Toxic Thyroid Adenoma Presenting as Apathetic Hyperthyroidism: A Case Report.

The thyroid gland is an essential endocrine organ that secretes hormones to regulate homeostasis across multiple organ systems throughout the body. It is actively regulated by the hypothalamic-pituitary-thyroid (HPT) axis, where negative feedback modulates the amounts of active hormone being released; thus, lesions that disrupt the proper functioning of this gland or its regulatory mechanisms can be destructive. Toxic thyroid adenomas are usually singular benign functioning nodules in the thyroid gland that cause thyrotoxicosis. Hyperthyroidism is commonly clinically silent, however, in most symptomatic cases, patients will be diagnosed based on abnormal laboratory findings and typical hyperthyroid symptoms. This case report examines an 81-year-old male with an extensive medical history who presented with complaints of new-onset generalized fatigue coupled with bilateral lower extremity muscle cramps. A positron emission tomography (PET) scan for other medical conditions incidentally noted mildly increased uptake in the thyroid gland, prompting a further investigation that resulted in a diagnosis of toxic thyroid adenoma. The patient responded well to treatment with methimazole and has remained in a euthyroid state.

How the Xenopus eleutheroembryonic thyroid assay compares to the amphibian metamorphosis assay for detecting thyroid active chemicals.

The Xenopus Eleutheroembryonic Thyroid Assay (XETA) was recently published as an OECD Test Guideline for detecting chemicals acting on the thyroid axis. However, the OECD validation did not cover all mechanisms that can potentially be detected by the XETA. This study was therefore initiated to investigate and consolidate the applicability domain of the XETA regarding the following mechanisms: thyroid hormone receptor (THR) agonism, sodium-iodide symporter (NIS) inhibition, thyroperoxidase (TPO) inhibition, deiodinase (DIO) inhibition, glucocorticoid receptor (GR) agonism, and uridine 5'-diphospho-glucuronosyltransferase (UDPGT) induction. In total, 22 chemicals identified as thyroid-active or -inactive in Amphibian Metamorphosis Assays (AMAs) were tested using the XETA OECD Test Guideline. The comparison showed that both assays are highly concordant in identifying chemicals with mechanisms of action related to THR agonism, DIO inhibition, and GR agonism. They also consistently identified the UDPGT inducers as thyroid inactive. NIS inhibition, investigated using sodium perchlorate, was not detected in the XETA. TPO inhibition requires further mechanistic investigations as the reference chemicals tested resulted in opposing response directions in the XETA and AMA. This study contributes refining the applicability domain of the XETA, thereby helping to clarify the conditions where it can be used as an ethical alternative to the AMA.

Impact of metformin on hypothalamic-pituitary-thyroid axis activity in women with autoimmune and non-autoimmune subclinical hypothyroidism: a pilot study.

BACKGROUND: Metformin reduces plasma TSH levels if these levels are elevated. No study has investigated whether the hormonal effects of metformin are impacted by thyroid autoimmunity. The current study aimed to compare the effect of metformin on hypothalamic-pituitary-thyroid axis activity between subjects with mild hypothyroidism of different origins. METHODS: The study population consisted of two groups of women with prediabetes and mildly elevated TSH levels, matched by age, insulin sensitivity, TSH, and thyroid hormone levels. Group A included 26 women with autoimmune thyroiditis, while group B enrolled 26 individuals with hypothyroidism of non-autoimmune origin. Both groups were treated with metformin (2.55-3 g daily). Circulating levels of TSH, total and free thyroid hormones, glucose, insulin, prolactin, high-sensitivity C-reactive protein (hsCRP) and 25-hydroxyvitamin D, concentrations of thyroid antibodies, and structure parameters of thyroid homeostasis were assessed at baseline and 6 months later. RESULTS: All patients completed the study. At baseline, both groups differed in concentrations of thyroid peroxidase antibodies, thyroglobulin antibodies, hsCRP, and 25-hydroxyvitamin D. The drug reduced TSH and Jostel's index, with no difference between the study groups. The improvement in insulin sensitivity, observed in both groups, was more pronounced in group B than in group A. In women with autoimmune hypothyroidism, the drug increased SPINA-GT and decreased hsCRP levels. The remaining markers did not change throughout the study. CONCLUSIONS: The obtained results suggest that, despite differences in thyroid output, the impact of metformin on TSH levels is similar in hypothyroid women with and without thyroid autoimmunity.

Effects of cooling on thyroid hormone secretion and growth of eastern bluebird (Sialia sialis) nestlings.

Achieving endothermic homeothermy is a critical aspect of avian development. In pre-homeothermic altricial nestlings, variation in parental brooding behavior results in variable exposure of nestlings to cooling, with consequences for the developing endocrine system. Nestlings facing repeated cooling challenges may benefit from upregulation of thyroid hormone secretion, allowing for earlier onset of thermoregulatory capability to mitigate the potentially negative effects of exposure to non-optimal temperatures during development. We examined the effects of (1) a single cooling challenge on thyroid hormone secretion in pre-homeothermic nestlings, and (2) repeated cooling challenges prior to the onset of homeothermy on nestling growth and thyroid hormone secretion prior to fledging. We found that pre-homeothermic eastern bluebird nestlings exposed to a single cooling challenge increased circulating triiodothyronine (T3), demonstrating that the thyroid system can be activated by cooling early in life. However, we found no consequences of repeated cooling during the first week of life on nestling growth or baseline T3 levels prior to fledging. This work addresses how the nestling hypothalamic-pituitary-thyroid axis responds to acute cooling challenges prior to the development of endothermic homeothermy; future work will confirm whether such responses allow nestlings to hasten the onset of physiological thermoregulation when conditions demand it.

Individual Features of the Hypothalamic-Pituitary-Thyroid Axis Functioning during Aging in Non-Human Primates.

Individual features of age-related changes in the function of the neuroendocrine systems are an important problem as the basic component of a personalized approach to predicting and treating age-related pathologies. We studied the age-related features of the function of the hypothalamic-pituitary-thyroid axis in laboratory primates with depression- and anxiety-like behavior (DAB). It was found that in young female rhesus monkeys with DAB, the basal and thyrotropin-releasing hormone-stimulated levels of thyroid-stimulating hormone were significantly lower than in young animals with standard behavior (control). During aging, the levels of thyroid-stimulating hormone increased in DAB animals and free thyroxine concentrations decreased both at baseline (fasting) and in response to the thyrotropin-releasing hormone test, while in animals with standard behavior, only a trend towards similar hormonal changes was revealed.

Paternal developmental thyrotoxicosis disrupts neonatal leptin leading to increased adiposity and altered physiology of the melanocortin system.

Background: The genetic code does not fully explain individual variability and inheritance of susceptibility to endocrine conditions, suggesting the contribution of epigenetic factors acting across generations. Methods: We used a mouse model of developmental thyrotoxicosis (Dio3-/- mouse) to analyze endocrine outcomes in the adult offspring of Dio3-/- males using standard methods for body composition, and baseline and fasting hormonal and gene expression determinations in serum and tissues of relevance to the control of energy balance. Results: Compared to controls, adult females with an exposed father (EF females) exhibited higher body weight and fat mass, but not lean mass, a phenotype that was much milder in EF males. After fasting, both EF females and males exhibited a more pronounced decrease in body weight than controls. EF females also showed markedly elevated serum leptin, increased white adipose tissue mRNA expression of leptin and mesoderm-specific transcript but decreased expression of type 2 deiodinase. EF females exhibited decreased serum ghrelin, which showed more pronounced post-fasting changes in EF females than in control females. EF female hypothalami also revealed significant decreases in the expression of pro-opiomelanocortin, agouti-related peptide, neuropeptide Y and melanocortin receptor 4. These markers also showed larger changes in response to fasting in EF females than in control females. Adult EF females showed no abnormalities in serum thyroid hormones, but pituitary expression of thyrotropin-releasing hormone receptor 1 and thyroid gland expression of thyroid-stimulating hormone receptor, thyroid peroxidase and iodotyrosine deiodinase were increased at baseline and showed differential regulation after fasting, with no increase in Trhr1 expression and more pronounced reductions in Tshr, Tpo and Iyd. In EF males, these abnormalities were generally milder. In addition, postnatal day 14 (P14) serum leptin was markedly reduced in EF pups. Discussion: A paternal excess of thyroid hormone during development modifies the endocrine programming and energy balance in the offspring in a sexually dimorphic manner, with baseline and dynamic range alterations in the leptin-melanocortin system and thyroid gland, and consequences for adiposity phenotypes. We conclude that thyroid hormone overexposure may have important implications for the non-genetic, inherited etiology of endocrine and metabolic pathologies.

Epigenetic developmental programming and intergenerational effects of thyroid hormones.

Mounting evidence is showing that altered signaling through the nuclear hormone receptor superfamily can cause abnormal, long-term epigenetic changes which translate into pathological modifications and susceptibility to disease. These effects seem to be more prominent if the exposure occurs early in life, when transcriptomic profiles are rapidly changing. At this time, the coordination of the complex coordinated processes of cell proliferation and differentiation that characterize mammalian development. Such exposures may also alter the epigenetic information of the germ line, potentially leading to developmental changes and abnormal outcomes in subsequent generations. Thyroid hormone (TH) signaling is mediated by specific nuclear receptors, which have the ability to markedly change chromatin structure and gene transcription, and can also regulate other determinants of epigenetic marks. TH exhibits pleiotropic effects in mammals, and during development, its action is regulated in a highly dynamic manner to suit the rapidly evolving needs of multiple tissues. Their molecular mechanisms of action, timely developmental regulation and broad biological effects place THs in a central position to play a role in the developmental epigenetic programming of adult pathophysiology and, through effects on the germ line, in inter- and trans-generational epigenetic phenomena. These areas of epigenetic research are in their infancy, and studies regarding THs are limited. In the context of their characteristics as epigenetic modifiers and their finely tuned developmental action, here we review some of the observations underscoring the role that altered TH action may play in the developmental programming of adult traits and in the phenotypes of subsequent generations via germ line transmission of altered epigenetic information. Considering the relatively high prevalence of thyroid disease and the ability of some environmental chemicals to disrupt TH action, the epigenetic effects of abnormal levels of TH action may be important contributors to the non-genetic etiology of human disease.

Cardamom (Elettaria cardamomum (L.) Maton) Seeds Intake Increases Energy Expenditure and Reduces Fat Mass in Mice by Modulating Neural Circuits That Regulate Adipose Tissue Lipolysis and Mitochondrial Oxidative Metabolism in Liver and Skeletal Muscle.

Cardamom seed (Elettaria cardamomum (L.) Maton; EC) is consumed in several countries worldwide and is considered a nutraceutical spice since it exerts antioxidant, anti-inflammatory, and metabolic activities. In obese individuals, EC intake also favors weight loss. However, the mechanism for these effects has not been studied. Here, we identified that EC modulates the neuroendocrine axis that regulates food intake, body weight, mitochondrial activity, and energy expenditure in mice. We fed C57BL/6 mice with diets containing 3%, 6%, or 12% EC or a control diet for 14 weeks. Mice fed the EC-containing diets gained less weight than control, despite slightly higher food intake. The lower final weight of EC-fed mice was due to lesser fat content but increased lean mass than control. EC intake increased lipolysis in subcutaneous adipose tissue, and reduced adipocyte size in subcutaneous, visceral, and brown adipose tissues. EC intake also prevented lipid droplet accumulation and increased mitochondrial content in skeletal muscle and liver. Accordingly, fasting and postprandial oxygen consumption, as well as fasting fat oxidation and postprandial glucose utilization were higher in mice fed with EC than in control. EC intake reduced proopiomelanocortin (POMC) mRNA content in the hypothalamic arcuate nucleus, without an impact on neuropeptide Y (NPY) mRNA. These neuropeptides control food intake but also influence the hypothalamic-pituitary-thyroid (HPT) and hypothalamic-pituitary-adrenal (HPA) axes. Thyrotropin-releasing hormone (TRH) mRNA expression in the hypothalamic paraventricular nucleus (PVN) and circulating triiodothyronine (T3) were lower in EC-fed mice than in control. This effect was linked with decreased circulating corticosterone and weight of adrenal glands. Our results indicate that EC modulates appetite, increases lipolysis in adipose tissue and mitochondrial oxidative metabolism in liver and skeletal muscle, leading to increased energy expenditure and lower body fat mass. These metabolic effects were ascribable to the modulation of the HPT and HPA axes. LC-MS profiling of EC found 11 phenolic compounds among which protocatechuic acid (23.8%), caffeic acid (21.06%) and syringic acid (29.25%) were the most abundant, while GC-MS profiling showed 16 terpenoids among which costunolide (68.11%), ambrial (5.3%) and cis-α-terpineol (7.99%) were identified. Extrapolation of mice-to-human EC intake was performed using the body surface area normalization equation which gave a conversion equivalent daily human intake dose of 76.9-308.4 mg bioactives for an adult of 60 kg that can be obtained from 14.5-58.3 g of cardamom seeds (18.5-74.2 g cardamom pods). These results support further exploration of EC as a coadjuvant in clinical practice.

Stress, Thyroid Dysregulation, and Thyroid Cancer in Children and Adolescents: Proposed Impending Mechanisms.

Stress is a potential catalyst for thyroid dysregulation through cross-communication of the hypothalamic-pituitary-adrenal and hypothalamic-pituitary-thyroid (HPT) axes. Stress and stressors exposure motivates molecular mechanisms affecting compound feedback loops of the HPT axis. While there is evidence of connection between stress and thyroid dysregulation, the question whether this connection is implicated in the development of thyroid cancer (TC) remains unanswered. In view of the rising incidence of TC in both adults and children alongside the increasing stress in our modern society, there is a need to understand possible interrelations between stress, thyroid dysregulation, and TC. Prolonged glucocorticoid secretion due to stress interferes with immune system response by altering the cytokines, inducing low-grade chronic inflammation, and suppressing function of immune-protective cells. Chronic inflammation is a risk factor linked to TC. The role of autoimmunity has been a matter of controversy. However, there is epidemiological connection between autoimmune thyroid disease (AITD) and TC; patients with AITD show increased incidence in papillary thyroid carcinoma (PTC), and those with TC show a high prevalence of intrathyroidal lymphocyte infiltration and thyroid autoantibodies. Timing and duration-dependent exposure to specific endocrine disrupting chemicals (EDCs) has an impact on thyroid development, function, and proliferation, leading to thyroid disease and potentially cancer. Thyroid hormone imbalance, chronic inflammation, and EDCs are potential risk factors for oxidative stress. Oxygen free radicals are capable of causing DNA damage via stimulation of the mitogen-activating protein kinase or phosphatidylinositol-3-kinase and/or nuclear factor kB pathways, resulting in TC-associated gene mutations such as RET/PTC, AKAP9-BRAF, NTRK1, RAASF, PIK3CA, and PTEN. Stressful events during the critical periods of prenatal and early life can influence neuroendocrine regulation and induce epigenetic changes. Aberrant methylation of tumor suppressor genes such as P16INK4A, RASSF, and PTEN is associated with PTC; histone H3 acetylation is shown to be higher in TC, and thyroid-specific noncoding RNAs are downregulated in PTC. This review focuses on the above proposed mechanisms that potentially lead to thyroid tumorigenesis with the aim to help in the development of novel prognostic and therapeutic strategies for TC.

Sex-specific thyroid disruption caused by phenanthrene in adult zebrafish (Danio rerio).

Polycyclic aromatic hydrocarbons (PAHs) are well-known contaminants with widespread distribution in environment and food. Phenanthrene is one of the most abundant PAHs in food and aquatic environment and generates reproductive and developmental toxicity in zebrafish. Nonetheless, whether phenanthrene caused sex-specific thyroid disruption in adult zebrafish is unclear. To determine this, adult zebrafish (male and female) were treated with phenanthrene (0, 0.85, 8.5, and 85 µg/L) for 60 days. After the treatment period, we assessed the concentrations of thyroid hormones (THs) and expression levels of genes in the hypothalamic-pituitary-thyroid (HPT) axis. The results showed that phenanthrene exposure can lead to thyroid disruption in both male and female zebrafish. Exposure to phenanthrene dramatically reduced the levels of L-thyroxine (T4) and L-triiodothyronine (T3) in both male and female zebrafish, with a similar trend in both. However, the genes expression profiles of hypothalamic-pituitary-thyroid (HPT) axis were sex-specific. In all, the present study demonstrated that phenanthrene exposure could result in sex-specific thyroid disruption in adult zebrafish.

Peripubertal soy isoflavone consumption leads to subclinical hypothyroidism in male Wistar rats.

Exposure to endocrine-disrupting chemicals during critical windows of development may lead to functional abnormalities in adulthood. Isoflavones are a flavonoid group of phytoestrogens that are recognized by their estrogenic activity and are highly abundant in soybean. Since the thyroid gland presents estrogen receptors and infants, toddlers and teenagers may consume isoflavones from soy-based infant formula and beverages as alternatives to animal milk, we propose to investigate the potential effects of relevant concentrations of soy isoflavones in the regulation of the hypothalamic-pituitary (HP) thyroid axis using peripubertal male rats as an experimental model. Thirty-two 23-day-old male rats were exposed to 0.5, 5, or 50 mg of soy isoflavones/kg from weaning to 60 days of age, when they were euthanized, and the tissues were collected to evaluate the mRNA expression of genes involved in the regulation of the HP thyroid axis and dosages of thyroid hormones (THs). Serum TSH concentrations were increased, while alterations were not observed in serum concentrations of triiodothyronine and thyroxine. Regarding mRNA gene expression, Mct-8 was increased in the hypothalamus, Mct-8, Thra1, and Thrb2 were decreased in the pituitary, and Nis and Pds were reduced in the thyroid. In the heart, Mct8 and Thrb2 were increased, and Thra1 was decreased. In the liver, Mct8, Thra1, and Thrb2 were decreased. These results suggest that the consumption of relevant doses of soy isoflavones during the peripubertal period in males may induce subclinical hypothyroidism, with alterations in the regulation of the HP thyroid axis, modulation of TH synthesis, and peripheral alterations in TH target organs.

Thyrotropin Levels in Patients with Coronavirus Disease 2019: Assessment during Hospitalization and in the Medium Term after Discharge.

BACKGROUND: The objectives of this study were (1) to compare TSH levels between inpatients with critical versus non-critical coronavirus disease 19 (COVID-19), and (2) to describe the status of TSH levels three months after hospitalization. METHODS: We collected data on adult patients hospitalized with COVID-19 at Amiens University Hospital. We compared TSH levels between inpatients with critical (intensive care unit admission and/or death) versus non-critical COVID-19. Thereafter, survivors were invited to return for a three-month post-discharge visit where thyroid function tests were performed, regardless of the availability of TSH measurement during hospitalization. RESULTS: Among 448 inpatients with COVID-19, TSH assay data during hospitalization were available for 139 patients without prior thyroid disease. Patients with critical and non-critical forms of COVID-19 did not differ significantly with regard to the median (interquartile range) TSH level (0.96 (0.68-1.71) vs. 1.27 mIU/L (0.75-1.79), p = 0.40). Abnormal TSH level was encountered in 17 patients (12.2%); most of them had subclinical thyroid disease. TSH assay data at the three-month post-discharge visit were available for 151 patients without prior thyroid disease. Only seven of them (4.6%) had abnormal TSH levels. Median TSH level at the post-discharge visit was significantly higher than median TSH level during hospitalization. CONCLUSIONS: Our findings suggest that COVID-19 is associated with a transient suppression of TSH in a minority of patients regardless of the clinical form. The higher TSH levels three months after COVID-19 might suggest recovery from non-thyroidal illness syndrome.

Gluten-free diet attenuates the impact of exogenous vitamin D on thyroid autoimmunity in young women with autoimmune thyroiditis: a pilot study.

Although both exogenous vitamin D and a gluten-free diet were found to reduce thyroid antibody titers, no study investigated interactions between gluten intake and vitamin D status in patients with autoimmune thyroid disorders. The aim of the present study was to assess whether the gluten-free diet determines the effect of vitamin D treatment on thyroid autoimmunity and thyroid function in young women with autoimmune (Hashimoto's) thyroiditis. The study compared two groups of euthyroid premenopausal women with this disorder, matched for thyroid antibody titers: 31 women with non-celiac gluten sensitivity complying for at least 12 months with the gluten-free diet and 31 unaffected sisters of women with non-celiac gluten sensitivity remaining without any dietary intervention. Plasma titers of thyroid peroxidase and thyroglobulin antibodies, as well as plasma concentrations of thyrotropin, free thyroid hormones, prolactin, 25-hydroxyvitamin D and high-sensitive C-reactive protein were measured at entry and after a six-month follow-up. Moreover, at both time points, the structure parameters of thyroid homeostasis were assessed. Although exogenous vitamin D decreased titers of thyroid peroxidase and thyroglobulin antibodies and increased 25-hydroxyvitamin D levels in each treatment group, this effect was less pronounced in patients on the gluten-free diet than in patients not following any dietary recommendations. Only in the latter group of patients, vitamin D increased SPINA-GT. Treatment-induced changes in thyroid peroxidase and thyroglobulin antibodies correlated with the impact of treatment on 25-hydroxyvitamin D levels. The obtained results suggest that gluten-free diet may impair beneficial effects of exogenous vitamin D in individuals with Hashimoto's thyroiditis.

Role of N-methyl-d-aspartate receptors in anxiety disorder with thyroid lesions.

OBJECTIVE: Patients with anxiety disorder (AD) often have structural and functional abnormalities of the thyroid gland, but their specific causes remain unclear. N-methyl- d-aspartate receptors (NMDARs) play an important role in many psychosomatic diseases and tumorigenesis, but there are few reports on the role of NMDARs in AD with thyroid lesions, especially thyroid nodules (TNs). METHODS: A cross-sectional study was conducted on patients admitted to the hospital with AD (n = 71) as the main diagnosis from April to October 2021. Meanwhile, patients with TNs with no AD (NAD-TN group, n = 20) and healthy subjects (HS group, n = 37) with matched age, sex, and education were randomly collected as controls. Patients with AD were sub-grouped into the AD with TNs (AD-TN group, n = 41) and the AD with no TNs (AD-NTN group, n = 30). The thyroid ultrasound reports, Hamilton Anxiety Scale (HAMA) scores, and the expression of NMDARs and their subunits (NR1, NR2A, and NR2B) and hypothalamic-pituitary-thyroid (HPT) axis-related hormones were analyzed in all subjects. Some patients with TNs underwent surgery and postoperative pathological examination. RESULTS: Patients with AD showed a lower level of free triiodothyronine (FT3) and higher levels of thyrotropin-releasing hormone (TRH) and NMDARs and their subunits compared to the healthy controls. The expression of the NR2A subunit was higher in the AD-TN group than that in other three groups (AD-NTN, NAD-TN, and HS groups, F = 13.650, p < 0.001). Regression analysis showed that the level of NMDARs was positively correlated with the HAMA scores (B = 1.622, p = 0.029) and the maximum diameter of TNs (B = 3.836, p = 0.005). Immunohistochemical results showed that the NR2A subunit was widely expressed in multinodular goiter (MNG) and papillary thyroid carcinoma (PTC) tissues, while the expression of the NR2B subunit was lower in PTC adjacent and MNG tissues and almost absent in PTC tissues. CONCLUSION: In a sample of mostly women hospitalized with generalized anxiety disorder (GAD) or panic disorder, abnormal expression of NMDARs is closely related to AD with thyroid lesions, NMDAR subunits may have various activities and exert diverse effects in TNs, and the NR2A subunit may be an important regulator in AD with TNs.

Rosuvastatin potentiates the thyrotropin-lowering effect of metformin in men with non-autoimmune subclinical hypothyroidism and prediabetes.

WHAT IS KNOWN AND OBJECTIVE: Metformin treatment decreases thyrotropin levels in individuals with hypothyroidism and this effect seems to be mediated by the 5'-adenosine monophosphate-activated protein kinase pathway in the pituitary. The activity of this pathway is also stimulated by statins. The current study was aimed at investigating whether the impact of metformin on hypothalamic-pituitary-thyroid axis activity is affected by statin use. METHODS: The study included three matched groups of men with non-autoimmune hypothyroidism and prediabetes: patients treated for at least 6 months with high-intensity rosuvastatin therapy (20-40 mg daily) [groups A (n = 24) and C (n = 19)] and men not receiving statin therapy [group B (n = 24)]. Over the entire study period (6 months), groups A and B received metformin (2.55-3 g daily). Moreover, groups A and C continued rosuvastatin therapy. The lipid profile, glucose homeostasis markers, and plasma concentrations of thyrotropin, total and free thyroid hormones, prolactin, FSH, LH, ACTH and insulin-like growth factor-1 were determined at baseline and 6 months later. RESULTS AND DISCUSSION: Fifty-nine patients completed the study. There were differences between groups A and C and group B in baseline values of total cholesterol, LDL-cholesterol, gonadotropins and ACTH. Although observed in both groups of metformin-treated patients, the effect on thyrotropin levels was more pronounced in group A than in group B. The impact on fasting glucose and insulin sensitivity was stronger in group B than group A. In turn, only in group A metformin tended to reduce gonadotropin levels. There were no differences between follow-up and baseline values of lipids, total and free thyroid hormones, prolactin, ACTH and insulin-like growth factor-1 in both these groups. In group C, all assessed variables remained at a similar level. WHAT IS NEW AND CONCLUSION: The results of the current study suggest that rosuvastatin potentiates the inhibitory effect of metformin on thyrotrope secretory function.

The impact of vitamin D on thyroid autoimmunity and hypothalamic-pituitary-thyroid axis activity in myo-inositol-treated and myo-inositol-naïve women with autoimmune thyroiditis: A pilot study.

WHAT IS KNOWN AND OBJECTIVE: Vitamin D and myo-inositol reduce thyroid antibody titers in subjects with autoimmune thyroiditis. No previous study has investigated interactions between these agents. The aim of the current study was to determine whether the impact of exogenous vitamin D on thyroid autoimmunity and thyroid function in women with Hashimoto's thyroiditis depends on myo-inositol supplementation. METHODS: The study population consisted of three thyroid antibody- and insulin sensitivity-matched groups of women with autoimmune thyroiditis and high-normal or slightly elevated TSH levels. Forty-one women (21 in group A and 20 in group C) had been treated for at least 6 months with myo-inositol (group A), while 21 women (group B) had not received myo-inositol preparations. Over the entire study period (6 months), groups A and C continued treatment with myo-inositol (2 g daily), while groups A and B received exogenous vitamin D (4000 IU daily). Plasma titers of thyroid peroxidase and thyroglobulin antibodies, as well as plasma concentrations of glucose, insulin, TSH, free thyroid hormones, prolactin, and 25-hydroxyvitamin D (25-OH-D) were assessed at entry and 6 months later. Moreover, baseline and follow-up values of the structure parameters of thyroid homeostasis were calculated RESULTS AND DISCUSSION: In groups A and B, vitamin D improved insulin sensitivity and increased 25-OH-D levels. Although follow-up antibody titers in both these groups were lower than baseline ones, the impact of vitamin D on thyroid peroxidase and thyroglobulin antibodies was stronger in group A than in group B. Only in group A, vitamin D decreased TSH levels and increased SPINA-GT. There were no differences between baseline and follow-up free values of glucose, thyroid hormones, prolactin, Jostel's index, and SPINA-GD. The impact of vitamin D treatment on antibody titers correlated with treatment-induced changes in 25-OH-D levels and the degree of improvement in insulin sensitivity. In group C, glucose homeostasis markers, antibody titers and hormone levels remained at a similar level throughout the study period. WHAT IS NEW AND CONCLUSION: The obtained results suggest that the impact of vitamin D on thyroid autoimmunity and hypothalamic-pituitary-thyroid axis activity in subjects with autoimmune thyroiditis is more pronounced if they receive myo-inositol.

Principles of Endocrine Regulation: Reconciling Tensions Between Robustness in Performance and Adaptation to Change.

Endocrine regulation in the hypothalamic-pituitary-thyroid (HPT) axis is orchestrated by physiological circuits which integrate multiple internal and external influences. Essentially, it provides either of the two responses to overt biological challenges: to defend the homeostatic range of a target hormone or adapt it to changing environmental conditions. Under certain conditions, such flexibility may exceed the capability of a simple feedback control loop, rather requiring more intricate networks of communication between the system's components. A new minimal mathematical model, in the form of a parametrized nonlinear dynamical system, is here formulated as a proof-of-concept to elucidate the principles of the HPT axis regulation. In particular, it allows uncovering mechanisms for the homeostasis of the key biologically active hormone free triiodothyronine (FT3). One mechanism supports the preservation of FT3 homeostasis, whilst the other is responsible for the adaptation of the homeostatic state to a new level. Together these allow optimum resilience in stressful situations. Preservation of FT3 homeostasis, despite changes in FT4 and TSH levels, is found to be an achievable system goal by joining elements of top-down and bottom-up regulation in a cascade of targeted feedforward and feedback loops. Simultaneously, the model accounts for the combination of properties regarded as essential to endocrine regulation, namely sensitivity, the anticipation of an adverse event, robustness, and adaptation. The model therefore offers fundamental theoretical insights into the effective system control of the HPT axis.

Multi-level hypothalamic neuromodulation of self-regulation and cognition in preterm infants: Towards a control systems model.

Preterm infants, age-corrected for prematurity, score on average, 10 points lower on IQ tests than full-term infants tested at comparable ages. This review focuses on the potential contribution of the hypothalamus to cognitive neuro-regulatory development in preterm infants through its bidirectional neural connections with the prefrontal cortex and its neuroendocrine activity. It aims to clarify the central role of the hypothalamus in preterm high stress situations and in influencing cognitive development via its connectivity to the cerebral cortex. The review further evaluates epigenomic sensitivity to environmental inputs. Recent results suggest that an optimal range of DNA methylations (via a continuous process of decreasing levels of receptor methylations that are too high, and increasing levels that are too low) appears necessary in order to reach an adaptive level of receptor availability. Several studies have demonstrated amelioration of preterm infants' stress while in the Newborn Intensive Care Unit (NICUs) and following discharge. The authors postulate that feedback mechanisms and correction signals are the basis for a hypothalamic homeostatic modulating function, a "hypothalamic resistance response", which may account for the stress reduction brought about by in- and post-NICU early interventions and their results of promoting self-regulation and cognition.

Short-Term Exposure Effects of the Environmental Endocrine Disruptor Benzo(a)Pyrene on Thyroid Axis Function in Zebrafish.

Benzo(a)Pyrene (BaP) is one of the most widespread polycyclic aromatic hydrocarbons (PAHs) with endocrine disrupting properties and carcinogenic effects. In the present study, we tested the effect of BaP on thyroid development and function, using zebrafish as a model system. Zebrafish embryos were treated with 50 nM BaP from 2.5 to 72 h post fertilization (hpf) and compared to 1.2% DMSO controls. The expression profiles of markers of thyroid primordium specification, thyroid hormone (TH) synthesis, hypothalamus-pituitary-thyroid (HPT) axis, TH transport and metabolism, and TH action were analyzed in pools of treated and control embryos at different developmental stages. BaP treatment did not affect early markers of thyroid differentiation but resulted in a significant decrease of markers of TH synthesis (tg and nis) likely secondary to defective expression of the central stimulatory hormones of thyroid axis (trh, tshba) and of TH metabolism (dio2). Consequently, immunofluorescence of BaP treated larvae showed a low number of follicles immunoreactive to T4. In conclusion, our results revealed that the short-term exposure to BaP significantly affects thyroid function in zebrafish, but the primary toxic effects would be exerted at the hypothalamic-pituitary level thus creating a model of central hypothyroidism.

Filtered air intervention modulates hypothalamic-pituitary-thyroid/gonadal axes by attenuating inflammatory responses in adult rats after fine particulate matter (PM2.5) exposure.

We have previously reported that filtered air (FA) intervention reduces inflammation and hypothalamus-pituitary-adrenal axis activation after fine particulate matter (PM2.5 exposure). Whether FA also modulates the hypothalamic-pituitary-thyroid (HPT) and hypothalamic-pituitary-gonadal (HPG) axes in rats after PM2.5 exposure is still unknown. Adult Sprague-Dawley rats were exposed to PM2.5 by using a "real-world" PM2.5 exposure system, and the FA intervention was conducted by renewing for 15 days. PM2.5 inhalation decreased thyrotropin-releasing hormone (TRH) and thyroxine (T4) levels in both male and female rats, and thyroid-stimulating hormone (TSH) level in male rats. FA intervention attenuated the reduction in TRH and TSH levels in male rats and reduction in T4 level in female rats. PM2.5 inhalation also reduced testosterone (T) level in male rats, and estradiol (E2) and progesterone (PROG) levels in female rats, and these changes were attenuated after FA intervention. The FA intervention attenuated the decreases in CD8 T cells and T cells induced by PM2.5 inhalation in female rats only by flow cytometry analysis. In blood, FA interventions ameliorated IL-6 and IL-1ß mRNA levels in both male and female rats after PM2.5 exposure. FA intervention restored the IL-4 and IL-10 levels in female rats after PM2.5 exposure. Moreover, FA intervention ameliorated the inflammatory responses induced by PM2.5 inhalation in the thyroid and gonads in both male and female rats. These data indicate that FA intervention exerted an effect on modulating the hormonal balance of the HPT and HPG axes, and this may be related to a reduction in the inflammatory responses in the thyroid and gonads of PM2.5-treated rats, respectively.