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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. [ABSTRACT FROM AUTHOR]

BACKGROUND. Hypoactive sexual desire disorder (HSDD) is characterized by a persistent deficiency of sexual fantasies and desire for sexual activity, causing marked distress and interpersonal difficulty. It is the most prevalent female sexual health problem globally, affecting approximately 10% of women, but has limited treatment options. Melanocortin 4 receptor (MC4R) agonists have emerged as a promising therapy for women with HSDD, through unknown mechanisms. Studying the pathways involved is crucial for our understanding of normal and abnormal sexual behavior. METHODS. Using psychometric, functional neuroimaging, and hormonal analyses, we conducted a randomized, double-blinded, placebo-controlled, crossover clinical study to assess the effects of MC4R agonism compared with placebo on sexual brain processing in 31 premenopausal heterosexual women with HSDD. RESULTS. MC4R agonism significantly increased sexual desire for up to 24 hours after administration compared with placebo. During functional neuroimaging, MC4R agonism enhanced cerebellar and supplementary motor area activity and deactivated the secondary somatosensory cortex, specifically in response to visual erotic stimuli, compared with placebo. In addition, MC4R agonism enhanced functional connectivity between the amygdala and the insula during visual erotic stimuli compared with placebo. CONCLUSION. These data suggest that MC4R agonism enhanced sexual brain processing by reducing self-consciousness, increasing sexual imagery, and sensitizing women with HSDD to erotic stimuli. These findings provide mechanistic insight into the action of MC4R agonism in sexual behavior and are relevant to the ongoing development of HSDD therapies and MC4R agonist development more widely. TRIAL REGISTRATION. ClinicalTrials.gov NCT04179734. FUNDING. This is an investigator-sponsored study funded by AMAG Pharmaceuticals Inc., the Medical Research Council (MRC) (MR/T006242/1), and the National Institute for Health Research (NIHR) (CS-2018-18-ST2-002 and RP-2014-05-001)., Introduction Sexual arousal and desire are fundamental physiological processes in humans and are designed to drive sexual activity and ultimately reproduction at a population level. The presence of sexual arousal [...]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

** denotes P <= 0.01 gl C-peptide levels and pre-existing diabetes C-peptide values at follow-up at least 3 months after initial presentation with COVID-19 compared with those without (median [IQR] C-peptide [pmol/L]: pre-existing diabetes 1550 [1285, 2638], no diabetes 1239 [675, 1622], I P i = .008) (Figure 1B). C-peptide and COVID-19 disease severity and management C-peptide levels were higher in those who had severe or critical disease compared with those with mild disease (median [IQR] C-peptide mild: 762 [510, 1289] pmol/L, severe/critical: 1538 [1143, 2906] pmol/L, I P i = .004) (Figure 1C). Hyperglycaemia1 and new diagnoses of diabetes (including autoantibody-negative type 1 diabetes2) have been reported in patients with coronavirus disease 2019 (COVID-19).1 Moreover, 77% of patients with COVID-19 and ketoacidosis (a condition typically associated with type 1 diabetes or pancreatic destruction) had type 2 diabetes.3 The receptor necessary for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) cellular entry, ACE2, and its permissive protein, TMPRSS2, are present in the pancreatic microvasculature4 and, at postmortem, SARS-CoV-2 viral RNA has been detected in pancreatic beta cells.5 In islets infected with SARS-CoV-2, in vitro insulin secretion, particularly glucose-stimulated insulin secretion, is attenuated.6 Given this, it has been speculated that insulin secretory capacity may be curtailed by direct cytopathic action of SARS-CoV-2 on beta cells. C-peptide is preserved at follow-up at >=3 months following presentation with COVID-19 At the study visit appointment, which took place at least 3 months after initial presentation with COVID-19, median (IQR) C-peptide was 1319 (849, 1905) pmol/L and no patients had undetectable C-peptide levels (<3.3 pmol/L). [Extracted from the article]

Given that long COVID is a complex, multi-system disorder, that remains little understood, larger long-term studies comparing patients diagnosed with COVID-19 and persistent symptoms, to those without, as well as healthy controls, might provide interesting insights into the prevalence of subtle perturbations in adrenal function. Keywords: adrenal cortex hormones; adrenal insufficiency; COVID-19; mineralocorticoids EN adrenal cortex hormones adrenal insufficiency COVID-19 mineralocorticoids 270 272 3 01/03/23 20230201 NES 230201 It is widely recognised that the effects of COVID-19 extend beyond the respiratory system. Letter to the editor of clinical endocrinology: Assessment of adrenal function in patients who survive COVID-19. [Extracted from the article]

Context: Antenatal complications such as hypertensive disorders of pregnancy (HDP), fetal growth restriction (FGR), gestational diabetes (GDM), and preterm birth (PTB) are associated with placental dysfunction. Kisspeptin has emerged as a putative marker of placental function, but limited data exist describing circulating kisspeptin levels across all 3 trimesters in women with antenatal complications. Objective: We aimed to assess whether kisspeptin levels are altered in women with antenatal complications. Methods: Women with antenatal complications (n = 105) and those with uncomplicated pregnancies (n = 265) underwent serial ultrasound scans and blood sampling at the Early Pregnancy Assessment Unit at Hammersmith Hospital, UK, at least once during each trimester (March 2014 to March 2017). The women with antenatal complications (HDP [n = 32], FGR [n = 17], GDM [n = 35], PTB [n = 11], and multiple complications [n=10]) provided 373 blood samples and the controls provided 930 samples. Differences in circulating kisspeptin levels were assessed. Results: Third-trimester kisspeptin levels were higher than controls in HDP but lower in FGR. The odds of HDP adjusted for gestational age, maternal age, ethnicity, BMI, smoking, and parity were increased by 30% (95% CI, 16%-47%; P < 0.0001), and of FGR were reduced by 28% (95% CI, 4-46%; P = 0.025), for every 1 nmol/L increase in plasma kisspeptin. Multiple of gestation-specific median values of kisspeptin were higher in pregnancies affected by PTB (P = 0.014) and lower in those with GDM (P = 0.020), but not significantly on multivariable analysis. Conclusion: We delineate changes in circulating kisspeptin levels at different trimesters and evaluate the potential of kisspeptin as a biomarker for antenatal complications. [ABSTRACT FROM AUTHOR]

Reproductive hormones play a crucial role in the growth and maintenance of the mammalian skeleton. Indeed, the biological significance for this hormonal regulation of skeletal homeostasis is best illustrated by common clinical reproductive disorders, such as primary ovarian insufficiency, hypothalamic amenorrhea, congenital hypogonadotropic hypogonadism, and early menopause, which contribute to the clinical burden of low bone mineral density and increased risk for fragility fracture. Emerging evidence relating to traditional reproductive hormones and the recent discovery of newer reproductive neuropeptides and hormones has deepened our understanding of the interaction between bone and the reproductive system. In this review, we provide a contemporary summary of the literature examining the relationship between bone biology and reproductive signals that extend beyond estrogens and androgens, and include kisspeptin, gonadotropin-releasing hormone, follicle-stimulating hormone, luteinizing hormone, prolactin, progesterone, inhibin, activin, and relaxin. A comprehensive and up-to-date review of the recent basic and clinical research advances is essential given the prevalence of clinical reproductive disorders, the emerging roles of upstream reproductive hormones in bone physiology, as well as the urgent need to develop novel safe and effective therapies for bone fragility in a rapidly aging population. [ABSTRACT FROM AUTHOR]

Context: The hormone kisspeptin has crucial and well-characterized roles in reproduction. Emerging data from animal models also suggest that kisspeptin has important metabolic effects including modulation of food intake. However, to date there have been no studies exploring the effects of kisspeptin on brain responses to food stimuli in humans.Objective: This work aims to investigate the effects of kisspeptin administration on brain responses to visual food stimuli and psychometric parameters of appetite, in healthy men.Design: A double-blinded, randomized, placebo-controlled, crossover study was conducted.Participants: Participants included 27 healthy, right-handed, eugonadal men (mean ± SEM: age 26.5 ± 1.1 years; body mass index 23.9 ± 0.4 kg/m2).Intervention: Participants received an intravenous infusion of 1 nmol/kg/h of kisspeptin or rate-matched vehicle over 75 minutes.Main Outcome Measures: Measurements included change in brain activity on functional magnetic resonance imaging in response to visual food stimuli and change in psychometric parameters of appetite, during kisspeptin administration compared to vehicle.Results: Kisspeptin administration at a bioactive dose did not affect brain responses to visual food stimuli or psychometric parameters of appetite compared to vehicle.Conclusions: This is the first study in humans investigating the effects of kisspeptin on brain regions regulating appetite and demonstrates that peripheral administration of kisspeptin does not alter brain responses to visual food stimuli or psychometric parameters of appetite in healthy men. These data provide key translational insights to further our understanding of the interaction between reproduction and metabolism. [ABSTRACT FROM AUTHOR]