Melanocortin 4 receptor agonism enhances sexual brain processing in women with hypoactive sexual desire disorder
Layla Thurston, … , Alexander N. Comninos, Waljit S. Dhillo
Layla Thurston, … , Alexander N. Comninos, Waljit S. Dhillo
Published October 3, 2022
Citation Information: J Clin Invest. 2022;132(19):e152341. https://doi.org/10.1172/JCI152341.
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Clinical Research and Public Health Endocrinology

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).

Authors

Layla Thurston, Tia Hunjan, Edouard G. Mills, Matthew B. Wall, Natalie Ertl, Maria Phylactou, Beatrice Muzi, Bijal Patel, Emma C. Alexander, Sofiya Suladze, Manish Modi, Pei C. Eng, Paul A. Bassett, Ali Abbara, David Goldmeier, Alexander N. Comninos, Waljit S. Dhillo

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Figure 1

Experimental protocol.

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Experimental protocol. A final group of 31 premenopausal women with HSDD...
A final group of 31 premenopausal women with HSDD participated in a randomized, double-blinded, 2-way crossover, placebo-controlled study. They attended 2 study visits each: 1 for subcutaneous administration of MC4Ra and 1 for subcutaneous administration of an equivalent volume of placebo in random order. Blood samples were taken at the time points shown (denoted with an “X”). Participants underwent 2 fMRI scans and completed baseline, inter-scan, and post-scan psychometric questionnaires (denoted with an inverted triangle▼). Participants underwent two 60-minute scans per study visit, scan 1 at t = 45 minutes and scan 2 at t = 240 minutes, to cover the whole time course of possible objective and subjective responses to MC4Ra, which are known to occur from 45 minutes onward. Each 60-minute fMRI scan period included the following types of scans and tasks: anatomical and T2 proton density (to evaluate any structural abnormality and for subsequent anatomical location); resting state (to evaluate regional interactions that occur in a task-negative state, when an explicit task is not being performed); 20 × 20-second “short” erotic videos with 20 × 20-second exercise control videos, a 10-minute “long” erotic video, and an fMRI control task (to identify and control for global vascular or systemic effects of MC4R agonism).