Bremelanotide enhances sexual brain processing in women with hypoactive sexual desire

A randomized, double-blind, placebo-controlled, crossover clinical study has found that a single subcutaneous injection of bremelanotide significantly increases sexual desire for up to 24 hours through enhancing sexual brain processing in women with hypoactive sexual desire disorder (HSDD).

HSDD is characterized by a persistent or recurrent deficiency of sexual fantasies and desire for sexual activity, resulting in marked distress and interpersonal difficulties. The disorder is not due to a coexisting medical or psychiatric condition, problems with the relationship, or any medication side effects. [Sex Med Rev 2016;4:103-120] It is estimated that approximately 10 percent of women suffer from HSDD, making it the most prevalent global female sexual health complaint. [Obstet Gynecol 2008;112:970-978]

“Sexual therapy and education presently form the basis of treatment for HSDD, with limited pharmacologic therapeutic options available,” wrote the investigators. [Sex Med 2018;6:59-74] “The melanocortin 4 receptor agonist [MC4Ra] bremelanotide, an as-required subcutaneous injection, was approved by the US FDA in 2019 for premenopausal women with generalized, acquired HSDD. However, the mechanism by which MC4Ra mediates effects on sexual behaviour is unknown. We thus sought to define the brain processes underpinning MC4Ra’s effects in this regard.” [J Clin Invest 2022;doi:10.1172/JCI152341]

The study included 31 heterosexual premenopausal women in a stable and monogamous relationship of ≥6 months who were concerned and/or distressed by their low sexual desire. On one visit, the participants received bremelanotide, and on another, identically presented placebo. Following the subcutaneous injection, they were shown a set of erotic videos whilst undergoing functional MRI. In addition, the participants were asked to rate their level of arousal. “The participants acted as their own controls, thereby minimizing the effects of interparticipant variation and maximizing the power of the study,” highlighted the investigators.

Participants were contacted 24 hours after each study visit and asked if they had experienced increased sexual desire in the 24 hours since administration of bremelanotide or placebo. A significantly larger number of participants reported increased sexual desire following bremelanotide administration compared with placebo (p=0.007).

Interestingly, MRI showed that under placebo conditions, functional connectivity between the amygdala and the insula, as well as between the amygdala and the thalamus, which are important regions involved in normal response to erotic stimuli, was relatively high in the resting state, but was decreased by exposure to the erotic stimulus. “This may be because when women with HSDD are exposed to erotic stimuli, they interpret this as a negative rather than a positive stimulus, with resulting suppression of connectivity being due to the hyperfunctional ‘top-down’ inhibition of sexual desire pathways,” explained the investigators.

In contrast, bremelanotide prevented the reduction of functional connectivity between the amygdala and the insula, which occurred with placebo. In addition, compared with placebo, bremelanotide enhanced cerebellar and supplementary motor area brain activity and deactivated the secondary somatosensory cortex vs placebo in response to erotic stimuli.

“In summary, these data define the neural substrates and connections through which MC4R agonism modulates sexual brain processing to increase sexual desire. These changes in brain activation reduce self-monitoring and spectatoring of the sexual response, increase sexual imagery, and sensitize women with HSDD to erotic stimuli,” concluded the researchers.