Investigating Kisspeptin-signalling in sexual and emotional brain processing in men

Abstract

The reproductive neuropeptide kisspeptin acts as the master regulator of the hypothalamic-pituitary-gonadal axis, where it has important roles in controlling downstream reproductive hormone secretion. Beyond the hypothalamus, kisspeptin and its cognate receptor are expressed throughout the rodent and human limbic systems, which are areas implicated in the control of socio-reproductive behaviours. Consistent with this, emerging data reveals that kisspeptin has important neuromodulatory functions in reproductive behaviour. However, data in this area remains limited to predominantly animal models. Using a combination of physiological, behavioural, hormonal and functional neuroimaging, this thesis investigates kisspeptin’s effects on three unexplored areas in human reproductive neuroendocrinology: 1) brain responses to olfactory and visual cues of attraction in healthy men; 2) brain responses to sexual stimuli in men with Hypoactive Sexual Desire Disorder (HSDD); 3) reproductive hormone secretion following intranasal delivery. The results broaden our understanding of kisspeptin’s physiological roles in humans beyond the classical reproductive axis by supporting and extending the animal data implicating kisspeptin in the control of reproductive behaviour. Moving from healthy men into a patient group, my findings reveal kisspeptin as the first effective treatment option for men with HSDD. From a clinical development perspective, the identification that intranasal kisspeptin delivery stimulates reproductive hormone secretion, highlights kisspeptin as a feasible and realistic treatment strategy for patients with reproductive and related psychosexual disorders. To this end, these data provide key mechanistic and pharmacological insight for the neurophysiological actions of kisspeptin and unlock kisspeptin as a therapeutic target for the management of reproductive and related psychosexual disorders.