THE ESTROGEN DILEMMA

Many women won't take the hormone for fear of cancer. Could new designer drugs be the answer'? Evelyn Levin, an artist in had a tough decision to make. The bones in her hips, thighs and spine were losing mass. But Levin, whose mother also suffered from the general weakening of the bones known as osteoporosis, didn't want to take estrogen. Although the hormone can reverse the bone‑weakening process, it may also increase the risk of breast cancer. So Levin volunteered for a study of an experimental drug called raloxifene, which may confer most of the benefits of estrogen therapy without the risks. Although her doctors won't tell her whether she's on the drug or the placebo, Levin is prettv sure she's getting the real thing, Every time they do a scan, she notes, my bone density keeps improving.

Sooner or later, every woman of a certain age has to face the question of whether or not to take estrogen. Once she reaches menopause, her body's supply of the natural hormone plummets, triggering such symptoms as night sweats and hot flashes. Decades of research have shown that estrogen is the closest thing to a perfect antiaging potion. It moisturizes the skin, maintains strong bones and protects against heart disease. It may even delay the onset of Uzheimer's disease. There is one big catch, however: estrogen may increase as much as 40% the risk of developing breast or uterine cancer.

Now a new generation of compounds, often called designer estrogens, promises to tip the balance in favor of treatment. Last week the experimental drug that Levin thinks she's taking, raloxifene, became the first of them to win endorsement from an advisory panel to the U.S. Food and Drug Administration, the initial step toward full‑scale approval. Barring any complications, Eli Lilly could bring the drug to the U.S. market in a matter of months.

Raloxifene is one of a group of compounds whose formal name (which only a scientist could love) is selective estrogen response modulators, or SERMS. They are designed to mimic the hormone's good qualities while avoiding its bad ones or at least that's the theory. Although SERMS have been widely publicized and are likely to find a big market, some doctors and women's health groups are sounding a note of caution. To get the best protection against osteoporosis, they note, women might have to take raloxifene for decades. And because the drug has been studied in humans for only a few years, nobody knows what its long‑term effects might be.

Scientists first became interested in designer estrogens in the early 1990s. While studying a powerful new anticancer drug called tamoxifen, which works by blocking estrogen's ability to stimulate breast tissue, they discovered that it also helped prevent osteoporosis. The drug seemed to act like an estrogen in the bone but an anti‑estrogen in the breast. Unfortunately, it also acted like an estrogen in the uterus, dramatically increasing the risk of uterine cancer. So researchers set out to find a chemical cousin of tamoxifen that would be easier on the uterus.

Raloxifene seemed to fit the bill. Studies showed it increased older women's bone density 1% to 2%. It also seemed to reduce the incidence of breast cancer by 58% over the course of a year in one study and to cut the level of so‑called bad cholesterol in the blood. Best of all researchers have found no hint of trouble in their patients' uterine or breast tissue at least not yet.

The greatest unknown, from a scientific point of view, is raloxifene's effect on the brain. The drug is known to increase the number of hot flashes, which are usually triggered by the brain's attempts to deal with falling hormone levels. This suggests that raloxifene might act as an anti estrogen in the brain. Recent studies have shown that estrogen may provide some protection against dementia and other types of nerve disorders. Therefore, taking raloxifene for long periods of time could theoretically increase the risk of developing Alzheimer's disease.

Just as troubling, a woman who has taken raloxifene and then develops breast cancer may reduce her options for fighting the malignancy. Because raloxifene is a distant cousin of the cancer fighting drug tamoxifen, some scientists are worried that any tumor cells that survive are likeiy to be resistant to tamoxifen as well.

Women like Evelyn Levin may be left weighing the poten­tial benefits of the new drugs against their unknown risks. For example, asks Dr. Ethel Siris, an endocrinologist at Columbia Presbyterian Medical Center in New York City, what do you do about the woman whose father had a heart attack and whose mother had breast cancer and also broke a hip? Raloxifene won't make her problems go away, but it may give her a little more room to maneuver.