Title: Using hormones to improve reproductive health
Funder: Department of Health and Social Care

Abstract: Disorders of reproductive health affect millions of patients worldwide. Infertility affects 1 in 6 couples and can cause a devastating effect on a couple's mental and physical wellbeing. Whilst current treatments are available for infertility, they are often associated with suboptimal success rates and can result in life threatening side effects in otherwise healthy women. Postmenopausal flushing affects 70% of menopausal women and can result in severe symptoms which cause depression and poor quality of life. Hormone Replacement Therapy (HRT) is an effective treatment for menopausal flushing but is contraindicated in many women with post-menopausal symptoms due to safety concerns e.g. breast cancer, stroke and coronary artery disease. The hormones kisspeptin and neurokinin B have recently been identified as potential novel targets for the treatment of infertility and menopausal flushing, respectively. Kisspeptin is vital for normal puberty and stimulates the release of endogenous GnRH which then stimulates gonadotrophin release and subsequently sex hormones. Hence the advantage of kisspeptin over current treatments is that its effects will depend upon the endogenous release of an individual's GnRH pool. This will result in a more physiological stimulation of gonadotrophins and prevent excessive stimulation which limits current fertility treatments. Kisspeptin therefore has the potential to treat patients with infertility in a more physiological manner to improve outcomes and eliminate life-threatening side effects. Recent studies demonstrate that neurokinin B signalling within the hypothalamus mediates menopausal-like flushing. Consistent with this I have shown that administration of neurokinin B to women causes hot flush symptoms. Neurokinin B predominantly activates the NK3-receptor (NK3R). Therefore NK3R antagonists have potential as a novel treatment approach to treat menopausal flushing. Aims: To investigate the efficacy of kisspeptin to improve fertility outcomes in women with infertility I will determine the: 1. Optimal protocol for the use of kisspeptin to trigger oocyte maturation during IVF treatment. 2. Efficacy of a kisspeptin analogue to treat infertility in women with polycystic ovarian syndrome (PCOS). To investigate the efficacy of NK3R antagonists as a novel treatment approach to treat menopausal flushing I will: 3. Determine the efficacy of a NK3R antagonist to treat post-menopausal flushing. Plan of investigation: Study 1: to determine the optimal protocol for the use of kisspeptin to trigger oocyte maturation during IVF treatment. Patients with infertility undergoing IVF treatment will be randomised to one or two kisspeptin injections to trigger oocyte maturation and oocyte yield determined. This study will determine the optimal protocol for the use of kisspeptin in IVF treatment. Study 2: TAK-448 is a long acting analogue of kisspeptin developed by Takeda. I will perform a dose finding study to determine the optimal dose of TAK-448 to stimulate reproductive hormone release in patients with infertility due to PCOS. Following this a multi-dose study will be performed to determine the efficacy of TAK-448 to restore ovulation (and hence fertility) in these patients. Study 3: I will perform a proof-of-concept study to determine if an NK3R antagonist (AZD2624) is effective in treating post-menopausal flushing. Patients will receive 4 weeks of AZD2624 or placebo in random order separated by a 2 week washout period and hot flush frequency determined. Summary of potential benefits to patients and the NHS: This programme of work could offer new treatments for the millions of patients suffering from disorders of reproductive health. New treatment protocols will be developed based on kisspeptin signalling which will improve fertility outcomes and eliminate the life-threatening risks and side effects associated with current fertility treatments. Patients suffering with post-menopausal flushing will have a potential novel safe treatment to alleviate their distressing symptoms.

Lay abstract: The overall aim of this Programme of work is to develop new treatments for patients with medical disorders of reproductive health which affect millions of patients worldwide. Background: Infertility affects 1 in 6 couples and can cause a devastating effect on a couple's mental and physical wellbeing. Infertility is commonly caused by a condition in which women have many cysts on their ovaries and is called polycystic Ovarian Syndrome (PCOS). Whilst current treatments are available for infertility, they sometimes do not work and in addition can cause life-threatening side effects. Flushing affects 70% of women going through the menopause (menopausal flushing) and can result in severe symptoms which can last up to 20years resulting in depression and poor quality of life. Hormone Replacement Therapy (HRT) is an effective treatment for menopausal flushing but cannot be taken by many women as there are safety concerns associated with using HRT, for example increased risk of breast cancer, stroke and heart disease. Hormones are your body's chemical messengers. They travel in your bloodstream to tissues or organs. They work slowly, over time, and affect many different processes, including reproductive health. Two naturally occurring hormones have recently been discovered called kisspeptin and neurokinin B. They could form the basis of new treatments for patients with infertility and menopausal flushing, respectively. Kisspeptin is vital for normal puberty because kisspeptin naturally and gently stimulates the body to release sex hormones. Current fertility treatments are drugs which powerfully stimulate the release of sex hormones and hence can cause too much stimulation and life-threatening side effects in women who are otherwise healthy. Kisspeptin could be used to treat patients with infertility to improve their chance of conceiving but also eliminate life-threatening side effects of current treatments. Recent research has shown that the hormone neurokinin B is important in causing menopausal flushing in animals. In keeping with this I have shown that giving an injection of neurokinin B to women causes hot flush symptoms. Hence a drug which blocks the action of neurokinin B could be a new effective medicine for treating menopausal flushing. Aims: To test if kisspeptin is effective in safely improving the chances of women with infertility conceiving I will: 1. determine the best way to use kisspeptin in women with infertility having IVF treatment. 2. Test how effective a new drug which has similar properties as kisspeptin is to treat infertility in women with PCOS. To test how effective drugs which block the action of neurokinin B could be as a new treatment for menopausal flushing I will: 3. Measure the reduction in menopausal flushing observed in post-menopausal women who are treated with a drug which blocks the action of neurokinin B. Research plan: Study 1: I will determine the best way to use kisspeptin in women with infertility having IVF treatment. Patients will be given either one or two kisspeptin injections during their IVF treatment and the number of mature eggs collected by their IVF doctor recorded. I will determine if it is better to give one or two kisspeptin injections during IVF treatment to achieve the highest number of mature eggs obtained and hence chances of women conceiving. Study 2: I will test how effective a new drug which has similar properties as kisspeptin is to treat infertility in women with PCOS. I will first give single injections of increasing amounts of this drug to women with PCOS and measure release of sex hormones. This will allow me to work out the amount of this drug to give to women with PCOS to stimulate the right amount of sex hormones. I will then give several injections of the drug over 2 weeks to women with PCOS and see if the drug can re-start regular periods and hence restore fertility. Study 3: To test how effective drugs which block the action of neurokinin B could be as a new treatment for menopausal flushing. I will measure the reduction in menopausal flushing observed in post-menopausal women who are treated with a drug which blocks the action of neurokinin B. This programme of work could result in new treatments for the millions of patients suffering from disorders of reproductive health. There will be involvement of patient groups and the public at all stages of this research to ensure that the most appropriate research question is investigated and patients' research needs are met. I will disseminate my findings widely as possible through the public media, YouTube, patient groups, science festivals as well as scientific meetings and publications.

Research activity codes: 6.1 PHARMACEUTICALS
Health categories: REPRODUCTIVE HEALTH AND CHILDBIRTH