ESPE Abstracts

Infertility affects one in six couples in the UK. Identification of novel factors which are critical to reproductive function could lead to improved therapies for infertility. Kisspeptin has been identified as a key regulator of the reproductive system. Defective kisspeptin signalling causes a failure of reproductive hormone release (hypogonadotrophic hypogonadism) in rodents and man leading to a failure to go through puberty. My group have determined the effects of kisspeptin on stimulation of reproductive hormone release in humans. Kisspeptin infusion to male volunteers significantly increased plasma LH, FSH and testosterone. Administration of kisspeptin to female volunteers increased plasma LH in all phases of the menstrual cycle with the greatest effect in the preovulatory phase.

We have recently determined the therapeutic potential of kisspeptin in patients with infertility:

i) Hypothalamic amenorrhea is defined as the cessation of menstruation due to abnormal signalling between the hypothalamus and the pituitary gland. It accounts for over 30% of cases of amenorrhea in women of reproductive age. We have shown that kisspeptin administration stimulates reproductive hormone release and can restore LH pulsatility in with hypothalamic amenorrhea.

ii) IVF treatment is now widely and successfully used to enable infertile couples to conceive. However, IVF treatment can result in the potentially life threatening condition, ovarian hyperstimulation syndrome (OHSS) due to the pharmacological use of human chorionic gonadotrophin (hCG) to stimulate oocyte maturation in current IVF protocols. A more physiological stimulus for oocyte maturation, such as kisspeptin, may avoid this dangerous side effect and improve the safety and efficacy of IVF treatment. We have shown that kisspeptin can effectively and safely trigger oocyte maturation resulting in the birth of healthy children without OHSS.

iii) Hypogonadotropic hypogonadism is hypogonadism due to either hypothalamic or pituitary dysfunction. Whilst gonadotropin releasing hormone (GnRH) can directly test pituitary function, no specific test of hypothalamic function exists. Kisspeptin-54 (KP54) is a neuropeptide that directly stimulates hypothalamic GnRH-release and thus could be used to specifically interrogate hypothalamic function. Our work shows that KP54 fully discriminated men with CHH from healthy men. Thus, KP54 could be used to specifically interrogate hypothalamic GnRH neuronal function in patients with congenital hypogonadotropic hypogonadism.

Our future work aims to deliver novel kisspeptin based therapies into the clinic to improve the outcomes of patients with reproductive disorders.