<![CDATA[Introduction: Vasomotor symptoms (VMS) are the most common and disruptive menopausal complaints, impairing sleep, daily functioning, and quality of life. Limitations of hormonal therapy and modest benefit of current non-hormonal options underscore the need for targeted alternatives. Neurokinin-3 receptor (NK3R) antagonists represent a novel non-hormonal therapy that modulates hypothalamic KNDy neuron dysregulation linked to estrogen decline. This study aimed to evaluate the efficacy and safety of NK3R antagonists in menopausal women with VMS. Methods: A systematic review and meta-analysis were conducted following PRISMA guidelines. Searches across PubMed, Cochrane, ScienceDirect, Epistemonikos, Scopus, ProQuest, and EBSCO through November 2025 identified clinical trials assessing NK3R antagonists for VMS. Independent reviewers performed data extraction and risk-of-bias assessment using the Cochrane RoB 2.0 tool. Pooled analyses were calculated using standardized mean differences (SMDs) or odds ratios (ORs) with 95% confidence intervals. Results: Sixteen clinical trials met the inclusion criteria. NK3R antagonists significantly improved menopause-specific quality of life (SMD −0.46; 95% CI −0.67 to −0.25), PROMIS sleep-related outcomes (SMD −0.23; 95% CI −0.32 to −0.13), and work productivity (SMD −0.52; 95% CI −0.97 to −0.06). Patients were more likely to report meaningful improvement on PGI-C (OR 6.34; 95% CI 1.25–32.00). Adverse event rates were comparable to placebo (OR 0.84; 95% CI 0.36–1.93), with most events mild and transient. Conclusion: NK3R antagonists effectively reduce vasomotor symptoms and improve quality of life with a safety profile similar to placebo. These findings support NK3R antagonists as a valuable non-hormonal therapeutic option, particularly for women unable or unwilling to use hormonal therapy.]]>
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