Endocrine Abstracts

A decade ago, genetic disruption of the kisspeptin signalling pathway was observed to cause hypogonadotrophic hypogonadism. Hypothalamic kisspeptin acts by stimulating secretion of endogenous GnRH. Our research has investigated the physiological effects of kisspeptin in women, with the overarching aim of determining if kisspeptin could be used to treat women with infertility.

We initially observed that s.c. bolus injection of kisspeptin acutely stimulated gonadotrophin secretion in healthy women, and patients with functional hypothalamic amenorrhoea due to weight loss or exercise (FHA). Furthermore, the mean amplitude of LH pulses was increased by kisspeptin in healthy women and patients with FHA. By contrast, we observed that exogenous neurokinin B (co-expressed with kisspeptin) does not alter sex hormone secretion in healthy women. We also investigated the clinical effects of chronic kisspeptin administration. In healthy women, twice-daily kisspeptin advanced the menstrual cycle by 2 days. In patients with FHA, 8 h i.v. infusion of kisspeptin increased only basal LH secretion at low doses, increased basal and pulsatile LH secretion at intermediate doses, and caused tachyphylaxis at the highest dose. Like GnRH, kisspeptin may therefore have distinct and paradoxical effects on the human reproductive axis. Kisspeptin is needed for ovulation in multiple species. We therefore conducted a phase 2 trial determining if a single injection of kisspeptin induces oocyte maturation during IVF treatment. Oocyte maturation and fertilisation was observed in 45/47 and 43/47 of patients, respectively. Clinical pregnancy has been confirmed in 14/44 patients; two patients have already given birth to healthy babies.

Our human studies reveal that kisspeptin potently stimulates gonadotropin secretion, and accentuates LH pulsatility in women. Furthermore kisspeptin can induce oocyte maturation in women undergoing IVF treatment. Further studies are underway to determine if kisspeptin offers a therapeutic advantage over existing treatments for infertility.