SUN-083 Distinct Temporal Onset of Kisspeptin Action via Intranasal and Intravenous Administration Highlights a Novel Olfactory-Reproductive Pathway in Humans

Abstract 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