Julia Prague

Background Neurokinin 3 receptor (NK3R) antagonism is a promising novel treatment for menopausal flashes. However, to avoid adverse hormonal effects it is clinically important to first confirm whether gonadotropin and estradiol concentrations change as a result of their administration. Methods Single-center, randomized, double-blind, placebo-controlled, crossover trial of an oral NK3R antagonist (MLE4901) in 28 women aged 40-62yrs, experiencing >7 hot flashes/24h; some bothersome or severe (Clinicaltrials.gov NCT02668185). Weekly serum gonadotropins and estradiol levels were measured using commercially available automated immunoassays a priori. Serum estradiol was also measured post hoc using a highly sensitive direct assay by liquid chromatography tandem mass spectrometry. Hormone levels were compared by the paired sample t-tests or by the Wilcoxon matched-pairs signed rank test, as appropriate for the distribution of the data. Results Mean (SD) serum FSH concentration was not s...

Reproduction and metabolism are inter-dependent, but our understanding of the hormones which regulate both these systems is currently limited. Kisspeptin has well-established crucial roles in mammalian reproduction, and recent reports in animal models suggest kisspeptin may have additional roles in metabolism. However, the effects of kisspeptin on metabolism in humans are as yet unknown. To investigate the effect of kisspeptin on glucose-stimulated insulin secretion and appetite in humans. In 15 healthy men (age 25.2±1.1years; BMI 22.3±0.5kg.m ), we compared the effects of 1nmol.kg .hr kisspeptin versus vehicle administration on glucose-stimulated insulin secretion, metabolites, gut hormones, appetite and food intake. In addition, we assessed the effect of kisspeptin on glucose-stimulated insulin secretion in vitro in human pancreatic islets and a human β-cell line (EndoC-βH1 cells). Kisspeptin administration to healthy men enhanced insulin secretion following an intravenous glucose...

Seventy percent of postmenopausal women experience vasomotor symptoms, which can be highly disruptive and persist for years. Hormone therapy and other treatments have variable efficacy and/or side effects. Neurokinin B signaling increases in response to estrogen deficiency and has been implicated in hot flash (HF) etiology. We recently reported that a neurokinin 3 receptor (NK3R) antagonist reduces HF in postmenopausal women after 4 weeks of treatment. In this article we report novel data from that study, which shows the detailed time course of this effect. Randomized, double-blind, placebo-controlled, single-center, crossover trial of an oral NK3R antagonist (MLE4901) for vasomotor symptoms in women aged 40 to 62 years, experiencing ≥7 HF/24 hours some of which were reported as bothersome or severe (Clinicaltrials.gov NCT02668185). Thirty-seven women were randomized and included in an intention-to-treat analysis. To ascertain the therapeutic profile of MLE4901, a post hoc time cour...

Hot flushes affect 70% of menopausal women and often severely impact physical, psychosocial, sexual, and overall wellbeing. Hormone replacement therapy is effective but is not without risk. Neurokinin B signalling is increased in menopausal women, and has been implicated as an important mediator of hot flushes. This phase 2, randomised, double-blind, placebo-controlled, single-centre, crossover trial assessed the effectiveness of an oral neurokinin 3 receptor antagonist (MLE4901) on menopausal hot flushes. Eligible participants were healthy women aged 40-62 years, having seven or more hot flushes in every 24 h of which some were reported as being severe or bothersome, who had not had a menstrual period for at least 12 months, and who had not been taking any medication shown to improve menopausal flushes in the preceding 8 weeks. Participants received 4 weeks of MLE4901 (40 mg, orally, twice daily) and placebo (orally, twice daily) in random order separated by a 2 week washout period...

Kisspeptin stimulates hypothalamic GnRH secretion resulting in gonadotrophin release and has potential as a future therapeutic. Chronic subcutaneous infusion of kisspeptin via a pump (similar to an insulin pump) may provide an alternative route of administration in the future. We investigated for the first time in humans, the gonadotrophin response to subcutaneous (SC) infusions of kisspeptin-54 in healthy women. Women are markedly more responsive to exogenous kisspeptin in the late follicular phase pre-ovulation when oestradiol levels are naturally high. Therefore we further investigated whether there was a correlation between baseline oestradiol levels and LH response to kisspeptin. A prospective, single-blinded placebo-controlled study. Healthy women (n=4) received an 8 hour SC infusion of kisspeptin-54 0.1, 0.3 or 1.0nmol/kg/h or saline in the early follicular phase of 4 separate menstrual cycles. Gonadotrophins and oestradiol were measured every 10 minutes during the infusions. SC infusion of kisspeptin-54 increased LH and FSH. The LH response to SC infusion of kisspeptin-54 (0.3 and 1.0nmol/kg/h) positively correlated with baseline oestradiol levels (p<0.001). Further statistical analyses showed that in the 1.0nmol/kg/h group a 100pmol/L rise in baseline oestradiol was associated with a 1.0 IU/L increase in LH. Kisspeptin administered via a SC infusion could be a viable future therapeutic route of administration for patients with infertility. Baseline oestradiol levels may be an important determinant of the gonadotropin response to kisspeptin treatment in women and should be taken into consideration when evaluating gonadotrophin response. This article is protected by copyright. All rights reserved.

Over the last ten years, kisspeptins - peptide products of varying lengths encoded by the KISS1 gene - have been found to be key regulators of normal reproductive function throughout life in animals and humans. By activating the kisspeptin receptor (previously known as orphan G protein-coupled receptor 54 (GPR54)) they elicit an effect on the central gonadotrophin releasing hormone (GnRH) neurons. Administration of kisspeptin by either the subcutaneous or intravenous route potently stimulates endogenous gonadotrophin hormone release in healthy men and women and animals. Kisspeptin also stimulates endogenous release of gonadotrophins in subfertile as well as healthy volunteers, and therefore kisspeptin has potential as a novel therapeutic agent in reproductive disorders. Further human studies have shown that chronic, high dose administration of kisspeptin causes desensitization with rapid subsequent suppression of the hypothalamic-pituitary-gonadal axis, and therefore high dose long-...

Over the last ten years, kisspeptins - peptide products of varying lengths encoded by the KISS1 gene - have been found to be key regulators of normal reproductive function throughout life in animals and humans. By activating the kisspeptin receptor (previously known as orphan G protein-coupled receptor 54 (GPR54)) they elicit an effect on the central gonadotrophin releasing hormone (GnRH) neurons. Administration of kisspeptin by either the subcutaneous or intravenous route potently stimulates endogenous gonadotrophin hormone release in healthy men and women and animals. Kisspeptin also stimulates endogenous release of gonadotrophins in subfertile as well as healthy volunteers, and therefore kisspeptin has potential as a novel therapeutic agent in reproductive disorders. Further human studies have shown that chronic, high dose administration of kisspeptin causes desensitization with rapid subsequent suppression of the hypothalamic-pituitary-gonadal axis, and therefore high dose long-acting analogues may have a clinical role in treating sex-hormone dependent malignancies. By further elucidating the intricacies and mechanisms of the kisspeptin signalling system, and the tissues it acts on during different phases of the reproductive timeline (including during puberty, fertility, pregnancy and menopause), pharmacologic analogues could become clinically useful. © 2015 S. Karger AG, Basel.

In Vitro Fertilization (IVF) treatment is an effective therapy for infertility, but can result in the potentially life-threatening complication 'ovarian hyperstimulation syndrome' (OHSS). To investigate whether kisspeptin-54 can be used to effectively and safely trigger oocyte maturation in women undergoing IVF treatment at high risk of developing OHSS. Phase 2 multi-dose open label randomized clinical trial carried out during 2013-2014. Hammersmith Hospital IVF unit, London, UK. Sixty women at high risk of developing OHSS. Following a standard recombinant FSH/GnRH antagonist protocol, patients were randomized to receive a single injection of kisspeptin-54 to trigger oocyte maturation using an adaptive design for dose allocation (3.2nmol/kg, n=5; 6.4nmol/kg, n=20; 9.6nmol/kg, n=15; 12.8nmol/kg, n=20). Oocytes were retrieved 36hrs after kisspeptin-54 administration, assessed for maturation, and fertilized by intra-cytoplasmic sperm injection (ICSI) with subsequent transfer of...