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<p>Vasomotor symptoms (VMS), including hot flushes and night sweats, affect approximately 70% of people experiencing menopause and have a notable effect on quality of life. Until the past few years, the underlying neuroendocrine mechanisms remained poorly understood, limiting therapeutic options beyond menopausal hormone therapy. The discovery that neurons expressing kisspeptin, neurokinin B and dynorphin (KNDy neurons) in the hypothalamic arcuate nucleus trigger VMS through modulation of neurons expressing neurokinin 3 receptor (NK3R) in the median preoptic area has revolutionized our understanding of VMS pathophysiology. During oestrogen withdrawal, hyperactivated KNDy neurons release excessive levels of neurokinin B, inappropriately triggering heat dissipation responses that are characteristic of hot flushes. This mechanistic insight has enabled the development of NK3R antagonists as the first non-hormonal therapeutic specifically targeting VMS neurobiology. These new treatments offer promise for populations in which hormone therapy is contraindicated. This Review synthesizes the current understanding of VMS neurobiological pathways, examines translational approaches from preclinical animal models to clinical studies, and discusses the evolution of treatments and mechanism-based interventions that might fundamentally transform the management of menopausal symptoms.</p>

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Neurokinin receptor antagonists for vasomotor symptoms: from KNDy neurons to clinical translation

  • 期刊论文

  • 发表日期：

    2026年4月14日

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  • Encarnación Torres,
  • Ellen G. Wall,
  • Víctor M. Navarro

摘要

Vasomotor symptoms (VMS), including hot flushes and night sweats, affect approximately 70% of people experiencing menopause and have a notable effect on quality of life. Until the past few years, the underlying neuroendocrine mechanisms remained poorly understood, limiting therapeutic options beyond menopausal hormone therapy. The discovery that neurons expressing kisspeptin, neurokinin B and dynorphin (KNDy neurons) in the hypothalamic arcuate nucleus trigger VMS through modulation of neurons expressing neurokinin 3 receptor (NK3R) in the median preoptic area has revolutionized our understanding of VMS pathophysiology. During oestrogen withdrawal, hyperactivated KNDy neurons release excessive levels of neurokinin B, inappropriately triggering heat dissipation responses that are characteristic of hot flushes. This mechanistic insight has enabled the development of NK3R antagonists as the first non-hormonal therapeutic specifically targeting VMS neurobiology. These new treatments offer promise for populations in which hormone therapy is contraindicated. This Review synthesizes the current understanding of VMS neurobiological pathways, examines translational approaches from preclinical animal models to clinical studies, and discusses the evolution of treatments and mechanism-based interventions that might fundamentally transform the management of menopausal symptoms.