Kisspeptin administration does not induce anxiety in humans

Mills Edouard G; Layla Thurston; Lisa Yang; Sofiya Suladze; Tia Hunjan; Maria Phylactou; Bijal Patel; Clarke Sophie A.; Shah Amar J.; Chioma Izzi-Engbeaya; Jovanna Tsoutsouki; Megan Young; Paul Bech; Natalie Ertl; Lysia Demetriou; Wall Matthew B.; David Goldmeier; Ali Abbara; Comninos Alexander N.; Dhillo Waljit S.

doi:10.1530/endoabs.109.OP1.2

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Endocrine Abstracts (2025) 109 OP1.2 | DOI: 10.1530/endoabs.109.OP1.2

SFEBES2025 Poster Oral Presentations Neuroendocrinology and Pituitary (4 abstracts)

Kisspeptin administration does not induce anxiety in humans

Edouard G Mills ^1,2 , Layla Thurston ¹ , Lisa Yang ¹ , Sofiya Suladze ¹ , Tia Hunjan ¹ , Maria Phylactou ^1,2 , Bijal Patel ¹ , Sophie A. Clarke ^1,2 , Amar J. Shah ¹ , Chioma Izzi-Engbeaya ^1,2 , Jovanna Tsoutsouki ¹ , Megan Young ¹ , Paul Bech ¹ , Natalie Ertl ^1,3 , Lysia Demetriou ^1,3 , Matthew B. Wall ¹ , David Goldmeier ⁴ , Ali Abbara ^1,2 , Alexander N. Comninos ^1,2 & Waljit S. Dhillo ^1,2

Author affiliations

¹Section of Endocrinology and Investigative Medicine, Imperial College London, London, United Kingdom; ²Department of Endocrinology, Imperial College Healthcare NHS Trust, London, United Kingdom; ³Invicro London, London, United Kingdom; ⁴Jane Wadsworth Sexual Function Clinic, Imperial College Healthcare NHS Trust, London, United Kingdom

Background: Kisspeptin is a critical endogenous activator of the reproductive system, with escalating clinical interest as a novel therapeutic agent for reproductive and psychosexual disorders. However, conflicting animal data suggest that kisspeptin can have anxiolytic, neutral, or anxiogenic effects. Given the rapid development of kisspeptin-based therapeutics, it is important to clarify kisspeptin’s effects on behavioural, biochemical, and physiological measures of anxiety in humans.

Methods: Ninety-five eugonadal participants (n = 63 men, n = 32 women) completed a double-blind, randomised, placebo-controlled, crossover protocol (mean age±SEM 30.9±0.9yrs, BMI 24.0±0.4 kg/m²). Participants attended for a 75-minute intravenous kisspeptin-54 infusion (1nmol/kg/h) and again for a rate-matched placebo. Blood sampling (for reproductive hormones and cortisol) and heart rate measurements took place at 15-minute intervals throughout the infusions. Participants completed a state anxiety psychometric questionnaire (‘STAI Y1-State’) before and at the end of the infusions to assess for any dynamic effects of the infusions on anxiety.

Results: Intravenous kisspeptin robustly increased serum LH to similar levels previously described using this administration protocol, confirming that the dose was biologically active (P < 0.001). As expected, kisspeptin had no significant effects on downstream sex-steroid levels during the 75-minute study period, thereby excluding these as possible confounders. State anxiety was not significantly altered by kisspeptin (mean difference in ‘STAI Y1-State’ scores during the infusions: kisspeptin -0.4±0.8, placebo 1.3±0.8, P = 0.09). Moreover, kisspeptin had no significant effects on circulating cortisol (P = 0.73) and heart rate (P = 0.52) during the infusions.

Summary: This is the largest study demonstrating that administration of a biologically active dose of kisspeptin to humans does not affect behavioural, biochemical, and physiological measures of anxiety. Given that animal studies have yielded contradictory results, this provides key clinical data and reassurance that kisspeptin does not induce anxiety in humans and so supports the advancing development of kisspeptin-based therapeutics for reproductive and psychosexual disorders.