madman
Super Moderator
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 38 mins (IQR:30-79) compared to 300 mins (IQR:285-308) for intravenous administration (P=0.0002). Similar temporal patterns were observed for FSH, peaking at 38 mins (IQR:30-79) after intranasal administration vs 345 mins (IQR:345-360) with intravenous kisspeptin-54 (P=0.0002). Testosterone also peaked earlier after intranasal kisspeptin-54, reaching a median maximum at 165 mins (IQR:109-240), compared to 345 mins (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.
