We are delighted to publish this summary of Edouard G Mills’ award-winning 2023 Early Career Prize Lecture (Clinical) from SfE BES 2023 in Glasgow.

LOW SEXUAL DESIRE: A COMMON CAUSE OF PERSONAL DISTRESS

The human sexual response is essential for reward, satisfaction and, most significantly, reproduction and species survival. Under normal physiological conditions, sexual response depends on an appropriate balance between sexual excitatory and sexual inhibitory brain pathways, which together regulate human sexual behaviour.

However, dysregulation in this system can result in persistent low sexual desire, with resultant marked distress to the individual, termed hypoactive sexual desire disorder (HSDD). Epidemiological studies indicate that HSDD affects around 8% of men and 10% of women,¹ making it one of the most prevalent sexual health conditions. Recent insights indicate that, in response to sexual stimuli, those suffering with HSDD display excessive activation of higher level cognitive brain regions (involved in self-monitoring and self-judgement), which suppresses lower level sexual brain centres, thereby impeding normal sexual function.² Consequently, HSDD has marked detrimental effects on quality of life, interpersonal relationships and fertility. Remarkably, despite the considerable clinical burden, there are no licensed therapies for men, and in women the available treatments are limited by their effectiveness and side-effect profiles.

Taken together, there is a significant unmet need to identify novel, safe and effective therapeutic strategies for HSDD and for psychosexual disorders more broadly. Indeed, a potential therapeutic target could be the reproductive neuropeptide kisspeptin, which has been the focus of our recent research, as summarised here.

KISSPEPTIN AS THE MASTER REGULATOR OF THE REPRODUCTIVE AXIS

Over the last two decades, kisspeptin (encoded by the non-human Kiss1 gene and human KISS1 gene) has emerged as the master regulator of reproduction, due to its position at the apex of the reproductive axis.³ The principal site of kisspeptin action is in the hypothalamus. Here, kisspeptin acts as a crucial upstream regulator of gonadotrophin- releasing hormone secretion, which, in turn, controls downstream gonadal function via luteinising hormone and follicle-stimulating hormone. Due to this key role in regulating physiological reproductive hormone secretion, research interest in targeting kisspeptin pathways to treat common reproductive disorders in humans has accelerated, including for hypothalamic amenorrhoea, hyperprolactinaemia and male hypogonadism, and as a safe ovulation trigger in an in vitro fertilisation setting.

KISSPEPTIN AND SEXUAL BEHAVIOUR

Beyond the hypothalamus, both kisspeptin and its receptor are extensively distributed throughout important cortico-limbic brain regions (i.e. the behavioural and emotional control centres of the brain) in rodents and humans.⁴ Accordingly, this sets the scene and provides a neuroanatomical framework for an expanding pool of preclinical animal data demonstrating that kisspeptin signalling modulates key aspects of reproductive behaviour, including sexual motivation⁵ and erections.⁶

Turning to humans, we were the first to show that kisspeptin administration enhances limbic brain activity in response to sexual stimuli in healthy men with normal sexual function, with associated reductions in sexual aversion.⁷ In subsequent work, we demonstrated that kisspeptin administration also potently enhances brain responses to olfactory and visual cues of attraction in healthy men.⁸

Collectively, these preclinical animal findings and our earlier data in healthy men led us to postulate that kisspeptin could have translational potential in people who are distressed by low sexual desire.

CAN KISSPEPTIN IMPROVE SEXUAL FUNCTION IN MEN WITH LOW SEXUAL DESIRE?

The introduction of functional magnetic resonance imaging (fMRI) affords an exciting tool to non-invasively investigate the clinical and mechanistic effects of kisspeptin administration on human sexual behaviour. This specialised neuroimaging technique measures brain activity by detecting changes in blood flow during a specific task, and so produces a brain activation map showing which regions are involved in a particular process (such as sexual desire and arousal).

To test our hypothesis that kisspeptin administration may enhance sexual brain activity in people with low sexual desire, we first recruited 32 eugonadal men with HSDD.⁹ Each participant attended for two study visits, for intravenous infusion of kisspeptin for 75 minutes and for administration of a rate-matched placebo, as part of a randomised and double-blind protocol. At each study visit, we examined changes in fMRI brain activity in response to the participants watching erotic videos in the MRI scanner, as well as physiological (using continuous penile rigidity monitoring) and behavioural measures of sexual desire and arousal.

Here, we demonstrated that kisspeptin administration robustly deactivated brain regions involved in self-monitoring and self-judgement (such as the parahippocampus), whilst simultaneously increasing brain activity in sexual arousal centres (such as the anterior cingulate and middle frontal gyrus). Indeed, in response to kisspeptin’s acute restoration of sexual brain activity, we observed significant increases in penile tumescence (by 56% more than placebo) and behavioural measures of sexual desire (including increased ‘happiness about sex’), providing functional and behavioural relevance.

CAN KISSPEPTIN IMPROVE SEXUAL FUNCTION IN WOMEN WITH LOW SEXUAL DESIRE?

Having demonstrated robust clinical effects in men, our next important and logical step was to investigate whether kisspeptin could offer promise for women. In a subsequent study of 32 premenopausal women with HSDD, participants undertook a similar fMRI protocol to that described above.¹⁰ Indeed, highly congruent with our earlier findings in men with HSDD, in response to erotic videos, kisspeptin again deactivated brain regions involved in self-monitoring and self-judgement (such as the inferior frontal and middle frontal gyri), whilst increasing brain activity in sexual arousal centres (such as the postcentral and supramarginal gyri). Of behavioural relevance, this acute restoration of sexual brain activity was associated with significant increases in self-reported ratings of ‘feeling sexy’, which is important as a positive body image is a key determinant of sexual desire and arousal.

SUMMARY AND FUTURE DIRECTIONS

Across a series of clinical studies, we provide the first human evidence showing that kisspeptin administration in people with low sexual desire acutely and safely modulates sexual brain activity, which ultimately enhances sexual desire and arousal. Given this, further studies are now warranted, investigating more prolonged chronic kisspeptin protocols and in broader patient cohorts (such as different sexual identities and orientations).

Our exciting data raise additional directions for future clinical investigation. Kisspeptin can easily and safely be administered via subcutaneous and intranasal delivery. These simpler administration routes therefore warrant evaluation in this patient cohort, as they are advantageous compared with the intravenous route utilised in our work to date.

To this end, our data identify kisspeptin-based therapeutics as an exciting, much-needed and well-tolerated potential addition to the treatment armamentarium for managing low sexual desire and psychosexual disorders more broadly.

EDOUARD G MILLS
Clinical Lecturer in Endocrinology, Imperial College London

WALJIT S DHILLO
Professor in Endocrinology and Metabolism and Consultant Endocrinologist, Imperial College London

ALEXANDER N COMNINOS
Professor of Practice (Endocrinology) and Consultant Endocrinologist, Imperial College London

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REFERENCES

1. Briken P et al. 2020 Deutsches Ärzteblatt International https://doi.org/10.3238/arztebl.2020.0653.
2. Cacioppo S 2017 Sexual Medicine Reviews https://doi.org/10.1016/j.sxmr.2017.07.006.
3. Patel B et al. 2024 Endocrine Reviews https://doi.org/10.1210/endrev/bnad023.
4. Mills EG et al. 2022 Frontiers in Endocrinology https://doi.org/10.3389%2Ffendo.2022.928143.
5. Adekunbi DA et al. 2018 Journal of Neuroendocrinology https://doi.org/10.1111/jne.12572.
6. Gresham R et al. 2016 Neuroscience Letters https://doi.org/10.1016%2Fj.neulet.2016.05.042.
7. Comninos AN et al. 2017 Journal of Clinical Investigation https://doi.org/10.1172/jci89519.
8. Yang L et al. 2020 JCI Insight https://doi.org/10.1172/jci.insight.133633.
9. Mills EG et al. 2023 JAMA Network Open https://doi.org/10.1001/jamanetworkopen.2022.54313.
10. Thurston L et al. 2022 JAMA Network Open https://doi.org/10.1001/jamanetworkopen.2022.36131.