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Stanford Report, May 17, 2000

Despite new finding, hormone replacement therapy still considered promising  

BY CAROLINE SEYDEL

Many women going through menopause take hormones to reduce their risk of heart disease. Now, a huge national study indicates that a woman's risk of heart disease increases slightly during the first two years of hormone use. Despite the slight increase, however, researchers remain optimistic that over the long term, hormone therapy may have cardiovascular benefits.

The study indicates that women taking active hormones experienced heart attacks, strokes and blood clots in the legs and lungs slightly more often than women taking a placebo. Less than one percent of the women in either the hormone or placebo group experienced these symptoms. Although the excess risk among hormone users was extremely small, it probably represents a real increase, the researchers said.

Marcia L. Stefanick, PhD, associate professor of medicine and principal investigator of the Stanford portion of the Women's Health Initiative, cautions that it's too early to make sweeping statements about hormone therapy. "When we get to the 2005 mark, we're going to be able to provide the long-term picture that we don't have yet," Stefanick said.

The study, the hormone replacement therapy (HRT) trial of the Women's Health Initiative (WHI), is a nationwide investigation of either estrogen combined with progestin (in women with a uterus) or estrogen alone (in women who have had a hysterectomy). Women were randomly assigned to receive either hormones or a placebo.

More than 27,000 women are enrolled in the study, and nearly all of them have completed two years of therapy. About half have passed the three-year mark, one-quarter the four-year mark, and a few have even completed five years. Most did not have heart disease at enrollment.

Early data suggest that the mild increase in risk decreases over time, but since only half the women have reached the third year of therapy, it's too soon to say with certainty.

The rate of heart disease among study participants in both groups was lower than that of the general population, Stefanick said, and as a result, the long-term picture may be more useful than the short-term one. Women who participate in lengthy clinical trials are often healthier than average, at least at the outset of the trial, she said.

"You certainly don't attract women who are sick to come into a 10 year study," Stefanick said. "Within a few years, we expect they're going to look more like the general population ... the aging effects are going to set in."

The low number of cardiovascular events among the study participants makes it difficult to determine whether a particular subgroup of women is more vulnerable to such events. No specific trait characterizes the women who react negatively to the hormones, Stefanick said.

Stefanick also pointed out that women who "try out" hormone therapy to alleviate the immediate problems of menopausal symptoms, such as hot flashes, may not continue long enough to enjoy the potential benefits to their bones and their cardiovascular system.

"It may be that the favorable outcome happens later," she said. "It's pretty unlikely it's going to do much for their bones in two years, and for a very small percentage of women, they may have added a risk ... with respect to their heart."

An earlier study, the Heart and Estrogen/progestin Replacement Study (HERS), discovered a similar pattern of increased heart disease within the first year of hormone therapy. By the third and fourth years, however, the hormone users had a decreased risk. Overall, the study found no added benefit or risk to cardiac health for hormone users.

Unlike the WHI, women in HERS had heart disease before they began the trial. HERS also studied a much smaller group, about 2,700 women.

When the HERS data came out, researchers were surprised because estrogen was thought to reduce the risk of heart disease. But because HERS only studied women with existing heart disease, the short-term increase in risk was thought to be specific to those women.

That's why the early WHI data are unexpected, Stefanick said. Because the women in the WHI have a lower risk of heart disease than the women in HERS, only a study as large as WHI could detect such a slight increase.

"These findings that everybody got so excited about would never have been detected in a smaller study," Stefanick said.

The WHI Clinical Center at Stanford held a Special WHI Hormone Trial Event on May 13 in Fairchild Auditorium to discuss the findings with the women participating in the study. Because the results are unexpected, the researchers say, it is imperative the study continue so the long-term effects of hormone use can be observed.

In general, women in the trial seem unperturbed by the results, Stefanick said. None has expressed concern to her, and she doesn't expect many to drop out.

"Perhaps the real surprise has been their reaction," she said. A few of the women who had cardiovascular events even feel proud to have contributed to a new finding, she said. SR