Hypothalamo-pituitary-thyroid Axis Research Articles

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.

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.

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.

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.

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.

Serum Thyroid Hormone Levels in Preterm Infants Born before 33 Weeks of Gestation and Association of Transient Hypothyroxinemia with Postnatal Characteristics

Fetal thyroid function and the hypothalamopituitary-thyroid axis continue to mature throughout pregnancy. Therefore, thyroid hormone levels of premature infants differ from those of mature ones. Our primary objective was to evaluate the reference values of serum thyroid hormones in preterm infants born before 33 wk gestation. The second objective was to define a cut-off value for transient hypothyroxinemia of prematurity (THOP) according to gestational age and association of THOP with postnatal characteristics in these infants. We recruited a cohort of 200 infants (26-32 wk gestation) admitted to neonatal intensive care units (NICU) between March 2008 and February 2009. We assessed serum levels of thyroid hormones and thyrotropin (TSH), at 1st, 2nd, and 3rd-4th wk of life. Thyroid-binding globulin (TBG), thyroglobulin (Tg), and urinary iodine values were also measured at the 1st wk of life. The infants were divided into two groups according to gestational ages; group 1: 26-29 wk and group 2: 30-32 wk. Association of THOP with postnatal characteristics of these infants were evaluated. TT4 and TT3 values steadily increased from 1st wk to 3rd-4th wk while FT4 value did not significantly changed. FT3 value slightly decreased from 1st wk to 2nd wk and not significantly changed after this period. TSH value steadily decreased from 1st wk to 3rd-4th wk. For all postnatal ages, TT4, TT3, and FT3 values were lower in the lower gestational age group, while there was no significant difference for FT4 and TSH values between two gestational age groups. THOP rate decreased from first wk (24.0%, n=47) to 3rd-4th (14.0%, n=24) in all infants. When adjusted for age, THOP was associated with need for mechanical ventilation (P=0.03, OR:0.65, CI 95% 0.4-0.9) and for having respiratory distress syndrome (RDS) (P=0.02, OR:0.61 CI95%: 0.4-0.9). Longer hospital stay (P=0.006, OR:0.96, CI 95% 0.94-0.99) was also found to be associated with THOP. In preterm infants below 30 wk, thyroid hormones were lower and urinary iodine values were higher compared to infants with older gestational age. THOP at the first wk of life may convey important prognostic information about neonatal morbidity and length of hospitalization stay.

Effects of a 5-day treatment with the UV-filter octyl-methoxycinnamate (OMC) on the function of the hypothalamo-pituitary–thyroid function in rats

Octyl-methoxycinnamate (OMC) is one of the most frequently used UV-filters in sunscreens to protect the skin against the noxious influence of UV radiation. Recently, OMC was suspected to act as an “endocrine active chemical” (EAC) with estrogenic actions. While EACs have been investigated thoroughly for interference with reproductive function in mammalians, surprisingly little efforts have been made to investigate an interference of EACs with the hypothalamo-pituitary–thyroid (HPT) axis despite the expression of estrogen receptors in all parts of this axis. Therefore, we conducted an in vivo study with ovariectomised rats treated for 5 days with different doses of OMC or 17β-estradiol (E2) as a control. Determined parameters comprised serum levels of TSH, T4 and T3, hypothalamic TRH mRNA expression, protein-expression of the sodium–iodide-symporter (NIS) and the TSH receptor and the activities of thyroid peroxidase (TPO) in the thyroid and the T3-responsive hepatic type I 5′deiodinase (Dio1) in the liver. While E2 did not affect TSH-, T4- or T3-levels, OMC caused a dose-dependent decrease of serum concentrations of all of these hormones. TRH expression remained unaffected, while in the thyroid, expression of the TSH receptor but not of NIS was stimulated by OMC. TPO activity was unaltered but Dio1 activity was reduced by OMC. Thus, our results demonstrate a non-estrogenic interference of OMC within the rodent HPT axis with inadequate feedback response to impaired thyroid hormone status, indicated by decreased serum thyroid hormone and hepatic Dio1 levels.

Molecular cloning and sequence analysis of the cDNA encoding thyroid-stimulating hormone β-subunit of common duck and mule duck pituitaries: In vitro regulation of steady-state TSHβ mRNA level

For better understanding of phylogenetic diversity and evolution of pituitary thyroid-stimulating hormone (TSH) in birds, we have cloned the cDNAs encoding TSH beta subunit (TSHβ), by reverse transcription-polymerase chain reaction (RT-PCR) and rapid amplification of cDNA ends (RACE) from two species of domestic ducks, common duck (Tsaiya duck and Pekin duck) ( Anas platyrhynchos domesticus) and mule duck (hybrid of male muscovy duck Cairina moschata and female A. platyrhynchos domesticus). The nucleotide sequences of isolated TSHβ cDNAs of the two species of ducks are identical, with each including 66 bp of 5′-untranslated region (UTR), 402 bp of coding region, and 82 bp 3′-UTR followed by 18 bp poly A tract. The deduced TSHβ subunit of the ducks contains 134 amino acids consisting of a putative signal peptide of 19 amino acids and a putative mature protein of 115 amino acids. However, the TSHβs of common duck and mule duck differ from the TSHβ of muscovy duck in one amino acid at position 97 of the mature protein: isoleucine for common duck and mule duck, and valine for muscovy duck. Our findings thus demonstrate that inter-genus variation of TSHβ exists in Family Anatidae, and that TSHβ gene in the mule duck is preferentially transcribed from the maternal genome rather than from the paternal genome. TSHβ mRNA expressions were investigated by culturing common duck pituitaries with various doses of hormones. Thyrotropin-releasing hormone (TRH) stimulated, while thyroid hormones, triiodothyronine (T 3) and thyroxine (T 4), inhibited the TSHβ mRNA levels, in dose-related manners. The findings thus support that the mode of regulation of TSH gene expression in hypothalamo–pituitary–thyroid axis in birds is similar to that in mammals. Cortisol and corticosterone decreased the steady-state TSHβ mRNA levels at the pituitary level, in a dose-related manner, the first-time demonstration in vertebrates. The results may suggest that glucocorticoids exert suppressive action directly at pituitary level in modulation of steady-state TSHβ mRNA level.

Effects of acute and chronic relaxin-3 on food intake and energy expenditure in rats

The effects of acute and repeated intraparaventricular (iPVN) administration of human relaxin-3 (H3) were examined on food intake, energy expenditure, and the hypothalamo–pituitary thyroid axis in male Wistar rats. An acute high dose iPVN injection of H3 significantly increased food intake 1 h post-administration [0.4 ± 0.1 g (vehicle) vs 1.6 ± 0.5 g (180 pmol H3), 2.4 ± 0.5 g (540 pmol H3) and 2.2 ± 0.5 g (1620 pmol H3), p < 0.05 for all doses vs vehicle]. Repeated iPVN H3 injection (180 pmol/twice a day for 7 days) significantly increased cumulative food intake in ad libitum fed animals compared with vehicle [211.8 ± 7.1 g (vehicle) vs 261.6 ± 6.7 g ( ad libitum fed H3), p < 0.05]. Plasma leptin was increased in the H3 ad libitum fed group. Plasma thyroid stimulating hormone was significantly decreased after acute and repeated administration of H3. These data suggest H3 may play a role in long-term control of food intake.

Effects of leptin and neuropeptide-Y on transcript levels of thyrotropin beta and common alpha subunits of rat pituitary cells in vitro

Leptin and neuropeptide-Y (NPY) are indicated to play a role in hypothalamo-pituitary-thyroid (HPT) axis in relation to regulation of energy homeostasis mediated through acting at hypothalamic synthesis and release of thyrotropin (TSH)-releasing hormone (TRH). Whether leptin and NPY also act at pituitary level in HPT axis remains unknown. This study aimed at investigating whether or not leptin and NPY exert actions at pituitary in modulation of transcript levels of TSHβ and the common pituitary glycoprotein hormone α (PGHα) subunits. The dispersed pituitary cells from 6 wk old male Wistar rats were incubated with or without TRH, leptin or NPY of 10 −8 M and 10 −10 M for 6 h at 37 °C in medium-199 under aeration of 95% O 2 and 5% CO 2. The mRNA levels of TSHβ and PGHα subunits of the incubated cells were measured by reverse transcription-polymerase chain reaction. The results revealed that leptin stimulated, while NPY inhibited, TSHβ mRNA levels in a dose-related manner. Both leptin and NPY increased α subunit mRNA levels. It is demonstrated for the first time that both leptin and NPY exert a direct action at rat pituitary affecting steady-state levels of mRNA of TSHβ and PGHα subunits. The present study supports that both leptin and NPY act at the pituitary as well besides the hypothalamus in HPT axis in relation to regulation of energy homeostasis.

Abnormalities of the hypothalamo-pituitary-thyroid axis in the pro-opiomelanocortin deficient mouse

The melanocortin system is an important regulator of body weight and the hypothalamo-pituitary-thyroid (HPT) axis. The pro-opiomelanocortin (POMC)-null mouse, deficient in all POMC-derived peptides, including alpha-melanocyte stimulating hormone (α-MSH), has an obese phenotype. We studied the HPT axis of POMC-null mice, which has not been previously investigated. Because α-MSH has a stimulatory effect on the HPT axis, we hypothesised that these mice would have a down-regulated thyroid axis, consistent with a recent study of POMC-null humans. The activity of the HPT axis was studied by collecting blood, pituitaries and hypothalami from ad libitum fed, adult POMC-null, heterozygous and wild-type mice. POMC-null mice had significantly elevated plasma total T 4 (TT 4) and free T 3 (fT 3) with reduced plasma thyroid stimulating hormone (TSH), pituitary TSH content and hypothalamic thyrotrophin stimulating hormone (TRH) content compared to wild-type mice. No significant differences between heterozygous and wild-type mice were observed. POMC-null mice have an abnormal HPT axis, which may contribute to their hyperphagia and obesity. These abnormalities are in contrast to those observed in POMC-null humans. These findings support a role for the melanocortin system in the regulation of the HPT axis.

Chronic daily ethanol and withdrawal: 5. Diurnal effects on plasma thyroid hormone levels.

We previously demonstrated that chronic daily ethanol consumption and daily withdrawal by male rats in a modified ethanol liquid diet paradigm produced (a) chronically increased adrenal glucocorticoid activity; (b) decreased plasma testosterone; (c) decreased forebrain proopiomelanocortin gene expression; and (d) corresponding alterations in plasma leptin levels-all of which are consistent with reported changes during alcohol abuse and alcoholism. Each of these systems interact with hypothalamo-pituitary-thyroid (HPT) regulation, and links between chronic alcohol abuse and thyroid dysfunction have been suggested by both human and rat studies. Accordingly, we have begun to investigate potential HPT mediation of, or response to, alterations in these systems by investigating plasma thyroid hormone levels in the same chronic daily ethanol/ withdrawal paradigm. Chronic daily episodes of ethanol consumption and withdrawal by male Sprague- Dawley rats decreased plasma levels of free (non-protein- bound) triiodothyronine (T3) (p < 0.01) and free thyroxine (T4) (p < 0.05) in the morning but not in the afternoon, relative to both ad libitum-fed and pair-fed controls (n = 9/treatment). Plasma total T4 levels were likewise suppressed (p < 0.01) in the morning, whereas total T3 levels were increased (p < 0.05) in the afternoon. These changes eliminated normal diurnal patterns (higher in the morning) of plasma free T3, free T4, and total T3 concentrations. Three weeks after cessation of ethanol consumption, morning plasma levels of free and total T3 and T4, as well as plasma thyroid-stimulating hormone (TSH), were all not significantly changed by the prior ethanol consumption or pair-feeding. These results reveal that plasma thyroid hormone concentrations are suppressed in a time of day dependent manner by chronic daily ethanol consumption and daily withdrawal in this model of chronic ethanol abuse. During subsequent long-term "abstinence," these thyroid hormones returned to control levels. These results are consistent with evidence that thyroid function is commonly diminished in alcoholism, with variable reports of recovery during abstinence. Further investigations with this rat model of daily ethanol consumption and daily withdrawal will help resolve interactions and roles of the HPT axis in alcohol abuse.

Effect of low dose mono- ortho 2,3′,4,4′,5 pentachlorobiphenyl on thyroid hormone status and EROD activity in rat offspring: consequences for risk assessment

Toxic equivalency factor (TEF) has been proposed to estimate the risk of polychlorinated biphenyl (PCB) congeners. However, ortho chlorine substitution in the two phenyl rings gives each PCB its own pattern of toxicity which is different from the mechanism of action of 2,3,7,8-tetrachlorodibenzo- p-dioxin. The present study evaluated the effect of prenatal and postnatal exposure to a low dose of the mono- ortho pentachlorobiphenyl PCB 118 on thyroid hormone concentrations and EROD activity in rats. Moreover, the tissue distribution of PCB 118 following one oral dose was evaluated. Sprague–Dawley rats were treated by gavage on GD 6 with 375 μg of PCB 118/kg b.w. Decreases in thyroxine and TSH levels were observed in dams at the end of lactation. Perinatal exposure to a low dose of PCB 118 permanently disrupted the hypothalamo-pituitary-thyroid (HPT) axis leading to a significant increase in thyroxine levels in offspring, as a ‘thyroid resistance syndrome’. It is noteworthy that no changes in hepatic EROD activity were detected in dams at the end of lactation, even in the presence of high amounts of PCB in liver. Based on hepatic EROD activity (as a biomarker for aryl hydrocarbon receptor (AhR) induction), the mechanism of thyroid homeostasis disruption seems to be AhR-independent. Additionally, the ‘thyroid resistance syndrome’ observed in our study indicates the need for further detailed investigations on the HPT axis. We conclude that not only TEF, but also AhR-independent responses should be taken into account for risk assessment of mono- ortho PCB congeners.

Disturbances in hypothalamo pituitary adrenal and thyroid axis identify different sleep EEG patterns in major depressed patients

This study was aimed at investigating the relationships between sleep EEG abnormalities and hypothalamo pituitary adrenal (HPA) and hypothalamo pituitary thyroid (HPT) disturbances in major depressive disorder. Post dexamethasone (DXM) cortisol levels and the dual TSH response to 08:00 h and 23:00 h TRH administration were determined after a 2 weeks wash-out period in a group of 113 DSM-IV major depressed patients (72 females aged 44.3±13.0 and 41 males aged 45.7±11) who were consecutively admitted to undergo sleep EEG recordings. Post-DXM cortisolemia, 08:00 and 23:00 post-TRH TSH values, time spent in rapid eye movement sleep (REMS), in slow wave sleep (SWS), and in stage 2 as well as time awake after sleep onset were introduced in a principal component (PC) analysis. The four 3 PC scores explaining up to 74% of the data set were further calculated for each patients and used in a cluster analysis. A three-cluster solution was retained. Controlling for the effects of age and gender, patients belonging to these three clusters could clearly be differentiated on the basis of their neuroendocrine responses and on their sleep EEG profiles. Compared to the two other clusters, cluster I ( n=26) patients showed the most severe sleep continuity disturbances. Post-DXM cortisol escape and sleep architecture disturbances (consisting of a shortening of REMS latency and a decreased SWS) identified patients belonging to cluster II ( n=39). Patients in cluster III ( n=48) had the lowest TSH response to TRH and the less marked sleep EEG alteration. Clinical or demographic variables were unable to differentiate the three clusters. Our results suggest that different biological dysfunctions could each underlie particular neuroendocrine and sleep EEG disturbances in major depression.