Kisspeptin Administration Stimulates Reproductive Hormones but Does Not Affect Anxiety in Humans

Kisspeptin is a critical endogenous activator of the reproductive system, with escalating clinical interest as a novel therapeutic for common 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 comprehensively investigate the effects of kisspeptin administration on behavioral, biochemical, and physiological measures of anxiety in humans.

Ninety-five participants (N = 63 male, N = 32 female) completed a double-blind, randomized, placebo-controlled, crossover protocol (mean age ± SEM 30.9 ± 0.9 y, body mass index 24.0 ± 0.4), attending both for a 75-minute intravenous kisspeptin-54 infusion (1 nmol/kg/h) and rate-matched placebo (in random order). Behavioral, biochemical, and physiological measures of anxiety were compared between kisspeptin and placebo visits, using a state-anxiety psychometric questionnaire before and at the end of the infusions, and blood sampling (for reproductive hormones and cortisol) and heart rate measurements at 15-minute intervals. Blood pressure assessment took place before and at the end of the infusions.

Kisspeptin administration robustly increased serum luteinizing hormone to similar levels previously described using this administration protocol, confirming that the dose was biologically active (P < .001). State anxiety was not significantly altered by kisspeptin, compared to placebo (P = .13). Moreover, kisspeptin had no significant effects on circulating cortisol (P = .73), systolic (P = .74) or diastolic blood pressure (P = .90), or heart rate (P = .52).

This is the first study demonstrating that a biologically active dose of kisspeptin to men and women does not affect behavioral, biochemical, or 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 informs the current development of kisspeptin-based therapeutics for common reproductive and psychosexual disorders.