Melanocortin 4 receptor agonism enhances sexual brain processing in women with hypoactive sexual desire disorder

Abstract

BACKGROUND Hypoactive sexual desire disorder (HSDD) is characterized by a persistent deficiency of sexual fantasies and desire for sexual activity, causing marked distress and interpersonal difficulty. It is the most prevalent female sexual health problem globally, affecting approximately 10% of women, but has limited treatment options. Melanocortin 4 receptor (MC4R) agonists have emerged as a promising therapy for women with HSDD, through unknown mechanisms. Studying the pathways involved is crucial for our understanding of normal and abnormal sexual behavior. METHODS Using psychometric, functional neuroimaging, and hormonal analyses, we conducted a randomized, double-blinded, placebo-controlled, crossover clinical study to assess the effects of MC4R agonism compared with placebo on sexual brain processing in 31 premenopausal heterosexual women with HSDD. RESULTS MC4R agonism significantly increased sexual desire for up to 24 hours after administration compared with placebo. During functional neuroimaging, MC4R agonism enhanced cerebellar and supplementary motor area activity and deactivated the secondary somatosensory cortex, specifically in response to visual erotic stimuli, compared with placebo. In addition, MC4R agonism enhanced functional connectivity between the amygdala and the insula during visual erotic stimuli compared with placebo. CONCLUSION These data suggest that MC4R agonism enhanced sexual brain processing by reducing self-consciousness, increasing sexual imagery, and sensitizing women with HSDD to erotic stimuli. These findings provide mechanistic insight into the action of MC4R agonism in sexual behavior and are relevant to the ongoing development of HSDD therapies and MC4R agonist development more widely. TRIAL REGISTRATION ClinicalTrials.gov NCT04179734. FUNDING This is an investigator-sponsored study funded by AMAG Pharmaceuticals Inc., the Medical Research Council (MRC) (MR/T006242/1), and the National Institute for Health Research (NIHR) (CS-2018-18-ST2-002 and RP-2014-05-001).

Associations between regular cannabis use and brain resting-state functional connectivity in adolescents and adults

“…The inclusion of WM and CSF regressors is similar to the CompCor approach (Behzadi et al, 2007), and it is a principled, robust and effective method of reducing the influence of a range of noise sources (e.g. physiological, motion, thermal), and is useful for both resting-state (Comninos et al, 2018; Demetriou et al, 2018; Wall et al, 2023) and task fMRI data (Thurston et al, 2022). Functional connectivity with each seed region was assessed using a positive contrast for the regressor of interest (the time series from each seed region) in each model.…”

Associations between regular cannabis use and brain resting-state functional connectivity in adolescents and adults

“…The inclusion of WM and CSF regressors is similar to the CompCor approach (Behzadi et al, 2007), is a principled, robust, and effective method of reducing the influence of a range of noise sources (e.g. physiological, motion, thermal), and is useful for both resting-state (Comninos et al, 2018; Demetriou et al, 2018; Wall, Lam, et al, 2022) and task fMRI data (Thurston et al, 2022). Functional connectivity with each seed region was assessed using a positive contrast for the regressor of interest (the time series from each seed-region) in each model.…”

Care for breast cancer survivors in Asian countries: A review of sexual dysfunction

“… 56 Alongside, the use of transdermal testosterone therapy and melanocortin four receptor (MC4R) agonists should be encouraged, as these amplify signaling between the amygdala and insula, thereby increasing visual erotic stimuli. 57 Another modern non-pharmacologic approach to the management of SD among BCSs includes group education therapy. 57 Group education intervention for BCSs has proved to increase acceptability and self-satisfaction among these women.…”

“… 57 Another modern non-pharmacologic approach to the management of SD among BCSs includes group education therapy. 57 Group education intervention for BCSs has proved to increase acceptability and self-satisfaction among these women. Women experienced a significant decrease in intercourse-related anxiety and pain after receiving the first round of education therapy.…”