OR14-07 Gonadotropin Response Following Intranasal Kisspeptin Administration Is Augmented in Women With Hypothalamic Amenorrhoea Compared To Healthy Women

Abstract 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