Combination Hormone May Cause Dementia in Older Women

May 28, 2003
Hormone Use Found to Raise Dementia Risk
By DENISE GRADY


ormone therapy doubled the risk of Alzheimer's disease and other types of dementia in women who began the treatment at age 65 or older, a large study has found.

The finding disappointed many researchers and doctors, who had hoped for the opposite result: that hormone therapy would prevent Alzheimer's disease.

"No one anticipated this outcome," said Dr. Marilyn Albert, a professor of neurology at Johns Hopkins, in a statement issued by the Alzheimer's Association.

The new report on dementia, being published today in The Journal of the American Medical Association, is one more piece of bad news about hormone therapy. Indeed, it is the latest in a string of studies showing that purported benefits do not exist and that the hormones actually raise the risk of several serious diseases, including some they were thought to prevent.

The latest finding is based on a four-year experiment involving 4,532 women at 39 medical centers. Half took placebos, and half took Prempro, a combination of estrogen and progestin, the most widely prescribed type of hormone therapy.

In four years, there were 40 cases of dementia in the hormone group, and 21 in the placebo group. Translated to an annual rate for a larger population, the results mean that for every 10,000 women 65 and older who take hormones, there will be 45 cases of dementia a year, with 23 of them attributable to the hormones.

"The clear message is that there's no reason for older women to be taking combination hormone therapy," said Dr. Sally A. Shumaker, the director of the study and a professor of public health sciences at Wake Forest University, in Winston-Salem, N.C.

Wyeth, the company that makes Prempro, said it would add a new warning about the increased risk of dementia to the drug's labeling.

Researchers said the risk to individual women was slight, and that even though the numbers worked out to a doubling of the risk, 23 cases for every 10,000 women should not be cause for alarm.

"A small number doubled is still a small number," said Dr. Samuel E. Gandy, vice chairman of the medical and scientific advisory council of the Alzheimer's Association, and director of the Farber Institute of Neurosciences at Thomas Jefferson University in Philadelphia.

Still, Dr. Shumaker said, women 65 and older who are taking Prempro or other hormone combinations should discuss why they are taking the drugs with their doctors and decide whether to quit.

Because the women in the study were 65 or older, it is not known whether the findings apply to younger postmenopausal women. It is not known, either, whether the results apply to women who take other hormone combinations or estrogen alone. Women who take estrogen alone are being studied separately.

Estrogen alone can cause cancer of the uterus and so is prescribed only for women who have had hysterectomies. But adding progestin protects the uterus, so women who have not had hysterectomies are given combination treatment.

The report on the study is accompanied in the journal by two other reports that also have unfavorable findings on combined hormone therapy and the brain. One study found that women on the drugs did not perform as well on cognitive tests as women on placebos; the other confirmed previous research showing that the combination therapy increased the risk of stroke.

About 2.7 million American women take combination hormone therapy, including 1.2 million who use Prempro. Wyeth said that the majority of users were 51 to 55 years old, and only 14 percent of all new prescriptions were for women 65 or older.

The hormones were never approved to prevent or treat Alzheimer's disease. They are approved by the Food and Drug Administration for only two purposes: to treat menopausal symptoms like hot flashes, night sweats and vaginal irritation; and to prevent the bone-thinning disease osteoporosis. But because the hormones can slightly increase the risk of breast cancer, strokes and heart attacks, the agency recommends that women use the lowest dose for the shortest time possible, and that they consider other treatments to prevent osteoporosis.

Last July, a large federal study of the combination therapy was halted ahead of schedule because the drugs were found to cause a small but significant increase in the risk of invasive breast cancer. That study, the Women's Health Initiative, also found that hormones increased the risks of heart attack and stroke, which they were once thought to prevent. The drugs increased the odds of blood clots as well. The study, which included 16,000 women, was the first and the largest to compare women on hormones with a group taking placebos.

Many women gave up hormone therapy after the study came out. Before it was published, about 6 million women were taking combination therapy.

After the disappointing findings, the last great hope for hormone therapy was that it might protect the brain and help prevent Alzheimer's disease. Some women, encouraged by their doctors, clung to that belief and continued taking the drugs despite the negative reports, figuring that the risks would be worthwhile if hormones could offer that protection from dementia.

The dementia study is part of the Women's Health Initiative. Dr. Shumaker said it was the most comprehensive and rigorous study to investigate whether combination hormone therapy could prevent Alzheimer's.

"Unfortunately, the risks outweigh the benefits," she said.

The theory that estrogen might prevent Alzheimer's was based on earlier, survey-type studies suggesting that women on hormones had lower rates of dementia than women not on hormones. But those studies were not considered as reliable as the Women's Health Initiative, because they were smaller and did not contain control groups. Evidence also came from studies in test tubes and in laboratory animals showing that estrogen seemed almost to nourish the brain, making new connections sprout in areas that control learning and memory.

The new study suggests that what goes on in the body is much more complicated than what happens in laboratory rats and test tubes. Even if hormones have some good effects on brain cells, Dr. Shumaker said, those benefits may be offset by harmful effects.

She said that it was not known how the combination therapy might increase the risk of dementia, but one possibility was that it increased the risk of blood clots and clogged tiny blood vessels in the brain, which might injure brain cells and contribute to Alzheimer's disease and a condition called vascular dementia.

Some researchers have suggested that hormone therapy may help protect the brain if women take it around the time of menopause, when natural hormone levels plummet, instead of waiting until age 65.

They think there may be a "critical period" in which hormone therapy can protect brain cells from the sudden withdrawal of hormones and that once the period is over the damage is done and it is too late. But no one knows whether such a period exists, and no studies now under way will answer that question.

Dr. Gandy said that some of the most promising earlier results on hormone therapy and the brain came from studies of estrogen alone, and that the progestin in the combination pills might cancel out estrogen's good effects. He said that another part of the Women's Health Initiative, still in progress, was studying women who take estrogen alone. That study is scheduled to be completed in 2005.

"That is the most likely place to show any benefit against Alzheimer's, if indeed one does exist," Dr. Gandy said.

Dr. Wolf Utian, executive director of the North American Menopause Society, agreed that benefits might come from estrogen alone, and suggested that research should be done to find out whether hormone regimens that use lower doses over all and give progestin only on some days of the month might have less of a negative effect than Prempro and other treatments that use progestin every day.

Shares of Wyeth were hit hard last summer when the Women's Health Initiative study was published. Prempro and related products had been the company's top-selling drugs, accounting for more than $2 billion in sales in 2001. The stock, which traded as high as $58.48 in May, fell by roughly half to a low of $28.25 in July.

Copyright 2003 The New York Times Company