Kisspeptin

In a phase 2 open-label trial in 60 women at high risk of ovarian hyperstimulation syndrome undergoing IVF, randomised between kisspeptin-54 dose arms with no hCG or placebo comparator, a single injection matured oocytes in 95% of women; across 51 embryo transfers the biochemical, clinical and live-birth pregnancy rates were 63%, 53% and 45%, rising to 85%, 77% and 62% in the 9.6 nmol/kg arm.¹⁴

In the first-in-human, uncontrolled study of kisspeptin-54 as an oocyte-maturation trigger, 53 subfertile women undergoing IVF each received a single subcutaneous injection across four dose arms from 1.6 to 12.8 nmol/kg, with randomisation only between dose cohorts and no placebo or active comparator; eggs were fertilised and embryos transferred in 92% (49/53), biochemical pregnancy occurred in 40% (21/53) and clinical pregnancy in 23% (12/53), and mature eggs per patient generally increased with dose.⁵

In 8 healthy women with regular menstrual cycles given a 0.4 nmol/kg subcutaneous bolus of kisspeptin-54 or saline in random order in each cycle phase, LH rose in every phase but the response depended on cycle stage: the mean increase over baseline was 20.64 +/- 2.91 IU/L preovulatory versus 0.12 +/- 0.17 IU/L follicular (P < 0.001) and 2.17 +/- 0.79 IU/L luteal (P < 0.01 versus follicular).¹⁵

In a double-blind, placebo-controlled crossover study in 6 healthy men, a 90-minute intravenous infusion of kisspeptin-54 at 4 pmol/kg/min raised mean 90-minute LH to 10.8 +/- 1.5 U/L versus 4.2 +/- 0.5 U/L on saline and mean 90-minute FSH to 3.9 +/- 0.7 versus 3.2 +/- 0.6 U/L, with mean 180-minute testosterone 24.9 +/- 1.7 versus 21.7 +/- 2.2 nmol/L (all P < 0.001).¹⁶

In healthy men receiving 3-hour intravenous infusions (five men per arm), GnRH was more potent than either kisspeptin fragment at 1.0 nmol/kg/h: mean LH area under the curve was 34.06 +/- 5.18 h.IU/L for GnRH versus 14.43 +/- 1.27 for kisspeptin-54 (approximately 2-fold, P < 0.01) and 10.81 +/- 1.73 for kisspeptin-10 (approximately 3-fold, P < 0.001), while the two kisspeptin fragments produced similar responses.⁴

In women with hypothalamic amenorrhoea given 6.4 nmol/kg subcutaneous kisspeptin-54 (five per group versus saline), LH rose by 24.0 +/- 3.5 IU/L within four hours on day 1, but after two weeks of twice-daily injection the day-14 rise had fallen to 2.5 +/- 2.2 IU/L (P < 0.05) while the response to GnRH itself was preserved, indicating desensitisation upstream of the pituitary rather than pituitary failure.¹⁷

In mice lacking Gpr54, males had small testes and females showed delayed vaginal opening and no follicular maturation, yet hypothalamic GnRH content was normal and the animals responded to exogenous GnRH and gonadotropins, locating the defect in kisspeptin signalling onto GnRH neurons rather than in the neurons or the pituitary; the same report described a consanguineous human family homozygous for the GPR54 L148S mutation with idiopathic hypogonadotropic hypogonadism.⁹

In a double-blind, placebo-controlled crossover trial in men with hypoactive sexual desire disorder (37 randomised, 32 completed), a 75-minute intravenous kisspeptin-54 infusion at 1 nmol/kg/h modulated activity across the brain's sexual-processing network on the primary whole-brain analysis (Cohen d = 0.81; 95% CI 0.41-1.21; P = .003); in secondary analyses penile tumescence in response to sexual stimuli rose by up to 56% more than placebo (mean difference 0.28 units; 95% CI 0.04-0.52; P = .02).¹⁸

In a double-masked, placebo-controlled crossover trial in premenopausal women with hypoactive sexual desire disorder (40 randomised, 32 completed both visits), the same 75-minute kisspeptin-54 infusion at 1 nmol/kg/h altered sexual and facial-attraction brain processing relative to placebo, including deactivation of the left inferior frontal gyrus (Z max 3.76; P = .01) and activation of the right postcentral and supramarginal gyrus (Z max 3.73; P < .001).¹³

In 15 healthy men infused with kisspeptin at 1 nmol/kg/h versus vehicle, insulin secretion following an intravenous glucose load was enhanced and serum metabolites were altered, an effect reproduced in isolated human pancreatic islets and EndoC-betaH1 cells, while gut hormones, appetite and food intake were unchanged from vehicle.¹²

In female mice lacking the kisspeptin receptor (Kiss1r knockouts), body weight, leptin and adiposity were higher than in wild-type littermates despite lower food intake, with reduced locomotor activity, respiratory rate and energy expenditure and impaired glucose tolerance; male knockouts had normal body weight and glucose handling, and the female phenotype persisted in ovariectomised animals, so it is not explained by absent gonadal oestrogen alone.¹⁹