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Risks of Hormone Therapy Stop Study

Medicine: Large clinical trial finds more cases of breast cancer and cardiovascular disease after long-term use of post-menopause drugs.


Three years ahead of schedule, scientists have unexpectedly halted a critical clinical trial testing the effects of hormone replacement therapy on women after menopause because of a slight but significant increase in the risk of breast cancer, heart attacks, blood clots and strokes.

The trial, which tracked 16,608 women taking either the hormones estrogen and progestin or a placebo for five years, was brought to an end after a review in late May made it clear that the risks of the hormone regimen outweighed the benefits.

The findings are to be published in the Journal of the American Medical Assn. next week but were released Tuesday because of their medical importance.

The study, part of a large government-funded research program known as the Women's Health Initiative, deals a serious blow to the long-term use of hormone replacement therapy as a disease prevention strategy. The therapy is used for varying durations by an estimated 38% of post-menopausal women.

"This is the study we've been waiting for, for years and years," said Dr. Howard Judd, chairman of obstetrics and gynecology at Olive View-UCLA Medical Center and a principal investigator at one of the three study sites in the Los Angeles area. "The results should have profound effects on hormone replacement--or if they don't, they should."

Many women may still opt to take hormones for short spells to treat symptoms of menopause such as hot flashes, night sweats, mood swings and vaginal dryness.

The researchers also found in their study that hormone replacement therapy led to reductions in risks for colorectal cancer and hip fractures.

Such benefits, however, can be achieved with other drugs and lifestyle changes that do not confer the same risks as hormone replacement therapy, the researchers said.

"You're hard pressed to say 'take estrogen to prevent colorectal cancer' if you see someone's more likely to develop breast cancer, have a heart attack, a stroke or a clot in the lungs or the legs," said Marcia Stefanick, associate professor of medicine at Stanford University, principal investigator of one of the 40 clinical centers and chairwoman of the Women's Health Initiative steering committee.

The authors concluded there is no longer any rationale for taking hormones for long-term protection of the heart. Despite a wealth of epidemiological evidence suggesting such protection, this more rigorous, placebo-controlled study failed to find it.

"The findings are important--and I think they're conclusive," commented Dr. Stephen Hulley, professor and chairman of the department of epidemiology at UC San Francisco.

Experts also noted that the heightened risks are small. Out of 10,000 women in a year, the therapy would lead to eight more cases of breast cancer, seven more heart attacks, eight more strokes and 18 more cases of blood clots in the veins or lungs.

Because the effect is small, there is plenty of time for women to digest the new information and carefully weigh the options with their doctors. Some may decide, after doing so, to continue taking hormones.

It could still turn out that estrogen alone does not carry the same risk as taking estrogen with progestin, which is added to hormone replacement regimes to protect against the risk of uterine cancer. Another trial within the Women's Health Initiative is testing the effects of estrogen on women who have had hysterectomies. That study, which is continuing, has so far detected no increase in breast cancer rates.

Tuesday's study was initiated in 1993. A plethora of epidemiological evidence suggested that women who opted for hormone replacement therapy were less likely to develop heart disease.

To conclusively show the link, the study enrolled 16,608 healthy women ages 50 to 69, all of whom had entered menopause.

The health outcomes were reviewed periodically by a safety monitoring board. Twice earlier--in 2000 and 2001--the board reported that there were slight increases of heart disease, stroke and deep-vein blood clot risks. However, at those earlier points there was no statistically significant increase in overall risk.

But the risks persisted and were joined by that of an increase in breast cancer in later years.

The results of the study were not entirely surprising, experts said. After the Women's Health Initiative had begun, other trials had reported on the effects of hormone replacement on patients who had preexisting heart disease. They, too, reported an increased risk of cardiovascular problems in early years and no overall benefit to the heart.

Scientists do not know why the earlier epidemiological studies should have led them to believe that hormones confer a significant protection against heart disease.

It has been suspected for some time that women who opt to take hormones and continue to take them may be different from those who either never take them or soon drop them. They may have healthier lifestyles, are richer and have better access to health care.

It may be impossible to control for such differences, and that is problematic for a condition like heart disease, which depends so much on lifestyle choices, said Dr. JoAnn Manson, a Women's Health Initiative investigator and chief of preventive medicine at Brigham and Women's Hospital in Boston.

Dr. Wulf Utian, executive director of the North American Menopause Society, said the results are "disappointing."

However, he and others point out, it is still possible that different doses and forms of estrogen and progestin, perhaps delivered by a patch instead of orally, could turn out to have different risks and benefits.

But to prove it would take more studies on the scale of the Women's Health Initiative, and few scientists believe the funding would be forthcoming.

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