Effects of Kisspeptin on Sexual Brain Processing and Penile Tumescence in Men With Hypoactive Sexual Desire Disorder

Abstract

ImportanceThe human physiological sexual response is crucial for reward, satisfaction, and reproduction. Disruption of the associated neurophysiological pathways predisposes to low sexual desire; the most prevalent psychological form is hypoactive sexual desire disorder (HSDD), which affects 8% of men but currently has no effective pharmacological treatment options. The reproductive neuropeptide kisspeptin offers a putative therapeutic target, owing to emerging understanding of its role in reproductive behavior.ObjectiveTo determine the physiological, behavioral, neural, and hormonal effects of kisspeptin administration in men with HSDD.Design, Setting, and ParticipantsThis double-blind, 2-way crossover, placebo-controlled randomized clinical trial was performed at a single academic research center in the UK. Eligible participants were right-handed heterosexual men with HSDD. Physiological, behavioral, functional magnetic resonance imaging (fMRI), and hormonal analyses were used to investigate the clinical and mechanistic effects of kisspeptin administration in response to visual sexual stimuli (short and long video tasks). The trial was conducted between January 11 and September 15, 2021, and data analysis was performed between October and November 2021.InterventionsParticipants attended 2 study visits at least 7 days apart, in balanced random order, for intravenous infusion of kisspeptin-54 (1 nmol/kg/h) for 75 minutes or for administration of a rate-matched placebo.Main Outcomes and MeasuresChanges in (1) brain activity on whole-brain analysis, as determined by fMRI blood oxygen level–dependent activity in response to visual sexual stimuli during kisspeptin administration compared with placebo, (2) physiological sexual arousal (penile tumescence), and (3) behavioral measures of sexual desire and arousal.ResultsOf the 37 men randomized, 32 completed the trial. Participants had a mean (SD) age of 37.9 (8.6) years and a mean (SD) body mass index of 24.9 (5.4). On viewing sexual videos, kisspeptin significantly modulated brain activity in key structures of the sexual-processing network on whole-brain analysis compared with placebo (mean absolute change [Cohen d] = 0.81 [95% CI, 0.41-1.21]; P = .003). Furthermore, improvements in several secondary analyses were observed, including significant increases in penile tumescence in response to sexual stimuli (by up to 56% more than placebo; mean difference = 0.28 units [95% CI, 0.04-0.52 units]; P = .02) and behavioral measures of sexual desire—most notably, increased happiness about sex (mean difference = 0.63 points [95% CI, 0.10-1.15 points]; P = .02).Conclusions and RelevanceCollectively, this randomized clinical trial provides the first evidence to date showing that kisspeptin administration substantially modulates sexual brain processing in men with HSDD, with associated increases in penile tumescence and behavioral measures of sexual desire and arousal. These data suggest that kisspeptin has potential as the first pharmacological treatment for men with low sexual desire.Trial Registrationisrctn.org Identifier: ISRCTN17271094

Women and men with distressing low sexual desire exhibit sexually dimorphic brain processing

“…To compare neural correlates in distressing low sexual desire in women and men, data was collected from the placebo visits of our parallel studies exploring the effects of hormone administration on sexual-brain processing in premenopausal women and men with HSDD (full methods described in 29 , 30 ).…”

“…Participants were required to have no current or past psychiatric illness and be free of current medications. Detailed inclusion and exclusion criteria can be found in 29 , 30 . Of note, participants were required to be in a stable, communicative, and monogamous relationship for > 6 months.…”

“…Blood samples were taken to ensure normal health status and exclude any endocrine abnormalities. All participants were biochemically eugonadal, with a normal circulating testosterone level (in men) and premenopausal status (in women) (as reported in 29 , 30 ).…”

Oral sodium oxybate does not alter plasma kisspeptin levels in healthy male volunteers

“…In humans, GHB has prosexual effects and stimulates the release of progesterone, but not oxytocin and testosterone (Bosch et al, 2015). An important modulator of sexual functioning is the peptide hormone kisspeptin, which was demonstrated to regulate GABAergic transmission in the limbic system (Comninos et al, 2021) and to induce prosexual effects in patients with low sexual desire (Mills et al, 2023). Kisspeptin expression is both regulated by GABA-B receptor stimulation (Di Giorgio et al, 2019) and progesterone release (Marraudino et al, 2018).…”

Post-orgasmic Illness Syndrome

“…There are many rare and unusual disorders in neuropsychiatry that have captured attention in recent years; these range from misophonia 1 to leg stereotypy disorder 2 . There are many rare and unusual disorders in sexual medicine, as well; these include Koro 3 , persistent genital arousal syndrome 4,5 , coital cephalgia 6,7 , hypoactive sexual desire disorder specifically in men 8 , and post-orgasmic illness syndrome (POIS), the subject of this editorial.…”