Menopausal Estrogen Therapy Benefits and Risks Vary by Age, WHI Analysis Suggests

Long-term follow-up data from the Women’s Health Initiative (WHI) provide important new information about the potential risks and benefits of hormone therapy to treat symptoms or conditions related to menopause, including its effect on breast cancer risk. The results were published April 5, 2011, in the Journal of the American Medical Association.

Overall, the study found, among postmenopausal women who had had a hysterectomy, use of conjugated equine estrogens alone for an average of 6 years had little to no effect on the risk of death, coronary heart disease, colorectal cancer, and hip fractures, or on other serious health problems, compared with placebo treatment. Estrogen-only treatment was associated with a statistically significant decrease in the risk of breast cancer.

However, there were some notable differences in estrogen effects by age. Estrogen therapy decreased the risk of heart disease and mortality among women in their 50s but markedly increased these risks for women in their 70s. In contrast, the decreased breast cancer risk associated with estrogen use was seen regardless of age.

The WHI estrogen-alone clinical trial, launched in 1993, randomly assigned more than 10,739 women between the ages of 50 and 79—all of whom were past menopause and had had a hysterectomy—to take daily estrogen or a placebo. In 2004, the study was stopped early because of an increased risk of stroke and blood clots in women receiving estrogen. Nearly 80 percent of the trial participants agreed to be monitored beyond the study’s termination; this most recent analysis covers nearly 11 years of follow-up in trial participants.

The findings reinforce the concept that “estrogen affects many organ systems in the body and changes the risk of many diseases,” said the study’s lead investigator, Andrea LaCroix, Ph.D., of the Fred Hutchinson Cancer Research Center in Seattle. “Depending on age group and hysterectomy status, the consequences [of estrogen-only therapy] can vary dramatically.”

The increased risks of stroke and blood clots that were seen while women were actively receiving treatment were no longer present after women halted therapy, the study authors noted.

The analysis is the latest update in an ongoing, large-scale effort to establish more definitively the risks and benefits of menopausal hormone therapy, including its effect on cancer risk and mortality. Previous studies from the WHI, for example, have clearly shown that combination therapy with estrogen plus progestin increases breast cancer incidence and death, as well as lung cancer mortality. And just 2 months ago, British researchers reporting on longer-term follow-up from the Million Women Study (MWS) also found that combination estrogen and progestin therapy, when started immediately after menopause, increased breast cancer risk regardless of hysterectomy status.

Earlier analyses from the WHI estrogen-alone trial suggested that there may be a reduction in breast cancer incidence, but it was only with longer-term follow-up that this trend reached statistical significance, according to Leslie Ford, M.D., of NCI’s Division of Cancer Prevention and the Institute’s WHI liaison. In absolute terms, the current analysis indicated, there would be eight fewer cases of breast cancer for every 10,000 women who had undergone menopause and had a hysterectomy if they took estrogen daily for 6 years.

The WHI findings also contrast with some of the recent findings from the MWS, wrote Emily Jungheim, M.D., and Graham Colditz, M.D., Dr.P.H., of the Washington University School of Medicine in St. Louis, in an accompanying editorial. In the MWS—which was an observational study and not a randomized clinical trial like the WHI estrogen-alone trial—there was an increased breast cancer risk in women who began estrogen-only therapy within 5 years of menopause. The editorialists also pointed out that 68 percent of women in the WHI trial were 60 years of age or older when they entered the study.

“Given this fact and the findings from the Million Women Study, an important question that emerges is whether the WHI population is appropriate for reaching definitive conclusions regarding younger women and the risk of breast cancer associated with [menopausal hormone therapy],” they wrote.

Although she acknowledged the somewhat conflicting findings, Dr. Ford stressed that the WHI results are from a large, randomized clinical trial. Randomized clinical trials are considered to be the highest level of evidence and, consequently, are routinely used to inform clinical decision making.

Use of menopausal hormone therapy has continued to decline since the early 2000s, when the initial findings of the WHI clinical trial of estrogen plus progestin showed an increased risk of breast cancer and serious cardiac events with the combination. That decline has since been linked to a parallel decrease in breast cancer incidence rates.

In terms of breast cancer risk, Dr. Ford believes the results from the WHI estrogen-alone trial should be reassuring for younger postmenopausal women who have had a hysterectomy and are receiving or considering estrogen therapy. “For younger women,” she continued, “they can feel more comfortable following the current guidelines for using the lowest dose of estrogen for the shortest time.”

But both Drs. Ford and LaCroix agreed that for older women, the potential benefits of menopausal hormone therapy of any kind do not outweigh the risks.

“Our data clearly indicate that hormone therapy use in older women is potentially dangerous,” Dr. LaCroix said.