Revisiting the Women’s Health Initiative Estrogen-Alone Trial

Concern that risks outweighed the possible benefits of estrogen use caused the cessation of the Women's Health Initiative Estrogen-Alone Trial. However, researchers decided to continue monitoring patients for outcomes despite the study protocol discontinuation to gain insight into the long-term effects of the conjugated equine estrogens (CEE) therapy. What they found was surprising-and somewhat positive.

The researchers followed 7645 (78%) surviving participants from the original trial; 3778 were in the treatment group and 3867 were from the placebo group. The mean length of follow-up was 47.2 months. Data were collected via semiannual mailed questionnaires and annual clinic visits, and annual mammograms were encouraged. During this follow-up study, a small percentage of women reported use of estrogen-alone medication (3.6% to 4.7% from the original treatment group and 2.7% to 3.0% from the placebo group).

Overall, much of the negative and positive effects of CEE therapy were not maintained during the postintervention period (Figure). For instance, during the intervention phase, the researchers had noted an increased stroke risk; this increased risk was not present in the postintervention phase. The same held true for increased risk in deep vein thrombosis and pulmonary embolism-both of which were noted with estrogen use during the study protocol but were not evident following medication discontinuation. The researchers noticed a slightly higher hip fracture incidence in patients from the active medication group as compared to the placebo group during the postintervention phase, thus ceasing the reduced hip fracture risk associated with CEE use. The hazard ratios for coronary heart disease remained null after stopping the intervention. Age, however, did play a role in the outcomes/effect, with more favorable results seen in younger women than their older menopausal counterparts.

Figure. Comparison of hazard ratios during intervention and after discontinuation.

Interestingly, the protective effect of CEE against breast cancer lingered after the intervention was discontinued. The researchers found that the hazard ratios were similar during the intervention and postintervention phases. Moreover, they found a statistically significant lower cumulative breast cancer incidence (0.27%) in the CEE group as compared with the placebo group (0.35%).

“Our results emphasize the need to counsel women about hormone therapy differently depending on their age and hysterectomy status,” concluded the authors. “A postmenopausal woman who has had a hysterectomy and is considering initiation of CEE should be counseled about the increased risks of venous thromboembolism and stroke during treatment, which diminish with treatment cessation. Among younger women, no new safety concerns emerged and some risk reductions became apparent during the postintervention period. Among older women, risks of colorectal cancer, death, and the global index of chronic diseases were elevated over the cumulative follow-up period.”

More Information

• Women’s Health Initiative
• Women’s Health Initiative: Estrogen-Alone Study

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• WHI: Effects of Estrogen Plus Progestin on Health

Reference

LaCroix AZ, Chlebowski RT, Manson JE, et al. Health outcomes after stopping conjugated equine estrogens among postmenopausal women with prior hysterectomy: a randomized controlled trial. JAMA. 2011; 305(13):1305-1314.