Imaging the neuroendocrinology of appetite.

Functional magnetic resonance imaging has become a powerful tool to investigate the neuroendocrinology of appetite. In a recent study, we demonstrated that the brain activation pattern seen following the infusion of the anorectic gut hormones PYY3-36and GLP-17-36 amideto fasted individuals resembles the brain activation pattern seen in the physiological satiated state. This commentary discusses the significance of these findings and compares them with other landmark studies in the field, with specific reference to the brain areas involved in appetite regulation. We highlight the importance of this type of research in order to pave the way for the development of efficacious and safe anti-obesity therapies

Invited review: Translating kisspeptin and neurokinin B biology into new therapies for reproductive health

The reproductive neuropeptide kisspeptin has emerged as the master regulator of mammalian reproduction due to its key roles in the initiation of puberty and the control of fertility. Alongside the tachykinin neurokinin B and the endogenous opioid dynorphin, these peptides are central to the hormonal control of reproduction. Building on the expanding body of experimental animal models, interest has flourished with human studies revealing that kisspeptin administration stimulates physiological reproductive hormone secretion in both healthy men and women, as well as patients with common reproductive disorders. In addition, emerging therapeutic roles based on neurokinin B for the management of menopausal flushing, endometriosis and uterine fibroids are increasingly recognised. In this review, we focus on kisspeptin and neurokinin B and their potential application as novel clinical strategies for the management of reproductive disorders

Assessing hypothalamic pituitary gonadal function in reproductive disorders

Reproductive conditions secondary to disorders of the hypothalamic–pituitary–gonadal (HPG) axis are common and are associated with important health implications and considerable psychosocial impact. Basal and dynamic tests enable interrogation of individual components of the HPG axis, facilitating diagnosis and understanding of the pathophysiology of reproductive disorders. Onset of puberty is controlled by hypothalamic gonadotrophin-releasing hormone (GnRH) neuronal function. To date, a dynamic test of hypothalamic function is not yet available. Therefore, accurate differentiation of pubertal disorders such as constitutional delay of growth and puberty (CDGP) and congenital hypogonadotrophic hypogonadism (CHH) as causes of delayed puberty is challenging due to similar clinical presentations and hormonal profiles. Likewise, although the two commonest reproductive disorders in women, polycystic ovary syndrome (PCOS) and functional hypothalamic amenorrhoea (FHA) have disparate hypothalamic function, oligo/amenorrhoea frequently poses a diagnostic conundrum owing to the overlap in the criteria used to define both conditions. This review aims to describe pubertal and reproductive disorders secondary to pathologies affecting the HPG axis. Challenges encountered in clinical practice in differentiating pubertal and reproductive conditions are reviewed in conjunction with the utility of baseline and dynamic endocrine tests to interrogate specific components of the HPG axis. We also highlight putative hypothalamic, pituitary, and gonadal markers in development that could improve the diagnosis of patients presenting with disorders of puberty or reproduction

A systematic review of randomised controlled trials investigating the efficacy and safety of testosterone therapy for female sexual dysfunction in postmenopausal women

The clinical sequelae of oestrogen deficiency during menopause are undoubted. However, the pathophysiological role of testosterone during the menopause is less clear. Several randomised, placebo-controlled clinical trials suggest that testosterone therapy improves sexual function in post-menopausal women. Some studies suggest that testosterone therapy has additional effects which include increased bone mineral density and decreased serum high density lipoprotein (HDL) cholesterol. Furthermore, the long-term safety profile of testosterone therapy in post-menopausal women is not clear. This article will provide a concise and critical summary of the literature, to guide clinicians treating post-menopausal women. This article is protected by copyright. All rights reserved

Effects of distinct Polycystic Ovary Syndrome phenotypes on bone health

Polycystic Ovary Syndrome (PCOS) is a highly prevalent and heterogenous endocrinopathy affecting 5-18% of women. Although its cardinal features include androgen excess, ovulatory dysfunction, and/or polycystic ovarian morphology, women often display related metabolic manifestations, including hyperinsulinaemia, insulin resistance, and obesity. Emerging data reveal that the hormonal alterations associated with PCOS also impact bone metabolism. However, inconsistent evidence exists as to whether PCOS is a bone-protective or bone-hindering disorder with an accumulating body of clinical data indicating that hyperandrogenism, hyperinsulinaemia, insulin resistance, and obesity may have a relative protective influence on bone, whereas chronic low-grade inflammation and vitamin D deficiency may adversely affect bone health. Herein, we provide a comprehensive assessment of the endocrine and metabolic manifestations associated with PCOS and their relative effects on bone metabolism. We focus principally on clinical studies in women investigating their contribution to the alterations in bone turnover markers, bone mineral density, and ultimately fracture risk in PCOS. A thorough understanding in this regard will indicate whether women with PCOS require enhanced surveillance of bone health in routine clinical practice

Investigating the KNDy hypothesis in humans by co-administration of kisspeptin, neurokinin B and naltrexone in men

Context: A subpopulation of hypothalamic neurons co-localise three neuropeptides namely kisspeptin, neurokinin B (NKB) and dynorphin collectively termed KNDy neurons. Animal studies suggest they interact to affect pulsatile GnRH release (KNDy hypothesis); kisspeptin stimulates, NKB modulates and dynorphin (an opioid) inhibits. Objective: To investigate the KNDy hypothesis in humans, we assessed for the first time the effects of co-administration of kisspeptin-54, NKB and an opioid receptor antagonist, naltrexone on LH pulsatility (surrogate marker for GnRH pulsatility) and gonadotropin release. Design, setting and participants: Ethically approved prospective, single-blinded placebo-controlled study. Healthy male volunteers (n=5/group) attended our research facility for 8 study visits. Intervention and main outcome measure: After 1h baseline blood sampling, participants received a different intervention at each visit: oral 50mg naltrexone (NAL), 8h intravenous infusions of vehicle, 2.56nmol/kg/h NKB (NKB), 0.1nmol/kg/h kissspeptin-54 (KP) alone and in combination. Frequent blood sampling to measure plasma gonadotropins and sex steroids was conducted and LH pulsatility was determined using blinded deconvolution analysis. Results: All kisspeptin and naltrexone containing groups potently increased LH and LH pulsatility (p<0.001 vs vehicle). NKB alone did not affect gonadotropins. NKB+KP had significantly lower increases in gonadotropins compared with kisspeptin alone (p<0.01). NAL+KP was the only group to significantly increase LH pulse amplitude (p<0.001 vs vehicle). Conclusions: Our results suggest significant interactions between the KNDy neuropeptides on LH pulsatility and gonadotropin release in humans. This has important implications for improving our understanding of GnRH pulse generation in humans