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LIKE A PLACEBO - How Estrogen Gained a Healthy Skepticism IT seemed so clear a decade ago. Hormone replacement therapy would protect women's hearts after menopause. After all, their risk of heart disease rises in middle age, around the time their ovaries stop making estrogen. And there was indirect evidence that the drug was working: women who chose to take it lived longer and had less heart disease than those who did not. There even was a biological reason. Estrogen makes a woman's total cholesterol level drop; it reduces the levels of LDL cholesterol, the bad actor, while raising levels of HDL cholesterol, which protects against heart disease. "All the elements were in place for estrogen to protect against heart disease," said Dr. Deborah Grady, a professor of medicine and epidemiology at the University of California in San Francisco. She and other experts were so persuaded that they wrote a set of widely adopted guidelines for the American College of Physicians recommending that women at high risk of heart disease take estrogen after menopause. But new data show that even the best-intentioned analysis can go astray relying on indirect evidence. Last week, the prestigious New England Journal of Medicine published a report of a study on whether estrogen taken alone or combined with the hormone methoxyprogesterone can retard heart disease in women whose arteries were already narrowing. It was one of the first truly rigorous studies of the estrogen hypothesis. The women in the study were randomly assigned to take hormone replacement therapy or go without; they were followed for three years. Such studies avoid a pitfall of those that simply observe who chooses to take or go without a drug. Often, those who take a drug differ significantly from those who do not. Women who take estrogen are better educated, wealthier and more concerned about their health, all associated with less heart disease. As it turned out, no estrogen effect ever emerged. The study participants' arteries narrowed by the same amount whether they took a placebo, estrogen or estrogen plus methoxyprogesterone. The study was the second blow to the estrogen hypothesis. Recently another similarly randomized study concluded that women with heart disease who were assigned the hormone had the same rate of heart attacks, including fatalities, as those women with heart disease who took placebos. For the millions of women reaching menopause, the real question is: what happens if you don't have heart disease yet? Will estrogen offer protection from the leading killer of Americans? That answer is not yet in. A federal study of 25,000 healthy women assigned estrogen at random will not be completed until around 2006. But, some say, the signs so far are not promising. Ordinarily, drugs and behavior changes, like diets and exercise, are tested first in people who already have the disease in question. Every time treatments have slowed a disease in people who are already ill, they have prevented the disease in people who are well. Is it possible for a drug, like estrogen, to fail to protect sick people and yet prevent disease in the healthy? If so, it would be a first, researchers suspect. Dr. Elizabeth Barrett-Connor, a professor of preventive and family medicine at the University of California in San Diego, said she has been looking for an example of a drug that prevents heart disease but does not slow its progress. "I always ask whenever I have a group of cardiologists in the room, 'Can you give me the name of a medication that is good for the primary prevention of heart disease but not for the secondary prevention?' " she said. "I have not gotten an answer." The federal study of the 25,000 healthy women has hit a snag. In April, its directors informed the participants that there was a slight trend in the data toward more heart disease and strokes in those taking estrogen. While the trend could turn around, it does not bode well for the study, some say. Now that they know more about estrogen, researchers say, it is sounding reasonable that the hormone would not protect women's hearts after all. The hormone turns out to have many effects, some that might protect the blood vessels and the heart, others that might promote heart disease. The hormone lowers LDL cholesterol, but promotes clotting, a leading factor in heart attacks and strokes. It raises HDL cholesterol, but also raises levels of C-reactive protein, which is associated with inflammation. There is increasing evidence that inflammation contributes to heart disease. Of course, the estrogen story is not finished yet. For women with heart disease, most experts would agree with Dr. Nanette Wenger, a cardiologist at Emory University. "Women with established heart disease should not use estrogen," she said. For healthy women, she added, "the final chapter is not yet written." The heart disease story is also a lesson in scientific evidence, experts said. As scientists and the public seize upon indirect evidence for other effects, like the current hope that estrogen may prevent Alzheimer's, they might do well to remember how clear estrogen's effects on the heart once appeared. "We thought it was very likely that heart disease risk would be reduced and that therefore those most at risk should take estrogen," Dr. Grady said. "Now, I think that's wrong." By GINA KOLATA Copyright 2000 The New York Times Company http://www.nytimes.com/library/review/0827000sci-estrogen-review.html janet paterson 53 now / 44 dx cd / 43 onset cd / 41 dx pd / 37 onset pd tel: 613 256 8340 url: "http://www.geocities.com/janet313/" email: [log in to unmask] smail: POBox 171 Almonte Ontario K0A 1A0 Canada