Effectiveness and safety of hormone replacement therapy in the treatment of menopausal syndrome: a meta-analysis

Objective: To comprehensively evaluate the efficacy and safety of hormone replacement therapy (HRT) in managing menopausal syndrome through a meta-analysis.Methods: A systematic search was conducted across Pubmed, Embase, and Cochrane Library databases utilizing keywords such as "menopause", "hormone replacement therapy", and "menopausal syndrome" from their inception until July 2024.Randomized controlled trials (RCTs) related to HRT's role in treating menopausal symptoms were included.Two researchers independently reviewed literature, extracted data, and assessed study quality.Meta-analysis was performed using RevMan 5.3 software, incorporating calculations of standardized mean difference (SMD) and odds ratio (OR), using either fixedeffects or random-effects models.Results: A total of 24 studies, involving 5089 patients, were included in the analysis.Among these, 3062 patients received HRT as the HRT group, while 2027 patients without HRT comprised the control group.The pooled results: (1) In subgroups with estradiol-containing drugs, the change in Kupperman menopause index (KMI) in the HRT group was significantly smaller than that in the control group [SMD=-1.21(-1.43, -0.98), P<0.001]; while in the subgroups didn't use estradiol as control intervention, the change in KMI in the HRT group was also smaller than that of the control group [SMD=-0.39(-0.67, -0.10), P=0.007].(2) The change in menopause-specific quality of life questionnaire (MENQOL) scores in the HRT group was significantly smaller than that of the control group [SMD=-0.43(-0.60, -0.27), P<0.001].(3) The improvement in estradiol (E 2 ) levels in the HRT group was greater than that of the control group [SMD=1.08(0.66, 1.49), P<0.001].(4) In the subgroup where the control intervention was placebo, the change in follicle stimulating hormone (FSH) level in the HRT group was significantly lower than that of the control group [SMD=-0.65 (-1.05, -0.24), P=0.002]; while in the subgroup where the control intervention was acupuncture, there was no significant difference of the change in FSH level between the HRT group and the control group [SMD=0.13(-0.21, 0.47), P=0.45].(5) The vaginal pH in the HRT group was significantly lower than that of the control group [SMD=-0.97(-1.08, -0.87), P<0.001].(6) The maturity change in vaginal exfoliated cells in the HRT group was greater than that of the control group [SMD=0.99(0.82, 1.16), P<0.001].(7) The improvement in lumbar bone density in the HRT group was significantly greater than in the control group [SMD=1.52[1.33, 1.71], P<0.001].(8) In the three subgroups with different drug regimens of estradiol plus norethindrone acetate, estradiol, and conjugated equine estrogen/estradiol, the improvements in hip bone density in the HRT group were all greater than in the control group [SMD=1.00(0.72, 1.27), P<0.001/SMD=1.36 (1.11, 1.60), P<0.001/SMD=0.57(0.11, 1.04), P=0.02].(9) No significant difference in the changes in total cholesterol (TC) [SMD=0.20 (-0.25, 0.64), P=0.39], low-density lipoprotein (LDL) [SMD=0.29 (-0.16, 0.74), P=0.20], and highdensity lipoprotein (HDL) [SMD=0.01(-0.43, 0.46), P=0.95] between the two groups.(10) Treatment-emergent ad-verse events (TEAE) occurred equally in both groups [OR=0.93(0.78, 1.13), P=0.48].Conclusion: HRT can enhance the quality of life and vaginal health in women experiencing menopausal symptoms, elevate estrogen levels, and improve bone density, while demonstrating a favorable safety profile with no significant increase in adverse events or dyslipidemia risk.Further investigations involving multi-center, large-scale studies with long-term follow-up are warranted to substantiate this conclusion.