Primary outcomes were cardiovascular morbidity, cardiovascular and all-cause mortality, and a composite of cardiovascular morbidity and cardiovascular mortality, quantified as random-effects pooled hazard ratios (PHRs) with 95% CIs, irrespective of heterogeneity and with age at menopause as a moderator. Meta-regression estimates were clustered by source cohort.
Of 14 409 records, 36 studies were included with 2 617 942 women (mean [SD] age, 55.52 [12.41] years for the iatrogenic menopause cohort and 45.58 [16.02] years for comparators); median follow-up was 16.0 years (range, 4.8-36.0 years). Iatrogenic menopause vs comparators was associated with higher risk of all-cause mortality (PHR, 1.08; 95% CI, 1.01-1.16), cardiovascular events (PHR, 1.25; 95% CI, 1.12-1.39), coronary heart disease (PHR, 1.48; 95% CI, 1.07-2.03), and stroke (PHR, 1.22; 95% CI, 1.15-1.28). Mortality excesses were confined to iatrogenic menopause before age 45 years (cardiovascular mortality: PHR, 1.20 [95% CI, 1.04-1.37]; all-cause mortality: PHR, 1.15 [95% CI, 1.06-1.25]), with null estimates at or after age 45 years (cardiovascular mortality: PHR, 0.95 [95% CI, 0.81-1.11]; all-cause mortality: PHR, 0.99 [95% CI, 0.89-1.09]). In a post hoc meta-regression on the composite outcome, each increasing 5-year increment in age at iatrogenic menopause was associated with lower risk (HR, 0.89; 95% CI, 0.83-0.97) based on 37 estimates from 11 independent populations.
In this study, iatrogenic menopause was associated with higher cardiovascular morbidity, most consistently stroke, and with cardiovascular and all-cause mortality excesses before age 45 years at menopause. Older age at iatrogenic menopause was associated with progressively lower risk of cardiovascular morbidity and mortality, supporting a period of elevated risk before age 45 years rather than a single threshold age.
