Disclosure: E. Mills: None. J. Tsoutsouki: None. L. Thurston: None. M. Phylactou: None. B. Patel: None. L. Yang: None. S. Clarke: None. M. Young: None. E. Alexander: None. S. Nyunt: None. A. Yeung: None. M. Choudhury: None. A. Newman: None. P. Bech: None. A. Abbara: None. M. Swedrowska: None. B. Forbes: None. A. Comninos: None. W. Dhillo: None. Background: Kisspeptin administration by intravenous or subcutaneous routes activates hypothalamic GnRH neurons to stimulate downstream reproductive hormone release and is under rapid development for treating common reproductive disorders, including hypothalamic amenorrhea (HA). However, these invasive routes limit patient acceptability and clinical use. Intranasal administration offers a novel non-invasive delivery route, which would be clinically preferable to patients and clinicians. Herein, we compare the reproductive endocrine responses after intranasal kisspeptin administration in healthy women to women with HA. Methods: Randomized, double-blinded, placebo-controlled, crossover study in 12 healthy (ovulatory) women during the follicular phase (mean age ± SEM 22.1 ± 0.9 yrs, BMI 22.1 ± 0.8 kg/m2) and 10 women with HA (age 25.8 ± 2.7 yrs, BMI 19.9 ± 1.3 kg/m2). After intranasal delivery of kisspeptin-54 (12.8 nmol/kg) or 0.9% saline (placebo), reproductive hormones were measured every 15 minutes for 4 hours. Groups were compared by unpaired t-tests. Results: Intranasal kisspeptin-54 administration rapidly and robustly stimulated gonadotropin release in both study cohorts. However, LH and FSH release were significantly augmented in women with HA, compared to healthy women: mean area under the curve (AUC) for the change in LH across 4 hours 96.0 ± 45.8 h·IU/L (healthy women) vs. 600.6 ± 146.7 h·IU/L (women with HA) (P = 0.002). Consistently, mean AUC for the change in FSH was -36.1 ± 23.4 h·IU/L (healthy women) vs. 474.9 ± 237.3 h·IU/L (women with HA) (P = 0.02). The mean maximal increase in LH following kisspeptin-54 was over three-fold greater in women with HA at 4.4 ± 0.2 IU/L vs. 1.4 ± 0.3 IU/L in healthy women (P < 0.001). Similarly, the mean maximal increase in FSH was over ten-fold greater in women with HA at 3.1 ± 0.3 IU/L vs. 0.3 ± 0.1 IU/L in healthy women (P = 0.03). Summary: Intranasal kisspeptin robustly stimulates reproductive hormone release in healthy women, with an even greater stimulation in women with HA. Therefore, intranasal kisspeptin offers not only a novel, effective, safe, and non-invasive route of administration for the management of reproductive disorders but also a potential simple diagnostic test to identify women with HA. Presentation: Sunday, July 13, 2025

Disclosure: J. Tsoutsouki: None. E. Mills: None. M. Phylactou: None. S.A. Clarke: None. L. Thurston: None. L. Yang: None. B. Patel: None. P. Eng: None. C. Izzi-Engbeaya: None. E.C. Alexander: None. P. Bech: None. M. Swedrowska: None. B. Forbes: None. A. Abbara: None. A.N. Comninos: None. W.S. Dhillo: None. Background: The neuropeptide kisspeptin is known to activate the reproductive axis primarily by stimulating kisspeptin receptors on hypothalamic GnRH neurons. However, recent rodent evidence has identified an extra-hypothalamic population of GnRH neurons in the olfactory bulb, which also express kisspeptin receptors. Intranasal kisspeptin administration may directly activate these extra-hypothalamic olfactory bulb-GnRH neurons, triggering reproductive hormone release and revealing a novel olfactory-reproductive pathway. Herein, we compare the reproductive hormone responses to intranasal and intravenous kisspeptin administration in humans, providing mechanistic insights and highlighting the potential of intranasal kisspeptin as an effective and non-invasive delivery route. Methods: Healthy male participants received 12.8 nmol/kg of kisspeptin-54 via either intranasal delivery (n=12) or intravenous bolus injection (n=5). Reproductive hormone levels were measured every 15 minutes for 6 hours following administration. The mean maximum increase in reproductive hormones from baseline and the median time to peak response between the two groups were analyzed using an unpaired t-test and Mann-Whitney test, respectively. Results: Both intranasal and intravenous kisspeptin-54 elicited significant reproductive hormone responses. The peak LH response was lower with intranasal, compared to intravenous administration (mean change from baseline ± SEM [IU/L]: 4.5 ± 0.6 intranasal vs. 11.3 ± 1.4 intravenous, p<0.0001). However, intranasal kisspeptin-54 induced a markedly earlier LH peak, with a median time of 38 minutes, compared to 300 minutes for intravenous administration (p=0.0002). A similar pattern was observed for FSH, with a peak of 0.7 ± 0.2 above baseline at 38 minutes following intranasal, compared to 2.3 ± 0.22 above baseline at 345 minutes with intravenous kisspeptin-54 administration (p=0.0003 for magnitude, p=0.0002 for timing). The peak testosterone responses did not differ significantly between intranasal and intravenous kisspeptin-54 (p=0.1864), although the median peak occurred earlier following intranasal (165 minutes), compared to intravenous administration (345 minutes; p=0.0116). No adverse effects were reported with either delivery route. Discussion: The significantly faster onset of reproductive hormone responses following intranasal compared to intravenous kisspeptin-54 administration suggests a direct olfactory-reproductive pathway, likely mediated by kisspeptin receptors on olfactory GnRH neurons. These findings have significant clinical implications for the therapeutic use of kisspeptin in managing common reproductive and psychosexual disorders, whilst also providing evidence for a novel kisspeptin-mediated olfactory-reproductive pathway in humans. Presentation: Sunday, July 13, 2025

CONTEXT:Kisspeptin is a critical endogenous activator of the reproductive system, with escalating clinical interest as a novel therapeutic for common reproductive and psychosexual disorders. However, conflicting animal data suggest that kisspeptin can have anxiolytic, neutral, or anxiogenic effects. OBJECTIVE:Given the rapid development of kisspeptin-based therapeutics, it is important to comprehensively investigate the effects of kisspeptin administration on behavioral, biochemical, and physiological measures of anxiety in humans. METHODS:Ninety-five participants (N = 63 male, N = 32 female) completed a double-blind, randomized, placebo-controlled, crossover protocol (mean age ± SEM 30.9 ± 0.9 y, body mass index 24.0 ± 0.4), attending both for a 75-minute intravenous kisspeptin-54 infusion (1 nmol/kg/h) and rate-matched placebo (in random order). Behavioral, biochemical, and physiological measures of anxiety were compared between kisspeptin and placebo visits, using a state-anxiety psychometric questionnaire before and at the end of the infusions, and blood sampling (for reproductive hormones and cortisol) and heart rate measurements at 15-minute intervals. Blood pressure assessment took place before and at the end of the infusions. RESULTS:Kisspeptin administration robustly increased serum luteinizing hormone to similar levels previously described using this administration protocol, confirming that the dose was biologically active (P < .001). State anxiety was not significantly altered by kisspeptin, compared to placebo (P = .13). Moreover, kisspeptin had no significant effects on circulating cortisol (P = .73), systolic (P = .74) or diastolic blood pressure (P = .90), or heart rate (P = .52). CONCLUSION:This is the first study demonstrating that a biologically active dose of kisspeptin to men and women does not affect behavioral, biochemical, or physiological measures of anxiety. Given that animal studies have yielded contradictory results, this provides key clinical data and reassurance that kisspeptin does not induce anxiety in humans and so informs the current development of kisspeptin-based therapeutics for common reproductive and psychosexual disorders.

BACKGROUND:Kisspeptin administration by intravenous or subcutaneous routes activates hypothalamic gonadotropin-releasing hormone (GnRH) neurons and is being developed to treat reproductive disorders. However, these invasive routes markedly limit patient acceptability and clinical use. Recent rodent data has identified a large GnRH population within the olfactory system communicating directly with hypothalamic GnRH neurons. Intranasal kisspeptin administration may be able to capitalise on this novel pathway and thus offer a potential non-invasive approach to stimulate reproductive hormones. Herein, we examine intranasal kisspeptin using human, pharmaceutical, and rodent studies. METHODS:Reproductive hormone profiles were measured after intranasal kisspeptin administration in healthy volunteers and patients with reproductive disorders as part of a randomised, double-blinded, crossover, placebo-controlled clinical study. Pharmaceutical testing evaluated the chemical stability and nasal kisspeptin delivery, and rodent studies provided mechanistic insight. FINDINGS:Intranasal kisspeptin-54 rapidly stimulates gonadotropin release in healthy men and women, and in patients with a common reproductive disorder (hypothalamic amenorrhoea), without any side effects or adverse events encountered. Specifically, intranasal kisspeptin (at 12.8 nmol/kg) induced clinically-significant mean maximal increases above baseline in serum luteinising hormone in all study groups: 4.4 ± 0.6 IU/L (mean difference = 3.1 IU/L [95% CI, 1.2-4.9], P = 0.002 vs. placebo) in healthy men; 1.4 ± 0.3 IU/L (mean difference = 1.0 IU/L [95% CI, 0.4-1.7], P = 0.004 vs. placebo) in healthy women; 4.4 ± 0.2 IU/L (mean difference = 4.3 IU/L [95% CI, 2.7-6.0], P < 0.001 vs. placebo) in patients with hypothalamic amenorrhoea. Kisspeptin-54 was delivered effectively via nasal spray and was stable for up to 60 days at 4 °C. Mirroring the human effects, intranasal kisspeptin-54 in adult C57BL/6J male mice stimulates luteinising hormone release. Further mechanistic insights reveal the accumulation of fluorescently-tagged kisspeptin in the olfactory epithelium, as well as the presence of kisspeptin receptors in olfactory bulb GnRH neurons, implicating the involvement of these extra-hypothalamic GnRH neurons in the pathway mediating intranasal kisspeptin's effects on reproductive hormones. INTERPRETATION:We demonstrate the clinical potential for intranasal kisspeptin delivery as the first non-invasive method to robustly and safely stimulate gonadotropins with kisspeptin and potentially transform the management of reproductive disorders. FUNDING:National Institute for Health and Care Research (NIHR)/NIHR Imperial Biomedical Research Centre/Medical Research Council (MRC).

Abstract Disclosure: J. Tsoutsouki: None. N. Ertl: None. E.G. Mills: None. M.B. Wall: None. L. Thurston: None. L. Yang: None. S. Suladze: None. T. Hunjan: None. M. Phylactou: None. B. Patel: None. J. Howard: None. A. Abbara: None. D. Golmeier: None. A.N. Comninos: None. W.S. Dhillo: None. Background: Distressing low sexual desire, termed Hypoactive Sexual Desire Disorder (HSDD), affects 10% of women and 8% of men. The established ‘top-down’ neurofunctional model of HSDD in women suggests that in response to erotic cues, excessive activation of higher-level cognitive brain regions (involved in introspection/self-monitoring) suppresses lower-level sexual brain centres, thereby impeding normal sexual function. By contrast, the neurodysfunction in men with HSDD remains to be fully characterised and crucially unlike in women, there are currently no licensed therapies. Herein, we report the first direct comparison of the neural bases of HSDD in women and men. Methods: 32 premenopausal women with HSDD [mean age±SD (y) 29.2±6.7] and 32 men with HSDD [age 37.9±8.6] underwent a task-based functional MRI (fMRI) measuring sexual brain activity during erotic versus control (exercise) videos. Participants completed psychometric questionnaires before and after the fMRI scan, providing functional relevance for the brain activity changes. Results: Women displayed significantly greater activation in higher-level cortical regions (e.g. inferior frontal gyrus, superior frontal gyrus) and lower-level limbic brain regions (e.g. amygdala, striatum, thalamus) in response to erotic videos, compared to the men. Lower activation in lower-limbic sexual regions in women correlated with more severe HSDD, which along with a hyperactivation in the inferior-frontal gyrus relative to the men, supports the ‘top-down’ mechanism underlying HSDD in women. By contrast, men exhibited lower activation in both higher-cortical and lower-limbic regions, but greater activation than the women in the visual cortex in response to erotic videos. Hence, a heightened sensitivity to visual erotic cues in men might not be effectively relayed to the limbic system. In women only, hypothalamic hyperactivation in response to erotic videos correlated with ‘increased heartbeat’ (r=0.5, P=0.001), and ‘tingling all over’ (r=0.6, P<0.001), while higher striatal activation correlated with feeling more ‘stimulated’ (r=0.4, P=0.001) and ‘genital tingling’ (r=0.6, P<0.001) on the psychometric questionnaires. Crucially, these findings were specific to erotic stimuli as no differences were identified in the control comparison (exercise>baseline contrast). Discussion: This is the first study to directly compare the neural bases of distressing low sexual desire in women and men. While supporting the ‘top-down’ mechanism of HSDD in women, it suggests a different neurodysfunctional process in men with HSDD, highlighting a potential functional disconnection between sensory/attention and sexual centres. Our findings have key clinical implications as they identify a sexual dimorphism in the neural bases of low sexual desire relevant to the escalating development of therapeutics for patients with HSDD. Presentation: 6/3/2024

Abstract Disclosure: E.G. Mills: None. L. Thurston: None. L. Yang: None. S. Suladze: None. T. Hunjan: None. M. Phylactou: None. B. Patel: None. S.A. Clarke: None. A.J. Shah: None. C. Izzi-Engbeaya: None. J. Tsoutsouki: None. P. Bech: None. N. Ertl: None. L. Demetriou: None. M.B. Wall: None. D. Goldmeier: None. A. Abbara: None. A.N. Comninos: None. W.S. Dhillo: None. Background: The neuropeptide kisspeptin is a critical endogenous activator of the reproductive system. Due to its key role in regulating reproductive and behavioural processes, there has been escalating interest in targeting kisspeptin-pathways to treat reproductive and psychosexual disorders. However, conflicting evidence from pre-clinical animal models proposes that kisspeptin can have an anxiolytic, anxiogenic or have no effects on anxiety. Given the rapid development of kisspeptin-based therapeutics, it is important to clarify kisspeptin’s effects on anxiety in humans. Herein, we report the largest study examining the effects of kisspeptin on psychometric measures of anxiety and circulating cortisol levels in humans. Methods: Ninety-three eugonadal participants (n=29 healthy men, n=32 men with low sexual desire, n=32 women with low sexual desire) completed a double-blind, randomised, placebo-controlled, crossover study. Participants attended twice: once for intravenous infusion of kisspeptin-54 (1nmol/kg/h) over 75mins and for a rate-matched placebo. Blood sampling took place at 15-minute intervals from -30 to 75mins to measure circulating kisspeptin, LH, testosterone and cortisol [in men] and oestradiol [in women]. The validated ‘State-Trait Anxiety Inventory (STAI) Y2-Trait’ was completed prior to the infusions to exclude abnormal anxiety traits, with all scores within normal limits. Participants also completed the ‘STAI Y1-State’ before and prior to the end of the infusions to assess for any dynamic effects of the infusions on anxiety. Results: Ninety-three participants (mean age ±SD 30.9±8.7yrs, BMI 24.0±3.7kg/m2) completed the study. Intravenous kisspeptin significantly increased serum LH to similar levels previously described using this administration protocol, confirming that the dose was biologically active (P<0.001). Importantly, state anxiety was unaltered by kisspeptin, compared to placebo (mean difference in ‘STAI Y1-State’ scores during the infusions: kisspeptin -0.03±8.11, placebo 0.77±8.08, P=0.43). Moreover, kisspeptin had no effect on circulating cortisol compared to placebo during the 75minute study period (P=0.92). As expected, kisspeptin had no significant effects on downstream sex-steroid levels during the 75minute study period, thereby excluding these as confounders. Discussion: This is the largest study demonstrating that a biologically active dose of kisspeptin to healthy volunteers and patients with psychosexual disorders does not affect psychometric measures of anxiety and associated circulating cortisol levels. Given that animal studies have yielded conflicting results, this provides important clinical data and reassurance that kisspeptin administration in humans does not induce anxiety and so informs the rapid development of kisspeptin-based therapeutics for reproductive and psychosexual disorders. Presentation: 6/3/2024

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.

Searchable abstracts of presentations at key conferences in endocrinology ISSN 1470-3947 (print) | ISSN 1479-6848 (online)

Objectives Immune checkpoint inhibitors (ICIs) are associated with immune-related adverse events (irAEs), of which endocrinopathies are common. We characterized endocrine and non-endocrine irAEs in cancer patients receiving ICIs, identified risk factors for their development and established whether endocrine and non-endocrine irAEs were differentially associated with improved cancer prognosis.Design and methods Single-center, retrospective cohort study of patients with advanced or metastatic solid tumors receiving at least one ICI treatment cycle (242 men, 151 women, median age 65 years). Main outcome measures were incidence of any irAE during the study period, overall survival and time to treatment failure.Results Non-endocrine irAEs occurred in 32% and endocrine irAEs in 12% of patients. Primary thyroid dysfunction was the most common endocrine irAE (9.5%) and the majority of endocrinopathies required permanent hormone replacement. Women had an increased risk of developing endocrine irAEs (p = 0.017). The biggest survival advantage occurred in patients who developed both endocrine and non-endocrine irAEs (overall survival: HR 0.16, CI 0.09-0.28). Time to treatment failure was also significantly improved in patients who developed endocrine irAEs (HR 0.49, CI 0.34 - 0.71) or both (HR 0.41, CI 0.25 - 0.64) but not in those who only developed non-endocrine irAEs.Conclusions Women may have increased risk of endocrine irAEs secondary to ICI treatment. This is the first study to compare the effects of endocrine irAEs with non-endocrine irAEs on survival. Development of endocrine irAEs may confer survival benefit in ICI treatment and future, prospective studies are needed to elucidate this.

Searchable abstracts of presentations at key conferences in endocrinology ISSN 1470-3947 (print) | ISSN 1479-6848 (online)

Searchable abstracts of presentations at key conferences in endocrinology ISSN 1470-3947 (print) | ISSN 1479-6848 (online)

IMPORTANCE The human physiological sexual response is crucial for reward, satisfaction, and reproduction. Disruption of the associated neurophysiological pathways predisposes to low sexual desire; the most prevalent psychological form is hypoactive sexual desire disorder (HSDD), which affects 8% of men but currently has no effective pharmacological treatment options. The reproductive neuropeptide kisspeptin offers a putative therapeutic target, owing to emerging understanding of its role in reproductive behavior. OBJECTIVE To determine the physiological, behavioral, neural, and hormonal effects of kisspeptin administration in men with HSDD. DESIGN, SETTING, AND PARTICIPANTS This double-blind, 2-way crossover, placebo-controlled randomized clinical trial was performed at a single academic research center in the UK. Eligible participants were right-handed heterosexual men with HSDD. Physiological, behavioral, functional magnetic resonance imaging (fMRI), and hormonal analyses were used to investigate the clinical and mechanistic effects of kisspeptin administration in response to visual sexual stimuli (short and long video tasks). The trial was conducted between January 11 and September 15, 2021, and data analysis was performed between October and November 2021. INTERVENTIONS Participants attended 2 study visits at least 7 days apart, in balanced random order, for intravenous infusion of kisspeptin-54 (1 nmol/kg/h) for 75 minutes or for administration of a rate-matched placebo. MAIN OUTCOMES AND MEASURES Changes in (1) brain activity on whole-brain analysis, as determined by fMRI blood oxygen level-dependent activity in response to visual sexual stimuli during kisspeptin administration compared with placebo, (2) physiological sexual arousal (penile tumescence), and (3) behavioral measures of sexual desire and arousal. RESULTS Of the 37 men randomized, 32 completed the trial. Participants had a mean (SD) age of 37.9 (8.6) years and a mean (SD) body mass index of 24.9 (5.4). On viewing sexual videos, kisspeptin significantly modulated brain activity in key structures of the sexual-processing network on whole-brain analysis compared with placebo (mean absolute change [Cohen d] = 0.81 [95% CI, 0.41-1.21]; P =.003). Furthermore, improvements in several secondary analyses were observed, including significant increases in penile tumescence in response to sexual stimuli (by up to 56% more than placebo; mean difference = 0.28 units [95% CI, 0.04-0.52 units]; P =.02) and behavioral measures of sexual desire-most notably, increased happiness about sex (mean difference = 0.63 points [95% CI, 0.10-1.15 points]; P =.02). CONCLUSIONS AND RELEVANCE Collectively, this randomized clinical trial provides the first evidence to date showing that kisspeptin administration substantially modulates sexual brain processing in men with HSDD, with associated increases in penile tumescence and behavioral measures of sexual desire and arousal. These data suggest that kisspeptin has potential as the first pharmacological treatment for men with low sexual desire.

Searchable abstracts of presentations at key conferences in endocrinology ISSN 1470-3947 (print) | ISSN 1479-6848 (online)

Substantial leaps have been made in the drug discovery front in tackling the growing pandemic of obesity and its metabolic co-morbidities. Greater mechanistic insight and understanding of the gut-brain molecular pathways at play have enabled the pursuit of novel therapeutic agents that possess increasingly efficacious weight-lowering potential whilst remaining safe and tolerable for clinical use. In the wake of glucagon-like peptide 1 (GLP-1) based therapy, we look at recent advances in gut hormone biology that have fermented the development of next generation pharmacotherapy in diabesity that harness synergistic potential. In this paper, we review the latest data from the SURPASS and SURMOUNT clinical trials for the novel 'twincretin', known as Tirzepatide, which has demonstrated sizeable body weight reduction as well as glycaemic efficacy. We also provide an overview of amylin-based combination strategies and other emerging therapies in the pipeline that are similarly providing great promise for the future of chronic management of obesity.

Abstract Disclosure: E.G. Mills: None. M. Swedrowska: None. V. Delli: None. K. Chachlaki: None. M. Silva: None. L. Decoster: None. G. Ternier: None. L. Thurston: None. M. Phylactou: None. B. Patel: None. L. Yang: None. S.A. Clarke: None. B. Muzi: None. E.C. Alexander: None. M. Choudhury: None. P. Bech: None. A. Abbara: None. B. Forbes: None. P. Giacobini: None. V. Prevot: None. A.N. Comninos: None. W.S. Dhillo: None. Background: Kisspeptin is a key regulator of hypothalamic GnRH neurons with emerging potential to treat reproductive, psychosexual and bone disorders. However, current therapeutic application is limited to the subcutaneous or intravenous routes, which presents significant barriers to further development. Alternative delivery routes could overcome this and capitalise on the clinical utility of kisspeptin-based therapeutics. Herein, we comprehensively examine the translational potential of intranasal kisspeptin administration for the first time using a series of human, rodent and pharmaceutical studies. Methods:Human studies: Healthy men (n=12) and a patient group of women with Hypothalamic Amenorrhoea (HA) (n=5) completed a randomised, double-blind, crossover, placebo-controlled study investigating the acute effects of intranasal kisspeptin-54 administration (doses 3.2-25.6nmol/kg [healthy men] and 12.8nmol/kg [women with HA] vs 0.9% saline placebo). Plasma kisspeptin and serum reproductive hormones were measured every 15mins for 4hrs. Thereafter, we conducted rodent studies in adult C57BL/6J male mice to elucidate the possible mechanism by which intranasal kisspeptin induces reproductive hormone release, using intranasal administration of fluorescently-tagged kisspeptin-54 and a series of c-Fos experiments. From a medicines development perspective, we undertook pharmaceutical studies to evaluate the chemical stability of kisspeptin-54 in solution for nasal delivery in real-time. Results:Human studies: in healthy men, intranasal kisspeptin dose-dependently increased plasma kisspeptin at doses 6.4-25.6nmol/kg (p<0.01 for all doses vs placebo), with the maximal rises achieved within 15-30 minutes. Correspondingly, intranasal kisspeptin acutely and potently increased serum LH at doses 6.4-25.6nmol/kg (p<0.01 all doses vs placebo) with maximal rises at 30 minutes. Likewise, in women with HA, intranasal kisspeptin acutely increased plasma kisspeptin (p=0.004 vs placebo) and serum LH (p=0.004 vs placebo). Animal studies: To provide mechanistic insight, we demonstrate in male mice that GnRH neurons located in the olfactory bulb express kisspeptin receptors and that intranasal administration of fluorescently-tagged kisspeptin-54 binds to the olfactory epithelium. Pharmaceutical studies: Kisspeptin-54 in 0.9% saline remained within pharmaceutically accepted limits for stability for up to 60 days at 4°C demonstrating realistic pharmaceutical potential. Conclusion: We identify robust clinical effects and provide mechanistic and pharmaceutical data for intranasal delivery as a novel, non-invasive, safe and effective kisspeptin administration route for the management of common reproductive disorders that would be far preferable to patients and clinicians and so transform the ongoing rapid development of kisspeptin-based therapeutics. Presentation: Saturday, June 17, 2023

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.