Impact of Menopausal Hormone Therapy on cognitive function and dementia Risk: A systematic review and meta-analysis focusing on the timing hypothesis and administration route
Systematic review and meta-analysis reveals timing-dependent dementia risk from hormone therapy in postmenopausal women, suggesting early initiation provides cognitive protection.
Key Points
To systematically evaluate the impact of menopausal hormone therapy on cognitive outcomes and dementia risk, assessing effect modification by initiation timing, formulation, route, and duration.
Searched PubMed/MEDLINE, Embase, Cochrane CENTRAL, and Web of Science through May 2026 for randomized controlled trials and observational cohorts evaluating hormone therapy and cognition.
Identified 65 studies for qualitative synthesis and 12 studies (contributing 18 effect estimates) for quantitative random-effects meta-analysis using the DerSimonian–Laird estimator.
Stratified analyses by initiation timing (<5 versus >5 years from final menstrual period), formulation (estrogen-only versus combined), administration route (oral, transdermal, vaginal), and duration.
Any hormone therapy use versus never-use showed a neutral overall association with incident all-cause dementia (pooled aRR 1.06, 95% CI 0.97 to 1.15; k = 4; I2 = 96%).
Therapy initiation within five years of menopause significantly reduced dementia risk (pooled aRR 0.66, 95% CI 0.53 to 0.83; k = 3; I2 = 0%; p = 0.0003), whereas initiation after five years showed no protective effect (pooled aRR 1.02, 95% CI 0.80 to 1.29; k = 2; I2 = 0%).
Long-term combined estrogen–progestogen regimens were associated with increased dementia risk (pooled aRR 1.22, 95% CI 1.10 to 1.36; k = 4; I2 = 89%; p = 0.0002), while transdermal estradiol (pooled aRR 0.89, 95% CI 0.74 to 1.07; k = 2) and vaginal estrogen (pooled aRR 0.99, 95% CI 0.96 to 1.02) showed no significant risk elevation.