Efficacy and safety of menopausal hormone therapy for depressive symptoms in perimenopausal women: A systematic review and meta-analysis.

OBJECTIVE (S): Perimenopause is associated with an increased risk of depressive symptoms, potentially related to hormonal fluctuations during the menopausal transition. Although hormone replacement therapy (HRT) is widely used for vasomotor symptoms, its potential effects on depressive symptoms remain uncertain. This meta-analysis evaluated the association between HRT and depressive symptom severity in perimenopausal women. METHODS: We systematically searched PubMed, Embase, the Cochrane Library, Web of Science, and ClinicalTrials.gov from inception to December 23, 2025 for randomized controlled trials evaluating HRT in perimenopausal women with depressive symptoms. Eligible studies included comparisons of HRT versus placebo, HRT versus HRT combined with antidepressants, and comparisons between different HRT regimens. Standardized mean differences (SMDs) with 95% confidence intervals (CIs) were pooled using random-effects models. Prespecified subgroup analyses were conducted according to hormone type and route of administration. Risk of bias was assessed using the Cochrane RoB 2 tool, and the certainty of evidence was evaluated using the GRADE approach. RESULTS: Twelve randomized controlled trials were included. In placebo-controlled comparisons, HRT was associated with a small reduction in depressive symptom severity (SMD = -0.23, 95% CI -0.43 to -0.03). Subgroup analyses suggested larger effect estimates for tibolone or selective tissue estrogenic activity regulator-based regimens; however, tests for subgroup differences were not statistically significant, and the number of studies within subgroups was limited. No clear differences were observed according to route of administration. Evidence from comparisons involving active treatments was limited and did not support firm conclusions. Reported adverse events were generally mild to moderate. CONCLUSIONS: HRT may be associated with a modest reduction in depressive symptoms in perimenopausal women; however, the magnitude of effect is small and the certainty of evidence is limited. Evidence comparing different HRT strategies remains insufficient to draw firm conclusions. Further well-designed, adequately powered randomized controlled trials are needed to clarify comparative efficacy and long-term safety.