Context Despite decades of use and considerable research, the role of estrogen
alone in preventing chronic diseases in postmenopausal women remains uncertain.
Objective To assess the effects on major disease incidence rates of the most commonly
used postmenopausal hormone therapy in the United States.
Design, Setting, and Participants A randomized, double-blind, placebo-controlled disease prevention trial
(the estrogen-alone component of the Women's Health Initiative [WHI]) conducted
in 40 US clinical centers beginning in 1993. Enrolled were 10 739 postmenopausal
women, aged 50-79 years, with prior hysterectomy, including 23% of minority
Intervention Women were randomly assigned to receive either 0.625 mg/d of conjugated
equine estrogen (CEE) or placebo.
Main Outcome Measures The primary outcome was coronary heart disease (CHD) incidence (nonfatal
myocardial infarction or CHD death). Invasive breast cancer incidence was
the primary safety outcome. A global index of risks and benefits, including
these primary outcomes plus stroke, pulmonary embolism (PE), colorectal cancer,
hip fracture, and deaths from other causes, was used for summarizing overall
Results In February 2004, after reviewing data through November 30, 2003, the
National Institutes of Health (NIH) decided to end the intervention phase
of the trial early. Estimated hazard ratios (HRs) (95% confidence intervals
[CIs]) for CEE vs placebo for the major clinical outcomes available through
February 29, 2004 (average follow-up 6.8 years), were: CHD, 0.91 (0.75-1.12)
with 376 cases; breast cancer, 0.77 (0.59-1.01) with 218 cases; stroke, 1.39
(1.10-1.77) with 276 cases; PE, 1.34 (0.87-2.06) with 85 cases; colorectal
cancer, 1.08 (0.75-1.55) with 119 cases; and hip fracture, 0.61 (0.41-0.91)
with 102 cases. Corresponding results for composite outcomes were: total cardiovascular
disease, 1.12 (1.01-1.24); total cancer, 0.93 (0.81-1.07); total fractures,
0.70 (0.63-0.79); total mortality, 1.04 (0.88-1.22), and the global index,
1.01 (0.91-1.12). For the outcomes significantly affected by CEE, there was
an absolute excess risk of 12 additional strokes per 10 000 person-years
and an absolute risk reduction of 6 fewer hip fractures per 10 000 person-years.
The estimated excess risk for all monitored events in the global index was
a nonsignificant 2 events per 10 000 person-years.
Conclusions The use of CEE increases the risk of stroke, decreases the risk of hip
fracture, and does not affect CHD incidence in postmenopausal women with prior
hysterectomy over an average of 6.8 years. A possible reduction in breast
cancer risk requires further investigation. The burden of incident disease
events was equivalent in the CEE and placebo groups, indicating no overall
benefit. Thus, CEE should not be recommended for chronic disease prevention
in postmenopausal women.