Investigating Kisspeptin Signalling in Sexual and Emotional Brain Processing

Hypoactive Sexual Desire Disorder (HSDD) is characterised by a lack or absence of sexual fantasies and desire for sexual activity. Studies estimate that in the UK HSDD affects 17-40% of men and women, making it one of the most prevalent sexual health complaints. It can result in devastating distress and effects on a person's physical and mental wellbeing with established links to infertility and interpersonal difficulties. However, despite its significant burden, medical and psychological treatments have shown only modest benefit, indicating a need to better understand the underlying sexual and emotional brain activity in HSDD in order to help develop more effective treatments.


Kisspeptin is a naturally occurring hormone which is predominantly produced by a region of the brain called the hypothalamus. However, beyond the hypothalamus, kisspeptin is also found in areas of the limbic system - the part of the brain involved in behavioural and emotional responses - including the amygdala. Research in rodents has revealed that kisspeptin plays a key role in controlling important reproductive behaviours, including sexual partner preference and sexual arousal. Furthermore, recent research from my proposed laboratory has utilised the novel imaging technique functional MRI (fMRI) to measure and map the brains activity during tasks, demonstrating that an infusion of kisspeptin into the bloodstream of healthy men results in increased brain activity in regions linked to sexual arousal whilst viewing erotic images. Furthermore, I have generated preliminary pilot data revealing that in healthy men an infusion of kisspeptin whilst observing female faces also increases activity in brain regions involved in assessing facial attractiveness, including the medial prefrontal cortex. Taken together, these findings provide the scientific basis to investigate the kisspeptin pathway in patients suffering from HSDD. Given that this has yet to be studied, it will form the basis of my proposed PhD fellowship.


I will receive training and supervision from specialists in the field to complete my proposed experiments. In the first part, I have designed an fMRI study using tasks to determine how an infusion of kisspeptin into the bloodstream affects brain activation in men with HSDD. These tasks will include viewing erotic images and female faces, coupled with physiological parameters and psychometric questionnaires in to order to provide functional significance for the brain activity results. This study will allow me to establish the effects of kisspeptin on sexual and emotional brain activity in men with HSDD, encompassing sexual arousal and visual attraction.


Furthermore, to understand how kisspeptin affects brain responses and provide key mechanistic insights, it is important to explore the effects of kisspeptin in specific limbic brain regions on sexual behaviour. To investigate this, my proposed second host laboratory have previously utilised specialised techniques to activate kisspeptin neurones in living male mice, demonstrating the potential to heighten sexual partner preference. Therefore, for the second part of this PhD Fellowship, I will receive specialist training and teaching to use and optimise this technology in adult male mice to activate and also deactivate specific kisspeptin neuronal populations of interest in key limbic brain regions and observe the resultant effects on sexual behaviour.


To this end, the findings from these two experiments will provide a new insight into mammalian sexual function and dysfunction. The overall aim is to investigate kisspeptin neuroendocrinology in HSDD and sexual behaviours, to ultimately provide further evidence for the use of kisspeptin as a future treatment to address the significant burden related to HSDD.

Hypoactive Sexual Desire Disorder (HSDD) affects 17-40% of UK adults with devastating consequences to health, quality of life and fertility. Despite its significant psychosocial burden, our limited understanding of human sexual and emotional brain processing has constrained the development of effective treatments. The hypothalamic hormone kisspeptin has emerged as critical for integrating sexual and emotional behaviours with the reproductive axis. Beyond the hypothalamus, kisspeptin and its cognate receptor are expressed in key limbic brain structures, which govern emotional and behavioural responses. Using fMRI, recent work from my proposed laboratory has shown that kisspeptin administration in healthy men enhances limbic brain activity in response to sexual stimuli and modulates resting brain connectivity to enhance sexual and emotional processing. My pilot fMRI data reveals that kisspeptin administration in healthy men also enhances brain activity in aesthetic brain regions, including the medial prefrontal cortex, in response to female faces. To this end, these studies illustrate that manipulation of the kisspeptin-system may deliver therapeutic benefit for patients suffering psychosexual disorders, however its role in this context is undescribed. I therefore propose to use advanced fMRI techniques coupled with erotic stimuli, facial attraction, penile tumescence and psychometric tasks to determine how kisspeptin modulates limbic brain activity and associated behaviours in men with HSDD. Crucially, I will also perform in vivo rodent experiments using pharmacosynthetic techniques to establish the effects of endogenous kisspeptin activation and inactivation in specific limbic brain structures on sexual behaviour to provide mechanistic insights. Taken together, the data generated will provide fundamental insight into reproductive physiology, whilst laying the foundations for kisspeptin-based therapies for psychosexual disorders to address their significant burden.

Hypoactive Sexual Desire Disorder (HSDD) affects 17-40% of UK adults with profound consequences to health, quality of life and fertility. Given its significant socioeconomic burden, there is a vital need to unravel the kisspeptin-mediated neuroendocrine relationship which underlies sexual and emotional brain activity in HSDD. Improving our understanding of these important elements of sexual function and reproductive physiology will have a direct impact on academics, clinicians, industry and crucially patients.


Societal Impact

Favourable results from this project have the potential to directly impact patients with HSDD and their partners, particularly given current pharmacological and psychotherapeutic interventions have shown only modest benefit. The experiments will provide mechanistic pathways and improve our understanding of the effects of endogenous kisspeptin signalling on sexual behaviour, as well as establishing the effect of kisspeptin on sexual and emotional brain activity in HSDD.

The Section of Investigative Medicine at Imperial College London has strong established links with the local community to share research results. Over the course of my proposed Fellowship, I will participate in patient and public engagement activities, including presenting data at the annual Imperial Festival and collaborating with the public events venue Dana Centre at the Science Museum (South Kensington). On completion, I will work with the Imperial College communications and web team to produce media releases to promptly communicate results. I will also collaborate with key charities and organisations which provide education to patients with HSDD, including the Institute of Psychosexual Medicine.


Economic Impact

The consequences of HSDD are profound with a negative impact on overall well-being and quality of life. Patients with HSDD have significantly more comorbid conditions resulting in notably higher healthcare resource utilisation and expenditure costs compared with age-matched controls. As such, the economic burden associated with HSDD spans the spectrum from an individual household level through to national healthcare implications. Therefore, the results from this project will provide evidence for the use of kisspeptin as a future treatment to help address its significant economic burden.

The results generated by this project will have a direct impact on the pharmaceutical industry. My proposed human fMRI study and in vivo DREADDs experiments in rodents will help inform clinical trials of kisspeptin-based therapies which are currently underway for other common reproductive disorders, but also expand the development of kisspeptin as a potential therapeutic agent for patients with psychosexual disorders, thereby providing significant socioeconomic benefit.


Academic Impact

The Section of Investigative Medicine has a strong track record of maximising the impact and drawing attention to its scientific findings. My host laboratory was the first group to administer kisspeptin to humans in 2005 and also pioneer kisspeptin as a successful ovulation trigger in in vitro fertilisation demonstrating translation of findings to patient benefit.

To increase awareness of my research I will submit data to national and international conferences, as well as written publications to high impact peer-reviewed scientific journals. This will facilitate prompt communication of findings, aid future collaborations and sustain momentum in research related to psychosexual disorders.


The overriding objective of this project is to investigate kisspeptin neuroendocrinology in HSDD and sexual behaviours. The data generated will provide fundamental insight into sexual function and reproductive physiology, whilst laying the foundations for kisspeptin-based therapies for associated disorders of body and mind. As such, the research will impact and be of considerable interest to academics, industry and importantly patients.