Update on the Women’s Health Initiative Estrogen-Alone Trial

For women reaching menopause, choosing whether to use hormone therapy to treat symptoms is an important health care decision. Each woman, in tandem with her health care team, should carefully consider the benefits and risks of taking a medication, with attention given to both short-term and long-term health consequences.

The WHI Estrogen-Alone Trial

The WHI was established in 1991 to study strategies for preventing heart disease, breast and colorectal cancer, and osteoporosis in postmenopausal women. This 20-year project, administered by the National Heart, Lung, and Blood Institute (NHLBI), involved 161,808 women aged 50–79 years.

What was the study?

The present study, "Health outcomes after stopping conjugated equine estrogens among postmenopausal women with prior hysterectomy: A randomized controlled trial," was funded by the NHLBI and published in JAMA on April 6, 2011. This research was part of the WHI Estrogen-Alone Trial, which was a double-blind, placebo-controlled, randomized clinical trial.

Intervention phase

• A total of 10,739 postmenopausal women aged 50–79 years were enrolled at 40 U.S. clinical centers between 1993 and 1998. Each woman had previously had a hysterectomy and was not taking hormone therapy.
• Participants were randomly assigned to receive 0.625 milligrams a day of conjugated equine estrogens or matching placebo. (This dose exceeds the dose that is currently prescribed.)
• The intervention phase was stopped 1 year early (on February 29, 2004), after a mean of 7.1 years of followup. At this point 54 percent of participants had stopped taking their study medication. Participants took estrogen for a median of 5.9 years.
• Clinical outcomes were collected via semiannual mailed questionnaires and annual clinical visits.

Postintervention phase

• The postintervention period started on March 1, 2004, when participants were instructed to stop taking the study pills. Of the women in the study, 78 percent agreed to continue followup.
• Women were followed for an average of 3.9 years in this phase (through August 14, 2009).
• The total mean followup time (combined intervention and postintervention phases) for the participants was 10.7 years.

What did the study find?

This study examined whether the patterns of health risks and benefits that were seen in women taking estrogen, as compared with women taking placebo pills, during the intervention phase would be maintained during the postintervention phase, after the women stopped taking the study pills. Overall, several of the health risks and benefits were not maintained after the women stopped taking the pills.

Heart disease

• In the intervention phase, there was no overall difference in the rates of heart disease between women taking estrogen and women taking placebos.
• In the postintervention phase, there continued to be no difference in the rates of heart disease between the two groups.
• The results, however, varied by age. Women who began estrogen while in their fifties had a reduced risk of heart attacks, while women who took estrogen beginning in their seventies tended to have increased risk of heart attacks.

Stroke and blood clots

• During the intervention phase, there were increased rates of strokes and blood clots in women taking estrogen, compared with women taking placebos.
• In the postintervention phase, the increased rates of strokes and blood clots were no longer present. Thus the risks were reversed after the women stopped taking estrogen.

Breast cancer

• In the intervention phase, there was a reduced rate of breast cancer incidence in women taking estrogen, compared with women taking placebos. This reduced rate was not statistically significant.
• In the postintervention phase, there continued to be a reduced rate of breast cancer incidence in women who had taken estrogen, compared with women who had taken placebos. Thus at the end of 10.7 years of total followup, the women who had taken estrogen had a significantly reduced risk of breast cancer.

Colorectal cancer

• In the intervention phase, there was no overall difference in the rates of colorectal cancer between the women taking estrogen and the women taking placebos.
• In the postintervention phase, there continued to be no overall difference in the rates of colorectal cancer between the two groups.
• Women who took estrogen beginning in their seventies had a nearly twofold increased risk of colorectal cancer, compared with women taking placebos.

Hip fracture

• In the intervention phase, there was a reduced rate of hip fractures in women taking estrogen, compared with women taking placebos.
• At the end of 10.7 years of total followup, there was no difference in the hip fracture rates between the women who took estrogen and the women who took placebos. Thus during the postintervention phase, this benefit of taking estrogen gradually disappeared.

Overall illness and death

• During both the intervention and postintervention phases, there was no overall difference in total mortality or in a global index of chronic diseases between the women who took estrogen and the women who took placebos.
• The results, however, varied by age. Women who began taking estrogen in their fifties had a reduced risk of overall illness and death. Women who took estrogen beginning in their seventies had an increased risk of overall illness and death and an increased rate of colorectal cancer, compared with women who took placebos.

Rates per 10,000 women
Expressed as absolute rates per 10,000 women annualized over the 10.7 year followup period:

• Women aged 50–59 years who took estrogen, compared with women who took placebos, had 12 fewer heart attacks, 13 fewer deaths, and 18 fewer adverse events overall (such as coronary heart disease).
• Women aged 70–79 years who took estrogen, compared with women who took placebos, had 16 additional heart attacks, 19 additional deaths, and 48 additional adverse events.

What are the take-home messages?

• These findings are for women who had taken estrogen for an average of 6 years, and then stopped for an average of almost 4 years. The risks and benefits of taking estrogen alone for a longer period of time are not known.
• Women should be counseled about hormone therapy differently depending on their age. Postmenopausal women who have had a hysterectomy and are considering estrogen therapy may have an increased risk of stroke and blood clots. This risk may diminish after they stop the therapy.
• For women who start estrogen therapy in their fifties, there is a relatively good benefit-to-risk ratio. The risks of heart attack and overall illness and death are reduced, compared with women who take a placebo.
• For women in their sixties, the findings do not show an overall benefit, and for women in their seventies, there are elevations in overall rates of chronic diseases and death.
• It is important to recognize that these findings are only for postmenopausal women who had previously had a hysterectomy and who were only taking estrogen. The findings from the WHI study in which postmenopausal women who had not had a hysterectomy took a combination of estrogen and progestin are very different.
• The benefits and risks of taking any medication, especially one that may alter the risks for several diseases, should be carefully considered by each woman and her health care team. The final decision should be based on accurate and complete information regarding both short-term and long-term health consequences.

Where can I learn more?

• LaCroix, A.Z., Chlebowski, R.T., Manson, J.E., Aragaki, A.K., Johnson, K.C., Martin, L., …for the WHI Investigators. (2011). Health outcomes after stopping conjugated equine estrogens among postmenopausal women with prior hysterectomy: A randomized controlled trial. JAMA, 305(13),1305-1314.
• Jungheim, E.S., Colditz, G.A. (2011). Short-term use of unopposed estrogen: A balance of inferred risks and benefits. JAMA, 305(13),1354-1355.
• "Heart Disease in Women" From the NHLBI Diseases and Conditions Index (DCI)
• The Women’s Health Initiative
• Clinical Trials

Previous NHLBI news releases on the WHI

• Effect of hormone therapy on risk of heart disease may vary by age and years since menopause—additional analyses from the Women’s Health Initiative, April 7, 2007
• NIH Asks Participants in Women’s Health Initiative Estrogen-Alone Study to Stop Study Pills, Begin Follow-up Phase, March 2, 2004

May 2011