features specific to X. laevis account for the effects of organism growth, growth of the thyroid gland, and developmental changes in regulation of thyroid stimulating hormone (TSH) by circulating thyroid hormones (THs). Calibration was achieved by simulating observed changes in stored and circulating levels of THs during a critical developmental window (Nieuwkoop and Faber stages 54–57) that encompasses widely used in vivo chemical testing protocols. The resulting model predicts that multiple homeostatic processes, operating in concert, can act to preserve circulating levels of THs despite profound impairments in TH synthesis. Represented in the model are several biochemical processes for which there are high-throughput in vitro chemical screening assays. By linking the HPT axis model to a toxicokinetic model of chemical uptake and distribution, it may be possible to use this in vitro effects information to predict chemical effects in X. laevis larvae resulting from defined chemical exposures.

Intrauterine exposure to di(2-ethylhexyl) phthalate (DEHP) disrupts the function of the hypothalamus-pituitary-thyroid axis of the F1 rats during adult life.

DEHP is an endocrine disruptor widely used in the production of malleable plastics. DEHP exposure was associated with altered hypothalamic-pituitary-thyroid (HPT) axis function. Although previous studies reported deleterious effects of DEHP exposure during the intrauterine period, few studies have evaluated the direct effects triggered by this endocrine disruptor on the offspring animals' thyroid function. This study aimed to investigate the impact of intrauterine exposure to DEHP on the HPT axis function programming of the offspring animals during adulthood. Pregnant Wistar rats were orally treated with corn oil or corn oil supplemented with DEHP (0.48 or 4.8 mg/kg/day) throughout the gestational period. The offspring rats were euthanized on the 90th postnatal day. Hypothalamus, pituitary, thyroid, and liver were collected to analyze gene expression and protein content through qPCR and Western Blot. Blood was collected to determine TSH and thyroid hormone levels through fluorometric or chemiluminescence immunoassays. In the adult F1 female rats, the highest dose of DEHP decreased TSH serum levels. In the thyroid, DEHP reduced the gene expression and/or protein content of NIS, TSHR, TG, TPO, MCT8, NKX2.1, PAX8, and FOXE1. These data are consistent with the reduction in T4 serum levels of the F1 DEHP-exposed female rats. In the liver, DEHP exposure increased the mRNA expression of Dio1 and Ttr, while the highest dose of DEHP reduced the mRNA expression of Ugt1a1 and Ugt1a6. Conversely, in the F1 male adult rats, TSHB expression and TSH serum levels were increased in DEHP-exposed animals. In the thyroid, except for the reduced protein content of TSHR, none of the evaluated genes/proteins were altered by DEHP. TH serum levels were not changed in the DEHP-exposed F1 male rats compared to the control group. Additionally, there were no significant alterations in the expression of hepatic enzymes in these animals. Our results demonstrated, for the first time, that intrauterine exposure to DEHP disrupts the HPT axis function in male and female offspring rats and strongly suggest that DEHP exposure increases the susceptibility of the offspring animals to develop thyroid dysfunctions during adulthood.

Evaluation of the hypothalamic-pituitary-thyroid axis function in a non-human primate animal model with chronic exposure to methamphetamine

Psychostimulants, such as amphetamine-type stimulants, induce alterations in hypothalamic-pituitary-thyroid (HPT) axis function. In this study, we sought to investigate the changes in the HPT axis using a wellcharacterized non-human primate model after chronic exposure to methamphetamine (MA). The data collected from 10 adult monkeys were retrospectively studied, assigning them into two groups—the control group (saline) and MA group. MA was injected for 4 weeks with gradually increasing dose, and later injected maintenance doses for 24 weeks. We collected and tested the blood samples on a weekly basis for T4, free T4, T3, free T3, TSH, TgAb, and TPOAb. We used western blotting and quantitative reverse transcription polymerase chain reaction techniques to test the protein and mRNA expression of bcl-2, Bax, and thyroid stimulating hormonereceptor. The MA group had significantly higher levels of T4, FT4, T3, and TSH than the control group. However, no significant difference was observed in FT3, TGAb, and TPOAb. Compared with the control group, most of the thyroid from the MA group consistently showed markedly disordered structure: varied size, lymphocytic infiltration, and local fibrosis. In the MA group, the protein and mRNA expression of Bax were significantly higher than the control group, whereas the protein and mRNA expression of Bcl-2 and TSH-R were significantly lower. These results indicate that chronic exposure to MA can lead to changes in the HPT axis function and induce apoptosis or other microdamage to the thyroid gland in a non-human primate model.

Differential effects of leptin administration on feeding and HPT axis function in early-life overfed adult rats

Early-life overfeeding (OF) disrupts neuroendocrine systems, energy homeostasis and food intake regulation inducing overeating and overweight in adults. Adult rats raised in small litters during lactation, display hyperphagia and overweight since weaning and exhibit a decrease in thyrotropin-releasing hormone (TRH) mRNA expression in hypothalamic paraventricular nucleus (PVN). This is counterintuitive because TRH expression should increase to activate the hypothalamic-pituitary-thyroid (HPT) axis and promote energy expenditure, thus, HPT axis seems inhibited in OF rats. Leptin, an adipocyte-synthesized hormone that stimulates hypothalamic TRH expression, enhances both TRH anorectic effects and HPT axis-induced metabolic rate. To evaluate hypothalamic resistance to the anorectic and HPT axis stimulatory actions of leptin, we injected leptin i.p. to ad libitum fed and to 48-h fasted adult control (reared in normal litters) and to small-litter reared (OF) male Wistar rats. Findings showed that HPT axis was still responsive to leptin, since PVN TRH mRNA levels, median eminence TRH release and T4 serum concentration increased in both, ad libitum and fasted OF rats after leptin administrations. Leptin was ineffective to reduce feeding of OF animals. By comparing leptin receptor (ObRb) expression changes between arcuate and PVN nuclei, we observed that arcuate ObRb was not modified in response to leptin administrations in OF rats, likely accounting for the differential effects in feeding and HPT axis function. Nevertheless, ObRb expression was modified by leptin in the PVN of OF rats to the same extent as controls; this supports the hormone’s role as a therapeutic agent for early onset obesity in adults.

Progressive hearing loss in the α-galactosidase A deficient rat model of Fabry disease

Early-life overfeeding (OF) disrupts neuroendocrine systems, energy homeostasis and food intake regulation inducing overeating and overweight in adults. Adult rats raised in small litters during lactation, display hyperphagia and overweight since weaning and exhibit a decrease in thyrotropin-releasing hormone (TRH) mRNA expression in hypothalamic paraventricular nucleus (PVN). This is counterintuitive because TRH expression should increase to activate the hypothalamic-pituitary-thyroid (HPT) axis and promote energy expenditure, thus, HPT axis seems inhibited in OF rats. Leptin, an adipocyte-synthesized hormone that stimulates hypothalamic TRH expression, enhances both TRH anorectic effects and HPT axis-induced metabolic rate. To evaluate hypothalamic resistance to the anorectic and HPT axis stimulatory actions of leptin, we injected leptin i.p. to ad libitum fed and to 48-h fasted adult control (reared in normal litters) and to small-litter reared (OF) male Wistar rats. Findings showed that HPT axis was still responsive to leptin, since PVN TRH mRNA levels, median eminence TRH release and T4 serum concentration increased in both, ad libitum and fasted OF rats after leptin administrations. Leptin was ineffective to reduce feeding of OF animals. By comparing leptin receptor (ObRb) expression changes between arcuate and PVN nuclei, we observed that arcuate ObRb was not modified in response to leptin administrations in OF rats, likely accounting for the differential effects in feeding and HPT axis function. Nevertheless, ObRb expression was modified by leptin in the PVN of OF rats to the same extent as controls; this supports the hormone’s role as a therapeutic agent for early onset obesity in adults.

Impaired hypothalamic cocaine- and amphetamine-regulated transcript expression in lateral hypothalamic area and paraventricular nuclei of dehydration-induced anorexic rats.

Negative energy balance promotes physiological adaptations that ensure the survival of animals. The hypothalamic-pituitary-thyroid axis regulates basal energy expenditure and its down-regulating adaptation to negative energy balance is well described: in fasting, the serum content of thyrotrophin (TSH) and thyroid hormones (TH) decreases, enhancing the survival odds of individuals. By contrast, dehydration-induced anorexic (DIA) rats present an impaired hypothalamic-pituitary-thyroid (HPT) axis adaptation despite their negative energy balance: increased circulating TSH levels. The implication of cocaine- and amphetamine-regulated transcript (CART), an anorexic peptide, in HPT axis function impairment and food-avoidance behaviour displayed by DIA animals is unknown. Because CART is co-expressed with the peptide that regulates the HPT axis in hypophysiotrophic paraventricular nucleus (PVN) neurones (TSH-releasing hormone), we analysed CART expression and possible implications with respect to high TSH levels of DIA animals. We examined whether changes in CART expression from the lateral hypothalamic area (LHA) and arcuate nucleus (ARC) could participate in food-avoidance of DIA rats. DIA and forced-food restricted (FFR) animals reduced their body weight and food intake. FFR rats had a down-regulation of their HPT axis (reduced serum TH and TSH content), whereas DIA animals had reduced TH but increased TSH levels. CART mRNA expression in the ARC decreased similarly between experimental groups and diminished in anterior, medial PVN and in LHA of FFR animals, whereas DIA animals showed unchanged levels. This impaired CART mRNA expression in the anterior PVN and LHA could be related to the aberrant feeding behaviour of DIA rats but not to their deregulated HPT axis function.

The intervention effects of fluoxetine hydrochloride on hypothalamic-pituitary-thyroid axis function deficiency in patients with poststrok depression

Objective To investigate the intervention effects of fluoxetine on hypothalamic-pituitary-thyroid (HPT) axis function changes in post-stroke depression (PSD) patients. Methods Mild to moderate stroke patients were enrolled and blood T3 , T4, FT3, FT4 and TSH were measured at day 0, 1, 7, 14, 21 and 3 months. At day 7, thyroid hormone releasing hormone (TRH) stimulation test were performed. After evaluated with the anxiety scale screening using the HAMD scale assessment at day 21, the subjects were divided into simple stroke subgroup (<8 points, 25 cases) and PSD sub-group (≥ 8 points, 18 cases), with 16 healthy age and sex matched individuals as control group. In the 2nd stage, TRH stimulation test were performed in PSD patients before and after 7 days of fluoxetine administration. Results Compared with control group, stroke patients presented lower FT3 (P 0.05). TRH test showed that the responses in PSD patients were lower than those in simple stroke patients((2.65±0.42)μIU/ml vs (5.31±0.68)μIU/ml, P<0.05). Correlation analysis showed HAMD scores correlated with TSH level changes and TSH0~30 in PSD subgroup closely(r=0.35, 0.25, P<0.01). In the 2nd stage, TRH test showed that PSD patients who took fluoxetine presented a lower TSH level change than PSD patients who did not((4.61±2.02)μIU/ml vs (7.05±2.12)μIU/ml, P<0.05). Conclusion PSD patients present a long and severe HPT axis function inhibition, which may due to TRH deficiency, and fluoxetine may improve this abnormality. Key words: Hypothalamic-pituitary-thyroid axis; Post-strok depression; Fluoxetine hydrochloride

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.

Thyroid circadian timing: roles in physiology and thyroid malignancies.

The circadian clock represents an anticipatory mechanism, well preserved in evolution. It has a critical impact on most aspects of the physiology of light-sensitive organisms. These rhythmic processes are governed by environmental cues (fluctuations in light intensity and temperature), an internal circadian timing system, and interactions between this timekeeping system and environmental signals. Endocrine body rhythms, including hypothalamic-pituitary-thyroid (HPT) axis rhythms, are tightly regulated by the circadian system. Although the circadian profiles of thyroid-releasing hormone (TRH), thyroid-stimulating hormone (TSH), thyroxine (T4), and triiodothyronine (T3) in blood have been well described, relatively few studies have analyzed molecular mechanisms governing the circadian regulation of HPT axis function. In this review, we will discuss the latest findings in the area of complex regulation of thyroid gland function by the circadian oscillator. We will also highlight the molecular makeup of the human thyroid oscillator as well as the potential link between thyroid malignant transformation and alterations in the clockwork.

Depression and alterations in hypothalamic–pituitary–adrenal and hypothalamic–pituitary–thyroid axis function in male abstinent methamphetamine abusers

The present study was to investigate depression and alterations in the hypothalamic-pituitary-adrenal (HPA) and hypothalamic-pituitary-thyroid (HPT) axis function in methamphetamine (METH) abusers after abstinence. Depression was assessed using the 13-item Beck Depression Inventory (BDI-13) scale; blood samples from in-patients who were METH abusers and age-matched and sex-matched healthy controls were collected. The demographic characteristics and history of METH abuse also was assessed. We found that serum levels of adrenocorticotropic hormone (ACTH) and thyroxine were increased; and serum levels of cortisol, triiodothyronine, and thyroid-stimulating hormone were decreased; and the BDI score was higher in METH abusers compared with control. In addition, there was no correlation between the BDI-13 score and any of hormones of HPA and HPT axis was found. Particularly, we found abnormally higher ACTH level and mismatched with lower cortisol level in abstinent METH abusers. These results indicate that METH abusers and that their HPA and HPT functions are all altered after abstinence. Chronically using METH may destroy the regulatory function of the HPA axis, especially the feedback regulation of cortisol to ACTH.

Alteration of Hypothalamic–Pituitary–Thyroid Axis Function in Non-Small-Cell Lung Cancer Patients

The aim of this study was to evaluate the hypothalamic-pituitary-thyroid (HPT) axis function in patients suffering from lung cancer. Thyrotropin-releasing hormone (TRH), thyroid-stimulating hormone (TSH), free thyroxine (FT4), interleukin (IL)-2, and melatonin serum levels were measured in blood samples collected every 4 hours for 24 hours from 11 healthy participants (H; ages 35-53 years) and 9 patients suffering from non-small-cell lung cancer (C; ages 43-63 years). Relationships between hormone levels overall and over time of day were evaluated within and among groups. A prominent circadian rhythm with peaks near midnight was present for TSH and melatonin serum levels in both H and C, indicating similar synchronization of the main body clock to the 24-hour environmental light-dark cycle. As regards 24-hour means in H and C, TSH was lower in C, whereas TRH, FT4, and IL-2 were higher in C, with no difference in melatonin levels. Simple linear regression, FT4 versus TRH, showed a positive correlation in H and a negative correlation in C, whereas FT4 versus TSH showed a negative correlation in both groups. For FT4 versus IL-2, a negative correlation was found in C but not for H, whereas TSH versus TRH showed no correlation for either group. Both groups were found to be similarly synchronized to the 24-hour sleep-wake schedule, but HPT axis function was altered in patients suffering from lung cancer. When compared with healthy controls, cancer patients showed modifications of hormone serum levels overall and a negative correlation between individual TRH and FT4 levels.

Hypothalamic–pituitary–thyroid-axis function in treatment resistant depression

Recently, there were some reports that the prevalence of various grades of hypothyroidism may be increased in patients with treatment resistant depression (TRD). The aim of the present study was to examine serum basal thyroid-stimulating hormone (TSH) and thyroxine (T4) levels in 36 major depressed subjects, of whom 27 had TRD and 15 were normal volunteers. There were no significant differences in serum basal TSH or T4 levels between major depressed subjects and normal controls, or between patients with TRD versus normal controls or subjects without TRD. There was a trend towards lower serum basal T4 concentrations in patients with TRD than in other depressed patients and normal controls. One patient with TRD had basal serum TSH levels in the hyperthyroid range. Two subjects, one with TRD and one normal control, had serum TSH values in the subclinical hypothyroid zone, but their serum T4 values were in the euthyroid range. There were no significant relationships between basal TSH or T4 and severity of illness, staging of depression based on prior treatment non-response, length of the depressive episode, duration of illness, or number of previous depressive episodes. In conclusion, the results of this study do not provide evidence that (subclinical) hypothyroidism occurs more than coincidentally in depressed patients with TRD.

Thyroid Disorders of Pregnancy

Practical aspects in the management of thyroid diseases in pregnancy are reviewed. Information on the hypothalamic-pituitary thyroid axis function in pregnancy and transplacental passages of thyroid hormones is discussed. Diagnosis and management of thyroid dysfunction in pregnancy are updated together with the management of women on thyroid replacement therapy at the time of conception. A practical evaluation of thyroid nodules in pregnancy is suggested. Finally, the syndrome of postpartum thyroid dysfunction is reviewed, stressing the importance of proper diagnosis and the need for long-term follow-up evaluation of these patients.

A further investigation of basal HPT axis function in unipolar depression: Effects of diagnosis, hospitalization, and dexamethasone administration

Hypothalamic-pituitary-thyroid (HPT) axis function was assessed in depressed subjects 1 and 8 days after hospital admission, and after the administration of 1 mg of dexamethasone. Plasma levels of thyroid stimulating hormone (TSH), free triiodothyronine (FT 3), and free thyroxine (FT 4) were measured by ultrasensitive assays in 16 patients with minor depression, 15 patients with simple major depression, and 13 patients with melancholia. The postdexamethasone adrenocorticotropic hormone (ACTH) (intact 1 –39 molecule) and cortisol values were determined. Basal TSH values were significantly lower in melancholic patients than in patients with minor and simple major depression on the day after admission and 1 week later. Basal TSH values determined 1 week after admission were significantly and negatively related to FT 4 values and severity of depression. There were no significant differences in basal TSH, FT 3, and FT 4 values obtained on day 1 and day 8 after hospital admission. Dexamethasone administration had a significant suppressant effect on basal TSH and FT 3 values. Patients who failed to suppress cortisol after the dexamethasone suppression test (DST) exhibited significantly less suppression of basal TSH values than did DST cortisol suppressors.

Endocrine responses to growth hormone‐releasing hormone, thyrotropin‐releasing hormone and corticotropin‐releasing hormone in depression

To explore and to compare hypothalamic-pituitary-somatotropic (HPS), hypothalamic-pituitary-thyroid (HPT) and hypothalamic-pituitary-adrenocortical (HPA) axis function in depression, 30 subjects (15 patients with a major depressive episode and individually matched controls) received 50 micrograms growth hormone-releasing hormone-44 amide at 9:00, 200 micrograms thyrotropin-releasing hormone (TRH) at 9:00 and 100 micrograms human corticotropin-releasing hormone (CRH) at 18:00 on consecutive days as an i.v. bolus dose. Compared with controls, depressed patients showed blunted growth hormone (GH) responses to GHRH, decreased TRH-induced thyrotropin (TSH) release and reduced corticotropin (ACTH) but normal cortisol secretion following CRH. ACTH secretion following CRH and TRH-induced TSH release were positively correlated across depressed patients and controls but no significant correlations between GH responses to GHRH and TRH-induced TSH release or ACTH and cortisol secretion following CRH administration were demonstrated. Our findings suggest that altered HPT and HPA axis function associated with depression are triggered by factors that are at least partly different from those that cause HPS system dysfunction. We conclude that the pathophysiological process resulting in aberrant neuroendocrine secretory dynamics associated with depression may primarily occur at a suprapituitary site, and that HPS, HPT and HPA axis dysfunction may be precipitated by complex central and peripheral regulatory mechanisms involving largely independent factors.