Investigating the effects of melanocortin-4 and kisspeptin receptor agonism on sexual brain processing in women

Abstract

Sexual behaviour is critical to most species’ survival, as well as being important for overall health and wellbeing. Sexual desire is a key component of the human sexual response. Hypoactive sexual desire disorder (HSDD) is defined as a persistent deficiency of sexual fantasies and desire for sexual activity, causing marked distress or interpersonal difficulty. HSDD is the most prevalent female sexual health complaint worldwide, affecting approximately 1 in 10 women, but has limited treatment options despite its substantial health, social, and economic burden.

Melanocortin-4 receptor (MC4R) agonists have become a promising therapy for women with HSDD, through unknown mechanisms. Studying the reproductive neuroendocrine pathways involved is crucial for our understanding of normal and abnormal sexual behaviour. The hormone kisspeptin is a key endogenous activator of the reproductive endocrine axis, with emerging roles in sexual and emotional behaviour, and thus could serve as a novel treatment option in women with HSDD.

I have performed two randomised, double-blind, placebo-controlled crossover clinical studies in a total of 63 premenopausal women with HSDD. In this thesis, I have used a combination of psychometric, functional neuroimaging and hormonal analyses to investigate the effects of 1) MC4R agonist, and 2) kisspeptin administration, compared to placebo, on sexual brain processing. My results show that MC4R agonist administration increases sexual desire and kisspeptin administration increases self-reported feelings of sexiness. I demonstrated that both neuropeptide analogues modulated and restored sexual brain processing, providing mechanistic insight behind the behavioural effects I observed. Collectively, the findings of this thesis have implications for the understanding of the pathophysiology of HSDD and the development of kisspeptin as a potential therapy for psychosexual disorders.