Hypoactive sexual desire disorder (HSDD) is characterised by a persistent lack of sexual desire and sexual fantasies, causing marked interpersonal distress. It is the most common global female sexual health problem, although the precise pathophysiology remains uncertain. Existing treatment options are limited by their efficacy and side effects. Melanocortin-4 receptor (MC4R) agonists and kisspeptin provide promising therapeutic avenues. The MC4Ra, Bremelanotide, is licensed for the treatment of HSDD in premenopausal women in the USA, although the mechanism of action remains unknown. Kisspeptin is known to play a key role in regulating the hypothalamic-pituitary-gonadal (HPG) axis and recently, evidence for a role in sexual behaviour has emerged. Investigating the effects of MC4Ra and kisspeptin in women with HSDD and the neural pathways involved will deepen our knowledge of normal and abnormal sexual behaviour and provide information which could contribute to the development of novel treatment strategies for this condition.

Using a combination of psychometric, neuroimaging and hormonal analyses, the role of MC4Ra and kisspeptin on sexual brain processing in premenopausal women with HSDD was investigated in two randomized, double-blind, placebo-controlled crossover trials.

Both MC4Ra and kisspeptin enhanced sexual psychometric parameters. MC4Ra led to modulation of brain activity and changes in functional connectivity in response to erotic stimuli. Similarly, kisspeptin also led to modulation of brain activity in response to erotic stimuli, as well as enhancement of the perception of facial attractiveness and reduced sexual aversion. The brain regions impacted, provide a basis for the observed changes in psychometric parameters.

These studies provide novel mechanistic insight for MC4Ra’s and kisspeptin’s effects on sexual desire in HSDD. These data also enhance our understanding of neural dysregulation in HSDD and have important and exciting implications for the future development of therapeutics for the treatment of HSDD.