Risks and Benefits of Estrogen Plus Progestin in Healthy Postmenopausal Women: Women's Health Initiative

The Women’s Health Initiative randomized 16,608 healthy postmenopausal women with an intact uterus to conjugated equine estrogen plus medroxyprogesterone acetate (HRT) versus placebo and followed them over approximately 5.6 years, measuring coronary heart disease, stroke, pulmonary embolism, breast cancer, colorectal cancer, and hip fracture as primary endpoints.

Combined HRT increased coronary heart disease by 29% (HR 1.29), stroke by 41% (HR 1.41), pulmonary embolism by 113% (HR 2.13), and invasive breast cancer by 26% (HR 1.26). It reduced hip fractures by 34% (HR 0.66) and colorectal cancer by 37% (HR 0.63). The overall risk-benefit balance — accounting for all endpoints — exceeded harms over benefits, and the trial was stopped early.

The WHI fundamentally altered the clinical landscape of postmenopausal hormone therapy. Before WHI, HRT was widely prescribed for primary cardiovascular prevention, based on observational data suggesting a 35–50% reduction in coronary disease with HRT use. WHI demonstrated that this observational association was confounded — likely by the healthier lifestyle and socioeconomic status of HRT users — and that in randomized assignment, combined HRT increased rather than decreased coronary events.

The WHI’s finding on coronary disease risk applies specifically to the combination estrogen-plus-progestin formulation in older, healthy postmenopausal women not recently menopausal. Subsequent analyses suggested that timing matters: HRT initiated near menopause (“timing hypothesis”) may not carry the same coronary risk increase as initiation in older postmenopausal women.

We rate the evidence strong. The landmark WHI trial demonstrating that combined estrogen-plus-progestin HRT increases rather than decreases coronary heart disease risk in healthy older postmenopausal women — ending HRT’s role as a cardiovascular prevention strategy.