Reproductive Health · 2002
Women's Health Initiative: Estrogen plus Progestin Hormone Therapy
By the mid-1990s, combined estrogen-progestin hormone replacement therapy had become one of the most widely prescribed treatments in American medicine. Its popularity rested largely on observational data, particularly the Nurses' Health Study, which suggested that postmenopausal women taking hormones had substantially lower rates of coronary disease. That signal was strong enough that cardiovascular protection became a leading justification for prescribing, not merely relief from menopausal symptoms. The Women's Health Initiative was designed to test that assumption in a proper randomized trial.
The estrogen-plus-progestin arm enrolled 16,608 postmenopausal women with an intact uterus at 40 clinical centers across the United States, randomizing them to conjugated equine estrogen at 0.625 mg plus medroxyprogesterone acetate at 2.5 mg daily, or matching placebo. Planned follow-up was 8.5 years. Jacques Rossouw at the National Heart, Lung, and Blood Institute served as project officer, with Garnet Anderson coordinating statistical analysis and JoAnn Manson serving as principal investigator at Brigham and Women's Hospital.
The data safety monitoring board halted the estrogen-progestin arm in July 2002 after 5.2 years when the prespecified stopping boundary for invasive breast cancer was crossed; the hazard ratio reached 1.26, corresponding to roughly eight additional breast cancers per 10,000 person-years. Coronary heart disease, stroke, and pulmonary embolism were all elevated in the hormone arm. There was no cardiovascular benefit, and the results contradicted directly the observational literature that had driven prescribing for nearly two decades.
The JAMA paper reporting these findings appeared in July 2002 and generated immediate and widespread attention outside academic medicine. Combined HRT prescriptions in the United States fell by roughly half within two years. Many patients contacted their physicians to stop treatment; many physicians stopped initiating it. The magnitude of the prescribing shift had few precedents in outpatient pharmacotherapy.
The trial also generated productive controversy. Researchers noted that most WHI participants were older, with a mean age of 63, and had been postmenopausal for many years before enrollment. Post-hoc analyses eventually gave rise to the timing hypothesis: women who started hormone therapy within 10 years of menopause appeared to show less coronary harm, and possibly some benefit, compared with those who started a decade or more later. That hypothesis continues to shape current guideline language on who might be appropriate candidates for short-term HRT use.
Key People
- Jacques Rossouw — WHI project officer, National Heart, Lung, and Blood Institute
- Garnet Anderson — Statistician, WHI Clinical Coordinating Center
- JoAnn Manson — Principal investigator, Brigham and Women's Hospital
JAMA. 2002;288(3):321-333
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