Kisspeptin is a novel neuropeptide that came to prominence in the field of fertility in 2003, when it was discovered that genetic mutations causing decreased kisspeptin signalling resulted in hypogonadotropic hypogonadism. Since then, several studies have established that kisspeptin is a key regulator of the hypothalamo-pituitary-gonadal axis, stimulating gonadotropin-releasing hormone (GnRH) secretion in the hypothalamus. Recent trials have demonstrated that kisspeptin can safely trigger oocyte maturation even in women at high risk of ovarian hyperstimulation syndrome (OHSS).1 In 2017, a randomised controlled trial was presented at the European Society of Human Reproduction and Embryology (ESHRE) congress to investigate whether administering a second dose of kisspeptin can safely optimise oocyte maturation in women at high risk of OHSS (serum anti-Müllerian hormone [AMH]: ≥40 pmol/L or antral follicle count: ≥23).
In this trial, oocyte maturation was assessed using a patient-centric primary outcome. Whilst mean oocyte maturation provides a reasonable estimate of the efficacy of a trigger across a group, from an individual patient’s perspective, it is more relevant to be advised of the likelihood of personally achieving a clinically effective oocyte yield that could increase the chance of progression to subsequent stages of in vitro fertilisation treatment. Thus, the primary outcome was the proportion of patients with retrieval of ≥60% of the oocytes that one would expect to be retrieved based on sonographic assessment on the day of trigger.
The results of this study showed that a second dose of kisspeptin significantly improved the proportion of patients achieving an oocyte yield ≥60%, increasing from 45% with one dose of kisspeptin to 71% with two doses of kisspeptin (p=0.042). Recently, there has been increasing focus to develop stimulation protocols that avoid ovarian under-response, but without induction of ovarian over-response. A second dose of kisspeptin eliminated the retrieval of <4 oocytes, but importantly this did not come at the expense of increasing the proportion of patients having ovarian over-response.
This finding may be due to a unique property of kisspeptin pharmacodynamics, which led to a variable rise in luteinising hormone (LH) following the second dose of kisspeptin. Those who had a lesser LH response following the first dose of kisspeptin had a greater subsequent rise following the second dose. Conversely, patients who already had a robust LH response following the first dose of kisspeptin had minimal further LH secretion following the second dose. Thus, a second dose of kisspeptin triggered an ‘individualised’ response, providing further LH exposure only to those patients requiring it. Thus, a second dose of kisspeptin could optimise the chance of an intermediate ovarian response whilst minimising the chance of ovarian under or over-response. The population studied was at high risk of OHSS (mean AMH: 52 pmol/L; mean antral follicle count: 40) and had a median of 24 follicles ≥11 mm on the day of trigger. Thus, almost half of patients would not usually be offered a fresh embryo transfer due to high risk of OHSS with current triggers. Importantly, 98% of patients in this trial had a fresh embryo transfer, all of whom had no evidence of moderate-to-severe OHSS and a second dose of kisspeptin resulted in a live birth rate per protocol of 39%.
In summary, a second dose of kisspeptin was able to optimise oocyte maturation and safely enable fresh embryo transfer without increasing rates of OHSS, even in a high-risk population.