Abstract: Our understanding of thyroid hormone action has been substantially altered by recent clinical observations of thyroid signaling defects in syndromes of hormone resistance and in a broad range of conditions, including profound mental retardation, obesity, metabolic disorders, and a number of cancers. The mechanism of thyroid hormone action has been informed by these clinical observations as well as by animal models and has influenced the way we view the role of local ligand availability; tissue and cell-specific thyroid hormone transporters, corepressors, and coactivators; thyroid hormone receptor (TR) isoform-specific action; and cross-talk in metabolic regulation and neural development. In some cases, our new understanding has already been translated into therapeutic strategies, especially for treating hyperlipidemia and obesity, and other drugs are in development to treat cardiac disease and cancer and to improve cognitive function.

Abstract: Pancreatic β-cell dysfunction plays an important role in the pathogenesis of both type 1 and type 2 diabetes. Insulin, which is produced in β-cells, is a critical regulator of metabolism. Insulin is synthesized as preproinsulin and processed to proinsulin. Proinsulin is then converted to insulin and C-peptide and stored in secretary granules awaiting release on demand. Insulin synthesis is regulated at both the transcriptional and translational level. The cis-acting sequences within the 5' flanking region and trans-activators including paired box gene 6 (PAX6), pancreatic and duodenal homeobox- 1(PDX-1), MafA, and β-2/Neurogenic differentiation 1 (NeuroD1) regulate insulin transcription, while the stability of preproinsulin mRNA and its untranslated regions control protein translation. Insulin secretion involves a sequence of events in β-cells that lead to fusion of secretory granules with the plasma membrane. Insulin is secreted primarily in response to glucose, while other nutrients such as free fatty acids and amino acids can augment glucose-induced insulin secretion. In addition, various hormones, such as melatonin, estrogen, leptin, growth hormone, and glucagon like peptide-1 also regulate insulin secretion. Thus, the β-cell is a metabolic hub in the body, connecting nutrient metabolism and the endocrine system. Although an increase in intracellular [Ca2+] is the primary insulin secretary signal, cAMP signaling- dependent mechanisms are also critical in the regulation of insulin secretion. This article reviews current knowledge on how β-cells synthesize and secrete insulin. In addition, this review presents evidence that genetic and environmental factors can lead to hyperglycemia, dyslipidemia, inflammation, and autoimmunity, resulting in β-cell dysfunction, thereby triggering the pathogenesis of diabetes.

Abstract: Histological Classification of Endocrine Tumours.- Definitions and Explanatory Notes.- Tumours of the Adenohypophysis.- Tumours of the Adrenal Cortex.- Tumours of Adrenal and Extra-adrenal Paraganglia.- Tumours of the Parathyroid Glands.- Endocrine Tumours of the Pancreas.- Endocrine Tumours of the Gastrointestinal Tract.- Multiple Endocrine Neoplasia Type 1.- Multiple Endocrine Neoplasia Type 2.- Ectopic Hormone Production.- Illustrations.

Abstract: We review the physiology and pharmacology of two atypical fibroblast growth factors (FGFs)—FGF15/19 and FGF21—that can function as hormones. Both FGF15/19 and FGF21 act on multiple tissues to coordinate carbohydrate and lipid metabolism in response to nutritional status. Whereas FGF15/19 is secreted from the small intestine in response to feeding and has insulin-like actions, FGF21 is secreted from the liver in response to extended fasting and has glucagon-like effects. FGF21 also acts in an autocrine fashion in several tissues, including adipose. The pharmacological actions of FGF15/19 and FGF21 make them attractive drug candidates for treating metabolic disease.

Abstract: Men have higher blood pressure than women through much of life regardless of race and ethnicity. This is a robust and highly conserved sex difference that it is also observed across species including dogs, rats, mice and chickens and it is found in induced, genetic and transgenic animal models of hypertension. Not only do the differences between the ovarian and testicular hormonal milieu contribute to this sexual dimorphism in blood pressure, the sex chromosomes also play a role in and of themselves. This review primarily focuses on epidemiological studies of blood pressure in men and women and experimental models of hypertension in both sexes. Gaps in current knowledge regarding what underlie male-female differences in blood pressure control are discussed. Elucidating the mechanisms underlying sex differences in hypertension may lead to the development of anti-hypertensives tailored to one's sex and ultimately to improved therapeutic strategies for treating this disease and preventing its devastating consequences.

Abstract: Background: Vitamin D has been well-known for its function in maintaining calcium and phosphorus homeostasis and promoting bone mineralization. There is some evidence that in addition to sex steroid hormones, the classic regulators of human reproduction, vitamin D also modulates reproductive processes in women and men. Aim: The aim of this review was to assess the studies that evaluated the relationship between vitamin D and fertility in women and men as well as in animals. Methods: We performed a systematic literature search in Pubmed for relevant English language publications published until October 2011. Results and discussion: The vitamin D receptor (VDR) and vitamin D metabolizing enzymes are found in reproductive tissues of women and men. Vdr knockout mice have significant gonadal insufficiency, decreased sperm count and motility, and histological abnormalities of testis, ovary and uterus. Moreover, we present evidence that vitamin D is involved in female reproduction including IVF outcome (clinical pregnancy rates) and polycystic ovary syndrome (PCOS). In PCOS women, low 25-hydroxyvitamin D (25(OH)D) levels are associated with obesity, metabolic, and endocrine disturbances and vitamin D supplementation might improve menstrual frequency and metabolic disturbances in those women. Moreover, vitamin D might influence steroidogenesis of sex hormones (estradiol and progesterone) in healthy women and high 25(OH)D levels might be associated with endometriosis. In men, vitamin D is positively associated with semen quality and androgen status. Moreover, vitamin D treatment might increase testosterone levels. Testiculopathic men show low CYP21R expression, low 25(OH)D levels, and osteoporosis despite normal testosterone levels.

Abstract: Aging is associated with a loss of sex hormone in both men (andropause) and women (menopause) In men, reductions in testosterone can trigger declines in muscle mass, bone mass, and in physical function In women, the impact of the loss of sex hormones, such as estradiol, on bone is well elucidated, but evidence is limited on whether the loss of estradiol negatively affects muscle mass and physical function However, deficiencies in multiple anabolic hormones have been shown to predict health status and longevity in older persons Thus, consideration should be given as to whether targeted hormone replacement therapies may prove effective at treating clinical conditions, such as age-related sarcopenia, cancer cachexia, and/or acute or chronic illnesses If initiated carefully in the appropriate clinical population, hormone replacement therapies in men and women may prevent and reverse muscle and bone loss and functional declines and perhaps promote healthy aging and longevity

Abstract: Thyroid hormones exert their effects through alpha (TRα1) and beta (TRβ1 and TRβ2) receptors. Here we describe a child with classic features of hypothyroidism (growth retardation, developmental retardation, skeletal dysplasia, and severe constipation) but only borderline-abnormal thyroid hormone levels. Using whole-exome sequencing, we identified a de novo heterozygous nonsense mutation in a gene encoding thyroid hormone receptor alpha (THRA) and generating a mutant protein that inhibits wild-type receptor action in a dominant negative manner. Our observations are consistent with defective human TRα-mediated thyroid hormone resistance and substantiate the concept of hormone action through distinct receptor subtypes in different target tissues.

Abstract: The relation between thyroid function and depression has long been recognized. Patients with thyroid disorders are more prone to develop depressive symptoms and conversely depression may be accompanied by various subtle thyroid abnormalities. Traditionally, the most commonly documented abnormalities are elevated T4 levels, low T3, elevated rT3, a blunted TSH response to TRH, positive antithyroid antibodies, and elevated CSF TRH concentrations. In addition, thyroid hormone supplements appear to accelerate and enhance the clinical response to antidepressant drugs. However, the mechanisms underlying the interaction between thyroid function and depression remain to be further clarified. Recently, advances in biochemical, genetic, and neuroimaging fields have provided new insights into the thyroid-depression relationship.

Abstract: The trace element selenium is an essential micronutrient that is required for the biosynthesis of selenocysteine-containing selenoproteins. Most of the known selenoproteins are expressed in the thyroid gland, including some with still unknown functions. Among the well-characterized selenoproteins are the iodothyronine deiodinases, glutathione peroxidases and thioredoxin reductases, enzymes involved in thyroid hormone metabolism, regulation of redox state and protection from oxidative damage. Selenium content in selenium-sensitive tissues such as the liver, kidney or muscle and expression of nonessential selenoproteins, such as the glutathione peroxidases GPx1 and GPx3, is controlled by nutritional supply. The thyroid gland is, however, largely independent from dietary selenium intake and thyroid selenoproteins are preferentially expressed. As a consequence, no explicit effects on thyroid hormone profiles are observed in healthy individuals undergoing selenium supplementation. However, low selenium status correlates with risk of goiter and multiple nodules in European women. Some clinical studies have demonstrated that selenium-deficient patients with autoimmune thyroid disease benefit from selenium supplementation, although the data are conflicting and many parameters must still be defined. The baseline selenium status of an individual could constitute the most important parameter modifying the outcome of selenium supplementation, which might primarily disrupt self-amplifying cycles of the endocrine-immune system interface rectifying the interaction of lymphocytes with thyroid autoantigens. Selenium deficiency is likely to constitute a risk factor for a feedforward derangement of the immune system-thyroid interaction, while selenium supplementation appears to dampen the self-amplifying nature of this derailed interaction.

Abstract: The primary function of the thyroid gland is to metabolize iodide by synthesizing thyroid hormones, which are critical regulators of growth, development and metabolism in almost all tissues. So far, research on thyroid morphogenesis has been missing an efficient stem-cell model system that allows for the in vitro recapitulation of the molecular and morphogenic events regulating thyroid follicular-cell differentiation and subsequent assembly into functional thyroid follicles. Here we report that a transient overexpression of the transcription factors NKX2-1 and PAX8 is sufficient to direct mouse embryonic stem-cell differentiation into thyroid follicular cells that organize into three-dimensional follicular structures when treated with thyrotropin. These in vitro-derived follicles showed appreciable iodide organification activity. Importantly, when grafted in vivo into athyroid mice, these follicles rescued thyroid hormone plasma levels and promoted subsequent symptomatic recovery. Thus, mouse embryonic stem cells can be induced to differentiate into thyroid follicular cells in vitro and generate functional thyroid tissue.

Abstract: There are several interactions between thyroid and kidney functions in each other organ's disease states. Thyroid hormones affect renal development and physiology. Thyroid hormones have pre-renal and intrinsic renal effects by which they increase the renal blood flow and the glomerular filtration rate (GFR). Hypothyroidism is associated with reduced GFR and hyperthyroidism results in increased GFR as well as increased renin - angiotensin - aldosterone activation. Chronic kidney disease (CKD) is characterized by a low T3 syndrome which is now considered a part of an atypical nonthyroidal illness. CKD patients also have increased incidence of primary hypothyroidism and subclinical hypothyroidism. The physiological benefits of a hypothyroid state in CKD, and the risk of CKD progression with hyperthyroidism emphasize on a conservative approach in the treatment of thyroid hormone abnormalities in CKD. Thyroid dysfunction is also associated with glomerulonephritis often by a common autoimmune etiology. Several drugs could affect both thyroid and kidney functions. There are few described interactions between thyroid and renal malignancies. A detailed knowledge of all these interactions is important for both the nephrologists and endocrinologists for optimal management of the patient.

Abstract: Thyroid hormones influence renal development, kidney structure, renal hemodynamics, GFR, the function of many transport systems along the nephron, and sodium and water homeostasis. These effects of thyroid hormone are in part due to direct renal actions and in part are mediated by cardiovascular and systemic hemodynamic effects that influence kidney function. As a consequence, both hypothyroidism and hyperthyroidism associate with clinically important alterations in kidney function and have relevance to its assessment. Disorders of thyroid function have also been linked to development of immune-mediated glomerular injury, and alterations in thyroid hormones and thyroid hormone testing occur in patients with kidney disease.

Abstract: Summary 1. Methods to measure metabolites of steroid hormones from faeces have become very popular in wildlife conservation and ecology, because they allow gathering physiological data without the necessity to capture the animals. However, this advantage comes at costs that are particularly relevant when studying free-living animals in their natural environments. Previous methodological reviews have stressed the importance of validations to prove that real metabolites of the hormone in question are measured, but the research community has largely ignored further caveats relating to sex, diet, metabolic rate and individual differences in hormone metabolite formation. 2. Often the sexes differ in how they metabolize hormones. As a consequence, one may not be able to compare hormone metabolite concentrations between males and females of one species. 3. Diet can alter the way hormones are metabolized, and different diets can change the amount of faecal bulk. Both phenomena can result in measurement artefacts that may seriously distort the estimation of hormone metabolite concentrations. As a consequence, comparisons of hormone metabolite concentrations, for example, between seasons or populations, may become problematic. 4. Changes in ambient temperature and food availability may trigger large fluctuations in metabolic rate of free-living animals. These fluctuations may then result in major distortions of faecal hormone metabolite concentrations without any change in bioactive hormone levels. 5. Bacteria metabolize hormones in the gut. Individual differences in bacterial composition can cause differences in how hormones are decomposed. Thus, individuals may differ with regard to what kind of hormone metabolites they form and with regard to the relative composition of these hormone metabolites. As only specific metabolites are measured, differences in metabolism may distort the results. 6. In summary, non-invasive hormone research measures various end products of a hormone after its clearance from the circulation and extensive modification by bacteria. Not only does this increase random variance, it may also generate systematic noise, which may seriously distort the signal (i.e. the hormonal status of the individual) in a non-random manner. Thus, we still need to learn much more about whether this widely used technique reliably measures the physiological status of animals in uncontrolled environments.

Abstract: A moderate elevation of thyrotropin (TSH) concentrations, which is associated with triiodothyronine (T3) values in or slightly above the upper normal range, is frequently found in obese humans. These alterations seem rather a consequence than a cause of obesity since weight loss leads to a normalization of elevated thyroid hormone levels. Elevated thyroid hormone concentrations increase the resting energy expenditure (REE). The underlying pathways are not fully understood. As a consequence of the increased REE, the availability of accumulated energy for conversion into fat is diminished. In conclusion, the alterations of thyroid hormones in obesity suggest an adaptation process. Since rapid weight loss is associated with a decrease of TSH and T3, the resulting decrease in REE may contribute towards the difficulties maintaining weight loss. Leptin seems to be a promising link between obesity and alterations of thyroid hormones since leptin concentrations influence TSH release.

Abstract: Vitamin D has emerged as a pleiotropic regulator of human physiology, and recent work has revealed that it has several roles in control of human immune system function. Vitamin D was originally characterized for its role in calcium homeostasis, and the active form, 1,25-dihydroxyvitamin D (1,25D), can be produced in the kidney by 1α-hydroxylation of circulating 25-hydroxyvitamin D catalyzed by the enzyme CYP27B1. Renal CYP27B1 expression is regulated by calcium regulatory inputs, and 1,25D produced in the kidney was thought to function largely as an endocrine hormone. However, it is now clear that CYP27B1 is expressed in numerous tissues, and that 1,25D acts at several sites in the body in an intracrine or paracrine manner. In particular, both CYP27B1 and the vitamin D receptor (VDR) are expressed in several cell types in the immune system, where CYP27B1 production is controlled by a number of immune-specific inputs. Recent research has opened several windows on the molecular mechanisms by which 1,25D signaling regulates both innate and adaptive immune responses in humans. Moreover, intervention trials are beginning to provide evidence that vitamin D supplementation can bolster clinical responses to infection. This review will discuss recent developments in our understanding of how immune signaling controls local vitamin D metabolism and how, in turn, the 1,25D-bound VDR modulates immune system function. A particular emphasis will be placed on the interplay between vitamin D signaling and signaling through different classes of pattern recognition receptors in the production of antimicrobial peptides during innate immune responses to microbial infection.

Abstract: For more than a century, thyroid hormones (THs) have been known to exert powerful catabolic effects, leading to weight loss. Although much has been learned about the molecular mechanisms used by TH receptors (TRs) to regulate gene expression, little is known about the mechanisms by which THs increase oxidative metabolism. Here, we report that TH stimulation of fatty acid β-oxidation is coupled with induction of hepatic autophagy to deliver fatty acids to mitochondria in cell culture and in vivo. Furthermore, blockade of autophagy by autophagy-related 5 (ATG5) siRNA markedly decreased TH-mediated fatty acid β-oxidation in cell culture and in vivo. Consistent with this model, autophagy was altered in livers of mice expressing a mutant TR that causes resistance to the actions of TH as well as in mice with mutant nuclear receptor corepressor (NCoR). These results demonstrate that THs can regulate lipid homeostasis via autophagy and help to explain how THs increase oxidative metabolism.

Abstract: The endocrinology of human pregnancy involves endocrine and metabolic changes that result from physiological alterations at the boundary between mother and fetus. Progesterone and oestrogen have a great role along with other hormones. The controversies of use of progestogen and others are discussed in this chapter. Progesterone has been shown to stimulate the secretion of Th2 and reduces the secretion of Th1 cytokines which maintains pregnancy. Supportive care in early pregnancy is associated with a significant beneficial effect on pregnancy outcome. Prophylactic hormonal supplementation can be recommended for all assisted reproduction techniques cycles. Preterm labor can be prevented by the use of progestogen. The route of administration plays an important role in the drug's safety and efficacy profile in different trimesters of pregnancy. Thyroid disorders have a great impact on pregnancy outcome and needs to be monitored and treated accordingly. Method of locating review: Pubmed, scopus.

Abstract: The discovery of fibroblast growth factor 23 (FGF-23) has expanded our understanding of phosphate and vitamin D homeostasis and provided new insights into the pathogenesis of hereditary hypophosphatemic and hyperphosphatemic disorders, as well as acquired disorders of phosphate metabolism, such as chronic kidney disease. FGF-23 is secreted by osteoblasts and osteocytes in bone and principally targets the kidney to regulate the reabsorption of phosphate, the production and catabolism of 1,25-dihydroxyvitamin D and the expression of α-Klotho, an anti-ageing hormone. Secreted FGF-23 plays a central role in complex endocrine networks involving local bone-derived factors that regulate mineralization of extracellular matrix and systemic hormones involved in mineral metabolism. Inactivating mutations of PHEX, DMP1 and ENPP1, which cause hereditary hypophosphatemic disorders and primary defects in bone mineralization, stimulate FGF23 gene transcription in osteoblasts and osteocytes, at least in part, through canonical and intracrine FGF receptor pathways. These FGF-23 regulatory pathways may enable systemic phosphate and vitamin D homeostasis to be coordinated with bone mineralization. FGF-23 also functions as a counter-regulatory hormone for 1,25-dihydroxyvitamin D in a bone-kidney endocrine loop. FGF-23, through regulation of additional genes in the kidney and extrarenal tissues, probably has broader physiological functions beyond regulation of mineral metabolism that account for the association between FGF-23 and increased mortality and morbidity in chronic kidney disease.

Abstract: A father and daughter with a mutation in the nuclear receptor gene for thyroid hormone (THRA) have abnormal levels of thyroid hormone, normal thyrotropin levels, growth retardation, and mildly delayed motor and cognitive development.

Abstract: Exposure to stress during early development causes long-lasting alterations in behaviour and hypothalamic pituitary adrenal (HPA) axis activity, including increased expression of corticotrophin-releasing hormone (CRH). To determine whether early-life stress causes epigenetic changes in the CRH promoter leading to increased CRH transcription, 8-week old female and male rats, subjected to maternal deprivation (MD) between days 2 and 13 post-birth, were studied for HPA axis responses to stress and CRH promoter methylation in the hypothalamic paraventricular nucleus (PVN) and central nucleus of the amygdala (CeA). Plasma corticosterone and PVN CRH heteronuclear (hn)RNA responses to acute restraint stress were higher in MD rats of both sexes. DNA methylation analysis of the CRH promoter revealed a significantly lower percentage of methylation in two CpGs preceding (CpG1) and inside (CpG2) the cyclic AMP-response element (CRE) at -230 bp in the CRH promoter in the PVN but not the CeA of MD rats. Gel-shift assays, using nuclear proteins from forskolin-treated hypothalamic 4B cells and CRH promoter CRE oligonucleotides, unmethylated or methylated at CpG1, revealed a strong band that was supershifted by phospho-cAMP response element-binding antibody. This band was 50% weaker using oligonucleotides methylated at CpG2 (intra-CRE), or methylated at both CpG1 and CpG2. These findings demonstrate that HPA axis hypersensitivity caused by neonatal stress causes long-lasting enhanced CRH transcriptional activity in the PVN of both sexes. Hypomethylation of the CRH promoter CRE, a region critical for CRH transcriptional activation, could serve as a mechanism for the increased transcriptional responses to stress observed in MD rats.