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Excess levels of circulating androgens during prenatal or peripubertal development are an important cause of polycystic ovary syndrome (PCOS), with the brain being a key target. Approximately half of the women diagnosed with PCOS also experience metabolic syndrome; common features including obesity, insulin resistance and hyperinsulinemia. Although a large amount of clinical and preclinical evidence has confirmed this relationship between androgens and the reproductive and metabolic features of PCOS, the mechanisms by which androgens cause this dysregulation are unknown. Neuron‐specific androgen receptor knockout alleviates some PCOS‐like features in a peripubertal dihydrotestosterone (DHT) mouse model, but the specific neuronal populations mediating these effects are undefined. A candidate population is the agouti‐related peptide (AgRP)‐expressing neurons, which are important for both reproductive and metabolic function. We used a well‐characterised peripubertal androgenized mouse model and Cre‐loxP transgenics to investigate whether deleting androgen receptors specifically from AgRP neurons can alleviate the induced reproductive and metabolic dysregulation. Androgen receptors were co‐expressed in 66% of AgRP neurons in control mice, but only in <2% of AgRP neurons in knockout mice. The number of AgRP neurons was not altered by the treatments. Only 20% of androgen receptor knockout mice showed rescue of DHT‐induced androgen‐induced anovulation and acyclicity. Furthermore, androgen receptor knockout did not rescue metabolic dysfunction (body weight, adiposity or glucose and insulin tolerance). While we cannot rule out developmental compensation in our model, these results suggest peripubertal androgen excess does not markedly influence Agrp expression and does not dysregulate reproductive and metabolic function through direct actions of androgens onto AgRP neurons. [ABSTRACT FROM AUTHOR]

Infertility associated with insulin resistance is characterised by abnormal hormone secretion by the hypothalamus, pituitary gland and gonads. These endocrine tissues can maintain insulin sensitivity even when tissues such as the muscle and liver become insulin‐resistant, resulting in excessive insulin stimulation as hyperinsulinaemia develops. Experiments conducted to determine the role of neuronal insulin signalling in fertility were unable to recapitulate early findings of hypogonadotrophic hypogonadism in mice lacking insulin receptors throughout the brain. Rather, it was eventually shown that astrocytes critically mediate the effects of insulin on puberty timing and adult reproductive function. However, specific roles for neurones and gonadotrophs have been revealed under conditions of hyperinsulinaemia and by ablation of insulin and leptin receptors. The collective picture is one of multiple insulin‐responsive inputs to gonadotrophin releasing hormone neurones, with astrocytes being the most important player. [ABSTRACT FROM AUTHOR]

Agouti‐related peptide (AgRP) neurons are thought to indirectly regulate the activity of hypothalamic gonadotrophin‐releasing hormone neurons which control fertility. AgRP neurons also drive caloric intake and are modulated by metabolically‐relevant hormones, providing a link to the hypothalamic–pituitary‐gonadal axis. In mice expressing Cre‐dependant designer receptors (DREADDs) in AgRP neurons, we activated or silenced these neurons in vivo using the synthetic ligand clozapine‐N‐oxide (CNO) to observe the effect of AgRP neuron activity on timing of puberty. To validate these animals, we chronically treated both stimulatory (hM3Dq) and inhibitory (hM4Di) DREADD × AgRP‐Cre mice with CNO, observing a pronounced increase and decrease of food intake, respectively, consistent with the known orexigenic effects of these neurons. RNAscope was performed to visually confirm the activation of AgRP neurons. Puberty onset was assessed in males and females. There was no effect on preputial separation in males or vaginal opening and first oestrus in females after CNO treatment from day 26 to 30 to chronically modulate AgRP neurons. Next, to determine whether the delay in puberty onset occurring in response to neonatal underfeeding could be overcome by inhibiting AgRP neuronal activity, mice were raised in large (neonatally underfed) or normal litter sizes. The delay in puberty from underfeeding was completely reversed in CNO‐treated AgRP‐hM4Di male mice. These data highlight the inhibitory role of AgRP neurons to delay puberty onset when undernutrition occurs during the neonatal period, at least in male mice. Trail registration number: JNE‐22‐0081‐OA.R2 [ABSTRACT FROM AUTHOR]

Chronic stress exerts multiple negative effects on the physiology and health of an individual. In the present study, we examined hypothalamic, pituitary and endocrine responses to 14 days of chronic variable stress (CVS) in male and female C57BL/6J mice. In both sexes, CVS induced a significant decrease in body weight and enhanced the acute corticosterone stress response, which was accompanied by a reduction in thymus weight only in females. However, single‐point blood measurements of basal prolactin, thyroid‐stimulating hormone, luteinising hormone, growth hormone and corticosterone levels taken at the end of the CVS were not different from those of controls. Similarly, pituitary mRNA expression of Fshb, Lhb, Prl and Gh was unchanged by CVS, although Pomc and Tsh were significantly elevated. Within the adrenal medulla, mRNA for Th, Vip and Gal were elevated following CVS. Avp transcript levels within the paraventricular nucleus of the hypothalamus were increased by CVS; however, levels of Gnrh1, Crh, Oxt,Sst, Trh, Ghrh, Th and Kiss1 remained unchanged. Oestrous cycles were lengthened slightly by CVS and ovarian histology revealed a reduction in the number of preovulatory follicles and corpora lutea. Taken together, these observations indicate that 14 days of CVS induces an up‐regulation of the neuroendocrine stress axis and creates a mild disruption of female reproductive function. However, the lack of changes in other neuroendocrine axes controlling anterior and posterior pituitary secretion suggest that most neuroendocrine axes are relatively resilient to CVS. [ABSTRACT FROM AUTHOR]

During pregnancy, neuroendocrine control of prolactin secretion is markedly altered to allow a state of hyperprolactinaemia to develop. Prolactin secretion is normally tightly regulated by a short-loop negative-feedback mechanism, whereby prolactin stimulates activity of tuberoinfundibular dopamine (TIDA) neurones to increase dopamine secretion into the pituitary portal blood. Dopamine inhibits prolactin secretion, thus reducing prolactin concentrations in the circulation back to the normal low level. Activation of this feedback secretion by placental lactogen during pregnancy maintains relatively low levels of prolactin secretion during early and mid-pregnancy. Despite the continued presence of placental lactogen, however, dopamine secretion from TIDA neurones is reduced during late pregnancy. Moreover, the neurones become completely unresponsive to endogenous or exogenous prolactin at this time, allowing a large nocturnal surge of prolactin to occur from the maternal pituitary gland during the night before parturition. In this review, we describe the changing patterns of prolactin secretion during pregnancy in the rat, and discuss the neuroendocrine mechanisms controlling these changes. The loss of response to prolactin is an important maternal adaptation to pregnancy, allowing the prolonged period of hyperprolactinaemia required for mammary gland development and function and for maternal behaviour immediately after parturition, and possibly also contributing to a range of other adaptive responses in the mother. [ABSTRACT FROM AUTHOR]