Alexander Comninos

The Effects of Kisspeptin-10 on Reproductive Hormone Release Show Sexual Dimorphism in Humans

BACKGROUND Kisspeptin peptides are critical in human reproductive physiology and are potential therapies for infertility. Kisspeptin-10 stimulates gonadotropin release in both male and female rodents. However, few studies have investigated the effects of kisspeptin-10 on gonadotropin release in humans, and none have investigated the effect in women. If kisspeptin is to be useful for treating reproductive disease, its effects in both men and women must be established. AIM To compare the effects of kisspeptin-10 administration on reproductive hormone release in healthy men and women. METHODS Intravenous bolus kisspeptin-10 was administered to men and women (n = 4-5 per group). Subcutaneous bolus and i.v. infusion of kisspeptin-10 was also administered to female women (n = 4-5 per group). Circulating reproductive hormones were measured. RESULTS In healthy men, serum LH and FSH were elevated after i.v. bolus kisspeptin-10, at doses as low as 0.3 and 1.0 nmol/kg, respectively. In healthy women during the follicular phase of the menstrual cycle, no alterations in serum gonadotropins were observed after i.v. bolus, s.c. bolus, or i.v. infusion of kisspeptin-10 at maximal doses of 10 nmol/kg, 32 nmol/kg, and 720 pmol/kg/min, respectively. In women during the preovulatory phase, serum LH and FSH were elevated after i.v. bolus kisspeptin-10 (10 nmol/kg). CONCLUSION Kisspeptin-10 stimulates gonadotropin release in men as well as women during the preovulatory phase of menstrual cycle but fails to stimulate gonadotropin release in women during the follicular phase. The sexual dimorphism of the responsiveness of healthy men and women to kisspeptin-10 administration has important clinical implications for the potential of kisspeptin-10 to treat disorders of reproduction.

The relationship between gut and adipose hormones, and reproduction

BACKGROUND Reproductive function is tightly regulated by nutritional status. Indeed, it has been well described that undernutrition or obesity can lead to subfertility or infertility in humans. The common regulatory pathways which control energy homeostasis and reproductive function have, to date, been poorly understood due to limited studies or inconclusive data. However, gut hormones and adipose tissue hormones have recently emerged as potential regulators of both energy homeostasis and reproductive function. METHODS A PubMed search was performed using keywords related to gut and adipose hormones and associated with keywords related to reproduction. RESULTS Currently available evidence that gut (ghrelin, obestatin, insulin, peptide YY, glucagon-like peptide-1, glucose-dependent insulinotropic peptide, oxyntomodulin, cholecystokinin) and adipose hormones (leptin, adiponectin, resistin, omentin, chemerin) interact with the reproductive axis is presented. The extent, site and direction of their effects on the reproductive axis are variable and also vary depending on species, sex and pubertal stage. CONCLUSIONS Gut and adipose hormones interact with the reproductive axis as well as with each other. While leptin and insulin have stimulatory effects and ghrelin has inhibitory effects on hypothalamic GnRH secretion, there is increasing evidence for their roles in other sites of the reproductive axis as well as evidence for the roles of other gut and adipose hormones in the complex interplay between nutrition and reproduction. As our understanding improves, so will our ability to identify and design novel therapeutic options for reproductive disorders and accompanying metabolic disorders.

Kisspeptin-54 triggers egg maturation in women undergoing in vitro fertilization

BACKGROUND Patients with mutations that inactivate kisspeptin signaling are infertile. Kisspeptin-54, the major circulating isoform of kisspeptin in humans, potently stimulates reproductive hormone secretion in humans. Animal studies suggest that kisspeptin is involved in generation of the luteinizing hormone surge, which is required for ovulation; therefore, we hypothesized that kisspeptin-54 could be used to trigger egg maturation in women undergoing in vitro fertilization therapy. METHODS Following superovulation with recombinant follicle-stimulating hormone and administration of gonadotropin-releasing hormone antagonist to prevent premature ovulation, 53 women were administered a single subcutaneous injection of kisspeptin-54 (1.6 nmol/kg, n = 2; 3.2 nmol/kg, n = 3; 6.4 nmol/kg, n = 24; 12.8 nmol/kg, n = 24) to induce a luteinizing hormone surge and egg maturation. Eggs were retrieved transvaginally 36 hours after kisspeptin injection, assessed for maturation (primary outcome), and fertilized by intracytoplasmic sperm injection with subsequent transfer of one or two embryos. RESULTS Egg maturation was observed in response to each tested dose of kisspeptin-54, and the mean number of mature eggs per patient generally increased in a dose-dependent manner. Fertilization of eggs and transfer of embryos to the uterus occurred in 92% (49/53) of kisspeptin-54-treated patients. Biochemical and clinical pregnancy rates were 40% (21/53) and 23% (12/53), respectively. CONCLUSION This study demonstrates that a single injection of kisspeptin-54 can induce egg maturation in women with subfertility undergoing in vitro fertilization therapy. Subsequent fertilization of eggs matured following kisspeptin-54 administration and transfer of resulting embryos can lead to successful human pregnancy. TRIAL REGISTRATION ClinicalTrials.gov NCT01667406.

Increasing LH Pulsatility in Women With Hypothalamic Amenorrhoea Using Intravenous Infusion of Kisspeptin-54

Background: Hypothalamic amenorrhea (HA) is the one of the most common causes of period loss in women of reproductive age and is associated with deficient LH pulsatility. High-dose kisspeptin-54 acutely stimulates LH secretion in women with HA, but chronic administration causes desensitization. GnRH has paradoxical effects on reproductive activity; we therefore hypothesized that a dose-dependent therapeutic window exists within which kisspeptin treatment restores the GnRH/LH pulsatility in women with HA. Aim: The aim of the study was to determine whether constant iv infusion of kisspeptin-54 temporarily increases pulsatile LH secretion in women with HA. Methods: Five patients with HA each underwent six assessments of LH pulsatility. Single-blinded continuous iv infusion of vehicle or kisspeptin-54 (0.01, 0.03, 0.10, 0.30, or 1.00 nmol/kg/h) was administered. The LH pulses were detected using blinded deconvolution. Results: Kisspeptin increased LH pulsatility in all patients with HA, with peak responses observed at different doses in each patient. The mean peak number of pulses during infusion of kisspeptin-54 was 3-fold higher when compared with vehicle (number of LH pulses per 8 h: 1.6 ± 0.4, vehicle; 5.0 ± 0.5, kisspeptin-54, P < .01 vs vehicle). The mean peak LH pulse secretory mass during kisspeptin-54 was 6-fold higher when compared with vehicle (LH pulse secretory mass in international units per liter: 3.92 ± 2.31, vehicle; 23.44 ± 12.59, kisspeptin-54; P < .05 vs vehicle). Conclusions: Kisspeptin-54 infusion temporarily increases LH pulsatility in women with HA. Furthermore, we have determined the dose range within which kisspeptin-54 treatment increases basal and pulsatile LH secretion in women with HA. This work provides a basis for studying the potential of kisspeptin-based therapies to treat women with HA.

Efficacy of Kisspeptin-54 to Trigger Oocyte Maturation in Women at High Risk of Ovarian Hyperstimulation Syndrome (OHSS) During In Vitro Fertilization (IVF) Therapy.

Context: In vitro fertilization (IVF) treatment is an effective therapy for infertility, but can result in the potentially life-threatening complication, ovarian hyperstimulation syndrome (OHSS). Objective: This study aimed 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. Setting and Design: This was a phase 2, multi-dose, open-label, randomized clinical trial of 60 women at high risk of developing OHSS carried out during 2013–2014 at Hammersmith Hospital IVF unit, London, United Kingdom. Intervention: Following a standard recombinant FSH/GnRH antagonist protocol, patients were randomly assigned to receive a single injection of kisspeptin-54 to trigger oocyte maturation using an adaptive design for dose allocation (3.2 nmol/kg, n = 5; 6.4 nmol/kg, n = 20; 9.6 nmol/kg, n = 15; 12.8 nmol/kg, n = 20). Oocytes were retrieved 36 h after kisspeptin-54 administration, assessed for maturation, and fertilized by intracytoplasmic sperm injection with subsequent transfer of one or two embryos. Women were routinely screened for the development of OHSS. Main Outcome Measure: Oocyte maturation was measured by oocyte yield (percentage of mature oocytes retrieved from follicles ≥ 14 mm on ultrasound). Secondary outcomes include rates of OHSS and pregnancy. Results: Oocyte maturation occurred in 95% of women. Highest oocyte yield (121%) was observed following 12.8 nmol/kg kisspeptin-54, which was +69% (confidence interval, −16–153%) greater than following 3.2 nmol/kg. At all doses of kisspeptin-54, biochemical pregnancy, clinical pregnancy, and live birth rates per transfer (n = 51) were 63, 53, and 45%, respectively. Highest pregnancy rates were observed following 9.6 nmol/kg kisspeptin-54 (85, 77, and 62%, respectively). No woman developed moderate, severe, or critical OHSS. Conclusion: Kisspeptin-54 is a promising approach to effectively and safely trigger oocyte maturation in women undergoing IVF treatment at high risk of developing OHSS.

Neurokinin 3 receptor antagonism as a novel treatment for menopausal hot flushes: A phase 2, randomised, double-blind, placebo-controlled trial

Summary Background 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. Methods 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. Randomisation was completed by a central computer, and participants were allocated to treatment number in numerical order. The primary outcome was the total number of hot flushes during the final week of both treatment periods. Analyses were by intention to treat and per protocol using generalised linear mixed models and standard crossover analysis. All analyses were prespecified in the study protocol. The trial is registered at ClinicalTrials.gov, number NCT02668185. Findings 68 women were screened between Feb 3 and Oct 10, 2016, of which 37 were randomly assigned and included in an intention-to-treat analysis. 28 participants completed the trial and were included in a per-protocol analysis. MLE4901 significantly reduced the total weekly number of hot flushes by 45 percentage points (95% CI 22–67) compared with the placebo (intention-to-treat adjusted means: placebo 49·01 [95% CI 40·81–58·56] vs MLE4901 19·35 [15·99–23·42]; adjusted estimate of difference 29·66 [17·39–42·87], p<0·0001). Treatment was well tolerated. Three participants developed a transaminase rise (alanine aminotransferase 4·5–5·9 times the upper limit of normal) with a normal bilirubin 28 days after starting MLE4901, which normalised within 90 days. Interpretation Treatment with a neurokinin 3 receptor antagonist (MLE4901) could be practice changing as it safely and effectively relieves hot flush symptoms without the need for oestrogen exposure. Larger scale studies of longer duration are now indicated. Funding UK Medical Research Council and National Institute for Health Research.

Neurokinin B Administration Induces Hot Flushes in Women

Neurokinin B (NKB) is a hypothalamic neuropeptide binding preferentially to the neurokinin 3 receptor. Expression of the gene encoding NKB is elevated in postmenopausal women. Furthermore, rodent studies suggest that NKB signalling may mediate menopausal hot flushes. However, the effects of NKB administration on hot flushes have not been investigated in humans. To address this, we performed a randomised, double-blinded, placebo-controlled, 2-way cross-over study. Ten healthy women were admitted to a temperature and humidity-controlled research unit. Participants received 30 minute intravenous infusions of NKB and vehicle in random order. Symptoms, heart rate, blood pressure, sweating and skin temperature were compared between NKB and vehicle in a double-blinded manner. Eight of ten participants experienced flushing during NKB infusion with none experiencing flushing during vehicle infusion (P = 0.0007). Significant elevations in heart rate (P = 0.0106 vs. pre-symptoms), and skin temperature measured using skin probe (P = 0.0258 vs. pre-symptoms) and thermal imaging (P = 0.0491 vs. pre-symptoms) characteristic of menopausal flushing were observed during hot flush episodes. Our findings provide evidence that NKB administration can cause hot flushes in women. Further studies are required to determine if pharmacological blockade of NKB signalling could inhibit hot flushes during the menopause and during treatment for sex-steroid dependent cancers.

A single injection of kisspeptin-54 temporarily increases luteinizing hormone pulsatility in healthy women.

Kisspeptin is a novel hypothalamic peptide which stimulates endogenous gonadotrophin releasing hormone (GnRH) secretion. A single subcutaneous bolus injection of kisspeptin‐54 increases circulating luteinizing hormone (LH) levels in women, but its acute effects on LH pulsatility are not known.

The effects of long-term growth hormone and insulin-like growth factor-1 exposure on the development of cardiovascular, cerebrovascular and metabolic co-morbidities in treated patients with acromegaly.

Background  Acromegaly is characterized by the hypersecretion of growth hormone (GH) and insulin‐like growth factor‐1 (IGF‐1). This leads to an increased cardiovascular, cerebrovascular and metabolic morbidity resulting in excess mortality. There is controversy over which biomarker, GH or IGF‐1, better predicts this increased morbidity and mortality. The relationship between the cumulative exposure to GH and IGF‐1 with co‐morbidities in acromegaly has not previously been reported.

Kisspeptin modulates sexual and emotional brain processing in humans

BACKGROUND. Sex, emotion, and reproduction are fundamental and tightly entwined aspects of human behavior. At a population level in humans, both the desire for sexual stimulation and the desire to bond with a partner are important precursors to reproduction. However, the relationships between these processes are incompletely understood. The limbic brain system has key roles in sexual and emotional behaviors, and is a likely candidate system for the integration of behavior with the hormonal reproductive axis. We investigated the effects of kisspeptin, a recently identified key reproductive hormone, on limbic brain activity and behavior. METHODS. Using a combination of functional neuroimaging and hormonal and psychometric analyses, we compared the effects of kisspeptin versus vehicle administration in 29 healthy heterosexual young men. RESULTS. We demonstrated that kisspeptin administration enhanced limbic brain activity specifically in response to sexual and couple-bonding stimuli. Furthermore, kisspeptin’s enhancement of limbic brain structures correlated with psychometric measures of reward, drive, mood, and sexual aversion, providing functional significance. In addition, kisspeptin administration attenuated negative mood. CONCLUSIONS. Collectively, our data provide evidence of an undescribed role for kisspeptin in integrating sexual and emotional brain processing with reproduction in humans. These results have important implications for our understanding of reproductive biology and are highly relevant to the current pharmacological development of kisspeptin as a potential therapeutic agent for patients with common disorders of reproductive function. FUNDING. National Institute for Health Research (NIHR), Wellcome Trust (Ref 080268), and the Medical Research Council (MRC).