Kisspeptin infusion may restore lost libido in men

An infusion of kisspeptin appears to be beneficial to men with hypoactive sexual desire disorder (HSDD), modulating sexual brain processing, improving penile tumescence, and boosting sexual desire and arousal, as reported in a study.

On whole-brain analysis, kisspeptin was associated with significantly modulated activity in the brain’s key sexual-processing structures during a task that involved watching sexual videos as compared with placebo (mean absolute change, 0.81, 95 percent confidence interval [CI], 0.41–1.21; p=0.003). [JAMA Netw Open 2023;6:e2254313]

Moreover, penile tumescence in response to sexual stimuli went up by up to 56 percent with kisspeptin than with placebo (mean difference, 0.28 units, 95 percent CI, 0.04–0.52; p=0.02). Kisspeptin was also associated with other positive changes in behavioural measures of sexual desire, such as increased happiness about sex (mean difference, 0.63 points, 95 percent CI, 0.10–1.15 points; p=0.02) and participant-reported flushing (mean difference, 0.63 points, 95 percent CI, 0.11–1.14; p=0.02), which, according to the investigators, is normally experienced by a quarter of men during sexual arousal.

“Collectively, this randomized clinical trial provides the first evidence to date showing that kisspeptin administration substantially modulates sexual brain processing in men with HSDD … [and] that kisspeptin has potential as the first pharmacological treatment for men with low sexual desire,” the investigators said.

The two-way crossover, placebo-controlled trial included 32 men (mean age 37.9 years, mean body mass index 24.9 kg/m², 68 percent White) who received an infusion of kisspeptin-54 (1 nmol/kg/h) for 75 minutes and a rate-matched placebo at separate visits, conducted 7 days apart.

Mechanistic insights

“The neuropeptide kisspeptin is a crucial endogenous activator of the reproductive system, with extensive distribution throughout the rodent and human brain,” the investigators said. [N Engl J Med 2003;349:1614-1627; FEBS Lett 1999;446:103-107; J Biol Chem 2001;276:28969-28975; Nature 2001;411:613-617]

In animal models, kisspeptin signalling modulates reproductive behaviour, including sexual motivation, and erections. In healthy men, on the other hand, kisspeptin augments limbic activity in response to sexual stimuli while reducing sexual aversion. [Nat Rev Endocrinol 2021;17:97-113; J Neuroendocrinol 2018;30:e12572; Neurosci Lett 2016;627:13-17]

In the current study, the results of whole-brain analysis showed that kisspeptin increased activity in the left middle frontal gyrus (MFG) and left anterior cingulate cortex (ACC), deactivated the bilateral parahippocampus, and reduced activity in the right posterior cingulate cortex (PCC), bilateral precuneus, and left frontal pole.

The left MFG is an important component of the executive attention network, while the left ACC is involved in the motivational and autonomic components of sexual desire and arousal, the investigators pointed out. [Behav Brain Funct 2009;5:41; Hum Brain Mapp 2000;11:162-177]

Therefore, in the context of these brain regions’ established roles, the activation of left MFG and ACC “may enable men with HSDD to increase attentional capture of sexual cues … [and] heighten the motivation for sexual activity,” they added.

Meanwhile, the parahippocampus, right PCC and bilateral precuneus, and left frontal pole have been implicated in introspective self-monitoring and self-control. Kisspeptin’s effect on these three brain regions may serve to downregulate introspective processes and “promote attention to sexual stimuli, while reducing self-focus that may otherwise disrupt sexual function in HSDD,” according to the investigators. [J Comp Neurol 2005;493:132-139; Front Hum Neurosci 2013;7:666]

“Taken together, our data suggest that pharmacological use of kisspeptin-based therapeutics may offer the first safe and much-needed clinical strategy for men with HSDD and low sexual desire more broadly,” they said.