Search

Functional hypothalamic amenorrhea (FHA) is one of the most common causes of secondary amenorrhea, resulting in anovulation and infertility, and is a low estrogen state that increases the risk of cardiovascular disease and impairs bone health. FHA is characterized by acquired suppression of physiological pulsatile gonadotropin-releasing hormone (GnRH) release by the hypothalamus in the absence of an identifiable structural cause, resulting in a functional hypogonadotropic hypogonadism. FHA results from either decreased energy intake and/or excessive exercise, leading to low energy availability and weight loss-often in combination with psychological stress on top of a background of genetic susceptibility. The hypothalamic neuropeptide kisspeptin is a key component of the GnRH pulse generator, tightly regulating pulsatile GnRH secretion and the downstream reproductive axis. Here, we review the physiological regulation of pulsatile GnRH secretion by hypothalamic kisspeptin neurons and how their activity is modulated by signals of energy status to affect reproductive function. We explore endocrine factors contributing to the suppression of GnRH pulsatility in the pathophysiology of FHA and how hypothalamic kisspeptin neurons likely represent a final common pathway through which these factors affect GnRH pulse generation. Finally, we discuss the therapeutic potential of kisspeptin as a novel treatment for women with FHA., (© 2024 The Author(s). Annals of the New York Academy of Sciences published by Wiley Periodicals LLC on behalf of The New York Academy of Sciences.)

The neuropeptide kisspeptin and its cognate receptor have been extensively studied in reproductive physiology, with diverse and well-established functions, including as an upstream regulator of pubertal onset, reproductive hormone secretion, and sexual behavior. Besides classical reproduction, both kisspeptin and its receptor are extensively expressed in bone-resorbing osteoclasts and bone-forming osteoblasts, which putatively permits direct bone effects. Accordingly, this sets the scene for recent compelling findings derived from in vitro experiments through to in vivo and clinical studies revealing prominent regulatory interactions for kisspeptin signaling in bone metabolism, as well as certain oncological aspects of bone metabolism. Herein, we comprehensively examine the experimental evidence obtained to date supporting the interaction between kisspeptin and bone. A comprehensive understanding of this emerging facet of kisspeptin biology is fundamental to exploiting the future therapeutic potential of kisspeptin-based medicines as a novel strategy for treating bone-related disorders., (© 2024 The Author(s). Annals of the New York Academy of Sciences published by Wiley Periodicals LLC on behalf of The New York Academy of Sciences.)

Background: Low levels of testosterone cause male hypogonadism, which is associated with sexual dysfunction, tiredness and reduced muscle strength and quality of life. Testosterone replacement therapy is commonly used for ameliorating symptoms of male hypogonadism, but there is uncertainty about the magnitude of its effects and its cardiovascular and cerebrovascular safety., Aims of the Research: The primary aim was to evaluate the safety of testosterone replacement therapy. We also assessed the clinical and cost-effectiveness of testosterone replacement therapy for men with male hypogonadism, and the existing qualitative evidence on men's experience and acceptability of testosterone replacement therapy., Design: Evidence synthesis and individual participant data meta-analysis of effectiveness and safety, qualitative evidence synthesis and model-based cost-utility analysis., Data Sources: Major electronic databases were searched from 1992 to February 2021 and were restricted to English-language publications., Methods: We conducted a systematic review with meta-analysis of individual participant data according to current methodological standards. Evidence was considered from placebo-controlled randomised controlled trials assessing the effects of any formulation of testosterone replacement therapy in men with male hypogonadism. Primary outcomes were mortality and cardiovascular and cerebrovascular events. Data were extracted by one reviewer and cross-checked by a second reviewer. The risk of bias was assessed using the Cochrane Risk of Bias tool. We performed one-stage meta-analyses using the acquired individual participant data and two-stage meta-analyses to integrate the individual participant data with data extracted from eligible studies that did not provide individual participant data. A decision-analytic Markov model was developed to evaluate the cost per quality-adjusted life-years of the use of testosterone replacement therapy in cohorts of patients of different starting ages., Results: We identified 35 trials (5601 randomised participants). Of these, 17 trials (3431 participants) provided individual participant data. There were too few deaths to assess mortality. There was no difference between the testosterone replacement therapy group (120/1601, 7.5%) and placebo group (110/1519, 7.2%) in the incidence of cardiovascular and/or cerebrovascular events (13 studies, odds ratio 1.07, 95% confidence interval 0.81 to 1.42; p  = 0.62). Testosterone replacement therapy improved quality of life and sexual function in almost all patient subgroups. In the testosterone replacement therapy group, serum testosterone was higher while serum cholesterol, triglycerides, haemoglobin and haematocrit were all lower. We identified several themes from five qualitative studies showing how symptoms of low testosterone affect men's lives and their experience of treatment. The cost-effectiveness of testosterone replacement therapy was dependent on whether uncertain effects on all-cause mortality were included in the model, and on the approach used to estimate the health state utility increment associated with testosterone replacement therapy, which might have been driven by improvements in symptoms such as sexual dysfunction and low mood., Limitations: A meaningful evaluation of mortality was hampered by the limited number of defined events. Definition and reporting of cardiovascular and cerebrovascular events and methods for testosterone measurement varied across trials., Conclusions: Our findings do not support a relationship between testosterone replacement therapy and cardiovascular/cerebrovascular events in the short-to-medium term. Testosterone replacement therapy improves sexual function and quality of life without adverse effects on blood pressure, serum lipids or glycaemic markers., Future Work: Rigorous long-term evidence assessing the safety of testosterone replacement therapy and subgroups most benefiting from treatment is needed., Study Registration: The study is registered as PROSPERO CRD42018111005., Funding: This award was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme (NIHR award ref: 17/68/01) and is published in full in Health Technology Assessment ; Vol. 28, No. 43. See the NIHR Funding and Awards website for further award information.

Kisspeptin is an essential neuropeptide sitting at the apex of the hypothalamo-pituitary-gonadal (HPG) endocrine axis to regulate gonadotropin-releasing hormone (GnRH) neurons and downstream reproductive hormones. Kisspeptin neurons integrate feedback from sex steroids facilitating regulation of the menstrual cycle and mediate the effects of metabolic stressors on the reproductive axis. In this issue of the JCI, Torres and colleagues describe another pathway for kisspeptin signaling in astrocytes to influence GnRH neuronal output. Astrocytes had kisspeptin receptors that activated canonical intracellular signaling pathways to constrain the magnitude of kisspeptin-induced GnRH neuronal stimulation. Additionally, the appositions between kisspeptin and GnRH neurons were dynamic during the ovarian cycle, with astrocyte kisspeptin signaling proposed as a putative modulator of this neuroplasticity. Importantly, astrocyte kisspeptin signaling also mediated susceptibility to metabolic stressors and the development of obesity-induced hypogonadism, underscoring the physiological and pathological importance of this pathway and revealing the importance of nonneuronal signaling in reproductive health.

Menopausal hormone therapy (MHT) is an effective treatment for menopause-related symptoms. Menopause management guidelines recommend a personalized approach to menopause care, including MHT use. Decision-making around menopause care is a complex, iterative process influenced by multiple factors framed by perspectives from both women and healthcare providers (HCPs). This narrative review aims to summarize evidence around factors affecting decision-making regarding menopause-related care. For HCPs, the provision of individualized risk estimates is challenging in practice given the number of potential benefits and risks to consider, and the complexity of the data available, especially within time-limited consultations. Women seeking menopause care have the difficult task of making sense of the benefit versus risk profiles to make choices in line with their decisional needs influenced by sociocultural/economic, educational, demographic, and personal characteristics. The press, social media, and influential celebrities also impact the perception of menopause and decision-making around it. Understanding these factors can lead to improved participation in shared decision-making, satisfaction with the decision and decision-making process, adherence to treatment, reduced decisional regret, efficient use of resources, and ultimately long-term satisfaction with care., (© 2024 The Author(s). Annals of the New York Academy of Sciences published by Wiley Periodicals LLC on behalf of The New York Academy of Sciences.)

Glucocorticoid hormones (GC) are secreted in a circadian and ultradian rhythm and play a critical role in maintaining physiological homeostasis, with both excess and insufficient GC associated with adverse effects on health. Current assessment of GC status is primarily clinical, often in conjunction with serum cortisol values, which may be stimulated or suppressed depending on the GC disturbance being assessed. In the setting of extreme perturbations in cortisol levels i.e. markedly low or high levels, symptoms and signs of GC dysfunction may be overt. However, when disturbances in cortisol GC status values are less extreme, such as when assessing optimization of a GC replacement regimen, signs and symptoms can be more subtle or non-specific. Current tools for assessing GC status, are best suited to identifying profound disturbances but may lack sensitivity for confirming optimal GC status. Moreover, single cortisol values do not necessarily reflect an individual's GC status, as they are subject to inter- and intra-individual variation, do not take into account the pulsatile nature of cortisol secretion, variation in binding proteins, or local tissue concentrations as dictated by 11βeta-hydroxysteroid dehydrogenase (11β-HSD) activity, as well as GC receptor sensitivity. In the present review, we evaluate possible alternative methods for the assessment of GC status that do not solely rely on measurement of circulating cortisol levels. We discuss the potential of changes in metabolomic profiles, miRNA, gene expression, epigenetic, and other novel biomarkers such as GDF-15 and osteocalcin, that could in future aid in the objective classification of GC status., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Endocrine Society.)

Distressing low sexual desire, termed Hypoactive Sexual Desire Disorder (HSDD), affects approximately 10% of women and 8% of men. In women, the 'top-down' theory of HSDD describes hyperactivity in higher-level cognitive brain regions, suppressing lower-level emotional/sexual brain areas. However, it is unknown how this neurofunctional disturbance compares to HSDD in men. To investigate this, we employed task-based functional MRI in 32 women and 32 men with HSDD to measure sexual-brain processing during sexual versus non-sexual videos, as well as psychometric questionnaires to assess sexual desire/arousal. We demonstrate that women had greater activation in higher-level and lower-level brain regions, compared to men. Indeed, women who had greater hypothalamic activation in response to sexual videos, reported higher psychometric scores in the evaluative (r = 0.55, P = 0.001), motivational (r = 0.56, P = 0.003), and physiological (r = 0.57, P = 0.0006) domains of sexual desire and arousal after watching the sexual videos in the scanner. By contrast, no similar correlations were observed in men. Taken together, this is the first direct comparison of the neural correlates of distressing low sexual desire between women and men. The data supports the 'top-down' theory of HSDD in women, whereas in men HSDD appears to be associated with different neurofunctional processes., (© 2024. The Author(s).)

Obesity-related hypogonadotropic hypogonadism is a well-characterized condition in men (termed male obesity-related secondary hypogonadism; MOSH); however, an equivalent condition has not been as clearly described in women. The prevalence of polycystic ovary syndrome (PCOS) is known to increase with obesity, but PCOS is more typically characterized by increased gonadotropin-releasing hormone (GnRH) (and by proxy luteinizing hormone; LH) pulsatility, rather than by the reduced gonadotropin levels observed in MOSH. Notably, LH levels and LH pulse amplitude are reduced with obesity, both in women with and without PCOS, suggesting that an obesity-related secondary hypogonadism may also exist in women akin to MOSH in men. Herein, we examine the evidence for the existence of a putative non-PCOS "female obesity-related secondary hypogonadism" (FOSH). We précis possible underlying mechanisms for the occurrence of hypogonadism in this context and consider how such mechanisms differ from MOSH in men, and from PCOS in women without obesity. In this review, we consider relevant etiological factors that are altered in obesity and that could impact on GnRH pulsatility to ascertain whether they could contribute to obesity-related secondary hypogonadism including: anti-Müllerian hormone, androgen, insulin, fatty acid, adiponectin, and leptin. More precise phenotyping of hypogonadism in women with obesity could provide further validation for non-PCOS FOSH and preface the ability to define/investigate such a condition., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Endocrine Society.)

Infertility affects one in six couples, with in vitro fertilization (IVF) offering many the chance of conception. Compared to the solitary oocyte produced during the natural menstrual cycle, the supraphysiological ovarian stimulation needed to produce multiple oocytes during IVF results in a dysfunctional luteal phase that can be insufficient to support implantation and maintain pregnancy. Consequently, hormonal supplementation with luteal phase support, principally exogenous progesterone, is used to optimize pregnancy rates; however, luteal phase support remains largely 'black-box' with insufficient clarity regarding the optimal timing, dosing, route and duration of treatment. Herein, we review the evidence on luteal phase support and highlight remaining uncertainties and future research directions. Specifically, we outline the physiological luteal phase, which is regulated by progesterone from the corpus luteum, and evaluate how it is altered by the supraphysiological ovarian stimulation used during IVF. Additionally, we describe the effects of the hormonal triggers used to mature oocytes on the degree of luteal phase support required. We explain the histological transformation of the endometrium during the luteal phase and evaluate markers of endometrial receptivity that attempt to identify the 'window of implantation'. We also cover progesterone receptor signalling, circulating progesterone levels associated with implantation, and the pharmacokinetics of available progesterone formulations to inform the design of luteal phase support regimens., (© 2023. Springer Nature Limited.)

Infertility affects 1-in-6 couples, with repeated intensive cycles of assisted reproductive technology (ART) required by many to achieve a desired live birth. In ART, typically, clinicians and laboratory staff consider patient characteristics, previous treatment responses, and ongoing monitoring to determine treatment decisions. However, the reproducibility, weighting, and interpretation of these characteristics are contentious, and highly operator-dependent, resulting in considerable reliance on clinical experience. Artificial intelligence (AI) is ideally suited to handle, process, and analyze large, dynamic, temporal datasets with multiple intermediary outcomes that are generated during an ART cycle. Here, we review how AI has demonstrated potential for optimization and personalization of key steps in a reproducible manner, including: drug selection and dosing, cycle monitoring, induction of oocyte maturation, and selection of the most competent gametes and embryos, to improve the overall efficacy and safety of ART., (© 2024. The Author(s).)

Background: Testosterone is safe and highly effective in men with organic hypogonadism, but worldwide testosterone prescribing has recently shifted towards middle-aged and older men, mostly with low testosterone related to age, diabetes and obesity, for whom there is less established evidence of clinical safety and benefit. The value of testosterone treatment in middle-aged and older men with low testosterone is yet to be determined. We therefore evaluated the cost-effectiveness of testosterone treatment in such men with low testosterone compared with no treatment., Methods: A cost-utility analysis comparing testosterone with no treatment was conducted following best practices in decision modelling. A cohort Markov model incorporating relevant care pathways for individuals with hypogonadism was developed for a 10-year-time horizon. Clinical outcomes were obtained from an individual patient meta-analysis of placebo-controlled, double-blind randomised studies. Three starting age categories were defined: 40, 60 and 75 years. Cost utility (quality-adjusted life years) accrued and costs of testosterone treatment, monitoring and cardiovascular complications were compared to estimate incremental cost-effectiveness ratios and cost-effectiveness acceptability curves for selected scenarios., Results: Ten-year excess treatment costs for testosterone compared with non-treatment ranged between £2306 and £3269 per patient. Quality-adjusted life years results depended on the instruments used to measure health utilities. Using Beck depression index-derived quality-adjusted life years data, testosterone was cost-effective (incremental cost-effectiveness ratio <£20,000) for men aged <75 years, regardless of morbidity and mortality sensitivity analyses. Testosterone was not cost-effective in men aged >75 years in models assuming increased morbidity and/or mortality., Conclusions and Future Research: Our data suggest that testosterone is cost-effective in men <75 years when Beck depression index-derived quality-adjusted life years data are considered; cost-effectiveness in men >75 years is dependent on cardiovascular safety. However, more robust and longer-term cost-utility data are needed to verify our conclusion., (© 2024 The Authors. Andrology published by Wiley Periodicals LLC on behalf of American Society of Andrology and European Academy of Andrology.)

The hypothalamus is the central regulator of reproductive hormone secretion. Pulsatile secretion of gonadotropin releasing hormone (GnRH) is fundamental to physiological stimulation of the pituitary gland to release luteinizing hormone (LH) and follicle stimulating hormone (FSH). Furthermore, GnRH pulsatility is altered in common reproductive disorders such as polycystic ovary syndrome (PCOS) and hypothalamic amenorrhea (HA). LH is measured routinely in clinical practice using an automated chemiluminescent immunoassay method and is the gold standard surrogate marker of GnRH. LH can be measured at frequent intervals (e.g., 10 minutely) to assess GnRH/LH pulsatility. However, this is rarely done in clinical practice because it is resource intensive, and there is no open-access, graphical interface software for computational analysis of the LH data available to clinicians. Here we present hormoneBayes, a novel open-access Bayesian framework that can be easily applied to reliably analyze serial LH measurements to assess LH pulsatility. The framework utilizes parsimonious models to simulate hypothalamic signals that drive LH dynamics, together with state-of-the-art (sequential) Monte-Carlo methods to infer key parameters and latent hypothalamic dynamics. We show that this method provides estimates for key pulse parameters including inter-pulse interval, secretion and clearance rates and identifies LH pulses in line with the widely used deconvolution method. We show that these parameters can distinguish LH pulsatility in different clinical contexts including in reproductive health and disease in men and women (e.g., healthy men, healthy women before and after menopause, women with HA or PCOS). A further advantage of hormoneBayes is that our mathematical approach provides a quantified estimation of uncertainty. Our framework will complement methods enabling real-time in-vivo hormone monitoring and therefore has the potential to assist translation of personalized, data-driven, clinical care of patients presenting with conditions of reproductive hormone dysfunction., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Voliotis et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Background: Selective oestrogen receptor modulators and aromatase inhibitors stimulate endogenous gonadotrophins and testosterone in men with hypogonadism. There are no systematic reviews/meta-analyses assessing the effects of selective oestrogen receptor modulators/aromatase inhibitors on semen parameters in men with secondary hypogonadism., Objectives: To assess the effect of monotherapy or a combination of selective oestrogen receptor modulators/aromatase inhibitors on sperm parameters and/or fertility in men with secondary hypogonadism., Materials and Methods: A systematic search was conducted in PubMed, MEDLINE, Cochrane Library and ClinicalTrials.gov. Study selection and data extraction were performed by two reviewers independently. Randomised controlled trials and non-randomised studies of interventions reporting effects of selective oestrogen receptor modulators and/or aromatase inhibitors on semen parameters or fertility in men with low testosterone with low/normal gonadotrophins were selected. The risk of bias was assessed using ROB-2 and ROBINS-I tools. The results of randomised controlled trials were summarised using vote counting while summarising effect estimates where available. Non-randomised studies of intervention meta-analysis were conducted using the random-effect model. The certainty of evidence was assessed using GRADE., Results: Five non-randomised studies of interventions (n = 105) of selective oestrogen receptor modulators showed an increase in sperm concentration (pooled mean difference 6.64 million/mL; 95% confidence interval 1.54, 11.74, I 2  = 0%) and three non-randomised studies of interventions (n = 83) of selective oestrogen receptor modulators showed an increase in total motile sperm count (pooled mean difference 10.52; 95% confidence interval 1.46-19.59, I 2  = 0%), with very low certainty of evidence. The mean body mass index of participants was >30 kg/m 2 . Four randomised controlled trials (n = 591) comparing selective oestrogen receptor modulators to placebo showed a heterogeneous effect on sperm concentration. Three included men with overweight or obesity. The results were of very low certainty of evidence. Limited pregnancy or live birth data were available. No studies comparing aromatase inhibitors with placebo or testosterone were found., Discussion and Conclusion: Current studies are of limited size and quality but suggest that selective oestrogen receptor modulators may improve semen parameters in those patients, particularly when associated with obesity., (© 2023 The Authors. Andrology published by Wiley Periodicals LLC on behalf of American Society of Andrology and European Academy of Andrology.)

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 (r 2 = 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., Competing Interests: Declaration of interests A.A. was supported by NIHR Clinician Scientist Award CS-2018-18-ST2-002. S.A. has nothing to disclose. M.P. was supported by an NIHR Academic Clinical Lectureship Award. C.I.E. was supported by an Imperial-BRC IPPRF Award (P79696). E.G.M. was supported by an NIHR Academic Clinical Lectureship Award. L.T. has nothing to disclose. K.K. was supported by NIHR Academic Clinical Fellowship Award ACF-2021-21-001. S.H. was supported by the UKRI CDT in AI for Healthcare http://ai4health.io (Grant number EP/S023283/1). T.H. has nothing to disclose. T.M.-M.T. was supported by the NIHR, Diabetes UK, and the JP Moulton Charitable Trust. K.T.A. was supported by the EPSRC via grant EP/T017856/1. A.N.C. was supported by the NHS. M.V. has nothing to disclose. W.S.D. was supported by an NIHR Senior Investigator Award., (Copyright © 2024. Published by Elsevier Inc.)

The human hypothalamus modulates mental health by balancing interactions between hormonal fluctuations and stress responses. Stress-induced progesterone release activates progesterone receptors (PR) in the human brain and triggers alterations in neuropeptides/neurotransmitters. As recent epidemiological studies have associated peripheral progesterone levels with suicide risks in humans, we mapped PR distribution in the human hypothalamus in relation to age and sex and characterized its (co-) expression in specific cell types. The infundibular nucleus (INF) appeared to be the primary hypothalamic structure via which progesterone modulates stress-related neural circuitry. An elevation of the number of pro-opiomelanocortin + (POMC, an endogenous opioid precursor) neurons in the INF, which was due to a high proportion of POMC + neurons that co-expressed PR, was related to suicide in patients with mood disorders (MD). MD donors who died of legal euthanasia were for the first time enrolled in a postmortem study to investigate the molecular signatures related to fatal suicidal ideations. They had a higher proportion of PR co-expressing POMC + neurons than MD patients who died naturally. This indicates that the onset of endogenous opioid activation in MD with suicide tendency may be progesterone-associated. Our findings may have implications for users of progesterone-enriched contraceptives who also have MD and suicidal tendencies., (© 2024. The Author(s).)

Introduction: Obesity increases risks of male infertility, but bariatric surgery does not improve semen quality. Recent uncontrolled studies suggest that a low-energy diet (LED) improves semen quality. Further evaluation within a randomized, controlled setting is warranted., Methods: Men with obesity (18-60 years) with normal sperm concentration (normal count) (n = 24) or oligozoospermia (n = 43) were randomized 1:1 to either 800 kcal/day LED for 16 weeks or control, brief dietary intervention (BDI) with 16 weeks' observation. Semen parameters were compared at baseline and 16 weeks., Results: Mean age of men with normal count was 39.4 ± 6.4 in BDI and 40.2 ± 9.6 years in the LED group. Mean age of men with oligozoospermia was 39.5 ± 7.5 in BDI and 37.7 ± 6.6 years in the LED group. LED caused more weight loss than BDI in men with normal count (14.4 vs 6.3 kg; P < .001) and men with oligozoospermia (17.6 vs 1.8 kg; P < .001). Compared with baseline, in men with normal count total motility (TM) increased 48 ± 17% to 60 ± 10% (P < .05) after LED, and 52 ± 8% to 61 ± 6% (P < .0001) after BDI; progressive motility (PM) increased 41 ± 16% to 53 ± 10% (P < .05) after LED, and 45 ± 8% to 54 ± 65% (P < .001) after BDI. In men with oligozoospermia compared with baseline, TM increased 35% [26] to 52% [16] (P < .05) after LED, and 43% [28] to 50% [23] (P = .0587) after BDI; PM increased 29% [23] to 46% [18] (P < .05) after LED, and 33% [25] to 44% [25] (P < .05) after BDI. No differences in postintervention TM or PM were observed between LED and BDI groups in men with normal count or oligozoospermia., Conclusion: LED or BDI may be sufficient to improve sperm motility in men with obesity. The effects of paternal dietary intervention on fertility outcomes requires investigation., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Endocrine Society.)

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., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Endocrine Society.)

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., Competing Interests: Conflict of interest statement WSD and AA have conducted consultancy work for Myovant Sciences Ltd. WSD has also conducted consultancy work for KaNDy therapeutics., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Background: Kisspeptin is an essential regulator of hypothalamic gonadotropin-releasing hormone release and is required for physiological ovulation. Native kisspeptin-54 can induce oocyte maturation during in vitro fertilization treatment, including in women who are at high risk of ovarian hyperstimulation syndrome. MVT-602 is a potent kisspeptin receptor agonist with prospective utility to treat anovulatory disorders by triggering oocyte maturation and ovulation during medically assisted reproduction (MAR). Currently, the endocrine profile of MVT-602 during ovarian stimulation is unreported., Objective: To determine the endocrine profile of MVT-602 in the follicular phase of healthy premenopausal women (phase-1 trial), and after minimal ovarian stimulation to more closely reflect the endocrine milieu encountered during MAR (phase-2a trial)., Design: Two randomized, placebo-controlled, parallel-group, dose-finding trials., Setting: Clinical trials unit., Patients: Healthy women aged 18-35 years, either without (phase-1; n = 24), or with ovarian stimulation (phase-2a; n = 75)., Interventions: Phase-1: single subcutaneous dose of MVT-602 (0.3, 1.0, or 3.0 μg) or placebo, (n = 6 per dose). Phase-2a: single subcutaneous dose of MVT-602 (0.1, 0.3, 1.0, or 3.0 μg; n = 16-17 per dose), triptorelin 0.2 mg (n = 5; active comparator), or placebo (n = 5)., Main Outcome Measures: Phase-1: safety/tolerability; pharmacokinetics; and pharmacodynamics (luteinizing hormone [LH] and other reproductive hormones). Phase-2a: safety/tolerability; pharmacokinetics; pharmacodynamics (LH and other reproductive hormones); and time to ovulation assessed by transvaginal ultrasound., Results: In both the trials, MVT-602 was safe and well tolerated across the entire dose range. It was rapidly absorbed and eliminated, with a mean elimination half-life of 1.3-2.2 hours. In the phase-2a trial, LH concentrations increased dose dependently; mean maximum change from baseline of 82.4 IU/L at 24.8 hours was observed after administration of 3 μg MVT-602 and remained >15 IU/L for 33 hours. Time to ovulation after drug administration was 3.3-3.9 days (MVT-602), 3.4 days (triptorelin), and 5.5 days (placebo). Ovulation occurred within 5 days of administration in 100% (3 μg), 88% (1 μg), 82% (0.3 μg), and 75% (0.1 μg), of women after MVT-602, 100% after triptorelin and 60% after placebo., Conclusions: MVT-602 induces LH concentrations of similar amplitude and duration as the physiological midcycle LH surge with potential utility for induction of oocyte maturation and ovulation during MAR., Clinical Trial Registration Number: EUDRA-CT: 2017-003812-38, 2018-001379-20., Competing Interests: Declaration of interests A.A. reports Myovant Sciences Ltd Consultancy Fee and NIHR Clinician Scientist Fellowship for the submitted work. M.U. has nothing to disclose. C.V.-P. is an employee of QPS Netherlands BV. L.B. reports contracting consultant to Myovant Sciences outside the submitted work. M.E. has nothing to disclose. R.W. has nothing to disclose. T.-Y.L. has nothing to disclose. J.C.A.F. has nothing to disclose. E.M has nothing to disclose. W.S.D. reports consulted for Myovant Sciences Ltd. for the submitted work; NIHR research professorship; consulting fees from Myovant Sciences outside the submitted work., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Objective: Symptomatic hypogonadism discourages men from stopping anabolic-androgenic steroids (AAS). Some men illicitly take drugs temporarily stimulating endogenous testosterone following AAS cessation (post-cycle therapy; PCT) to lessen hypogonadal symptoms. We investigated whether prior PCT use was associated with the normalization of reproductive hormones following AAS cessation., Methods: Retrospective analysis of 641 men attending a clinic between 2015-2022 for a single, nonfasting, random blood test <36 months following AAS cessation, with or without PCT. Normalized reproductive hormones (ie, a combination of reference range serum luteinizing hormone, follicle-stimulating hormone, and total testosterone levels) were the surrogate marker of biochemical recovery., Results: Normalization of reproductive hormones was achieved in 48.2% of men. PCT use was associated with faster biochemical recovery (13.0 (IQR8.0-19.0) weeks, PCT; 26.0 (IQR10.5-52) weeks, no-PCT; P < .001). Odds of biochemical recovery during multivariable analysis were: (1) higher with PCT (OR3.80) vs no-PCT (P = .001), in men stopping AAS ≤3 months previously; (2) reduced when 2 (OR0.55), 3 (OR0.46), or 4 (OR0.25) AAS were administered vs 1 drug (P = .009); (3) lower with AAS >6 vs ≤3 months previously (OR0.34, P = .01); (4) higher with last reported AAS >3 months (OR 5.68) vs ≤3 months (P = .001). PCT use was not associated with biochemical recovery in men stopping AAS >3 months previously., Conclusion: Without evidence-based withdrawal protocols, men commonly try avoiding post-AAS hypogonadism with PCT, which is illicit, ill-defined, and not recommended. Only half of men had complete biochemical testicular recovery after stopping AAS. The surprising association of self-reported PCT use with short-term biochemical recovery from AAS-induced hypogonadism warrants further investigation., (© The Author(s) 2023. Published by Oxford University Press on behalf of European Society of Endocrinology.)

Background: Anabolic-androgenic steroids (AAS) mimic the effects of testosterone and may include testosterone itself; they are used for body enhancement within the general population. AAS use has been linked with increased mortality, cardiovascular disease, mental health disorders, and infertility. AAS-induced hypogonadism can persist for an uncertain time period despite cessation, during which men may report physical and neuropsychiatric symptoms. In an attempt to mitigate these symptoms and expedite testicular recovery, many men self-administer post-cycle-therapy (PCT), typically involving human chorionic gonadotrophin (hCG) and selective oestrogen receptor modulators (SERMs), which are known to potently stimulate testicular function. However, this practice has no objective evidence of effectiveness to lessen the severity or duration of hypogonadal symptoms., Methods: An anonymous survey of four-hundred-and-seventy men using AAS explored the symptoms they experienced when ceasing AAS use; the effect of PCT on relieving their symptoms, and their perceived role for health service support., Results: The majority of respondents were white, aged 18-30 years old, and working in skilled manual work. 51.7% (n = 243) reported no issues with AAS use, but 35.3% reported increased aggression. 65.1% (n = 306) of respondents had attempted AAS cessation and 95.1% of these experienced at least one symptom upon AAS cessation. Low mood, tiredness and reduced libido were reported in 72.9%, 58.5% and 57.0% of men stopping AAS use, respectively, with only 4.9% reporting no symptoms. PCT had been used by 56.5% of respondents with AAS cessation and mitigated cravings to restart AAS use, withdrawal symptoms and suicidal thoughts by 60%, 60% and 50%, respectively. The effect of stopping AAS on body composition and recovery of testosterone or fertility was a concern in 60.5% and 52.4%, respectively. Most respondents felt PCT should be prescribed under medical supervision in the community., Conclusions: Our survey suggests that the majority of men stopping AAS use are using some form of PCT. Some self-reported symptoms of AAS-induced hypogonadism such as cravings to restart AAS use reduce by 60% and suicidal thoughts reduce by 50%. These individuals are concerned about the negative effect of AAS use and cessation. This study provides crucial information for planning future research to evaluate the effects of PCT on symptoms when men stop AAS use., (© 2023. The Author(s).)

Background: Testosterone replacement therapy is known to improve sexual function in men younger than 40 years with pathological hypogonadism. However, the extent to which testosterone alleviates sexual dysfunction in older men and men with obesity is unclear, despite the fact that testosterone is being increasingly prescribed to these patient populations. We aimed to evaluate whether subgroups of men with low testosterone derive any symptomatic benefit from testosterone treatment., Methods: We did a systematic review and meta-analysis to evaluate characteristics associated with symptomatic benefit of testosterone treatment versus placebo in men aged 18 years and older with a baseline serum total testosterone concentration of less than 12 nmol/L. We searched major electronic databases (MEDLINE, Embase, Science Citation Index, and the Cochrane Central Register of Controlled Trials) and clinical trial registries for reports published in English between Jan 1, 1992, and Aug 27, 2018. Anonymised individual participant data were requested from the investigators of all identified trials. Primary (cardiovascular) outcomes from this analysis have been published previously. In this report, we present the secondary outcomes of sexual function, quality of life, and psychological outcomes at 12 months. We did a one-stage individual participant data meta-analysis with a random-effects linear regression model, and a two-stage meta-analysis integrating individual participant data with aggregated data from studies that did not provide individual participant data. This study is registered with PROSPERO, CRD42018111005., Findings: 9871 citations were identified through database searches. After exclusion of duplicates and publications not meeting inclusion criteria, 225 full texts were assessed for inclusion, of which 109 publications reporting 35 primary studies (with a total 5601 participants) were included. Of these, 17 trials provided individual participant data (3431 participants; median age 67 years [IQR 60-72]; 3281 [97%] of 3380 aged ≥40 years) Compared with placebo, testosterone treatment increased 15-item International Index of Erectile Function (IIEF-15) total score (mean difference 5·52 [95% CI 3·95-7·10]; τ 2 =1·17; n=1412) and IIEF-15 erectile function subscore (2·14 [1·40-2·89]; τ 2 =0·64; n=1436), reaching the minimal clinically important difference for mild erectile dysfunction. These effects were not found to be dependent on participant age, obesity, presence of diabetes, or baseline serum total testosterone. However, absolute IIEF-15 scores reached during testosterone treatment were subject to thresholds in patient age and baseline serum total testosterone. Testosterone significantly improved Aging Males' Symptoms score, and some 12-item or 36-item Short Form Survey quality of life subscores compared with placebo, but it did not significantly improve psychological symptoms (measured by Beck Depression Inventory)., Interpretation: In men aged 40 years or older with baseline serum testosterone of less than 12 nmol/L, short-to-medium-term testosterone treatment could provide clinically meaningful treatment for mild erectile dysfunction, irrespective of patient age, obesity, or degree of low testosterone. However, due to more severe baseline symptoms, the absolute level of sexual function reached during testosterone treatment might be lower in older men and men with obesity., Funding: National Institute for Health and Care Research Health Technology Assessment Programme., Competing Interests: Declaration of interests CNJ reports a research grant from Logixx Pharma. ShB reports research grants from AbbVie and the US NIH; participation on the OKPO Health data safety monitoring board; consulting fees from Aditum, a leadership or fiduciary role from the Endocrine Society; and a patent relating to the diagnosis and treatment of androgen disorders (US patent number 10386375). SSE reports a research grant from AbbVie. MG reports research grants from Otsuka, Bayer, Lilly, Weight Watchers, Novartis, National Health and Medical Research Council (Australia); speaker honoraria from Besins Healthcare, Bayer, and Otsuka; consulting fees from Bayer; and royalties from Walter and Eliza Hall Institute Melbourne Australia. KLH is supported by the National Institute on Aging K23 Career Development Award; reports an unpaid role in the Executive Committee, Kavod Senior Life Board of Directors; and stock or stock options from Medaware Systems. NO reports research grants from Dexcom, Roche Diabetes, Medtronic Diabetes; speaker honoraria from Roche Diabetes; consulting fees from Roche Diabetes and Medtronic Diabetes; payment for expert testimony (Bird and Bird); and a patent issued for an automatic closed loop glucose control system with an adaptive meal bolus calculator. SR reports a research grant from North Staffordshire Medical Institute; and support for meetings or travel from Besins Healthcare. PJS reports a research grant from AbbVie; and payment for expert testimony from Teva. RQ reports speaker honoraria and support for attending meetings or travel from Bayer. SiB reports speaker honoraria from the Obstetrical & Gynaecological Society of Singapore and pharmaceutical companies (Merck and Ferring); a financial role as a non-executive member of NHS Grampian Health Board; and royalties from Cambridge University Press. GBB reports speaker honoraria and consulting fees from Acerus Pharmaceutical. HMT reports speaker honoraria from Besin Healthcare. EmJG reports provision of study materials from Bayer. All other authors declare no competing interests., (Copyright © 2023 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

Objective: Functioning gonadotroph adenomas (FGAs) are rare pituitary tumours stimulating ovarian function with potential life-threatening consequences in women. However, a lack of aggregated clinical experience of FGAs impairs management in affected women. The aim of this study is to present the clinical course of FGA-induced ovarian hyperstimulation syndrome (OHSS) cases as identified by some of the largest UK pituitary endocrine tertiary centres with a view to increasing awareness and improving diagnosis and management of women with FGA., Design: A retrospective observational study; audit of eight UK regional pituitary centres for cases of FGAs., Setting: Specialist neuroendocrine centres in the United Kingdom., Patients and Measurements: Women diagnosed with FGA-induced OHSS. Description of their clinical course., Results: Seven cases of FGA were identified in women, all causing OHSS. Mean age was 33.4 years at diagnosis. Abdominal pain, irregular periods, headache, and visual disturbances were reported at presentation by 100%, 71%, 57% and 43% of women, respectively. Three of seven women underwent ovarian surgery before FGA diagnosis. Six women underwent transsphenoidal surgery (TSS) with incomplete tumour resection in five of those, but all showed improvement or resolution in symptoms and biochemistry postoperatively., Conclusion: FGA is a rare cause of spontaneous OHSS. TSS improves clinical and biochemical features of ovarian hyperstimulation in FGAs. Improved awareness of FGA will prevent inappropriate emergency ovarian surgery., (© 2023 The Authors. Clinical Endocrinology published by John Wiley & Sons Ltd.)

Menopausal hot flashes are common and debilitating. Menopausal Hormone Therapy (MHT) is effective for hot flashes but has risks and side effects that limit its use. NK3 receptor antagonism has emerged as a novel therapeutic strategy, leading to the recent FDA approval of fezolinetant, a first-in-class nonhormonal treatment for menopausal hot flashes. To view this Bench to Bedside, open or download the PDF., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Non-alcoholic fatty liver disease (NAFLD) is a major cause of liver disease worldwide, affecting up to 30% of adults. Progression to non-alcoholic steatohepatitis (NASH) is a key risk factor for cirrhosis, hepatocellular carcinoma and cardiovascular events. Alterations in reproductive hormones are linked to the development and/or progression of NAFLD/NASH in women. Women with polycystic ovary syndrome and those with oestrogen deficiency are at increased risk of NAFLD/NASH, with higher mortality rates in older women compared to men of similar ages. NAFLD/NASH is currently the leading indication for liver transplantation in women without hepatocellular carcinoma. Therefore, a better understanding of NAFLD in women is needed to improve outcomes. In this review, we discuss the hormonal and non-hormonal factors that contribute to NAFLD development and progression in women. Furthermore, we highlight areas of focus for clinical practice and for future research., Competing Interests: All authors report no potential conflicts of interest. Please refer to the accompanying ICMJE disclosure forms for further details., (© 2023 The Authors.)

Context: Limited data exist regarding whether the endocrine response to the gonadotropin-releasing hormone receptor agonist (GnRHa) triptorelin differs in women with polycystic ovary syndrome (PCOS) compared with healthy women or those with hypothalamic amenorrhea (HA)., Objective: We compared the gonadotropin response to triptorelin in healthy women, women with PCOS, or those with HA without ovarian stimulation, and in women with or without polycystic ovaries undergoing oocyte donation cycles after ovarian stimulation., Methods: The change in serum gonadotropin levels was determined in (1) a prospective single-blinded placebo-controlled study to determine the endocrine profile of triptorelin (0.2 mg) or saline-placebo in healthy women, women with PCOS, and those with HA, without ovarian stimulation; and (2) a retrospective analysis from a dose-finding randomized controlled trial of triptorelin (0.2-0.4 mg) in oocyte donation cycles after ovarian stimulation., Results: In Study 1, triptorelin induced an increase in serum luteinizing hormone (LH) of similar amplitude in all women (mean peak LH: healthy, 52.3; PCOS, 46.2; HA, 41.3 IU/L). The AUC of change in serum follicle-stimulating hormone (FSH) was attenuated in women with PCOS compared with healthy women and women with HA (median AUC of change in serum FSH: PCOS, 127.2; healthy, 253.8; HA, 326.7 IU.h/L; P = 0.0005). In Study 2, FSH levels 4 hours after triptorelin were reduced in women with at least one polycystic morphology ovary (n = 60) vs normal morphology ovaries (n = 91) (34.0 vs 42.3 IU/L; P = 0.0003). Serum anti-Müllerian hormone (AMH) was negatively associated with the increase in FSH after triptorelin, both with and without ovarian stimulation., Conclusion: FSH response to triptorelin was attenuated in women with polycystic ovaries, both with and without ovarian stimulation, and was negatively related to AMH levels., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Endocrine Society.)

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., (© 2023 The Author(s).)

Coupling the release of pituitary hormones to the developmental stage of the oocyte is essential for female fertility. It requires estrogen to restrain kisspeptin (KISS1)-neuron pulsatility in the arcuate hypothalamic nucleus, while also exerting a surge-like effect on KISS1-neuron activity in the AVPV hypothalamic nucleus. However, a mechanistic basis for this region-specific effect has remained elusive. Our genomic analysis in female mice demonstrate that some processes, such as restraint of KISS1-neuron activity in the arcuate nucleus, may be explained by region-specific estrogen receptor alpha (ERα) DNA binding at gene regulatory regions. Furthermore, we find that the Kiss1-locus is uniquely regulated in these hypothalamic nuclei, and that the nuclear receptor co-repressor NR0B1 (DAX1) restrains its transcription specifically in the arcuate nucleus. These studies provide mechanistic insight into how ERα may control the KISS1-neuron, and Kiss1 gene expression, to couple gonadotropin release to the developmental stage of the oocyte., (© 2023. The Author(s).)

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., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Mills, Abbara, Dhillo and Comninos.)