Role of Vitamin D in Prevention of Chronic Diseases

Vitamin D is one of the essential nutrients to sustain the human health. Vitamin D functions in the body through both an endocrine mechanism (regulation of calcium absorption) and an autocrine mechanism (facilitation of gene expression). The role of Vitamin D deficiency in increasing the risk factor of many common and serious chronic diseases, including cancers, type 1 diabetes, cardiovascular disease and osteoporosis. Numerous epidemiologic studies suggest that exposure to sunlight, which enhances the production of Vitamin D₃ in the skin, is important in preventing many chronic diseases. 25(OH)D (25-hydrovitamin D) is the metabolite that should be measured in the blood to determine Vitamin D status. 25(OH)D deficiency is prevalent in infants who are solely breastfed and who do not receive Vitamin D₃ supplementation and in adults of all ages who have increased skin pigmentation or who always wear sun protection or limit their outdoor activities. It is therefore necessary to know the adverse health effects of 25(OH)D deficiency and to design intervention and early treatments for those who are likely to have low levels of 25(OH)D.

Cortisol responsiveness and dominance rank, but not baseline cortisol level, are repeatable traits in adult female guinea pigs

Social interactions among group members often lead to the formation of stable dominance hierarchies. Glucocorticoids (i.e. cortisol) have been proposed as an endocrine mechanism underlying social behavior, and previous studies have linked baseline as well as challenge glucocorticoid concentrations to dominance rank. Since the importance of rank on fitness differs between males and females, selection pressures acting on the underlying endocrine mechanisms may differ between the sexes. In male guinea pigs, for example, it is known that cortisol responsiveness mediates social behavior and that dominance rank and cortisol responsiveness are stable within individuals over time. It is unclear whether this is also the case for female guinea pigs. Thus the aim of this study was to investigate whether cortisol concentrations are repeatable in female guinea pigs and whether female rank is correlated to baseline cortisol concentrations or cortisol responsiveness. We show that cortisol responsiveness and dominance rank were significantly repeatable but not correlated in female guinea pigs. Furthermore, baseline cortisol was not repeatable and also did not correlate to dominance rank. Our results demonstrate that baseline cortisol and cortisol responsiveness represent different biological processes; cortisol responsiveness reflects a stable trait while baseline cortisol likely fluctuates with current state. Furthermore, cortisol responsiveness as a mediator of aggressive behavior and dominance acquisition might not be important for maintaining dominance hierarchies in stable groups of females displaying minimal aggression. Overall, this study reveals the remarkable stability of cortisol responsiveness and dominance rank in an adult female rodent and lays the groundwork for future investigations into the causes and consequences of this individual variation.

Changes of TLQP-21 in Response to Glucose Load

The TLQP-21 peptide peripherally potentiates glucose-stimulated insulin secretion. The aim of this study was to investigate a possible endocrine mechanism through which TLQP-21 increases the insulin secretion. Using an antibody specific for the common N-terminal portion of the TLQP peptides, we studied pancreas and plasma of mice subjected to intraperitoneal glucose load, by immunohistochemistry and immunosorbent assay (ELISA), alone or coupled to High Performance Liquid Chromatography (HLPC). Mice underwent a period of starvation hence have received a glucose load, or saline, and were sacrificed 30 or 120 minutes later. In normal endocrine pancreas, the TLQP-antiserum stained either peripheral or central cells. Interestingly, 30 min after a glucose load, TLQP immunostaining was disappeared in pancreas and, when analysed by ELISA, the TLQP-levels started to increase in plasma reaching peak concentration at 120 min. (controls vs. 30 and 120 min.: p<0.05 and p<0.001, respectively). The analysis of plasma and pancreas extracts using HLPC coupled to ELISA demonstrated the presence of the TLQP-21, with statistically significant increase of this peptide in plasma at 120 min (vs. controls p<0.05) in agreement to the changes seen by measuring the totality of the TLQP peptides. In pancreas sections we found the presence of the C3a-R1, involved in insulin secretion, and previously identified as a TLQP-21 receptor. Hence, after a glucose load, TLQP-21, may be released by the pancreas into the plasma, returning to the pancreas in order to modulate the insulin secretion through the C3a-R1.

Hypogonadotropic Hypogonadism and Kleefstra Syndrome due to a Pathogenic Variant in the EHMT1 Gene: An Underrecognized Association

Kleefstra syndrome is a genetic condition characterized by intellectual disability, childhood hypotonia, and facial dysmorphisms. Genital anomalies such as micropenis, cryptorchidism, and hypospadias have been reported in 30-40% of males diagnosed with the disease. However, endocrinological investigations have been limited. We describe a case of an adolescent male with Kleefstra syndrome due to a pathogenic variant in the EHMT1 gene whose workup for isolated micropenis is suggestive of a partial hypogonadotropic hypogonadism. A possible endocrine mechanism of the genital anomaly associated with Kleefstra syndrome is discussed.

Social and endocrine correlates of immune function in meerkats: implications for the immunocompetence handicap hypothesis

Social status can mediate effects on the immune system, with profound consequences for individual health; nevertheless, most investigators of status-related disparities in free-ranging animals have used faecal parasite burdens to proxy immune function in the males of male-dominant species. We instead use direct measures of innate immune function (complement and natural antibodies) to examine status-related immunocompetence in both sexes of a female-dominant species. The meerkat is a unique model for such a study because it is a cooperatively breeding species in which status-related differences are extreme, evident in reproductive skew, morphology, behaviour, communication and physiology, including that dominant females naturally express the greatest total androgen (androstenedione plus testosterone) concentrations. We found that, relative to subordinates, dominant animals had reduced serum bacteria-killing abilities; also, relative to subordinate females, dominant females had reduced haemolytic complement activities. Irrespective of an individual's sex or social status, androstenedione concentrations (but not body condition, age or reproductive activity) negatively predicted concurrent immunocompetence. Thus, dominant meerkats of both sexes are immunocompromised. Moreover, in female meerkats, androstenedione perhaps acting directly or via local conversion, may exert a double-edged effect of promoting dominance and reproductive success at the cost of increased parasitism and reduced immune function. Given the prominent signalling of dominance in female meerkats, these findings may relate to the immunocompetence handicap hypothesis (ICHH); however, our data would suggest that the endocrine mechanism underlying the ICHH need not be mediated solely by testosterone and might explain trade-offs in females, as well as in males.

The growth hormone–insulin-like growth factor-I axis in the diagnosis and treatment of growth disorders

The growth hormone (GH)–insulin-like growth factor (IGF)-I axis is a key endocrine mechanism regulating linear growth in children. While paediatricians have a good knowledge of GH secretion and assessment, understanding and use of measurements of the components of the IGF system are less current in clinical practice. The physiological function of this axis is to increase the anabolic cellular processes of protein synthesis and mitosis, and reduction of apoptosis, with each being regulated in the appropriate target tissue. Measurement of serum IGF-I and IGF-binding protein (IGFBP)-3 concentrations can complement assessment of GH status in the investigation of short stature and contribute to prediction of growth response during GH therapy. IGF-I monitoring during GH therapy also informs the clinician about adherence and provides a safety reference to avoid over-dosing during long-term management.

Nonneural Androgen Receptors Affect Sexual Differentiation of Brain and Behavior

Testosterone, acting via estrogenic and androgenic pathways, is the major endocrine mechanism promoting sexual differentiation of the mammalian nervous system and behavior, but we have an incomplete knowledge of which cells and tissues mediate these effects. To distinguish between neural and nonneural actions of androgens in sexual differentiation of brain and behavior, we generated a loxP-based transgenic mouse, which overexpresses androgen receptors (ARs) when activated by Cre. We used this transgene to overexpress AR globally in all tissues using a cytomegalovirus (CMV)-Cre driver (CMV-AR), and we used a Nestin-Cre driver to overexpress AR only in neural tissue (Nes-AR). We then examined whether neural or global AR overexpression can affect socio-sexual behaviors using a resident-intruder paradigm. We found that both neural and global AR overexpression resulted in decreased aggressive behaviors and increased thrusting during mounting of intruders, consistent with a neural site of action. Global, but not neural, AR overexpression in males led to an increase in same-sex anogenital investigation. Together, these results suggest novel roles for nonneural AR in sexual differentiation of mice, and indicate that excess AR can lead to a paradoxical reduction of male-typical behavior.

The agonistic adrenal: melatonin elicits female aggression via regulation of adrenal androgens

Classic findings have demonstrated an important role for sex steroids as regulators of aggression, but this relationship is lacking within some environmental contexts. In mammals and birds, the adrenal androgen dehydroepiandrosterone (DHEA), a non-gonadal precursor of biologically active steroids, has been linked to aggression. Although females, like males, use aggression when competing for limited resources, the mechanisms underlying female aggression remain understudied. Here, we propose a previously undescribed endocrine mechanism regulating female aggression via direct action of the pineal hormone melatonin on adrenal androgens. We examined this in a solitary hamster species, Phodopus sungorus , in which both sexes are highly territorial across the seasons, and display increased aggression concomitant with decreased serum levels of sex steroids in short ‘winter-like' days. Short- but not long-day females had increased adrenal DHEA responsiveness co-occurring with morphological changes in the adrenal gland. Further, serum DHEA and total adrenal DHEA content were elevated in short days. Lastly, melatonin increased DHEA and aggression and stimulated DHEA release from cultured adrenals. Collectively, these findings demonstrate that DHEA is a key peripheral regulator of aggression and that melatonin coordinates a ‘seasonal switch’ from gonadal to adrenal regulation of aggression by direct action on the adrenal glands.

Paracrine Regulation of Steroidogenesis in Theca Cells by Granulosa Cells Derived from Mouse Preantral Follicles

Interaction partners of follicular cells play a significant role in steroidogenesis, follicular formation, and development. Androgen secreted by theca cells (TCs) can initiate follicle development and ovulation and provide precursor materials for estrogen synthesis. Therefore, studies on ovarian microenvironment will not only lead to better understanding of the steroidogenesis but also have clinical significance for ovarian endocrine abnormalities such as hyperandrogenism in polycystic ovary syndrome (PCOS). This study applied the Transwell coculture model to investigate if the interaction between granulosa and theca cells may affect androgen production in theca cells. Concentrations of testosterone and androstenedione in the spent medium were measured by radioimmunoassay and enzyme linked immunosorbent assay, respectively. The results show that the coculture with granulosa cells (GCs) increases steroidogenesis in TCs. In addition, testosterone and androstenedione productions in response to LH stimulation were also increased in the coculture model. Significantly increased mRNA expressions of steroidogenic enzymes (Star,Cyp11a1,Cyp17a1, andHsd3b2) were observed in the cocultured TCs. Thus, GCs were capable of promoting steroidogenesis and LH responsiveness in TCs. This study provided a basis for further exploration of ovarian endocrine mechanism and pathologies.