Title: Improving the evaluation and treatment of patients with reproductive disorders using kisspeptin
Funder: Department of Health and Social Care

Abstract: Introduction Reproductive disorders affect a fifth of young women and no cause is identified in half of patients investigated for subfertility. Currently, only pituitary and gonadal axes can be directly assessed with available tests, thus hypothalamic contribution to many reproductive disorders remains uncertain. Restoration of pulsatile hormonal secretion with a GnRH pump requires specialist technology not readily available in the UK. Kisspeptin is an endogenous neuropeptide that regulates hypothalamic gonadotrophin releasing hormone (GnRH) secretion. Mutations impairing kisspeptin signalling result in hypogonadotrophic hypogonadism and a failure of pubertal development. Kisspeptin is a potent secretagogue of hypothalamic GnRH secretion. The advent of kisspeptin makes it possible to directly test hypothalamic function when assessing patients with reproductive disorders and may offer a novel therapy. Part 1- Developing a novel 'kisspeptin test' of hypothalamic function a) Establish reference range for a 'kisspeptin test' I shall quantify the gonadotrophin response to kisspeptin in 120 healthy men and 120 healthy women to establish a reference range for a 'kisspeptin test', against which hypothalamic function in patients with reproductive disorders can be compared. b) Kisspeptin test in children with delayed pubertyChildren who do not enter puberty by the same age as most (e.g.14yrs) are diagnosed with 'delayed puberty'. Most children with delayed puberty have a normal hypothalamus and will enter puberty spontaneously with conservative management ('Constitutional Delay of Growth and Puberty'; CDGP). However, a small subset of patients with delayed puberty have a genetic disorder causing reduced hypothalamic function ('Congenital Hypogonadotrophic Hypogonadism'; CHH). Children with CHH require hormonal induction of puberty. Currently, it is challenging to differentiate these two groups of children requiring different management. Therefore, I shall evaluate a 'kisspeptin test' in 88 teenage boys with delayed puberty to see if this can differentiate those with normal hypothalamic function (CDGP) from those with abnormal hypothalamic function (CHH). c) Kisspeptin test in men with 'Late Onset Hypogonadism' (LOH) Circulating free testosterone levels fall in men with increasing age. In conjunction with symptoms of hypogonadism, this is termed LOH. LOH is due to testicular dysfunction in some men, however the rise in serum gonadotrophin levels is also attenuated suggesting an additional element of hypothalamo-pituitary dysfunction. To date, it has not been possible to directly assess hypothalamic function, however I have recently demonstrated that the hypothalamic response to kisspeptin is preserved in healthy older men without LOH. Thus, I shall now use a kisspeptin test to evaluate the hypothalamic component of hypogonadism in 68 men with LOH. Part 2- Using kisspeptin as a novel therapy for women with hypothalamic amenorrhoeaHypothalamic amenorrhoea (HA) is diagnosed in a third of women with oligo/amenorrhoea. I have previously demonstrated that kisspeptin can restore normal gonadotrophin pulsatility in women with HA. Thus, I shall now investigate whether chronic subcutaneous administration of kisspeptin for a longer period can restore menstrual cyclicity in 16 women with HA. Summary This programme of research will use kisspeptin to improve the diagnosis and management of patients with reproductive disorders, and potentially a novel endocrine test and therapy.

Lay abstract: Introduction: Reproductive disorders affect over a fifth of young women and no cause is identified in up to half of patients investigated for fertility issues. Current tests of reproductive disorders can only evaluate part of the hormonal system that controls reproductive hormone secretion. Current treatments to restore normal hormonal function require complex technology to administer. Kisspeptin is a hormone that is normally present within the body. People lacking kisspeptin, do not go through puberty and have reduced fertility. This is because kisspeptin controls the function of an important part of the brain called the 'hypothalamus', which is the master regulator of reproductive hormones. Giving kisspeptin to people can safely stimulate the hypothalamus to release reproductive hormones. Research Plan Part 1: Developing kisspeptin as a novel test for reproductive disordersA) Establish the normal response to kisspeptin in 120 healthy men and 120 healthy women Until now, it has not been possible to directly test the function of the hypothalamus in patients with reproductive disorders. This part of the research will inform us of the expected response to a 'kisspeptin test' so that we can accurately interpret the results in patients with reproductive disorders. B) Kisspeptin test in children with delayed puberty Puberty can start at different times in children and some may enter puberty later than most (~14 years), which is called 'delayed puberty'. The hypothalamus is the part of the brain that controls the start of puberty. Most children with delayed puberty have a normal hypothalamus and will enter puberty spontaneously with time called 'Constitutional Delay of Growth and Puberty' (CDGP). However, a small subset of children with delayed puberty have an inherited disorder causing the hypothalamus to not function properly called 'Congenital Hypogonadotrophic Hypogonadism' (CHH). Children with CHH require treatment to start puberty. Currently, doctors do not have a good way of differentiating these two groups of children who require different treatment. Kisspeptin plays an important role in regulating the normal onset of puberty. Therefore, I shall perform a 'kisspeptin test' in 88 teenagers with delayed puberty to see if it can differentiate those with a normal hypothalamus (CDGP) from those with a dysfunctional hypothalamus (CHH). C) Kisspeptin test to evaluate reproductive function in older menAs men age, levels of the male hormone 'testosterone' can fall, which if causing symptoms is called 'late onset hypogonadism' (LOH). This fall in testosterone could be due to a problem in different parts of the body controlling testosterone levels. Before now, it was not possible to directly test the hypothalamus, however kisspeptin has recently been shown to do this in healthy older men. Therefore, I shall use a kisspeptin test to evaluate the function of the hypothalamus in 68 older men with low testosterone and provide them with a more accurate diagnosis. Part 2: Using kisspeptin to restore periods in women with irregular cycles 'Hypothalamic amenorrhoea' (HA) is the cause in a third of women presenting with irregular periods. It is due to a reduction in the function of the hypothalamus as a result of low body weight, stress, or excessive exercise. During my previous research, I found that kisspeptin is able to restore the normal secretion of hormones in women with HA. Therefore, I shall now assess whether giving kisspeptin for longer durations can restore normal cycles in 16 women with HA, potentially offering a novel treatment for these women.Publicising our findings: I shall co-produce a plain english summary with a lay colleague to inform the public about our findings. Summary: This programme of research will improve the diagnosis and management of people with reproductive disorders using kisspeptin.

Research activity codes: 4.2 EVALUATION OF MARKERS AND TECHNOLOGIES
Health categories: REPRODUCTIVE HEALTH AND CHILDBIRTH