Using hormones to improve reproductive health

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.