Menopausal hormone treatment cardiovascular disease: another look at an unresolved conundrum.

Cardiovascular disease (CVD) is the most common cause of death in women. Before the Women's Health Initiative (WHI) hormone trials, evidence favored the concept that menopausal hormone treatment (MHT) protects against CVD. WHI studies failed to demonstrate CVD benefit, with worse net outcomes for MHT versus placebo in the population studied. We review evidence regarding the relationship between MHT and CVD with consideration of mechanisms and risk factors for atherogenesis and cardiac events, results of observational case-control and cohort studies, and outcomes of randomized trials. Estrogen effects on CVD risk factors favor delay or amelioration of atherosclerotic plaque development but may increase risk of acute events when at-risk plaque is present. Long-term observational studies have shown ∼40% reductions in risk of myocardial infarction and all-cause mortality. Analyses of data from randomized control trials other than the WHI show a ∼30% cardioprotective effect in recently menopausal women. Review of the literature as well as WHI data suggests that younger and/or more recently menopausal women may have a better risk-benefit ratio than older or remotely menopausal women and that CVD protection may only occur after >5 years; WHI women averaged 63 years of age (12 years postmenopausal) and few were studied for >6 years. Thus, a beneficial effect of long-term MHT on CVD and mortality is still an open question and is likely to remain controversial for the foreseeable future.