6523 Kisspeptin Administration Does Not Induce Anxiety in Humans
Authors: Mills Edouard G , Thurston Layla , Yang Lisa , Suladze Sofiya , Hunjan Tia , Phylactou Maria , Patel Bijal , Clarke Sophie A , Shah Amar J , Izzi-Engbeaya Chioma , Tsoutsouki Jovanna , Bech Paul , Ertl Natalie , Demetriou Lysia , Wall Matthew B , Goldmeier David , Abbara Ali , Comninos Alexander N , Dhillo Waljit S 
Published: October 2024

Disclosure: E.G. Mills: None. L. Thurston: None. L. Yang: None. S. Suladze: None. T. Hunjan: None. M. Phylactou: None. B. Patel: None. S.A. Clarke: None. A.J. Shah: None. C. Izzi-Engbeaya: None. J. Tsoutsouki: None. P. Bech: None. N. Ertl: None. L. Demetriou: None. M.B. Wall: None. D. Goldmeier: None. A. Abbara: None. A.N. Comninos: None. W.S. Dhillo: None.

Background: The neuropeptide kisspeptin is a critical endogenous activator of the reproductive system. Due to its key role in regulating reproductive and behavioural processes, there has been escalating interest in targeting kisspeptin-pathways to treat reproductive and psychosexual disorders. However, conflicting evidence from pre-clinical animal models proposes that kisspeptin can have an anxiolytic, anxiogenic or have no effects on anxiety. Given the rapid development of kisspeptin-based therapeutics, it is important to clarify kisspeptin’s effects on anxiety in humans. Herein, we report the largest study examining the effects of kisspeptin on psychometric measures of anxiety and circulating cortisol levels in humans. Methods: Ninety-three eugonadal participants (n=29 healthy men, n=32 men with low sexual desire, n=32 women with low sexual desire) completed a double-blind, randomised, placebo-controlled, crossover study. Participants attended twice: once for intravenous infusion of kisspeptin-54 (1nmol/kg/h) over 75mins and for a rate-matched placebo. Blood sampling took place at 15-minute intervals from -30 to 75mins to measure circulating kisspeptin, LH, testosterone and cortisol [in men] and oestradiol [in women]. The validated ‘State-Trait Anxiety Inventory (STAI) Y2-Trait’ was completed prior to the infusions to exclude abnormal anxiety traits, with all scores within normal limits. Participants also completed the ‘STAI Y1-State’ before and prior to the end of the infusions to assess for any dynamic effects of the infusions on anxiety. Results: Ninety-three participants (mean age ±SD 30.9±8.7yrs, BMI 24.0±3.7kg/m2) completed the study. Intravenous kisspeptin significantly increased serum LH to similar levels previously described using this administration protocol, confirming that the dose was biologically active (P&lt;0.001). Importantly, state anxiety was unaltered by kisspeptin, compared to placebo (mean difference in ‘STAI Y1-State’ scores during the infusions: kisspeptin -0.03±8.11, placebo 0.77±8.08, P=0.43). Moreover, kisspeptin had no effect on circulating cortisol compared to placebo during the 75minute study period (P=0.92). As expected, kisspeptin had no significant effects on downstream sex-steroid levels during the 75minute study period, thereby excluding these as confounders. Discussion: This is the largest study demonstrating that a biologically active dose of kisspeptin to healthy volunteers and patients with psychosexual disorders does not affect psychometric measures of anxiety and associated circulating cortisol levels. Given that animal studies have yielded conflicting results, this provides important clinical data and reassurance that kisspeptin administration in humans does not induce anxiety and so informs the rapid development of kisspeptin-based therapeutics for reproductive and psychosexual disorders.

Presentation: 6/3/2024