The Emerging Therapeutic Potential of Kisspeptin and Neurokinin B.

Kisspeptin (KP) and neurokinin B (NKB) are neuropeptides that govern the reproductive endocrine axis through regulating hypothalamic gonadotropin-releasing hormone (GnRH) neuronal activity and pulsatile GnRH secretion. Their critical role in reproductive health was first identified after inactivating variants in genes encoding for KP or NKB signaling were shown to result in congenital hypogonadotropic hypogonadism and a failure of pubertal development. Over the past 2 decades since their discovery, a wealth of evidence from both basic and translational research has laid the foundation for potential therapeutic applications. Beyond KP's function in the hypothalamus, it is also expressed in the placenta, liver, pancreas, adipose tissue, bone, and limbic regions, giving rise to several avenues of research for use in the diagnosis and treatment of pregnancy, metabolic, liver, bone, and behavioral disorders. The role played by NKB in stimulating the hypothalamic thermoregulatory center to mediate menopausal hot flashes has led to the development of medications that antagonize its action as a novel nonsteroidal therapeutic agent for this indication. Furthermore, the ability of NKB antagonism to partially suppress (but not abolish) the reproductive endocrine axis has supported its potential use for the treatment of various reproductive disorders including polycystic ovary syndrome, uterine fibroids, and endometriosis. This review will provide a comprehensive up-to-date overview of the preclinical and clinical data that have paved the way for the development of diagnostic and therapeutic applications of KP and NKB.

New advances in menopause symptom management.

Vasomotor symptoms (VMS) are characteristic of menopause experienced by over 75% of postmenopausal women with significant health and socioeconomic implications. Although the average duration of symptoms is seven years, 10% of women experience symptoms for more than a decade. Although menopausal hormone therapy (MHT) remains an efficacious and cost-effective treatment, its use may not be suitable in all women, such as those at an increased risk of breast cancer or gynaecological malignancy. The neurokinin B (NKB) signaling pathway, together with its intricate connection to the median preoptic nucleus (MnPO), has been postulated to provide integrated reproductive and thermoregulatory responses, with a central role in mediating postmenopausal VMS. This review describes the physiological hypothalamo-pituitary-ovary (HPO) axis, and subsequently the neuroendocrine changes that occur with menopause using evidence derived from animal and human studies. Finally, data from the latest clinical trials using novel therapeutic agents that antagonise NKB signaling are reviewed.

Quantifying the variability in the assessment of reproductive hormone levels.

OBJECTIVE: To quantify how representative a single measure of reproductive hormone level is of the daily hormonal profile using data from detailed hormonal sampling in the saline placebo-treated arm conducted over several hours. DESIGN: Retrospective analysis of data from previous interventional research studies evaluating reproductive hormones. SETTING: Clinical Research Facility at a tertiary reproductive endocrinology centre at Imperial College Hospital NHS Foundation Trust. PATIENTS: Overall, 266 individuals, including healthy men and women (n = 142) and those with reproductive disorders and states (n = 124 [11 with functional hypothalamic amenorrhoea, 6 with polycystic ovary syndrome, 62 women and 32 men with hypoactive sexual desire disorder, and 13 postmenopausal women]), were included in the analysis. INTERVENTIONS: Data from 266 individuals who had undergone detailed hormonal sampling in the saline placebo-treated arms of previous research studies was used to quantify the variability in reproductive hormones because of pulsatile secretion, diurnal variation, and feeding using coefficient of variation (CV) and entropy. MAIN OUTCOME MEASURES: The ability of a single measure of reproductive hormone level to quantify the variability in reproductive hormone levels because of pulsatile secretion, diurnal variation, and nutrient intake. RESULTS: The initial morning value of reproductive hormone levels was typically higher than the mean value throughout the day (percentage decrease from initial morning measure to daily mean: luteinizing hormone level 18.4%, follicle-stimulating hormone level 9.7%, testosterone level 9.2%, and estradiol level 2.1%). Luteinizing hormone level was the most variable (CV 28%), followed by sex-steroid hormone levels (testosterone level 12% and estradiol level 13%), whereas follicle-stimulating hormone level was the least variable reproductive hormone (CV 8%). In healthy men, testosterone levels fell between 9:00 am and 5:00 pm by 14.9% (95% confidence interval 4.2, 25.5%), although morning levels correlated with (and could be predicted from) late afternoon levels in the same individual (r2 = 0.53, P<.0001). Testosterone levels were reduced more after a mixed meal (by 34.3%) than during ad libitum feeding (9.5%), after an oral glucose load (6.0%), or an intravenous glucose load (7.4%). CONCLUSION: Quantification of the variability of a single measure of reproductive hormone levels informs the reliability of reproductive hormone assessment.

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.

Current pharmacotherapy and future directions for neuroendocrine causes of female infertility.

INTRODUCTION: Infertility is recognized as a major global health issue, often associated with significant psychological distress for affected couples. Causes of female infertility include endocrine conditions leading to oligo/anovulation, in addition to structural causes such as tubal, uterine, or peritoneal disorders. Pharmacological treatments, targeting pathways in the hypothalamic-pituitary-ovarian axis, can improve rates of ovulation, conception, pregnancy, and birth. Some existing therapeutic options are hindered by limited efficacy or by a non-physiological mechanism, which can risk excessive stimulation and treatment-related adverse effects. Therefore, there is a continued need for novel therapies to improve care for patients suffering with infertility. AREAS COVERED: In this review, the authors focus on endocrine causes of oligo/anovulation in women and on advances in assisted reproductive technology. Current pharmacological treatments and putative future therapeutic avenues in development to aid fertility in women are outlined. EXPERT OPINION: A deeper understanding of the reproductive neuroendocrine network governing hypothalamic gonadotropin-releasing hormone release can offer novel therapeutic targets for the treatment of female subfertility, leading to improved clinical outcomes, less invasive routes of administration, and decreased treatment-related side-effects. The ultimate aim of development in female subfertility is to offer therapeutic interventions that are effective, reproducible, associated with minimal risks, and have an acceptable route of administration.

Insulin-like peptide 3 (INSL3) in congenital hypogonadotrophic hypogonadism (CHH) in boys with delayed puberty and adult men.

Background: Delayed puberty in males is almost invariably associated with constitutional delay of growth and puberty (CDGP) or congenital hypogonadotrophic hypogonadism (CHH). Establishing the cause at presentation is challenging, with "red flag" features of CHH commonly overlooked. Thus, several markers have been evaluated in both the basal state or after stimulation e.g. with gonadotrophin releasing hormone agonist (GnRHa).Insulin-like peptide 3 (INSL3) is a constitutive secretory product of Leydig cells and thus a possible candidate marker, but there have been limited data examining its role in distinguishing CDGP from CHH. In this manuscript, we assess INSL3 and inhibin B (INB) in two cohorts: 1. Adolescent boys with delayed puberty due to CDGP or CHH and 2. Adult men, both eugonadal and having CHH. Materials and methods: Retrospective cohort studies of 60 boys with CDGP or CHH, as well as 44 adult men who were either eugonadal or had CHH, in whom INSL3, INB, testosterone and gonadotrophins were measured. Cohort 1: Boys with delayed puberty aged 13-17 years (51 with CDGP and 9 with CHH) who had GnRHa stimulation (subcutaneous triptorelin 100mcg), previously reported with respect to INB. Cohort 2: Adult cohort of 44 men (22 eugonadal men and 22 men with CHH), previously reported with respect to gonadotrophin responses to kisspeptin-54. Results: Median INSL3 was higher in boys with CDGP than CHH (0.35 vs 0.15 ng/ml; p=0.0002). Similarly, in adult men, median INSL3 was higher in eugonadal men than CHH (1.08 vs 0.05 ng/ml; p<0.0001). However, INSL3 more accurately differentiated CHH in adult men than in boys with delayed puberty (auROC with 95% CI in adult men: 100%, 100-100%; boys with delayed puberty: 86.7%, 77.7-95.7%).Median INB was higher in boys with CDGP than CHH (182 vs 59 pg/ml; p<0.0001). Likewise, in adult men, median INB was higher in eugonadal men than CHH (170 vs 36.5 pg/ml; p<0.0001). INB performed better than INSL3 in differentiating CHH in boys with delayed puberty (auROC 98.5%, 95.9-100%), than in adult men (auROC 93.9%, 87.2-100%). Conclusion: INSL3 better identifies CHH in adult men, whereas INB better identifies CHH in boys with delayed puberty.

Kisspeptin-neuron control of LH pulsatility and ovulation.

Feedback from oestradiol (E2) plays a critical role in the regulation of major events in the physiological menstrual cycle including the release of gonadotrophins to stimulate follicular growth, and the mid-cycle luteinising hormone (LH) surge that leads to ovulation. E2 predominantly exerts its action via oestrogen receptor-alpha (ERα), however, as gonadotrophin releasing hormone (GnRH) neurons lack ERα, E2-feedback is posited to be indirectly mediated via upstream neurons. Kisspeptin (KP) is a neuropeptide expressed in hypothalamic KP-neurons that control GnRH secretion and plays a key role in the central mechanism regulating the hypothalamic-pituitary-gonadal (HPG) axis. In the rodent arcuate (ARC) nucleus, KP is co-expressed with Neurokinin B and Dynorphin; and thus, these neurons are termed 'Kisspeptin-Neurokinin B-Dynorphin' (KNDy) neurons. ARC KP-neurons function as the 'GnRH pulse generator' to regulate GnRH pulsatility, as well as mediating negative feedback from E2. A second KP neuronal population is present in the rostral periventricular area of the third ventricle (RP3V), which includes anteroventral periventricular (AVPV) nucleus and preoptic area neurons. These RP3V KP-neurons mediate positive feedback to induce the mid-cycle luteinising hormone (LH) surge and subsequent ovulation. Here, we describe the role of KP-neurons in these two regions in mediating this differential feedback from oestrogens. We conclude by considering reproductive diseases for which exploitation of these mechanisms could yield future therapies.

Use of kisspeptin to trigger oocyte maturation during in vitro fertilisation (IVF) treatment.

Infertility is a major global health issue and is associated with significant psychological distress for afflicted couples. In vitro fertilisation (IVF) utilises supra-physiological doses of stimulatory hormones to induce the growth of multiple ovarian follicles to enable surgical retrieval of several oocytes for subsequent fertilisation and implantation into the maternal endometrium. The supra-physiological degree of ovarian stimulation can lead to potential risks during IVF treatment, including ovarian hyperstimulation syndrome (OHSS) and multiple pregnancy. The choice of oocyte maturation trigger, such as human chorionic gonadotrophin (hCG) or gonadotrophin releasing hormone agonist (GnRHa), can impact both the efficacy of IVF treatment with a bearing on luteal phase hormonal dynamics and thus the degree of luteal phase support required to maintain optimal pregnancy rates, as well as on safety of treatment with particular respect to the risk of OHSS. Kisspeptin regulates gonadotrophin releasing hormone (GnRH) release and is therefore a key regulator of the hypothalamo-pituitary-gonadal (HPG) axis. Kisspeptin has been shown to be requisite for the occurrence of the physiological ovulatory luteinising hormone (LH) surge. In this review, we discuss the potential use of kisspeptin as a novel trigger of oocyte maturation.

Hypertriglyceridaemia in pregnancy: an unexpected diagnosis and its management.

A woman in her 30s with gestational diabetes presented at 36 weeks' gestation with reduced fetal movements and diminishing insulin requirements. In view of her gestation, she was induced and incidentally found to have profound hyponatraemia. Further biochemical investigations confirmed severe hypertriglyceridaemia and hypercholesterolaemia. This raises the possibility of secondary causes such as familial dysbetalipoproteinemia and polygenetic hypertriglyceridaemia. She was successfully managed by aggressive dietary modification. This involved a supervised fast followed by a fat-free diet. A fenofibrate was proposed but declined due to our patient's wish to breastfeed. Management required considerable input from the multidisciplinary team. Treatment options to consider are aggressive dietary restriction of fat or the addition of a cholesterol-lowering medication, such as a fibrate. In refractory cases, a supervised fast may be required or, in cases where complications have arisen, apheresis. The patient and her baby made a good recovery with no long-lasting health implications.

Combination therapy for systemic sclerosis-associated pneumatosis intestinalis.

We present a case of a patient with pneumatosis intestinalis and pneumoperitoneum secondary to gastrointestinal systemic sclerosis, who presented following recurrent accident and emergency attendances with abdominal pain. Pneumatosis intestinalis is a rare complication of systemic sclerosis; management approaches focus largely on exclusion of life-threatening surgical pathologies and subsequent symptom control. To date, there are still no established gold-standard treatment strategy and no large-scale trial data to support a specific management strategy. We describe a case of successful medical management with a combination of antimicrobial, elemental diet and high-flow inhalation oxygen therapy, with supporting evidence of CT image confirming resolution. This case therefore contributes to the literature, being the first to report both symptomatic and radiological improvement following combination therapy without the need for surgical intervention.

Determining Predictors for Intra-abdominal Septic Complications Following Ileocolonic Resection for Crohn's Disease-Considerations in Pre-operative and Peri-operative Optimisation Techniques to Improve Outcome.

BACKGROUND AND AIMS: Intra-abdominal septic complications [IASC] following ileocolonic resection for Crohn's disease are common. Determining risk factors for these complications can aid pre-operative and peri-operative strategies to reduced morbidity. This study aims to determine the incidence and predictors of intra-abdominal septic complications following ileocolonic resection for Crohn's disease. METHODS: A single-centre, retrospective study was conducted. The clinical case notes of patients with histopathologically proven Crohn's disease, who underwent an ileocolonic resection as a one-stage or two-stage procedure, were reviewed. The primary endpoint was the formation of intra-abdominal septic complications within a 30-day post-operative time frame. RESULTS: Overall 163 patients underwent 175 ileocolonic procedures. Post-operative intra-abdominal septic complications were demonstrated in 9% [13/142] of one-stage procedures and 12% [4/33] of two-stage procedures [p = 0.2]. Post-operative IASCs following a one-stage procedure demonstrated associations with smokers [p = 0.004], intraoperative abdominal sepsis [p = 0.005], concomitant upper gastrointestinal Crohn's [p = 0.015], the presence of peri-operative anaemia [p = 0.037], hypoalbuminaemia [< 25g/l] [p = 0.04], and histologically involved margins [p = 0.001]. Multivariate analysis demonstrated the presence of intra-abdominal sepsis (hazard ratio [HR] 8.6, 95% confidence interval [CI]: 1.2 60.1] and the use of peri-operative biologicals [HR 24.6, 95% CI: 2.0-298] as independent predictors of post-operative intra-abdominal septic complications. CONCLUSIONS: This study highlights specific variables that may be contributory to poor outcome. These findings may be important when optimising patients for surgery, as well as planning an appropriate operative strategy. Further prospective studies and a larger sample size are required to validate these findings.