Why the study?
Reanalysis of the Women's Health Initiative renewed debate on menopause hormone therapy and cardiovascular risk, and it remained unclear whether cardiometabolic effects differ by formulation, route, or timing of initiation in women with or at risk for CVD.
Does menopause hormone therapy affect cardiometabolic and cardiovascular outcomes differently depending on formulation, route of administration, or timing of initiation in women with or at risk for cardiovascular disease?
Meta-Analysis (n=28,431)
Does menopause hormone therapy affect cardiometabolic and cardiovascular outcomes differently depending on formulation, route of administration, or timing of initiation in women with or at risk for cardiovascular disease?
Answers are grounded in this paper and cite their sources.
In women with or at risk for CVD, early initiation of estrogen-alone therapy reduces CHD, MI, mortality, and diabetes, whereas adding progestin negates cardiac benefits and increases stroke/VTE risk, and transdermal delivery offers a safer thrombotic and metabolic profile than oral administration.
Introduction: Reanalysis of the Women's Health Initiative has renewed debate on menopause hormone therapy (MHT) and cardiovascular risk. Whether MHT's cardiometabolic effects differ by formulation, route, or timing of initiation in women with or at risk for cardiovascular disease (CVD) remains unclear. This meta-analysis synthesizes the latest RCT evidence. Methods: We systematically searched databases for RCTs reporting cardiometabolic endpoints in women with or at high risk for CVD, including long-term follow-up from KEEPS and ELITE. Random-effects meta-analyses stratified by estrogen-alone vs. estrogen-progestin, oral vs. transdermal route, and early vs. late initiation relative to menopause onset. Results: Twelve RCTs (N=28,431) were included. In women initiating MHT within 10 years of menopause (early timing), estrogen alone reduced coronary heart disease (CHD) risk (RR 0.78; 95% CI 0.66-0.92), all-cause mortality (RR 0.81; 95% CI 0.70-0.94), and myocardial infarction (RR 0.82; 95% CI 0.69-0.97) versus placebo. Estrogen plus progestin showed neutral CHD effects (RR 1.00; 95% CI 0.87-1.15) but increased stroke risk (RR 1.28; 95% CI 1.02-1.58) and venous thromboembolism (VTE) (RR 1.52; 95% CI 1.12-2.06). Late initiation (>10 years) conferred no cardioprotection for any formulation. Transdermal estradiol (vs. oral) was associated with lower triglycerides (mean difference -12.4 mg/dL; 95% CI -18.2 to -6.6), reduced VTE (RR 0.59; 95% CI 0.38-0.91), and lower systolic blood pressure (MD -3.1 mmHg; 95% CI -5.4 to -0.8). No significant differences in heart failure hospitalization were observed by route (RR 0.92; 95% CI 0.73-1.16). Early estrogen alone reduced diabetes incidence (RR 0.73; 95% CI 0.59-0.90). Conclusion: Early initiation of estrogen-alone MHT may reduce CHD, mortality, MI, and diabetes in women at risk for CVD, but adding progestin negates cardiac benefits and elevates stroke and VTE risk. Transdermal administration offers a safer metabolic and thrombotic profile. These findings support formulation-, route-, and timing-guided MHT recommendations.
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Patricia et al. (2026) conducted a meta-analysis in Menopause in women with or at high risk for cardiovascular disease (n=28,431). Menopause hormone therapy (estrogen alone or estrogen plus progestin; oral or transdermal) vs. Placebo (or oral vs. transdermal estradiol for route comparison) was evaluated on Coronary heart disease (with early initiation of estrogen alone) (RR 0.78, 95% CI 0.66-0.92).
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