Targeting estrogen receptor subtypes in menopausal syndrome: differential effects on vasomotor symptoms, mood, and bone health – a systematic review and meta-analysis

Background Management of menopausal syndrome is moving toward precision medicine, yet the differential effects of estrogen receptor (ER) subtype preference (estrogen receptor alpha (ERα) vs. estrogen receptor beta (ERβ)) remain poorly characterized. This systematic review and meta-analysis evaluates the impact of ER-targeted therapies on vasomotor symptoms, anxiety and depressive symptoms, and bone mineral density (BMD) in menopausal women, and explores whether outcomes vary by receptor selectivity. Methods We systematically searched PubMed, Embase, Cochrane Library, and Web of Science up to July 2025 for randomized controlled trials (RCTs) comparing ER-targeted therapies (including selective estrogen receptor modulators [SERMs], estetrol, and Phyto-SERMs) with placebo in menopausal women (naturally menopausal women, with emphasis on perimenopausal and early postmenopausal populations). Random-effects meta-analyses were conducted where sufficient data were available. A total of 13 randomized controlled trials involving 1,115 menopausal women, with treatment durations ranging from 8 to 48 weeks, were included in the quantitative synthesis. Results ER-targeted therapies were associated with improvements in overall menopausal symptom burden (Menopause Rating Scale [MRS], SMD = -1.95, 95% CI -3.18 to -0.72), hot flashes (SMD = -1.21, 95% CI -1.88 to -0.54), anxiety (SMD = -1.35, 95% CI -2.26 to -0.45), and depressive symptoms (SMD = -1.13, 95% CI -2.01 to -0.26). However, substantial heterogeneity was observed across symptom outcomes ( I² > 90%), prediction intervals were wide, and the depression estimate was not robust in sensitivity analyses. Exploratory subgroup analyses suggested that ERβ-preferential interventions were more consistently associated with symptom relief, whereas ERα-predominant modulation showed limited symptom benefit and may have skeletal benefits, although this conclusion is based on very limited evidence from a single raloxifene trial. Nevertheless, ERα-predominant evidence was generally derived from a single trial or comparison per outcome, precluding definitive receptor-subtype conclusions. Conclusions ER-targeted interventions may provide preliminary benefits for selected menopausal symptoms, particularly vasomotor and anxiety-related symptoms. However, the certainty of evidence remains limited by substantial heterogeneity, imprecision, small study numbers, and imbalanced receptor-subtype subgroups. The apparent distinction between ERβ-preferential symptom relief and possible ERα-predominant skeletal effects should be regarded as hypothesis-generating rather than clinically confirmatory.