Estrogen-Only Study Produces Mixed Results

Hormone helps menopausal symptoms, but raises stroke risk

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HealthDay Reporter

TUESDAY, April 13, 2004 (HealthDayNews) -- The results of the estrogen-only arm of the Women's Health Initiative, the first major trial to look at this hormone alone, appear to be a mixed bag.

Overall, they indicate that estrogen alone may be helpful in easing menopausal symptoms in women who have had a hysterectomy, but not for the prevention of chronic conditions such as heart disease.

The main negative outcome was an increased risk of stroke. The risk was troubling enough to halt the trial about a year ahead of schedule, in February.

On the positive and neutral sides, estrogen decreased the risk of fractures and had no apparent effect on preventing coronary heart disease in a large group of postmenopausal women.

Surprisingly, the hormone seemed to decrease the risk of breast cancer, although this did not reach statistical significance, according to an article in the April 14 issue of the Journal of the American Medical Association.

"This will be reassuring [to women who have had a hysterectomy who need to manage their menopausal symptoms]," said Garnet L. Anderson, co-principal investigator of the Women's Health Initiative (WHI) Clinical Coordinating Center, which conducted the trial. "The overall risk-benefit profile is really much more benign than it was for combined hormone therapy. This is not the best place to start for prevention, but if there is something that needs to be treated right now, menopausal symptoms, then this probably is an acceptable trade-off."

This early halting is the latest in a string of abrupt and unexpected endings to hormone trials. Two WHI trials using combination hormone therapy were halted because of unacceptably high risks of breast cancer, heart disease, stroke and blood clots. The memory arm of the WHI was stopped because of an increased risk of dementia in women over 65. A British trial and a Swedish trial, both looking at combination therapy, were also halted.

The National Institutes of Health reports that as of July 2003, about 10 million American women were taking some form of hormone therapy, about two-thirds estrogen alone and the remaining third a combination of estrogen and progestin. Estrogen can cause uterine cancer and therefore is only used in women who have had their uterus removed. Other women use a combination of estrogen and progestin, to protect the uterus.

The current study was designed to look at the effects of conjugated equine estrogen (CEE), or PremarinT, the most widely used postmenopausal therapy in the United States, on heart disease. In all, 10,739 postmenopausal women between the ages of 50 and 79 were randomly assigned to receive 0.625 milligrams per day of PremarinT or a placebo. The average age at enrollment was almost 64 and 70 when the study stopped.

After an average of almost seven years of follow-up, the researchers found that CEE had no effect on reducing the risk of coronary heart disease and no significant effect on pulmonary embolism or colorectal cancer.

It did cause a 39 percent increase in the risk of stroke, which was somewhat offset by a 39 percent reduction in the risk of hip fracture and a 23 percent reduction in the risk of breast cancer (which the researchers considered non-significant).

These findings translate into 12 more cases of stroke (both fatal and nonfatal) and six fewer hip fractures for every 10,000 women each year.

The breast cancer findings, while intriguing, will need to be investigated further.

Wyeth Pharmaceuticals, the makers of PremarinT, chose to look on the bright side of the report.

While acknowledging the seriousness of stroke as a side effect, Dr. Gary L. Stiles, Wyeth's executive vice president and chief medical officer, pointed out that the average age of the women in the study was higher than the average age of women taking estrogen, 64 in the study vs. about 55 in the population at large. "The risk for stroke is real but it's not large," he said. "The risk [for stroke] in the 50-to-59 age group [in the study] was the lowest. In fact, in that age group, it appeared that the risk was no different from placebo."

Still, everyone seems to agree the use of estrogen use should be confined to treating menopausal symptoms. "[The study] tells us that primary indication for this medicine are menopausal symptoms, and that does not change a single bit after this study whatsoever," Stiles said.

"Don't use estrogen for prevention and, when treating menopausal symptoms, try other strategies. Then, if the woman properly informed still wants to take hormone treatment, keep it at as low a dose as possible for as short a period as possible," said Dr. Stephen B. Hulley, author of an accompanying editorial and professor and chairman of the department of epidemiology and biostatistics at the University of California, San Francisco.

This is in line with current U.S. Food and Drug Administration recommendations on the subject.

Meanwhile, the researchers will continue to follow the women in the group until 2007.

More information

Visit the National Institutes of Health for more on the Women's Health Initiative and for questions and answers on the estrogen-alone study.

SOURCES: Stephen B. Hulley, M.D., professor and chairman, department of epidemiology and biostatistics, University of California, San Francisco; Garnet L. Anderson, Ph.D., writing group chair, Women's Health Initiative Steering Group Committee, co-principal investigator, WHI Clinical Coordinating Center, and member, Fred Hutchinson Cancer Research Center, Seattle; Gary L. Stiles, M.D., executive vice president and chief medical officer, Wyeth Pharmaceuticals, Collegeville, Pa.; April 14, 2004, Journal of the American Medical Association

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