Seventy percent of menopausal women are affected by hot flushes and 10% describe them as intolerable. Symptoms are often highly disruptive, affecting all aspects of daily life, and persist for many years secondary to oestrogen deficiency. Hormone replacement therapy is effective but is not without risk, and alternative therapies that are currently available are not without
side-effects and/or have variable efficacy. An effective novel therapy could therefore benefit 10 million women in the UK alone. Over the last 20 years, studies in animal and human models have implicated neurokinin B (NKB), a hypothalamic neuropeptide, together with its receptor (NK3R) in the aetiology of menopausal flushes. As such we hypothesised that an oral NK3R antagonist could attenuate menopausal flushes.
This thesis outlines the data from our first in human, proof of concept, randomised, placebo controlled study to test the efficacy of an oral NK3R antagonist in attenuating menopausal flushes. Furthermore, it includes the data of subsequent mathematical modelling to investigate
the association between luteinising hormone pulsatility and menopausal hot flushes, and basic science experiments to determine if genetic variation in the gene that encodes the neurokinin 3 receptor is important for experience of hot flushes and/or clinical response to an NK3R
antagonist.
The finding that pharmacological blockade of upregulated NKB/NK3R signalling with an oral NK3R antagonist significantly improves menopausal hot flush symptoms independent of any oestrogen effect suggests great promise for such agents as a novel therapeutic target to change future clinical practice. Larger scale studies of longer duration are the required next step in assessing the feasibility and likelihood of this.