SFEBES2025 Oral Communications Reproductive and Neuroendocrinology (6 abstracts)
Rapid onset of action of intranasal vs intravenous kisspeptin supports a direct kisspeptin-activated olfactory-reproductive pathway in humans
Jovanna Tsoutsouki 1 , Edouard G. Mills 1,2 , Maria Phylactou 1,2 , Sophie A. Clarke 1 , Layla Thurston 1 , Lisa Yang 1 , Bijal Patel 1 , Pei Chia Eng 1 , Chioma Izzi-Engbeaya 1,2 , Emma C. Alexander 1 , Germaine Chia 1 , Muhammad Choudhury 1 , Paul Bech 1 , Magda Swedrowska 3 , Ben Forbes 3 , Ali Abbara 1,2 , Alexander N. Comninos 1,2 & Waljit S. Dhillo 1,2
1Section of Endocrinology and Investigative Medicine, Imperial College London, London, United Kingdom; 2Department of Endocrinology, Imperial College Healthcare NHS Trust, London, United Kingdom; 3King’s College London, London, United Kingdom
Background: The most well-described pathway for kisspeptin’s activation of the reproductive axis relies on activation of kisspeptin receptors on GnRH-neurons in the hypothalamus. However, recent evidence has identified an extra-hypothalamic population of GnRH-neurons within the olfactory bulb that also express kisspeptin receptors. Intranasal delivery of kisspeptin could directly activate these olfactory bulb GnRH-neurons to stimulate reproductive hormone release and identify a novel olfactory pathway. Here, we compared reproductive hormone responses following intranasal and intravenous kisspeptin administration for the first time in humans, providing mechanistic insight and evidencing a novel, non-invasive clinical route of administration.
Methods: Healthy men received 12.8 nmol/kg of kisspeptin-54 either intranasally (4 sprays, n=12) or as an intravenous bolus (n=5). Reproductive hormone levels were measured every 15mins for 6hrs post-administration. The median time to maximal reproductive hormone response was compared using the Mann-Whitney test.
Results: Both intranasal and intravenous kisspeptin-54 elicited significant gonadotrophin and testosterone responses. Although the peak LH response was lower after intranasal compared to intravenous administration (mean±SEM (IU/l): 4.5±0.6 above baseline for intranasal vs 11.3±1.4 for intravenous, P<0.0001), the LH peak occurred much earlier following intranasal kisspeptin-54, with a median time of 38mins (IQR:30-79) compared to 300mins (IQR:285-308) for intravenous administration (P=0.0002). Similar temporal patterns were observed for FSH, peaking at 38mins (IQR:30-79) after intranasal administration vs 345mins (IQR:345-360) with intravenous kisspeptin-54 (P=0.0002). Testosterone also peaked earlier after intranasal kisspeptin-54, reaching a median maximum at 165mins (IQR:109-240), compared to 345mins (IQR:240-360) with intravenous kisspeptin-54 (P=0.0116).
Discussion: The strikingly faster onset of hormonal responses following intranasal compared to intravenous kisspeptin-54 suggests that this route capitalises on a direct olfactory-reproductive pathway via kisspeptin receptors on olfactory GnRH-neurons. These findings have important clinical implications for kisspeptin administration in common reproductive and psychosexual disorders and support the existence of a novel olfactory-reproductive pathway.
Volume 109
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Endocrine Abstracts
ISSN 1470-3947 (print) | ISSN 1479-6848 (online)
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