Thyroid Axis Research Articles

Lymphocytic hypophysitis - various course of the disease and individualized therapeutic approach. An algorithm of the follow-up.

Lymphocytic hypophysitis (LH) is a rare inflammatory disorder of the pituitary or/and hypothalamus with variable disease course: from spontaneous remission to pituitary atrophy. The diagnosis, treatment and follow-up remain challenging. The aim of the study is to present long-term data and an individualized therapeutic approach and propose an algorithm for the follow-up of patients with probable LH. A retrospective analysis of 18 consecutive adult patients (13 W/5 M, mean age 45.2 years) with LH diagnosed and treated in a tertiary referral center. The first manifestations were headaches (50.0%), polyuria/polydipsia (33.3%) and symptoms of hypopituitarism (16.7%). Somatotropic, adrenal, gonadal and thyroid axis insufficiencies were found in 44.4%, 33.3%, 33.3%, and 27.8% of patients, respectively. Arginine vasopressin deficiency was diagnosed in 8 patients (44.4%). Some of the dysfunctions were transient. Magnetic resonance imaging (MRI) revealed thickened pituitary stalk in all but 2 cases. In 2 patients an anterior pituitary lesion, most likely inflammatory was described. Four patients were given steroids (severe headaches) with clinical recovery and stable/improved MRI. One woman was operated on due to the progressive mass-related symptoms - histopathological examination confirmed LH. In the remaining 13/18 patients watchful waiting approach allowed to obtain hormonal and radiological stabilization/improvement. LH is a disease with a complex clinical picture and challenging diagnosis. Treatment requires an individual approach: vigilant observation is the cornerstone of therapy, with steroid/surgical treatment reserved for cases with mass-related symptoms. Further multicenter research might help in better understanding of the LH and creating standards of care in this rare disease.

Gut microbiota intervention attenuates thermogenesis in broilers exposed to high temperature through modulation of the hypothalamic 5-HT pathway

BackgroundBroilers have a robust metabolism and high body temperature, which make them less tolerant to high-temperature (HT) environments and more susceptible to challenges from elevated temperatures. Gut microbes, functioning as symbionts within the host, possess the capacity to significantly regulate the physiological functions and environmental adaptability of the host. This study aims to investigate the effects of gut microbial intervention on the body temperature and thermogenesis of broilers at different ambient temperatures, as well as the underlying mechanism involving the "gut-brain" axis.MethodsBroilers were subjected to gut microbiota interference with or without antibiotics (control or ABX) starting at 1 day of age. At 21 day of age, they were divided into 4 groups and exposed to different environments for 7 d: The control and ABX groups at room temperature (RT, 24 ± 1 °C, 60% relative humidity (RH), 24 h/d) and the control-HT and ABX-HT groups at high temperature (HT, 32 ± 1 °C, 60% RH, 24 h/d).Results The results demonstrated that the antibiotic-induced gut microbiota intervention increased body weight and improved feed conversion in broiler chickens (P < 0.05). Under HT conditions, the microbiota intervention reduced the rectal temperature of broiler chickens (P < 0.05), inhibited the expression of avUCP and thermogenesis-related genes in breast muscle and liver (P < 0.05), and thus decreased thermogenesis capacity. Furthermore, the gut microbiota intervention blunted the hypothalamic‒pituitary‒adrenal axis and hypothalamic–pituitary–thyroid axis activation induced by HT conditions. By analyzing the cecal microbiota composition of control and ABX chickens maintained under HT conditions, we found that Alistipes was enriched in control chickens. In contrast, antibiotic-induced gut microbiota intervention resulted in a decrease in the relative abundance of Alistipes (P < 0.05). Moreover, this difference was accompanied by increased hypothalamic 5-hydroxytryptamine (5-HT) content and TPH2 expression (P < 0.05).ConclusionsThese findings underscore the critical role of the gut microbiota in regulating broiler thermogenesis via the gut-brain axis and suggest that the hypothalamic 5-HT pathway may be a potential mechanism by which the gut microbiota affects thermoregulation in broilers.Graphical

A Novel Transgenic Model to Study Thyroid Axis Activity in Early Life Stage Medaka.

Identifying endocrine disrupting chemicals in order to limit their usage is a priority and required according to the European Regulation. There are no Organization for Economic Co-operation and Development (OECD) test guidelines based on fish available for the detection of Thyroid axis Active Chemicals (TACs). This study aimed to fill this gap by developing an assay at eleuthero-embryonic life stages in a novel medaka (Oryzias latipes) transgenic line. This transgenic line expresses green fluorescent protein (GFP) in thyrocytes, under the control of the medaka thyroglobulin gene promoter. The fluorescence expressed in the thyrocytes is inversely proportional to the thyroid axis activity. When exposed for 72 h to activators (triiodothyronine (T3) and thyroxine (T4)) or inhibitors (6-N-propylthiouracil (PTU), Tetrabromobisphenol A (TBBPA)) of the thyroid axis, the thyrocytes can change their size and express lower or higher levels of fluorescence, respectively. This reflects the regulation of thyroglobulin by the negative feedback loop of the Hypothalamic-Pituitary-Thyroid axis. T3, T4, PTU, and TBBPA induced fluorescence changes with the lowest observable effect concentrations (LOECs) of 5 μg/L, 1 μg/L, 8 mg/L, and 5 mg/L, respectively. This promising tool could be used as a rapid screening assay and also to help decipher the mechanisms by which TACs can disrupt the thyroid axis in medaka.

In vitro screening of per- and polyfluorinated substances (PFAS) for interference with seven thyroid hormone system targets across nine assays

The US Environmental Protection Agency is evaluating the ecological and toxicological effects of per- and polyfluorinated chemicals. A number of perfluorinated chemicals have been shown to impact the thyroid axis in vivo suggesting that the thyroid hormone system is a target of these chemicals. The objective of this study was to evaluate the activity of 136 perfluorinated chemicals at seven key molecular initiating events (MIE) within the thyroid axis using nine in vitro assays. The potential MIE targets investigated are Human Iodothyronine Deiodinase 1 (hDIO1), Human Iodothyronine Deiodinase 2 (hDIO2), Human Iodothyronine Deiodinase 3 (hDIO3), Xenopus Iodothyronine Deiodinase (xDIO3); Human Iodotyrosine Deiodinase (hIYD), Xenopus Iodotyrosine Deiodinase (xIYD), Human Thyroid Peroxidase (hTPO); and the serum binding proteins Human Transthyretin (hTTR) and Human Thyroxine Binding Globulin (hTBG). Of the 136 PFAS chemicals tested, 85 had sufficient activity to produce a half-maximal effect concentration (EC50) in at least one of the nine assays. In general, most of these PFAS chemicals did not have strong potency towards the seven MIEs examined, apart from transthyretin binding, for which several PFAS had potency similar to the respective model inhibitor. These data sets identify potentially active PFAS chemicals to prioritize for further testing in orthogonal in vitro assays and at higher levels of biological organization to evaluate their capacity for altering the thyroid hormone system and causing potential adverse health and ecological effects.

Can Ashwagandha Benefit the Endocrine System?-A Review.

Withania somnifera, also known as Ashwagandha, has been used in traditional medicine for thousands of years. Due to the wide range of its activities, there has been interest in its possible beneficial effects on the human body. It is proved that, among others, Ashwagandha has anti-stress, anti-inflammatory, antimicrobial, anti-cancer, anti-diabetic, anti-obesity, cardioprotective, and hypolipidemic properties. Particularly interesting are its properties reported in the field of psychiatry and neurology: in Alzheimer's disease, Parkinson's disease, multiple sclerosis, depression, bipolar disorder, insomnia, anxiety disorders and many others. The aim of this review is to find and summarize the effect that Ashwagandha root extract has on the endocrine system and hormones. The multitude of active substances and the wide hormonal problems faced by modern society sparked our interest in the topic of Ashwagandha's impact on this system. In this work, we also attempted to draw conclusions as to whether W. somnifera can help normalize the functions of the human endocrine system in the future. The search mainly included research published in the years 2010-2023. The results of the research show that Ashwagandha can have a positive effect on the functioning of the endocrine system, including improving the secretory function of the thyroid gland, normalizing adrenal activity, and multidirectional improvement on functioning of the reproductive system. The main mechanism of action in the latter appears to be based on the hypothalamus-pituitary-adrenal (HPA) axis, as a decrease in cortisol levels and an increase in hormones such as luteinizing hormone (LH) and follicle-stimulating hormone (FSH) in men were found, which results in stress level reduction and improvement in fertility. In turn, other studies prove that active substances from W. somnifera, acting on the body, cause an increase in the secretion of triiodothyronine (T3) and thyroxine (T4) by the thyroid gland and a subsequent decrease in the level of thyroid-stimulating hormone (TSH) in accordance with the hypothalamus-pituitary-thyroid (HPT) axis. In light of these findings, it is clear that Ashwagandha holds significant promise as a natural remedy for various health concerns, especially those related to the endocrine system. Future research may provide new insights into its mechanisms of action and expand its applications in both traditional and modern medicine. The safety and toxicity of Ashwagandha also remain important issues, which may affect its potential use in specific patient groups.

TSH Pulses Finely Tune Thyroid Hormone Release and TSH Receptor Transduction.

Detection of circulating TSH is a first-line test of thyroid dysfunction, a major health problem (affecting about 5% of the population) that, if untreated, can lead to a significant deterioration of quality of life and adverse effects on multiple organ systems. Human TSH levels display both pulsatile and (nonpulsatile) basal TSH secretion patterns; however, the importance of these in regulating thyroid function and their decoding by the thyroid is unknown. Here, we developed a novel ultra-sensitive ELISA that allows precise detection of TSH secretion patterns with minute resolution in mouse models of health and disease. We characterized the patterns of ultradian TSH pulses in healthy, freely behaving mice over the day-night cycle. Challenge of the thyroid axis with primary hypothyroidism because of iodine deficiency, a major cause of thyroid dysfunction worldwide, results in alterations of TSH pulsatility. Induction in mouse models of sequential TSH pulses that mimic ultradian TSH profiles in periods of minutes were more efficient than sustained rises in basal TSH levels at increasing both thyroid follicle cAMP levels, as monitored with a genetically encoded cAMP sensor, and circulating thyroid hormone. Hence, this mouse TSH assay provides a powerful tool to decipher how ultradian TSH pulses encode thyroid outcomes and to uncover hidden parameters in the TSH-thyroid hormone set-point in health and disease.

Sex differences in prevalence and clinical correlates of suicide attempts in first-episode and drug-naïve patients with anxious depression in a Chinese Han population: A large-scale cross-sectional study

BackgroundsAnxious depression (AD) has been extensively studied. However, fewer studies have examined sex differences in the prevalence of suicide attempts among AD patients. This study aimed to explore sex differences in suicide attempts and risk factors in patients with AD. Methods1380 first episode drug-naïve patients with AD were recruited. Sociodemographic and clinical characteristics were measured using a self-administered demographic questionnaire. The Hamilton Depression Scale (HAMD), Hamilton Anxiety Inventory (HAMA), and positive subscale of the Positive and Negative Syndrome Scale (PANSS) were used to assess patients' clinical symptoms. We also measured the patient's blood glucose, lipids, and thyroid axis hormone levels. ResultsThere were no sex differences in the prevalence of suicide attempts in patients with FEDN anxious depression. In addition, binary logistic regression analysis showed that HAMA score, TSH levels, and TPOAb levels significantly predicted suicide attempts in both male and female patients with AD, while HAMD score significantly predicted suicide attempts in female patients with AD only. ConclusionsThe severity of anxiety and higher levels of TSH and TPOAb were associated with an increased risk for suicide attempts in both male and female patients with AD, whereas the severity of depression was only associated with suicide attempts in females.

FRI378 Estetrol Prolongs Anagen In Healthy Female Scalp Hair Follicles By Positively Modulating Dermal Papilla Functions And Generation Of Progenitor Stem Cells Ex Vivo

Abstract Disclosure: C. Gerard: None. A. La Riche: None. S. Altendorf: None. V. Dion: None. L. Epping: None. T. Bíro: None. G. Dixon: None. M. Bertolini: None. The human hair follicle (HF) is a neuroendocrine mini-organ that responds to, but also generates, a wide range of hormones, which affect hair cycle and HF biology. HF functions are profoundly regulated by several intrafollicular neuroendocrine axes like the HF-equivalent of the hypothalamic-pituitary-adrenal and thyroid axes, as well as by local prolactin secretion. In this regard, estrogens exert a direct role in hair cycle regulation, since estrogen receptors are prominently expressed in the epithelium of scalp HFs. It has been shown that postmenopausal women increasingly experience female pattern hair loss (FPHL) due to the decrease in ovarian estrogen secretion. Conversely, elevated estrogen levels were found to correlate with enhanced numbers of anagen HFs during pregnancy. Estetrol (E4) is a natural estrogen produced by the fetal liver during pregnancy. E4 was recently approved as the estrogenic component of a new combined oral contraceptive and is currently in the late stage of clinical development for its use as a menopausal hormone therapy. In this study, we aimed to assess the capacity of E4 to regulate hair growth.Frontotemporal, full-length microdissected HFs from 4 healthy female donors (&amp;gt; 50 years) were exposed to different concentrations of E4 (300nM, 3µM and 30µM) ex vivo. Subsequently, hair cycle staging, hair matrix keratinocyte proliferation (Ki-67), dermal papilla (DP) inductivity (versican expression and alkaline phosphatase activity), fibroblast emigration (cell density in the DP, the dermal cup (DC) and the DP stalk), and the percentage of HFs stem cell (HFSC) progenitors (CD34+) was assessed by quantitative (immuno-)histomorphometry. E4 treatment led to a tendential (300nM and 30µM) or significant (3µM) increase in the number of anagen (growing) HFs, further supported by enhanced hair matrix keratinocyte proliferation. Although neither size nor cell density of DP was affected by the treatment with E4, a significant lower number of cells was detected in the DP stalk and DC, indicating less DP fibroblast emigration. Additionally, E4 treatment stimulated DP fibroblast inductivity as evidenced by a tendential up-regulation of versican expression and alkaline phosphatase activity in the DP, the latter even significantly in only anagen HFs. Moreover, application of 3µM E4 positively affected the generation of stem cell progeny by significantly increasing the percentage of CD34+ cells in the suprabulbar outer root sheath. Taken together, our data suggest that treatment with E4 boosts anagen maintenance, reduces DP fibroblast emigration, stimulates DP inductivity and promotes the expansion of HFSC progeny. Thus, these findings point at a potential role of E4 to prevent catagen development and changes known to be involved in HF miniaturization, and further encourage the exploration of E4 as possible treatment strategy for hair loss disorders such as FPHL. Presentation: Friday, June 16, 2023

FRI348 Ectopic Posterior Pituitary As A Cause Of Panhypopituitarism Presenting With Hyponatremia

Abstract Disclosure: C. Choo: None. Background: Ectopic posterior pituitary gland (EPP) can occur from defective embryogenesis affecting neuronal migration, or from neurodegeneration of the hypothalamic nuclei. While isolated growth hormone deficiency is most common, it is also associated with pan-hypopituitarism. The posterior pituitary function is often preserved. Clinical Case: We report a case of pan-hypopituitarism from congenital EPP, presenting with hyponatremia. A 63-year-old male with hyperlipidemia was admitted for gastroenteritis. Serum sodium was 106mmol/L [reference range 136-146mmol/L] on admission but he was otherwise asymptomatic and haemodynamically stable. This initially improved with intravenous fluids, however subsequently stagnated at 121mmol/L despite achieving euvolemia. Thyroid and cortisol axes were evaluated in view of persistent hyponatraemia. 8am cortisol was low at 119nmol/L with inappropriately normal ACTH 13.9 pg/mL [reference range 7.2 – 62.3 pg/mL]. Thyroid function test showed central hypothyroidism consistently on repeat testing with a low fT4 of 6.1 pmol/L and 7.7 pmol/L [reference range 8.8-14.4pmol/L] and inappropriately normal TSH of 2.98MU/L and 2.41MU/L respectively [reference range 0.65-3.70MU/L]. 1mcg short synacthen test done following suspicion of hypocortisolism peaked at 468 nmol/L. He had no symptoms or signs of hypocortisolism or hypothyroidism. He was a bachelor and had clinical features of hypogonadism including short stature (142cm), high-pitched voice, scarce sexual hair and pubescent sized testes. His mid-parental height is unknown as his parents were deceased. FSH, LH, testosterone and IGF-1 were all undetectable. Prolactin was otherwise normal 9.4ug/L [reference range 4.2-16.4ug/L]. Radiographs of the forearm showed unfused epiphyseal plates at the distal radius and ulna. Thus, the diagnosis of pan-hypopituitarism was made. Magnetic resonance imaging of the pituitary revealed a T1 hyperintense nodule at the floor of the third ventricle, suggestive of ectopic posterior pituitary. There was otherwise minimal normally enhancing tissue in the pituitary fossa, and the posterior pituitary bright spot and infundibulum were absent. He was started on hydrocortisone and subsequently levothyroxine replacement, with resolution of hyponatraemia (serum sodium 139nmol/L). He did not develop polyuria or polydipsia to suggest diabetes insipidus. Due to financial concerns however, he declined growth hormone and testosterone replacement therapy. Conclusion: Most reports of EPP are in the pediatric population often presenting with short stature. This was a seemingly ordinary case of hyponatraemia initially deemed to be from hypovolaemia. His atypical clinical features led to the eventual diagnosis of EPP with panhypopituitarism at a rather late age, highlighting the importance of a thorough clinical examination necessitating further evaluation. Presentation: Friday, June 16, 2023

FRI317 Simultaneous Occurrence Of A Pineal Germ Cell Tumor And Pituitary Macroprolactinoma In A Young Male

Abstract Disclosure: E.P. Monsour: None. S. Badour: None. J.M. Munoz Pena: None. W.T. Donahoo: None. Background: Germ Cell Tumors (GCTs) are a group of heterogeneous tumors that derive from pluripotent germ cells and originate in the yolk sac of the embryo in early gestation. They account for 10% of all central nervous system (CNS) GCTs, primarily occurring in the pediatric and adolescent populations. The co-existence of macroprolactinoma and a mixed CNS GCT is extremely rare, with an unknown worldwide prevalence. Here we report a case of a pituitary macroprolactinoma occurring with a separate primary CNS mixed GCT. Clinical Case: A 19-year-old male presented with a 2-month history of headaches associated with nausea and vomiting. Relevant physical exam findings included decreased visual acuity, absent facial and axillary hair, and prominence of the left testis. Brain MRI demonstrated a pituitary adenoma measuring 3.5 x 2.3 x 3.2 cm extending into the cavernous sinus and an enhancing necrotic lesion in the third ventricle measuring 5.0 x 3.7 x 4.9 cm. Testicular ultrasound revealed two sub-centimeter ill-defined masses in the left testis. Pre-operative labs showed intact thyroid, adrenal, and growth hormone axis. He had a low total testosterone [14.2 ng/dl, reference range (RR): 230-800 ng/dL] with inappropriately normal gonadotrophins and markedly elevated prolactin (PRL) level (2,517 ng/mL, RR &amp;lt;14 ng/mL). Testicular tumor marker, alpha-fetoprotein, was elevated (15.3 ng/dL, RR &amp;lt;9 ng/dL). He was started on glucocorticoids for vasogenic edema and cabergoline twice weekly. He underwent left orchiectomy and subsequent pineal tumor resection. Testicular tumor pathology was consistent with teratoma and a well-differential neuroendocrine tumor with negative margins. Pineal tumor pathology was diagnostic of a mixed GCT. Despite optimal medical therapy, the patient ultimately opted to pursue transsphenoidal tumor resection. Pituitary mass pathology was compatible with a pituitary adenoma, immunoreactive for PRL. Post-operative PRL levels decreased to 6 ng/dL. He achieved a surgical cure without the need to restart dopamine agonist therapy. Conclusion: Simultaneous occurrence of primary brain tumors with different pathologies is estimated to be ∼0.9% of all brain tumors. To our knowledge, only one other case report described an adolescent with a craniopharyngioma and intracranial GCT. This is the first report in the literature of a pituitary macroprolactinoma synchronous with a mixed CNS GCT, and testicular well-differential neuroendocrine tumor with teratoma. Presentation: Friday, June 16, 2023

FRI320 The Various Clinical Outcomes Of Giant Prolactinomas In Men

Abstract Disclosure: A. Gilis-Januszewska: None. A. Bogusławska: None. M. Godlewska: None. &amp;. Kluczyński: None. E. Rzepka: None. A. Hubalewska-D: None. Giant prolactinomas constitute 2-3% of all lactotroph PitNETs with male preponderance. We present a case series of giant prolactinomas with various clinical presentation. Case 1: A 66-year-old male hospitalized due to left peripheral facial palsy. In computer tomography (CT) pituitary mass (41x43x64mm) invading cavernous/sphenoid sinuses/optic chiasm was visualized. Bitemporal hemianopia/headaches were observed. Prolactin level (PRL) was 22083 uIU/ml(N: 86-324uIU/ml). Cabergoline (1mg/week) was implemented. After 3 months, regression of PitNET by 14mm and normoprolactinemia were observed. Milder headaches and improvement of visual field were reported. Case 2: A 62-year-old male presented with panhypopituitarism/diabetes insipidus at the age of 52. In MRI PitNET 36x62x35mm with extrasellar extension/ invading third ventricle was found. PRL was 223549uIU/ml. Despite dopamine agonist treatment progression of pituitary tumor/high prolactin level were observed-patient did not consent to neurosurgery. In 2019, significant visual filed deterioration was observed- patient consent to craniotomy. Histopathology revealed lactotroph-PitNET with Ki67&amp;gt;3%. After 6 months, tumor progression was noted. Patient was disqualified from radiotherapy. Temozolomide was introduced. After 9 cycles, regression of PitNET was observed and decrease of PRL by 2600%. Case 3: A 56-year-old male was hospitalized due to syncope. In CT pituitary tumor 40x30mm was diagnosed with bitemporal hemianopsia. PRL was 10446uIU/ml. Cabergoline(1mg/week) was implemented. After 3 months, regression of pituitary tumor/normal prolactin level/improvement of vision were noted. Case 4: A 23-year-old male presented with severe headaches and visual impairment at the age of 21. In MRI pituitary mass 52x52x41mm with extrasellar extension was found. PRL was 21522uIU/ml. Insufficiency of thyroid and gonadal axis was diagnosed. Cabergoline was implemented (4mg/week) with regression of the tumor, decrease of PRL (8400uIU/ml) and complete remission of headaches. Case 5: A 67-year-old male diagnosed with a PitNET (65x35x40mm) at the age of 50 years. Due to hyperprolactinemia, cabergoline was implemented (7mg/week). After few weeks, pituitary apoplexy occurred. Patient underwent emergency neurosurgery. MRI over next 20 years demonstrated stable residual tumor (22x28x11mm). Case 6: A 47-year-old male admitted to Emergency Unit due to severe headache. MRI showed PitNET (56x70x67mm). PRL was 22083 uIU/ml and plurihormonal pituitary insufficiency was observed. Cabergoline 2mg/week was implemented. After 3 months of treatment tumors regression was observed (56x68x50 mm) with normoprolactinemia. The management of giant prolactionomas in men is challenging. Further multicenter studies to understand the pathophysiology and prognostic factors of giant prolactionomas in men are needed. Presentation: Friday, June 16, 2023

Significant Variability in the Developmental Toxicity of Representative Perfluoroalkyl Acids as a Function of Chemical Speciation.

Current toxicological data of perfluoroalkyl acids (PFAAs) are disparate under similar exposure scenarios. To find the cause of the conflicting data, this study examined the influence of chemical speciation on the toxicity of representative PFAAs, including perfluorooctanoic acid (PFOA), perfluorobutane carboxylic acid (PFBA), and perfluorobutanesulfonic acid (PFBS). Zebrafish embryos were acutely exposed to PFAA, PFAA salt, and a pH-negative control, after which the developmental impairment and mechanisms were explored. The results showed that PFAAs were generally more toxic than the corresponding pH control, indicating that the embryonic toxicity of PFAAs was mainly caused by the pollutants themselves. In contrast to the high toxicity of PFAAs, PFAA salts only exhibited mild hazards to zebrafish embryos. Fingerprinting the changes along the thyroidal axis demonstrated distinct modes of endocrine disruption for PFAAs and PFAA salts. Furthermore, biolayer interferometry monitoring found that PFOA and PFBS acids bound more strongly with albumin proteins than did their salts. Accordingly, the acid of PFAAs accumulated significantly higher concentrations than their salt counterparts. The present findings highlight the importance of chemical forms to the outcome of developmental toxicity, calling for the discriminative risk assessment and management of PFAAs and salts.

An optimized radioimmunoassay for quantification of total serum thyroxine (T4) in fetal, neonatal, and pregnant rats

Identifying xenobiotics that interrupt the thyroid axis has significant public health implications, given that thyroid hormones are required for brain development. As such, some developmental and reproductive toxicology (DART) studies now require or recommend serum total thyroxine (T4) measurements in pregnant, lactating, and developing rats. However, serum T4 concentrations are normally low in the fetus and pup which makes quantification difficult. These challenges can be circumvented by technologies like mass spectrometry, but these approaches are expensive and not always widely available. To demonstrate the feasibility of measuring T4 using a commercially available assay, we examine technical replicates of rat serum samples measured both by liquid chromatography mass spectrometry (LC/MS/MS) and radioimmunoassay (RIA). These samples were obtained from rats on gestational day 20 (dams and fetuses) or postnatal day 5 (pups), following maternal exposure to the goitrogen propylthiouracil (0–3 ppm) to incrementally decrease T4. We show that with assay modification, it is possible to measure serum T4 using low sample volumes (25–50 μL) by an RIA, including in the GD20 fetus exposed to propylthiouracil. This proof-of-concept study demonstrates the technical feasibility of measuring serum T4 in DART studies.

Limits to sustained energy intake. XXXIII. Thyroid hormones play important roles in milk production but do not define the heat dissipation limit in Swiss mice.

The limits to sustained energy intake set physiological upper boundaries that affect many aspects of human and animal performance. The mechanisms underlying these limits however remain unclear. We exposed Swiss mice to either supplementary thyroid hormones (THs) or methimazole during lactation at 21 °C or 32.5 °C, and measured food intake, resting metabolic rate (RMR), milk energy output (MEO), serum THs and mammary gland gene expression of females, and litter size and mass of their offspring. Lactating females developed hyperthyroidism following exposure to supplementary THs at 21 °C, but they did not significantly change body temperature, asymptotic food intake, RMR or MEO, and litter and mass were unaffected. Hypothyroidism, induced by either methimazole or 32.5 °C exposure, significantly decreased asymptotic food intake, RMR and MEO, resulting in significantly decreased litter size and litter mass. Furthermore, gene expression of key genes in the mammary gland were significantly decreased by either methimazole or hot exposure, including gene expression of THs and prolactin receptors, and Stat5a and Stat5b. This suggests that endogenous THs are necessary to maintain sustained energy intake and milk energy output. Suppression of the thyroid axis seems to be an essential aspect of the mechanism by which mice at 32.5 °C reduce their lactation performance to avoid overheating. However, THs do not define the upper limit to sustained energy intake and milk energy output at peak lactation at 21 °C. Another, as yet unknown, factor, prevents supplementary thyroxine exerting any stimulatory metabolic impacts on lactating mice at 21 °C.

Mechanism difference of ginseng medicines with different natures on hyperthyroidism

Ethnopharmacological relevanceMedicinal nature is a unique index in traditional Chinese medicine (TCM) to measure the efficacy of Chinese medicines. Hyperthyroidism, qi-Yin deficiency syndrome in TCM was regarded as the classic heat syndrome category in Chinese medicine. Moreover, it is extensively employed to evaluate the medicinal nature of herbs within the framework of the ‘hot/cold’ nature theory. Ginseng, red and black ginseng (GS, RG, and BG, respectively), and ginseng leaves (GL) are qi-tonifying herbs with different medicinal natures and were just right used to examine the underlying mechanisms between the nature of ginseng medicines and their tonifying effect. Aim of the studyTo examine the different mechanisms between different natures of ginseng medicines and their qi-tonifying action by comparison of their effects on hyperthyroidism and elucidate the nature of BG. Materials and methodsThe hyperthyroidism model was induced through the oral administration of Euthyrox. Steroids belonging to hypothalamus pituitary adrenal (HPA) and hypothalamic pituitary gonadal (HPG) axes were determined with an ultra-performance liquid chromatography-triple quadrupole tandem mass spectrometry (UPLC-QqQ-MS/MS) method. Furthermore, the biochemical indexes associated with energy metabolism, including the serum cyclic nucleotide system and phosphatidylinositol-3-kinase (PI3K)/protein kinase B (Akt) signaling pathways were examined. Additionally, the gut microbiota was subjected to 16 S rDNA sequencing, followed by gas chromatography-mass spectrometry (GC-MS) analysis of short-chain fatty acids (SCFAs). ResultsGS, RG, and BG could treat hyperthyroidism rats by regulating the hypothalamus pituitary thyroid (HPT) axis. The RG also had a strong regulatory effect on the HPA and HPG axis. The BG has a regulatory effect on the HPG axis. GL had a strong regulatory effect on HPA, HPG, and HPT axes. GS had the ability to regulate Firmicutes/Bacteroides of the intestinal flora, and GS, RG, and BG ameliorated the decrease of SCFAs induced by hyperthyroidism. According to PCA, BG is similar to GS, indicating a mild-warm nature. ConclusionThe nature of BG was attributable to mild-warm and the GL with cold nature is best for the treatment of hyperthyroidism based on PCA analysis with all the bio-indices. In addition, the mechanism study indicated that the qi-tonifying effects of ginseng medicines are involved in HPT, HPA, and HPG axes to alleviate hyperthyroidism. In addition, the primary indexes reflected different natures of ginseng medicines are cyclic adenosine monophosphate (cAMP)/cyclic guanosine monophosphate (cGMP), AchE, and substance metabolism associated with Na+-K+-ATPase and PI3K/AKT signaling pathways, which are potential biomarkers for evaluation on the natures of qi-tonifying medicines.

Effects of sub-chronic exposure to microcystin-LR on the endocrine system of male rats

Microcystins (MCs) can cause reproductive and developmental toxicity and disrupt endocrine homeostasis in mammals. In the present study, male, Sprague-Dawley (SD) rats were administrated 3 or 30 μg MC-LR/kg, body mass (bm) per day via intraperitoneal (i.p.) injections for 6 weeks. Effects of MC-LR on histology, hormone concentrations, gene transcriptional profiles and protein expressions along the hypothalamic-pituitary-adrenal (HPA), ‐gonad (HPG) and -thyroid (HPT) axes were assessed. Sub-chronic administration with MC-LR caused histological damage to hypothalamus, pituitary, adrenal, testes and thyroid and affected relative masses of pituitary, adrenal and testes. The HPA axis was activated and serum concentrations of corticotropin-releasing hormone (CRH), adrenocorticotropic hormone (ACTH) and corticosterone (CORT) were significantly augmented. Along the HPG axis, serum concentrations of gonadotropin-releasing hormone (GnRH) and dihydrotestosterone (DHT) were diminished, while concentrations of luteinizing hormone (LH), follicle-stimulating hormone (FSH), testosterone (T) and estradiol (E2) were augmented. For the HPT axis, only concentrations of free tetra-iodothyronine (fT4) were significantly diminished, while concentrations of thyrotropin-releasing hormone (TRH), thyroid-stimulating hormone (TSH) or free tri-iodothyronine (fT3) were not significantly changed. Also, several genes and proteins related to synthesis of steroid hormones were significantly altered. Findings of the present study illustrate that MC-LR can cause endocrine-disrupting effects through the disruption of synthesis and secretion of hormones along the HPA, HPG and HPT axes and negative feedback regulation. Also, there could be crosstalk among HPA, HPG and HPT axes. These findings elucidate mechanisms of endocrine-disrupting effects of MCs.

Retrospective Evaluation of Gastrointestinal Signs in Hypothyroid Dogs.

Few observations about gastrointestinal (GI) signs in hypothyroid dogs (hypo-T dogs) are available. We aimed to evaluate the prevalence and characteristics of concurrent GI signs in hypo-T dogs, describe clinicopathological, hepato-intestinal ultrasound findings in hypo-T dogs, investigate changes in GI signs after thyroid replacement therapy (THRT). Medical records of suspected hypo-T dogs from two hospitals were retrospectively reviewed. The inclusion criteria were: (1) having symptoms and clinicopathological abnormalities related to hypothyroidism (i.e., mild anemia, hyperlipemia); (2) not being affected by systemic acute disease; (3) not having received any treatment affecting thyroid axis. Hypothyroidism had to be confirmed using low fT4 or TT4 with high TSH and/or inadequate TSH-stimulation test response; otherwise, dogs were assigned to a euthyroid group. Clinical history, GI signs, hematobiochemical parameters, and abdominal ultrasound findings were recorded. Hypo-T dogs were assigned to the GI group (at least 2 GI signs) and not-GI group (1 or no GI signs). Follow-up information 3-5 weeks after THRT was recorded. In total, 110 medical records were screened: 31 dogs were hypo-T, and 79 were euthyroid. Hypo-T dogs showed a higher prevalence of GI signs (44%), especially constipation and diarrhea (p = 0.03 and p = 0.001), than euthyroid dogs (24%) (p = 0.04). Among hypo-T dogs, no difference in hematological parameters between GI and non-GI groups was found. Hypo-T dogs had a higher prevalence of gallbladder alterations than euthyroid dogs (20/25; 80% and 32/61; 52% p = 0.04). The hypo-T GI group showed a significant improvement in the GI signs after THRT (p < 0.0001). Specific investigation for concurrent GI diseases in hypo-T dogs was lacking; however, improvement in GI signs following THRT supports this association between GI signs and hypothyroidism.

Thyroid axis participates in high-temperature-induced male sex reversal through its activation by the stress response.

Environmental changes alter the sex fate in about 15% of vertebrate orders, mainly in ectotherms such as fish and reptiles. However, the effects of temperature changes on the endocrine and molecular processes controlling gonadal sex determination are not fully understood. Here, we provide evidence that thyroid hormones (THs) act as co-players in heat-induced masculinization through interactions with the stress axis to promote testicular development. We first demonstrated that the thyroid axis (through thyroid-related genes and T3 levels) is highly active in males during the gonadal development in medaka (Oryzias latipes). Similarly, T3 treatments promoted female-to-male sex reversal in XX embryos. Subsequently, embryonic exposure to temperature-induced stress up-regulated the genes related to the thyroid and stress axes with a final increase in T3 levels. In this context, we show that blocking the stress axis response by the loss of function of the corticotropin-releasing hormone receptors suppresses thyroid-stimulating hormone expression, therefore, heat-induced activation of the thyroid axis. Thus, our data showed that early activation of the stress axis and, in consequence, the TH axis, too, leaves us with that both being important endocrine players in inducing female-to-male reversal, which can help predict possible upcoming physiological impacts of global warming on fish populations.

The effects of glyphosate-based herbicide on the hypothalamic-pituitary thyroid axis are tissue-specific and dependent on age exposure

The significant increase in glyphosate-based herbicide (GBH) use raises concerns about residues in the environment and food, potentially jeopardizing human health. The involvement of GBHs in the increased incidence of thyroid disorders is speculated, since glyphosate has been linked to an increased risk of thyroid disease in farmers. In this sense, this study aims to investigate the potential effects of low levels of GBH exposure (0, 0.5 or 5 mg/kg) from weaning (postnatal day PND23) to adult life (PND60 and PND90) in male Wistar rats on hypothalamic-pituitary-thyroid (HPT) axis function. The serum levels of T4 were increased. The hypothalamus showed reduced expression of Dio2, Thra1, and Thra2. The pituitary showed reduced expression of Mct8 and Dio2 and increased expression of Thra1. The thyroid showed increased expression of Tshr and Thra1. The heart showed increased expression of Mct8 and Myh6. The liver showed reduced expression of Mct8 and Thra2 and increased expression of Thra1. In thyroid morphometry, a decrease in both follicular diameter and area and decreased follicular and colloid diameters and areas were observed. These results suggested that GBH may affect several steps of HPT axis regulation at the transcriptional level in an age-dependent manner and alter the morphometric parameters of the thyroid gland and TH synthesis, with potential repercussions in the TH-target organs.

Thyroid hormones in development of coloration of two species of Neotropical cichlids.

Neotropical cichlids demonstrate an enormous diversity of pigment patterns, a morphological trait that plays an important role in the adaptation and speciation. It has been suggested that alterations of the activity of the thyroid axis, one of the main endocrine axes regulating fish ontogeny, are involved in the development and diversification of pigment patterns in the Neotropical cichlids. To test this hypothesis, we assessed the thyroid hormone developmental dynamics and pigment patterning, and experimentally induced hyper- and hypothyroidism at different developmental stages in convict cichlid, Amatitlania nigrofasciata, and blue-eye cichlid, Cryptoheros spilurus. We revealed that both species display a similar type of coloration development and similar reactions on changes of the thyroid hormone level, but species-specific differences in hormonal dynamics and thyroid hormone-responsiveness. These findings indicate that thyroid hormone is a necessary but not sufficient signal to induce the transition from larval to juvenile coloration, and is a component of a complex, concerted endocrine cascade that drives skin development.