SFEBES2021 Oral Communications Reproductive and Neuroendocrinology (6 abstracts)
Hypoactive sexual desire disorder (HSDD) is the most prevalent female sexual health complaint worldwide, affecting 1-in-10 women. It is characterised by a persistent lack of desire for sexual activity and sexual fantasies, causing distress or interpersonal difficulties. Treatment options are limited, however, melanocortin-4 receptor (MC4R) agonists have emerged as a promising therapy for HSDD, through unclear mechanisms. Investigating the pathways involved is crucial for our understanding of normal and abnormal sexual behaviour. We conducted a randomised, double-blind, placebo-controlled, crossover clinical study using psychometric, functional neuroimaging and hormonal analyses to assess the effects of MC4R agonist administration, compared to placebo, on sexual brain processing in 31 premenopausal women with HSDD. MC4R agonism significantly increased sexual desire for up to 24-hours post administration, compared to placebo (P = 10.007). During functional MRI, MC4R agonism enhanced cerebellar and supplementary motor area activity, and deactivated the secondary somatosensory cortex, specifically in response to visual erotic stimuli, compared to placebo (Z = 2.3, P < 0.05). In addition, MC4R agonism enhanced functional connectivity between the amygdala-insula during visual erotic stimuli, compared to placebo (P = 0.025). MC4R agonism resulted in a small mean increase in LH of 1.1iU/l (F [1,58]=13.38, P = 0.0005) and FSH of 0.35iU/l (F [1,60]=10.97, P = 0.0016) across the 300-minute duration of the study, with no effect observed on downstream circulating estradiol or progesterone levels. These findings identify novel neural substrates and connections through which MC4R agonism modulates sexual brain processing to increase sexual desire. These changes in brain activation may serve to reduce self-consciousness, increase sexual imagery, and disinhibit sexual responses in women with HSDD. Our data have widespread implications as understanding the effects of MC4R agonism on sexual behaviour is important, not only for the ongoing development of melanocortin-based therapies for psychosexual disorders but also for obesity medicine, where related MC4R agonists are rapidly being developed.
08 Nov 2021 - 10 Nov 2021