Estrogen therapy for menopause, study looks at risks-benefits

By Dr. Ananya Mandal, MDApr 6 2011

From the large Women's Health Initiative (WHI) study, researchers have found that risks to postmenopausal women who were taking estrogen-only hormone therapy faded rapidly after they ended the treatment.

The study reports that when women stopped taking estrogen, the risk of stroke and blood clots, which were elevated while they were on estrogen, dropped quickly in several years of follow-up after treatment. However the reduced risk of breast cancer persisted in women who had been on estrogen-only therapy.

Study’s lead author, Andrea LaCroix, a professor of epidemiology and WHI investigator from the Fred Hutchinson Cancer Research Center in Seattle said, “I think the findings are very reassuring. It doesn't appear that women have to be concerned about an increased risk of breast cancer from short-term use of estrogen therapy, and they might have a decreased risk of breast cancer, heart attack, and even dying.” Results of the study are published in the April 6 issue of the Journal of the American Medical Association.

The Women's Health Initiative estrogen-alone trial included 10,739 postmenopausal women between the ages of 50 and 79 who had previously had a hysterectomy (surgical removal of the uterus). More than 33 percent of U.S. women older than 50 have had hysterectomies. These women were randomized to receive either estrogen treatment or a placebo. The study recruited women from 1993 through 1998, and the planned end of the study was in 2005. However, the study was stopped in 2004 when researchers realized the therapy was causing an increased risk of stroke and no apparent health benefits, according to LaCroix. Thereafter 7,645 women agreed to continue participating in follow-up visits through 2009.

The results on follow up showed that risks that increase while a woman is taking estrogen therapy appear to dissipate rapidly over time. While the odds of stroke and blood clots increase while on estrogen therapy, the risk returns to normal several years after stopping the hormone therapy. Women who had taken estrogen also had similar rates of heart disease and an overall risk of mortality compared to women on placebo at follow-up, according to the study. One benefit that was seen during the treatment phase of the trial that meant a reduced risk of hip fractures however did not persist when the women stopped taking estrogen. The benefit that did seem to last, however, was a decreased risk of breast cancer. Over the entire follow-up period, the incidence of breast cancer was 0.27 percent in women who took estrogen, and 0.35 percent in women who took the placebo.

LaCroix and her team are uncertain why the benefits last while the risks fade. Normally, estrogen is implicated in the development of breast cancer, not in the prevention of the disease she explained. She said this aspect of the study definitely needs more research, but added of this finding, “It's reassuring, if you're a woman in your 50s who has menopausal symptoms and a reason for taking estrogen.”

The study also noted that the use of estrogen produced better outcomes for younger women than for women in their 70s. Heart disease risk, colorectal cancer risk and the overall risk of dying were lower in women in their 50s compared to those in their 70s, according to the study. “Women in their 50s - who are the best candidates for estrogen therapy - show the best benefit-to-risk profile for short-term use of estrogen therapy,” said LaCroix. “We now have a really good set of data on what happens after you stop taking hormones and you can use this information to discuss risks and benefits with your physician,” she added.

In an accompanying editorial in the same issue of the journal, Dr. Graham Colditz, chief of the division of public health sciences at the Washington University School of Medicine in St. Louis, said the reduction in breast cancer may be because these women were already past menopause when the estrogen was given. “There's an involution of breast cells after menopause, so there would appear to be fewer bad actors waiting to respond to the hormones,” he said.

Colditz also noted that the International Agency for Research on Cancer had concluded that the body of evidence suggests that estrogen-only hormone therapy and combination HRT are carcinogenic, and added that this study did not address longer-term estrogen hormone therapy use, which a meta-analysis of 16 studies has linked with an increased risk of breast cancer. In addition, he and his co-author wrote, the study showed “no substantial benefit” to women who undergo estrogen hormone therapy, compared to women who do not. “Women should use estrogen with caution,” Colditz concluded. “There are risks from taking hormone therapy. Even when using estrogen for one to two years for relief of menopausal symptoms, there are still risk-benefit issues to deal with.”

Dr. Sylvia Wassertheil-Smoller, a professor at Albert Einstein College of Medicine, said the study was not a blanket endorsement of hormone therapy. “What it does say is if [menopause] symptoms are intolerable and a woman does not have a uterus, she may not be harmed by estrogen alone if she takes it for a relatively short time,” she said.