MICA: Neurokinin 3 Receptor Antagonism as a Novel Treatment for Menopausal Hot Flushes

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Hot flushes (or flashes) are transient episodes of sweating and intense heat sensation associated with a chronic decrease in circulating sex steroid levels. Hot flushes are experienced by up to 70% of women during the menopausal transition and postmenopause, and negatively impact on quality of life. Hot flushes are also experienced by many patients undergoing sex steroid deprivation therapy for breast and prostate cancer. Hormone replacement therapy (HRT) is the most effective treatment for menopausal hot flushes. Unfortunately, current recommendations are that HRT be used at the lowest possible dose for the shortest possible duration due to associated risks of breast cancer, stroke, venous thromboembolism and coronary artery disease. Furthermore, HRT is contraindicated in many patients. Hence alternative therapies to HRT are needed for menopausal flushing.Neurokinin B (NKB) is a member of the tachykinin family of peptides. NKB is encoded by the TAC3 gene and binds preferentially to the neurokinin 3 receptor (NK3). Recent human and animal data have demonstrated that NKB signalling is an essential component in mediating menopausal flushing. We performed for the first time a double-blinded, placebo-controlled pilot study which demonstrated that NKB infusion induced hot flush symptoms in women. These data suggest that NK3 receptor antagonists could be a novel and effective therapy for menopausal flushing. The aim of the proposed research is to carry out a study to determine if a Neurokinin 3 Receptor Antagonist is effective in treating hot flushes in menopausal women. AstraZeneca have developed a NK3 receptor antagonist (AZD2624) and shown that it is safe when administered to humans. AstraZeneca have agreed to work with the University researchers by providing their NK3 receptor antagonist (AZD2624) at no cost for this proposed research. The proposed study will determine how effective an NK3 receptor antagonist (AZD2624) is in treating hot flush symptoms in post menopausal women.If the proposed study shows that an NK3 receptor antagonist is an effective new treatment for menopausal flushing then this could provide a new treatment for hot flushes without the potential risks of hormonal administration. This would be beneficial for the following groups of patients:1. The major clinical application would be as a second-line therapy for patients with contraindication to HRT (ischaemic heart disease, cerebrovascular disease, previous thrombosis or high thrombotic risk), or in patient preference for non-hormonal therapy due to previous or anticipated adverse effects. In practice, 25% of women aged 50 or over, cannot take the pill due to a contraindication. Therefore, our solution would benefit an estimated 5 million women per year a third of whom have 'troublesome' flushing symptoms.2. Patients previously treated with HRT for 5 years, who require further treatment for flush symptoms which may persist for a total of 10 years i.e. 5 years beyond the point at which HRT would usually be discontinued. 3. Women with flushes induced by hormonal deprivation therapy for breast cancer.4. Women with a contraindication to HRT due to the diagnosis of previous breast cancer.5. Men with flushes induced by hormonal deprivation therapy for prostate cancer.