The role of Kisspeptin and its analogue in the diagnosis and treatment of reproductive disorders in humans

Abstract

Kisspeptin, a hypothalamic neuropeptide encoded by the KISS1 gene, is a key regulator of the hypothalamic-pituitary-gonadal (HPG) axis, by stimulating pulsatile gonadotrophin releasing hormone (GnRH) secretion. Since 2005, there has been a huge body of work on the effects of exogenous kisspeptin administration on gonadotrophin responses in humans. These have demonstrated kisspeptin’s potential as a therapeutic agent in reproductive disorders and highlighted its potential as a diagnostic tool to probe hypothalamic GnRH neuronal function. The translational application of kisspeptin as a diagnostic and therapeutic tool in the field of reproductive endocrinology has been the focus of this research project. Firstly, I investigated kisspeptin’s ability to differentiate men with congenital hypogonadotrophic Hypogonadism (CHH) from healthy men compared to the currently available GnRH test. All circulating isoforms of kisspeptin have relatively short half-lives due to their rapid enzymatic degradation. Furthermore, repeated kisspeptin administration causes kisspeptin receptor desensitisation. Thus, a more stable, longer acting kisspeptin analogue would be an ideal candidate for use in the field of kisspeptin based therapeutics. MVT602 is one such agonist, and whilst it has shown promising results during application in men, its effects in women had not been previously explored. I thus investigated the effects of MVT602 on the gonadotrophin responses of healthy women in the follicular phase, and how these change after oestrogen pre-treatment. In the final study of this research project I compared the gonadotrophin responses elicited by both KP54 and MVT602 in women with the two commonest anovulatory disorders, namely Polycystic Ovarian Syndrome (PCOS) and Hypothalamic Amenorrhoea (HA). In summary, the results of this research project highlight the huge potential of KP54 and MVT602 to improve the diagnosis and treatment of patients with reproductive disorders, and also add to the existing body of work in the field of translational research for kisspeptin.