madman
Super Moderator
Background
The neuropeptide kisspeptin is a key endogenous activator of the reproductive system. Due to its crucial role in modulating reproductive and behavioural processes, there has been accelerating interest in targeting kisspeptin-pathways to treat reproductive and psychosexual disorders. However, contradictory pre-clinical data from animal models suggests that kisspeptin can have an anxiolytic, anxiogenic or have no effects on anxiety. Given the rapid development of kisspeptin-based therapeutics, it is imperative to elucidate kisspeptins effects on anxiety in humans. Herein, we report the largest study investigating the effects of kisspeptin on psychometric measures of anxiety and circulating cortisol levels.
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 (1 nmol/kg/h) over 75 mins and for rate-matched placebo. Blood was sampled at 15 min intervals from -30 to 75 mins 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 infusions to exclude abnormal anxiety traits, with all scores within normal limits. Subsequently, participants completed the ‘STAI Y1-State’ before and at the end of the infusions to assess for any dynamic effects on anxiety.
Results
Ninety-three participants (mean age±SD 30.9±8.7 yrs, BMI 24.0±3.7 kg/m2) completed the study. Baseline state anxiety and circulating cortisol levels were equivalent at the beginning of the kisspeptin and placebo visits. Intravenous kisspeptin potently increased serum LH to levels previously described using this administration protocol, confirming that the dose was biologically active (P>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). Furthermore, kisspeptin had no effect on circulating cortisol compared to placebo during the 75 min study period (P=0.92). As expected, kisspeptin had no significant effects on downstream sex-steroid levels during the 75 min study period, thereby removing these as possible confounders.
Discussion
This is the largest study demonstrating that a biologically active dose of kisspeptin to healthy participants and patients with psychosexual disorders does not affect psychometric measures of anxiety and associated circulating cortisol levels. Given that animal studies have yielded inconsistent results, this provides key clinical data and reassurance that kisspeptin administration in humans does not induce anxiety and so informs safety for the rapid development of kisspeptin-based therapeutics for reproductive and psychosexual disorders.
