1Imperial College London, London, United Kingdom; 2Invicro London, London, United Kingdom; 3Stats Consultancy Ltd, Amersham, United Kingdom; 4Imperial College Healthcare NHS Trust, London, United Kingdom
Hypoactive sexual desire disorder (HSDD) is a persistent lack of sexual desire, 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. The neuropeptide kisspeptin offers a potential therapeutic target given its emerging role in modulating reproductive behaviour. Using a combination of psychometric, neuroimaging and hormonal analyses, the role of kisspeptin in sexual brain processing in HSDD was investigated in a randomised, double-blind, placebo-controlled crossover study. Thirty-two premenopausal women with HSDD completed the study (mean age 29.2 ± SEM 1.2 years). Kisspeptin administration increased self-reported scores of feeling sexy, compared with placebo, measured using the Sexual Arousal and Desire Inventory (t=2.27, P=0.03). Functional magnetic resonance imaging (fMRI) demonstrated deactivation of the left inferior frontal gyrus and activation of the postcentral and supramarginal gyrus in response to erotic videos (Z=2.3, P<0.05). This modulation of brain activity may serve to diminish negative internal monologue, lessen negative emotion and decrease response inhibition. In the facial attractiveness task, kisspeptin caused deactivation of the secondary somatosensory cortex (Z=2.3, P<0.05) in response to male faces, which may be linked to a reduction in self-consciousness and self-focus. Increased activation in the posterior cingulate cortex with kisspeptin was associated with reduced sexual aversion (r=0.476, P=0.005), which may be explained by increased feelings of romantic love. Kisspeptin administration led to a mean increase in LH of 2.75iU/l (F(1,62)=6.084, P=0.02) and FSH of 0.37iU/l (F(1,62)=4.030, P=0.05), with no effect observed on downstream circulating oestradiol, progesterone or testosterone levels. The observed changes in brain activity provide mechanistic insight for the increase in sexual desire seen with kisspeptin. This research has exciting potential therapeutic implications for kisspeptin in the treatment of psychosexual disorders.