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SummaryBackgroundHot 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.MethodsThis 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.Findings68 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.InterpretationTreatment 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.FundingUK Medical Research Council and National Institute for Health Research.

STUDY QUESTIONCan increasing the duration of LH-exposure with a second dose of kisspeptin-54 improve oocyte maturation in women at high risk of ovarian hyperstimulation syndrome (OHSS)?SUMMARY ANSWERA second dose of kisspeptin-54 at 10 h following the first improves oocyte yield in women at high risk of OHSS.WHAT IS KNOWN ALREADYKisspeptin acts at the hypothalamus to stimulate the release of an endogenous pool of GnRH from the hypothalamus. We have previously reported that a single dose of kisspeptin-54 results in an LH-surge of ~12–14 h duration, which safely triggers oocyte maturation in women at high risk of OHSS.STUDY DESIGN, SIZE, DURATIONPhase-2 randomized placebo-controlled trial of 62 women at high risk of OHSS recruited between August 2015 and May 2016. Following controlled ovarian stimulation, all patients (n = 62) received a subcutaneous injection of kisspeptin-54 (9.6 nmol/kg) 36 h prior to oocyte retrieval. Patients were randomized 1:1 to receive either a second dose of kisspeptin-54 (D; Double, n = 31), or saline (S; Single, n = 31) 10 h thereafter. Patients, embryologists, and IVF clinicians remained blinded to the dosing allocation.PARTICIPANTS/MATERIALS, SETTING, METHODS Study participants: Sixty-two women aged 18–34 years at high risk of OHSS (antral follicle count ≥23 or anti-Mullerian hormone level ≥40 pmol/L). Setting: Single centre study carried out at Hammersmith Hospital IVF unit, London, UK. Primary outcome: Proportion of patients achieving an oocyte yield (percentage of mature oocytes retrieved from follicles ≥14 mm on morning of first kisspeptin-54 trigger administration) of at least 60%. Secondary outcomes: Reproductive hormone levels, implantation rate and OHSS occurrence.MAIN RESULTS AND THE ROLE OF CHANCEA second dose of kisspeptin-54 at 10 h following the first induced further LH-secretion at 4 h after administration. A higher proportion of patients achieved an oocyte yield ≥60% following a second dose of kisspeptin-54 (Single: 14/31, 45%, Double: 21/31, 71%; absolute difference +26%, CI 2–50%, P = 0.042).Patients receiving two doses of kisspeptin-54 had a variable LH-response following the second kisspeptin dose, which appeared to be dependent on the LH-response following the first kisspeptin injection. Patients who had a lower LH-rise following the first dose of kisspeptin had a more substantial ‘rescue’ LH-response following the second dose of kisspeptin. The variable LH-response following the second dose of kisspeptin resulted in a greater proportion of patients achieving an oocyte yield ≥60%, but without also increasing the frequency of ovarian over-response and moderate OHSS (Single: 1/31, 3.2%, Double: 0/31, 0%).LIMITATIONS, REASONS FOR CAUTIONFurther studies are warranted to directly compare kisspeptin-54 to more established triggers of oocyte maturation.WIDER IMPLICATIONS OF THE FINDINGSTriggering final oocyte maturation with kisspeptin is a novel therapeutic option to enable the use of fresh embryo transfer even in the woman at high risk of OHSS.STUDY FUNDING/COMP...

Introduction: Polycystic ovarian syndrome (PCOS) is a leading cause of female subfertility worldwide, however due to the heterogeneity of the disorder, the criteria for diagnosis remains subject to conjecture. In the present study, we evaluate the utility of serum Anti-Müllerian hormone (AMH) in the diagnosis of menstrual disturbance due to PCOS.Method: Menstrual cycle length, serum AMH, gonadotropin and sex-hormone levels, total antral follicle count (AFC), body mass index (BMI) and ovarian morphology on ultrasound were analyzed in a cohort of 187 non-obese women, aged 18–35 years, screened for participation in a clinical trial of fertility treatment between 2013 and 2016 at a tertiary reproductive endocrine center.Results: Serum AMH was higher in women with menstrual disturbance when compared to those with regular cycles (65.6 vs. 34.8 pmol/L; P < 0.0001). The odds of menstrual disturbance was increased 28.5-fold (95% CI 3.6–227.3) in women with serum AMH >60 pmol/L, in comparison to those with an AMH < 15 pmol/L. AMH better discriminated women with menstrual disturbance (area under ROC 0.77) from those with regular menstrual cycles than AFC (area under ROC 0.67), however the combination of the two markers increased discrimination than either measure alone (0.83; 95% CI 0.77–0.89). Serum AMH was higher in women with all three cardinal features of PCOS (menstrual disturbance, hyperandrogenism, polycystic ovarian morphology) when compared to women with none of these features (65.6 vs. 14.6 pmol/L; P < 0.0001). The odds of menstrual disturbance were increased by 10.7-fold (95% CI 2.4–47.1) in women with bilateral polycystic morphology ovaries than those with normal ovarian morphology. BMI was a stronger predictor of free androgen index (FAI) than either AMH or AFC.Conclusion: Serum AMH could serve as a useful biomarker to indicate the risk of menstrual disturbance due to PCOS. Women with higher AMH levels had increased rates of menstrual disturbance and an increased number of features of PCOS.

Summary Background  Gut hormones peptide YY (PYY) and glucagon‐like peptide‐1 (GLP‐1) play an integral role in appetite control and energy homeostasis. Entero‐endocrine L‐cells can be stimulated by nutrients and or bile acids to co‐secrete PYY and GLP‐1. The aim of this study was to determine the response of bile acids, PYY, GLP‐1 and ghrelin after a test meal. Design  Twelve subjects with a BMI of 22·8 (0·52) kg/m2 [mean (SEM)] received a 400 kcal test meal after which blood samples were taken every 30 min from 0 to 180 min. PYY, GLP‐1 and ghrelin were measured by radioimmunoassays. Fractionated bile acids were measured by HPLC‐MSMS. Results  PYY positively correlated with glycochenodeoxycholic acid (GCDCA) (rs = 0·23, P = 0·03) and taurochenodeoxycholic acid (TCDCA) (rs = 0·26, P = 0·02). GLP‐1 positively correlated with GCDCA (rs = 0·22, P = 0·047) and glycodeoxycholic acid (GDCA) (rs = 0·3, P = 0·005). Ghrelin negatively correlated with GDCA (rs = −0·45, P≤ 0·0001), TCDCA (rs = −0·23, P = 0·034) and taurodeoxycholic acid (TDCA) (rs = −0·44, P≤ 0·0001). Conclusion  PYY and GLP‐1 responses correlated with chenodeoxycholic acid (CDCA) counterparts, whereas ghrelin negatively correlated with deoxycholic acid (DCA) counterparts. Specific bile acids may thus differentially affect entero‐endocrine cells.

SummaryBackground 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.

Hypothalamic amenorrhoea (HA) accounts for approximately 30% of cases of secondary amenorrhoea in women of reproductive age. It is caused by deficient secretion of hypothalamic gonadotrophin-releasing hormone, which in turn leads to failure of pituitary gonadotrophin and gonadal steroid release. Functional HA (FHA) is defined as HA occurring in the absence of a structural lesion and is predominantly caused by significant weight loss, intense exercise or stress. Treatment of FHA is crucial in avoiding the long-term health consequences on fertility and bone health, in addition to reducing psychological morbidity. This article summarises our understanding of the mechanisms underlying FHA, the evidence base for its clinical management and emerging therapies.

Objective: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.Methods: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 course analysis was completed.Results:By day 3 of treatment with MLE4901, HF frequency reduced by 72% (95% CI, −81.3 to −63.3%) compared with baseline (51 percentage point reduction compared with placebo, P < 0.0001); this effect size persisted throughout the 4-week dosing period. HF severity reduced by 38% compared with baseline by day 3 (95% CI, −46.1 to −29.1%) (P < 0.0001 compared with placebo), bother by 39% (95% CI, −47.5 to −30.1%) (P < 0.0001 compared with placebo), and interference by 61% (95% CI, −79.1 to −43.0%) (P = 0.0006 compared with placebo); all continued to improve throughout the 4-week dosing period (to −44%, −50%, and −70%, respectively by day 28, all P < 0.0001 compared with placebo).Conclusions:NK3R antagonism rapidly relieves vasomotor symptoms without the need for estrogen exposure.