Neurokinin 3 receptor antagonists for menopausal vasomotor symptoms

70% of women have menopausal vasomotor symptoms (hot flashes, also called hot flushes, or night sweats), which can negatively affect aspects of daily life and persist for many years. 1 Stearns V Ullmer L López JF Smith Y Isaacs C Hayes D Hot flushes. Lancet. 2002; 360: 1851-1861 Summary Full Text Full Text PDF PubMed Scopus (349) Google Scholar 10–20% of women describe such symptoms as near intolerable. 1 Stearns V Ullmer L López JF Smith Y Isaacs C Hayes D Hot flushes. Lancet. 2002; 360: 1851-1861 Summary Full Text Full Text PDF PubMed Scopus (349) Google Scholar Hormone therapy restores circulating oestrogen and is the most effective available treatment, but is contraindicated in some people and avoided by others, and if treatment is continued for more than 5 years there are small but significant absolute risks of breast cancer in particular. Preclinical research has strongly implicated heightened signalling of neurokinin B together with its receptor (neurokinin 3 receptor [NK3R]) in causing menopausal vasomotor symptoms, via the hypothalamic median pre-optic nucleus and autonomic thermoregulatory pathway. 2 Rance NE Dacks PA Mittelman-Smith MA Romanovsky AA Krajewski-Hall SJ Modulation of body temperature and LH secretion by hypothalamic KNDy (kisspeptin, neurokinin B and dynorphin) neurons: a novel hypothesis on the mechanism of hot flushes. Front Neuroendocrinol. 2013; 34: 211-227 Crossref PubMed Scopus (199) Google Scholar Subsequent phase 2b trials of NK3R antagonists showed that pharmacological blockade of NK3R attenuated vasomotor symptoms almost as effectively as hormone treatment, without the need for oestrogen exposure. 3 Prague JK Roberts RE Comninos AN et al. Neurokinin 3 receptor antagonism as a novel treatment for menopausal hot flushes: a phase 2, randomised, double-blind, placebo-controlled trial. Lancet. 2017; 389: 1809-1820 Summary Full Text Full Text PDF PubMed Scopus (128) Google Scholar Fezolinetant for treatment of moderate-to-severe vasomotor symptoms associated with menopause (SKYLIGHT 1): a phase 3 randomised controlled studyData support the clinical use of fezolinetant as a non-hormonal treatment for vasomotor symptoms associated with menopause. The study was placebo-controlled for 12 weeks followed by a 40-week blinded extension to assess the maintenance of effect. Furthermore, the population studied was diverse and representative of the potential target population for fezolinetant therapy. Further characterisation of the benefit of fezolinetant on quality of life, including on symptoms of mood and sexual wellbeing, merits investigation. Full-Text PDF