Effects of Combined Hormones Continue Years After Stopping Therapy

A follow-up study from the Women’s Health Initiative, or WHI, combination hormone therapy trial has found that women who use estrogen plus progestin on a long-term basis can incur multiple risks that persist even after the therapy has been stopped. Specifically, the researchers found that nearly three years after combination therapy was halted, many of the adverse health effects seen during the intervention, such as increased cardiovascular risks, dissipated. Other effects, however, such as the increased risk of developing breast cancer, persisted well after treatment was stopped.

In July 2002, women in the WHI combination hormone therapy trial were instructed to stop taking the estrogen-progestin combination because researchers found the risks associated with combination therapy outweighed its benefits. Researchers then began a follow-up study of the 15,730 women who had participated in the original trial. About half of the women had taken the hormone combination, and the other half had been given a placebo. Study participants were followed for an average of 2.4 years. All of them were examined at least once a year by a WHI clinician, and all received annual breast examinations and mammograms, with biopsies performed as needed.

The results of the follow-up study, which was published March 5 in the Journal of the American Medical Association, show that the increased cardiovascular risk that had been seen among women in the active treatment group during therapy declined after therapy was stopped to the point where there was no significant difference between the treatment and placebo groups. In addition, the heightened risks for stroke and blood clots incurred during therapy diminished.

Other effects of combination hormone therapy, such as decreased risks for colorectal cancer and hip fractures, also stopped after therapy ended.

However, the risk of developing breast cancer remained about 27 percent higher in women who had taken the combination hormone therapy than in those who hadn’t, even more than two years after therapy was stopped. The women who had been in the active therapy group also were 24 percent more likely to develop any form of cancer. Researchers are conducting a more detailed analysis of the cancer findings.

The AAFP and the U.S. Preventive Services Task Force, or USPSTF, currently recommend against routine use of combination hormone therapy for the prevention of chronic conditions in postmenopausal women. The FDA recommends that combination hormone therapy should never be used to prevent heart disease and further urges that when it is used to treat menopausal symptoms, women take the smallest possible therapeutic dose for the shortest time required.

According to Michael LeFevre, M.D., M.S.P.H., professor of family and community medicine at the University of Missouri-Columbia and a USPSTF member, the new study doesn't "add much to where we are scientifically when it comes to hormone replacement therapy." But he says it is important in reinforcing the message that combination hormone therapy is not indicated for general disease prevention.

LeFevre, who also served on the AAFP's Commission on Clinical Policies and Research, acknowledges that the study's implications for women who have used long-term estrogen-progestin therapy are significant, particularly when it comes to breast cancer. Chief among lessons clinicians can take away from the study is to ensure they're aware of their female patients' experiences with long-term combination hormone therapy so those patients can be appropriately followed. The study likely will not "change existing recommendations," he says, "but it reminds physicians to be diligent about recommending breast cancer screening" for women who have been on long-term combination hormone therapy.

LeFevre also points out that a parallel estrogen-only WHI trial did not present findings on breast cancer incidence. He says it "will be interesting to see whether (the WHI researchers) publish a follow-up on this arm of the study" that would show whether there was any rise in breast cancer rates for women who took this type of hormone therapy.