Risks and Benefits of Estrogen Plus Progestin in Healthy Postmenopausal Women

Principal Results From the Women's Health Initiative Randomized Controlled Trial

Writing group for the Women's Health Initiative Investigators

JAMA 2002, 288(3):321-333.

Introduction: Despite decades of accumulated observational evidence, the balance of risks and benefits for hormone use in healthy postmenopausal women remains uncertain. The Women's Health Initiative (WHI) focuses on defining the risks and benefits of strategies that could potentially reduce the incidence of heart disease, breast and colorectal cancer, and fractures in postmenopausal women.

Aims: To assess the major health benefits and risks of the most commonly used combined hormone preparation in the United States.

Methods: Between the years 1993 and 1998 the WHI enrolled 161,809 postmenopausal women in the age range of 50 to 79 years into a set of clinical trials (trials of low-fat dietary pattern, calcium and vitamin D supplementation, and 2 trials of postmenopausal hormone use) and an observational study at 40 clinical centers in the United States. This report is limited to the 16,608 women who were on a combination of 0.625 mg/d conjugated equine estrogens plus 2.5 mg/d medroxyprogesterone acetate (MPA) (n = 8506) or placebo (n = 8102). The main outcome measures were primarily coronary heart disease (CHD) and breast cancer. A global index summarizing the balance of risks and benefits included the 2 primary outcomes plus stroke, pulmonary embolism (PE), endometrial cancer, colorectal cancer, hip fracture, and death due to other causes.

Results: After a mean of 5.2 years of follow-up, the data and safety monitoring board recommended stopping the trial of estrogen plus progestin vs. placebo because the test statistic for invasive breast cancer exceeded the stopping boundary for this adverse effect and the global index statistic supported risks exceeding benefits. The data of the estimated hazard ratios (nominal 95% confidence intervals) were as follows: CHD, 1.29 (1.02-1.63) with 286 cases; breast cancer, 1.26 (1.00-1.59) with 290 cases; stroke, 1.41 (1.07-1.85) with 212 cases; PE, 2.13 (1.39-3.25) with 101 cases; colorectal cancer, 0.63 (0.43-0.92) with 112 cases; endometrial cancer, 0.83 (0.47-1.47) with 47 cases; hip fracture, 0.66 (0.45-0.98) with 106 cases; and death due to other causes, 0.92 (0.74-1.14) with 331 cases. Corresponding hazard ratios for composite outcomes were 1.22 (1.09-1.36) for total cardiovascular disease (arterial and venous disease), 1.03 (0.90-1.17) for total cancer, 0.76 (0.69-0.85) for combined fractures, 0.98 (0.82-1.18) for total mortality, and 1.15 (1.03-1.28) for the global index. The absolute excess risks per 10,000 person-years attributable to estrogen plus progestin were 7 more CHD events, 8 more strokes, 8 more PE's, and 8 more invasive breast cancers, while absolute risk reductions per 10,000 person-years were 6 fewer colorectal cancers and 5 fewer hip fractures.

Conclusions: Overall health risks exceeded benefits from use of combined estrogen plus progestin for an average of 5.2 year follow-up among healthy postmenopausal US women. All-cause mortality was not affected during the trial. The risk-benefit profile found in this trial is not consistent with the requirements for a viable intervention for primary prevention of chronic disease, and the results indicate that this regimen should not be initiated for primary prevention of CHD.