Discussion
penile tumescence, Flushing, low sexual desire
CORTEX
This randomized clinical trial provides the first clinical evidence, to our knowledge, showing that kisspeptin administration in men with low sexual desire modulates sexual brain processing, enhances penile tumescence in response to sexual stimuli (by up to 56% more than placebo), and improves behavioral measures of sexual desire and arousal.Notably, in this study, kisspeptin increased happiness about sex as well as flushing. Flushing is a common feature encountered by 25% of men during sexual arousal.In the short videos task, kisspeptin modulated activity in 3 distinct and relevant brain regions (left MFG, left ACC, and bilateral parahippocampus). The left MFG, a region expressing kisspeptin receptors,In addition, kisspeptin enhanced left ACC activity. This brain region also expresses kisspeptin receptorsIn the short sexual videos task, we observed deactivation of the bilateral parahippocampus, which also expresses kisspeptin receptors.During the long video task, we observed that kisspeptin elicited a marked increase in penile tumescence, providing evidence for kisspeptin’s proerectile effects in humans. Regarding the neural pathways involved, kisspeptin increased activity in 2 key visual brain regions (right fusiform gyrus and bilateral visual cortex). This finding is consistent with a previous meta-analysis of fMRI studies in healthy men, which reported that exposure to sexual stimuli consistently induced marked fusiform gyrus activationRegarding the neural pathways involved in subjective arousal, kisspeptin decreased activity in 3 distinct brain regions (right PCC, bilateral precuneus, and left frontal pole) during the long video task. Kisspeptin’s deactivation of the right PCC and bilateral precuneus is concordant with a previous fMRI study in healthy men, which reported similar deactivations in response to sexual stimuli.Kisspeptin administration during the long video task also deactivated the left frontal pole, another region that expresses kisspeptin receptorsFurthermore, we observed significant correlations between kisspeptin-enhanced brain activity and important baseline behavioral parameters. In men reporting higher baseline sex-related distress, greater kisspeptin enhancement was observed in the PCC, a key reward and motivation structureIn addition to baseline behavioral parameters, we observed significant correlations between kisspeptin-enhanced brain activity and behavioral measures of sexual function in the current moment. The more kisspeptin enhanced globus pallidus activity during short sexual videos, the more sexually “naughty” the participants felt; this finding is relevant given that the globus pallidus expresses kisspeptin receptorsMechanistically, we administered peripheral kisspeptin-54, which can activate gonadotropin-releasing hormone neuron dendritic terminals before the blood-brain barrierThe promise of efficacy identified by our data raises several directions for future clinical investigation. Kisspeptin can easily and safely be administered via several routes, including by subcutaneous