Women's Health Initiative: Estrogen-Alone Hormone Therapy

When the estrogen-progestin arm of the Women's Health Initiative was halted in 2002, it left an important question unanswered: was the progestin component responsible for the cardiovascular and breast cancer harm, or did estrogen itself contribute? The WHI's parallel estrogen-alone arm, running separately in the 10,739 hysterectomized women who did not require progestin, was still ongoing and positioned to answer that question directly.

Garnet Anderson of the Fred Hutchinson Cancer Research Center in Seattle was first author of the main report. The arm had enrolled postmenopausal women aged 50 to 79, randomizing them to conjugated equine estrogen at 0.625 mg daily or placebo. The NIH ended the intervention in February 2004, after an average of 6.8 years, because of an increased incidence of stroke and no reduction in coronary heart disease. Jacques Rossouw of the NHLBI was a co-author. The JAMA paper published in April 2004 reported a hazard ratio for coronary heart disease of 0.91, with 95% confidence intervals of 0.75 to 1.12: no significant benefit, and no significant harm from a cardiac standpoint.

Stroke risk, however, was significantly elevated: a hazard ratio of 1.39, translating to roughly 12 additional strokes per 10,000 person-years. That finding matched the combination-arm result and showed that estrogen alone raised stroke risk. Breast cancer incidence trended lower with estrogen alone, with a hazard ratio of 0.77; in a 2020 analysis after more than 20 years of follow-up, the hazard ratio was 0.78 (95% CI 0.65 to 0.93), and breast cancer deaths were also lower.

Set side by side, the two WHI arms differed on breast cancer. Progestin appeared to drive most of the breast cancer excess seen in the combination arm; estrogen alone showed a different profile, with stroke risk elevated but breast cancer risk potentially reduced. Estrogen alone also made mammograms harder to read: after one year, 9.2% of women on estrogen had abnormalities needing follow-up, against 5.5% on placebo.

Both WHI arms confirmed the same core conclusion for guideline purposes: hormone therapy of either formulation could not be recommended for primary cardiovascular prevention. In the estrogen-alone arm, women aged 50 to 59 at entry had a hazard ratio for coronary events of 0.63, not statistically significant, and fewer coronary revascularizations. The North American Menopause Society's 2022 position statement judges the benefit-risk ratio favorable for treating symptoms and preventing bone loss in women under 60 or within 10 years of menopause, and less favorable for women who start later.