NIH reviews hormone replacement studies

Researchers will explain decisions on experiments


When a large study of hormone replacement therapy was abruptly halted last summer because of risks from the drugs, scientists immediately began to reassess all other studies involving the drugs. Another study has been halted, and participants in others have had to give their consent again.

Researchers say the ripples from the hormone replacement study will spread for years, making them think carefully about when, if ever, to subject healthy women to estrogen therapy in scientific studies.

"The Women's Health Initiative has given us an understanding of the risks," said Dr. Richard Hodes, the director of the National Institute on Aging, referring to the first study that was stopped. "We have to ask whether despite that knowledge there is reason to continue a study."

Often, said Dr. Joan McGowan, an administrator at the National Institute of Arthritis and Musculoskeletal and Skin Diseases, "it's a very tough call."

The questions will be discussed today at a meeting on hormone replacement therapy at the National Institutes of Health. Dr. Vivian Pinn, who directs the office of research on women's health at the institutes, said she asked each institute to tell what it decided to do about its hormones studies, and why. The decisions on whether to continue hormone studies were made by independent committees that oversee studies.

The questions about hormone replacement arose last spring when an independent group of experts that periodically examined accumulating data from the Women's Health Initiative, a federal study, decided that the study had to stop. Its 16,000 participants, all healthy women, were randomly assigned to take Prempro, a popular combination of estrogen and progestin, or a placebo for comparison.

The hope was that the drugs would generally improve women's health. But at a meeting on May 31, about three years before the study was scheduled to end, the committee saw data indicating that the women taking Prempro had slightly more heart attacks and strokes, more blood clots and more breast cancer. Those risks were not outweighed by the benefits, which were slightly fewer fractures and a slightly lower risk of colon cancer.

Although the danger to an individual woman was minuscule, the committee determined that it could not justify subjecting healthy women to the drug. The participants were sent letters telling them to immediately stop taking their drugs.

Another part of the study is continuing, however. It involves women who have had hysterectomies and so do not require progestin to offset estrogen's tendency to elicit uterine cancers. These women are taking estrogen alone, and so far there are no findings that tip the balance in favor of overall risk or benefit.

McGowan, who is chief of the musculoskeletal diseases branch at the institute, said the termination of the Prempro part of the Women's Health Initiative was enough to stop a nearly completed study of hormone therapy in women with lupus, an autoimmune disease.

That study, of 351 postmenopausal women, had begun with high hopes in the mid-1990s. Women with lupus have an increased risk of heart disease and osteoporosis, McGowan said, and at the time it was hoped that estrogen would help with both conditions. The study was investigating whether it was safe for women with lupus to take the drugs. McGowan said the lupus study was stopped because of safety concerns.

At the National Institute on Aging, scientists have come to the opposite conclusion. The institute had two studies under way testing whether hormone replacement therapy could prevent or slow the course of Alzheimer's disease.

One Alzheimer's study supported by the aging institute involves 900 women who are 65 or older and who had a close relative with the disease, doubling or tripling their own chances of developing it. Those who had not had hysterectomies took Prempro; the others, just estrogen. A group that oversees the study decided that the women's risk of Alzheimer's was so high and that it was so important to know if estrogen could lower their risk that continuing the study was worth the gamble.

The other study, which involved women who already had Alzheimer's, was testing an estrogen patch in combination with progestin for women who had not had hysterectomies and by itself for women who had.

The hope was that it might slow the course of the disease. It was a question that had been addressed before, in three studies that tested Prempro. Those studies found no benefit from the hormones, said Dr. Neil Buckholtz, who is chief of the institute's division on dementias of aging.

But the estrogen patch, he said, has a different estrogen formulation, and it is not known if the patch and progestin conveys the same risk as Prempro. It was decided that the study could go on. Yet, Hodes said, the Women's Health Initiative study made him question the future of hormone replacement studies.

"It's a very difficult judgment," he said. Studies would need to enroll thousands of women and continue for years. Is it worth the investment? Is there sufficient evidence that the women may benefit rather than be harmed? Hodes said, "There is no easy answer."

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