Effect of kisspeptin on reproductive function in women with hypothalamic amenorrhea

Amennorhea is the term used describe women who have no periods and this results in infertility. In many women the cause of the problem is due to a problem in a part of the brain called the hypothalamus and this is termed hypothalamic amenorrhea. The cause of hypothalamic amenorrhea is not known and treatments are associated with significant side effects. Recent evidence in rodents suggests that a new hormone called kisspeptin may be the missing factor in women with hypothalamic amenorrhea. Administration of kisspeptin to rodents with hypothalamic amenorrhea resulted in an increase in restoration of normal periods and fertility. Women with hypothalamic amenorrhea are infertile and have increased risk of osteoporosis and fractures, which is associated with increased illness and earlier death. The inability to have children is often devastating, and can result in severe depression which can lead to marital breakdown.
Investigators in the Department of Metabolic Medicine at Imperial College London will be carrying out the research in this application. They have considerable experience of human infusion studies in order to investigate the physiology of novel hormones and peptides and have developed protocols that ensure reliable, safe delivery of a dose of peptide into humans. The investigators have recently completed the first human infusion studies of kisspeptin in males and females and shown that it stimulates reproductive hormone secretion.
The investigators now intend to conduct a study to chronically administer subcutaneous kisspeptin to women with hypothalamic amenorrhea and investigate whether this can restore circulating reproductive hormones and restore their periods and fertility.

Hypothalamic amenorrhea is defined as the cessation of menstruation due to abnormal signalling between the hypothalamus and the pituitary gland. Women with hypothalamic amenorrhea are infertile and have increased risk of osteoporosis and fractures, which is associated with increased morbidity and mortality. The inability to have children can be devastating, and has important implications for mental, social, and reproductive health. The currently treatments for women with hypothalamic amenorrhea are associated with significant side effects. In healthy women, the reproductive cycle is controlled by the hypothalamic-pituitary gonadal (HPG) axis. Gonadotrophin-releasing hormone (GnRH) released from the hypothalamus stimulates the release of the gonadotrophins, luteinising hormone (LH) and follicle-stimulating hormone (FSH), from the anterior pituitary gland. These gonadotrophins in turn regulate ovarian function. Women with hypothalamic amenorrhea typically have reduced GnRH and gonadotrophin release, without obvious hypothalamic or pituitary structural abnormalities. Kisspeptin is a novel hypothalamic neuropeptide vital to the regulation of GnRH release which may represent a common signalling pathway disturbed in all forms of hypothalamic amenorrhea. We propose to investigate whether the peripheral administration of kisspeptin to women with hypothalamic amenorrhea can restore circulating reproductive hormones and ovarian follicular development.
Kisspeptin is the endogenous neuropeptide agonist of the G protein-coupled receptor, GPR54. Kisspeptin and GPR54 play a critical role in the central regulation of the HPG axis. GPR54 mutations in humans have been shown to cause hypogonadotrophic hypogonadism and pubertal delay, and GPR54 deficient mice have abnormal sexual development, low circulating gonadotrophin concentrations, and are incapable of reproducing. These findings demonstrate that GPR54 is necessary for normal pubertal development and reproductive function. Interestingly, kisspeptin can stimulate precocious activation of the reproductive axis even in rodent models of hypothalamic amenorrhoea. We have recently demonstrated for the first time that kisspeptin administration stimulates the HPG axis in human males and females, without side effects, demonstrating that kisspeptin represents a novel tool for HPG axis manipulation in disorders of the reproductive system in humans.
We now intend to chronically administer subcutaneous kisspeptin to women with hypothalamic amenorrhea and investigate whether this can restore circulating reproductive hormones and ovarian follicular development. These experiments will provide proof of concept that kisspeptin can stimulate the reproductive axis in females with hypothalamic amenorrhea.