Advent of NK3R Antagonists for the Treatment of Menopausal Hot Flushes: A Narrative Review

ABSTRACT The menopause transition is marked by symptoms predominantly attributed to declining oestrogen levels. Approximately 80% of women experience associated symptoms, and 25% experience severe symptoms. The commonest are vasomotor symptoms (VMS), collectively referring to hot flushes and/or night sweats. Menopause hormone therapy (MHT) is the most common treatment for menopause‐related symptoms; however, some treatment‐related risks mean that MHT may not be suitable for all. Furthermore, following the publication of seminal studies, perceived risks of MHT have also led to reduced uptake. Additionally, not all women receiving MHT have full resolution of their symptoms. Therefore, alternative non‐hormonal therapies are of therapeutic interest. Neurokinin B (NKB) signalling via its cognate receptor, neurokinin 3 receptor (NK3R), at the hypothalamus has been identified as a mediator of menopausal VMS. Recently, NK3R antagonists have been developed targeting the NKB signalling pathway as a novel effective non‐hormonal therapeutic option for menopausal VMS. Fezolinetant has received approval from drug regulatory authorities worldwide, with data from multiple clinical trials showing a marked 60%–80% reduction in the frequency and severity of daily moderate–severe VMS, including in those considered unsuitable for MHT. Very recently, elinzanetant has been approved by the MHRA in the UK for the treatment of VMS in menopause, though it has not yet been approved by the FDA in the US. This review explores the neuroendocrine changes that occur in menopause and evidence from animal and human models suggesting that increased NKB signalling is involved in the pathogenesis of menopausal VMS. Data from clinical trials identifying NK3R antagonists as novel therapeutic agents for menopausal VMS are reviewed. Finally, the current status of NK3R antagonists and future directions of study in this area are discussed.