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http://www.nytimes.com/2002/07/09/national/09HORM.html

Citing Risks, U.S. Will Halt Study of Drugs for Hormones

By GINA KOLATA

large federal study of hormone replacement therapy in postmenopausal women was abruptly halted, researchers say, because the drugs caused a slight but significant increase in the risk of invasive breast cancer.

An estimated six million women take the drugs, estrogen and progestin, to replace the hormones lost at menopause. The hope was that the drugs would not just relieve the hot flashes, night sweats and vaginal dryness that can plague women at menopause but that over all they would also improve women's health. That, the investigators report, did not happen.

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The results of the study have been long awaited since it is the first and only large one to compare the effects of hormone replacement therapy with placebos in healthy women.

The directors of the study, known as the Women's Health Initiative, sent letters to the study's 16,000 participants, which they should receive today, telling them to stop taking their medications.

The data indicate that if 10,000 women take the drugs for a year, 8 more will develop invasive breast cancer, compared with 10,000 who were not taking hormone replacement therapy. An additional 7 will have a heart attack, 8 will have a stroke, and 18 will have blood clots. But there will be 6 fewer colorectal cancers and 5 fewer hip fractures.

The study was to continue until 2005, said Dr. Jacques E. Rossouw, who is its acting director. For the first few years that the women took the drugs, they were at no increased risk of cancer, heart disease or blood clots, and the study did not address the benefits of using the drugs for a short period to relieve the symptoms of menopause.

The decision to end the study came on May 31, in a periodic look at its accumulating data by an expert panel, the data safety and monitoring board. Suddenly, Dr. Rossouw said, after women had taken the drugs for an average of 5.2 years, the data had crossed a line. "The breast cancer risk exceeded the predefined boundary for safety," he said.

While cautioning that the danger to an individual woman is tiny, the study investigators say that over all the drugs' risks exceed their benefits.

The study did not address the question of estrogen alone. Women who have had hysterectomies take estrogen by itself — progestin is added only to prevent estrogen from causing cancer of the uterine lining, and doctors do not prescribe estrogen alone for women with uteruses.

The risks and benefits of estrogen alone are under study in a second clinical trial, of 11,000 women, being conducted by the Women's Health Initiative. That study is continuing because there is no evidence so far that the drug's risks exceed its benefits. For now, Dr. Rossouw said, with just estrogen, "the risks and benefits remain unclear," but "we can say there is no indication of an increased risk of breast cancer."

The findings on the hormone combination will be published in the July 17 issue of The Journal of the American Medical Association. The journal planned to release them this morning so the data would be available to doctors and women at the same time as the women in the study received their letters telling them to stop taking the drugs. But Cox News Service published the story last night.

Now, with the cessation of this large study, many observers said, the tide may be turning. Hormone replacement therapy, once thought to be a way for women to remain forever young, protect them from heart disease and from osteoporosis, and generally leave them healthier than they would otherwise be, may be fast losing its allure. Some worry that the news will be seem so frightening that women will overreact.

"This is a bombshell," said Dr. Wulf Utian, executive director of the North American Menopause Society, a nonprofit group that has long advocated hormone replacement therapy for women with a clear reason for taking it, like hot flashes or bone loss. "I think there is a real danger of panicking literally hundreds of thousands, if not millions, of women."

Dr. Utian added that he advised women to discuss the findings with their doctors before deciding to throw away their hormones.

Dr. Suzanne Fletcher, who is professor of ambulatory care and preventive medicine at Harvard Medical School, also emphasized that there was no reason to panic.

Dr. Fletcher said she was disappointed by the conclusion but not surprised by it. The study's directors had told the women in the study twice before, in 2000 and in 2001, that those taking the drugs seemed to have slightly more heart attacks, blood clots and strokes than those taking placebos, although the risks were not enough to stop the study.

"Even though I was upset by these results, that's the reason you do clinical trials," Dr. Fletcher said.

Now the question is, what should women do?

Dr. Victoria Kusiak, who is vice president of clinical affairs and North American director at Wyeth, the largest maker of the hormones, emphasized that there were no other effective treatments for the symptoms of menopause. While some women are not bothered by those symptoms, others are miserable, Dr. Kusiak said.

"Eighty-five percent of women do have symptoms," she said. "The hot flushes, the night sweats, are not just annoying — they can interfere with your life."

Dr. Kusiak said 9 in 10 doctors cited relief of such symptoms as a reason they prescribed the drugs. "For the longer term, particularly beyond the four-year point, we would advise that it has to be an individualized risk-benefit analysis," she said.

Dr. Deborah Grady, who directs the University of California at San Francisco/Mount Zion Women's Health Clinical Research Center, said she would urge most women taking the hormone combination to stop.

"This is a dangerous drug," Dr. Grady said.

Many women, she said, can simply stop cold. If there is no return of menopausal symptoms, then great, she said, but if the symptoms return and are intolerable, the woman can take the hormones for another year and then try again to stop.

But, Dr. Grady said, if a woman has taken the hormones for four or more years, the time when her risk of breast cancer emerges, she should try harder, tapering her hormone dose until she can do without them.

Dr. Nannette Wenger, a cardiologist at Emory University, said the only reason she could see for taking the hormone combination was for the temporary relief of severe symptoms of menopause. But, Dr. Wenger said, "I would not tell anyone to start taking it."

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