July 9, 2002
By Lisa Ellis
InteliHealth News Service
Researchers have stopped a major study on long-term hormone replacement therapy, saying that after five years the harmful effects of the therapy — especially an increased risk of breast cancer — clearly outweighed the benefits.
The study, part of the large, federally funded Women's Health Initiative, is the first to examine how long-term use of the hormones estrogen and progestin affects the overall health of postmenopausal women who have not been diagnosed with heart disease.
But it reinforces one major conclusion of another large study — also released this month — that looked at the long-term use of hormone-replacement therapy (HRT) in women who already had heart disease. Both studies found that taking estrogen plus progestin did not prevent heart attacks or strokes.
The medical community had been waiting for the results from the Women's Health Initiative study, which were not expected until 2005, to show whether HRT would benefit healthy women.
But after an average follow-up period of five years, the study's safety-monitoring board decided to call an early halt. They based the decision on the following negative results for study participants who took estrogen plus progestin, compared with those who were given a placebo treatment:
These results were announced in a Washington, D.C., news conference and published online by the Journal of the American Medical Association (JAMA). The study will appear in the journal's July 17 issue.
The study enrolled 16,608 postmenopausal women, with an average age of 64. More than half were given a daily tablet containing a combination of 0.625 milligrams of estrogen and 2.5 milligrams of progestin. The others received a placebo pill, which contained no hormones.
JoAnn Manson, M.D., Dr. P.H., a Harvard Medical School researcher who is one of the principal investigators of the Women's Health Initiative, said the study reinforces earlier research in showing that women should not take estrogen and progestin for the prevention of heart disease.
"The combined form of estrogen plus progestin does not protect the heart, and overall the risks outweigh the benefits after five years of use," she said. "I think it's clear that this treatment is not a magic bullet and it's losing its luster for the prevention of chronic disease."
"On the upbeat side of this," Dr. Manson added, "women worldwide have been seeking these answers for decades and this is a landmark study that will help women make more informed choices."
Women who have been taking hormone replacement therapy should not panic but should talk about the study results with their doctors, said Dr. Manson, chief of preventive medicine and co-director of the Connors Center for Women's Health and Gender Biology at Brigham and Women's Hospital in Boston.
"Women taking this hormone combination should discuss with their physician whether to continue, which will depend on their health status and the duration of treatment," she said.
In the Washington news conference, Jacques Rossouw, M.D., acting director of the Women's Health Initiative, urged women to ask their doctors about other methods of preventing heart attack and stroke. "These include lifestyle changes and drugs, such as cholesterol-lowering statins and blood pressure medications."
Increased Rate Of Breast Cancer
The study also is important for its conclusions about hormones and breast cancer. "These findings are the first confirmation from a rigorous clinical trial that taking estrogen plus progestin increases the risk of breast cancer," Dr. Rossouw said.
"Women who had used the hormone therapy before entering the study were more likely to develop breast cancer, indicating that the estrogen plus progestin treatment may have a cumulative effect," he said.
Earlier studies also had shown a higher risk, but the design of the Women's Health Initiative study is considered more reliable.
There's no need to panic about risk from hormones taken in the past, Dr. Manson and Dr. Rossouw agreed. But both urged women to be vigilant in getting regular mammograms and breast examinations.
"While we want to get the word out to women and their doctors that long-term use of this therapy could be harmful, women should not conclude that they will develop breast cancer, or have a heart attack or stroke if they've taken this medication and, even in those who do suffer one of these diseases, the condition may not be due to the therapy," Dr. Rossouw said.
Short-Term Treatment May Be Fine
About 6 million U.S. women take the combination of estrogen and progestin for a variety of reasons, including menopause symptoms such as hot flashes and sleep disturbances. Studies have shown that HRT helps to relieve these symptoms.
For such short-term use, the benefits may still outweigh any risks, Dr. Manson said. The Women's Health Initiative did not examine the effects of short-term use for treatment of menopause symptoms.
Researchers found that HRT did provide some benefits for those who received it:
But the study's safety board found these effects did not outweigh the risks. "The increased risk of cardiovascular disease and breast cancer is too high a price to pay to prevent hip fractures," Dr. Manson said.
There are also alternative ways to help prevent osteoporosis, the brittle-bones disease that increases the risk of fractures, she notes.
It's important to recognize that the actual number of heart attacks, strokes, blood clots and cancers among the women in the study was small.
The study authors say that given the increased risks they found, a group of 10,000 women who took the hormone combination for one year would experience:
Compared with women who did not take the hormones, the hormone group also would have six fewer colorectal cancers and five fewer hip fractures.
On average, in a five-year period, the excess number of negative health events for women who took the two hormones would be one event for every 100 women, according to the study.
Even though an individual woman's risk might be small, Dr. Manson said, "On a population-wide basis this means tens of thousands of additional adverse events."
Findings Don't Apply To Estrogen Alone
The study results do not apply to women who take only estrogen, without progestin. Another part of the Women's Health Initiative study is examining the health results of taking estrogen alone. This part of the study will continue because the women in this part of the study have had different results than the women who took the combination of hormones.
"There's no evidence for an increased risk of breast cancer after five years in the estrogen-only group," Dr. Manson said.
Estrogen was the first hormone used in hormone replacement therapy. The estrogen and progestin combination was developed after women who took estrogen began to show a higher rate of endometrial cancer, which occurs in the uterus. The hormone combination apparently does not increase endometrial cancer.
Because of this risk, only women who have had their uteruses removed in a hysterectomy can participate in the Women's Health Initiative estrogen study.