The wonder, then, is not that estrogen is the most widely prescribed drug in the United States today but that 85 percent of the 37 million postmenopausal women want nothing to do with the stuff. A few rebel at taking a drug for a ““normal’’ condition. Some dislike feeling bloated, or having their periods return. Many reject estrogen out of simple, primal fear. ““Think of a balance scale,’’ says oncologist Melody Cobleigh of the University of Chicago. ““Hormone therapy protects your heart, it protects your bones, it improves your overall quality of life. But on the other side of the balance we have this one big thing, and it’s called breast cancer.’’ Soon, ““designer estrogens’’ that do not promote cancer (by stimulating the growth of breast cells) may remove the lingering worries about estrogen therapy. But for now, a study published last week offers the most definitive evidence yet of estrogen’s risks and benefits. Comparing some 40,000 postmenopausal women (all nurses), researchers led by Francine Grodstein of Brigham and Women’s Hospital in Boston found that the risk of death in the 16-year study period was 37 percent lower for women taking estrogen than for those who’d never taken it. The risk of fatal heart disease was 53 percent lower. But among women who received estrogen for 10 years or more, the death rate was only 20 percent lower ““because of an increase in mortality from breast cancer,’’ wrote the researchers. Specifically, fatal breast cancer was 43 percent higher among these women. And among women at lowest risk of heart disease, the estrogen-takers had only an 11 percent edge. That makes sense: if a woman is unlikely to get heart disease in the first place, then estrogen does not help her survival much. ““The survival benefit,’’ conclude the epidemiologists, ““diminishes with longer duration of use and is lower for women at low risk for coronary disease.''

‘Drug holidays’: Hidden in that conclusion is such a minefield of worrisome detail that two researchers from the National Cancer Institute, in an accompanying editorial in The New England Journal of Medicine, call for ““a reappraisal’’ of estrogen therapy. Their first concern is ““duration of use.’’ Taking estrogen for just a few years, long enough to get through the hot flashes, mood swings and insomnia of menopause, ““brings a very significant mortality benefit with no associated risk,’’ says Dr. Nananda Col of the New England Medical Center. Yet taking estrogen for 10 years or more cuts the benefit by almost half. Perhaps, suggests Chicago’s Cobleigh, women should take ““drug holidays’’: use estrogen for five years, stop for six months, then resume. That might protect the heart and bones but give breast cells a rest from the growth-stimulating effects of estrogen. The other issue is when long-term estrogen therapy should start. Dr. Wulf Utian of Case-Western Reserve University suggests that some women may want to time the therapy to begin just before 65, when their risk of heart disease rises.

These conclusions, of course, apply to the ““average’’ postmenopausal woman. But as the NCI’s Louise Brinton and Catherine Schairer point out, ““In some women at low risk for cardiovascular disease but at high risk for breast cancer, the benefits of hormone ther-apy may not outweigh the risk.’’ How can a woman tell which category she falls into? In April a landmark paper by NEMC’s Col and colleagues presented a computer model that calculates how much benefit an individual woman would derive from estrogen replacement. As Col explains in her upcoming book, ““A Woman Doctor’s Guide to Hormone Therapy: How to Choose What’s Right for You,’’ a woman tallies her risk factors for heart disease and for breast cancer (chart). The bottom line: those with the highest risk of cardiovascular disease and the lowest risk of breast cancer gain the most from estrogen therapy. Only women with virtually no risk of heart disease but a whopping risk of breast cancer do not benefit.

Many postmenopausal women, unaware that heart disease kills many more women, are convinced that they fall into that ““won’t benefit, may suffer’’ category. Dr. Susan Love, the breast surgeon whose new book, ““Dr. Susan Love’s Hormone Book,’’ is skeptical of estrogen therapy, has fostered this misperception. In a recent op-ed article in The New York Times, she claimed that ““in women younger than age 75 there are actually three times as many deaths from breast cancer as there are from heart disease.’’ But that’s wrong. In women 50 to 94, breast cancer kills 2.8 percent; heart disease kills 31 percent. Only in women under 50 does breast cancer kill more. Of course, as Col points out, ““there are many steps a woman can take to cut her risk of heart disease, such as exercising and not smoking. But risk factors for breast cancer, such as having a mother or sister with the disease, are not under our control.’'

Soon, women may not have to agonize over all this. Scientists are hot on the trail of new forms of estrogen that ““will bring virtually all of the bene-fits but none of the risks,’’ says endocrinologist Ethel Siris of Columbia University. Called ““selective estrogen receptor modulators,’’ these designer estrogens mimic the hormone’s beneficial effects on the cardio-vascular system and bones but not its dangerous effects on breast tissue. In clinical trials on 12,000 women, Eli Lilly’s raloxifene increased bone density by 2 to 3 percent and reduced ““bad’’ cholesterol. It did not stimulate growth of breast tissue. (Or stop hot flashes, unfortunately.) Lilly will seek government approval for the compound any week now; the Food and Drug Administration could OK the drug within the year. If it does, and if designer estrogens live up to their promise, today’s debate over estrogen therapy will become a quaint relic.

Skin: Estrogen helps keep skin thicker and less wrinkled by slowing the breakdown of collagen

Heart: Hormone therapy improves cholesterol counts, halving the death rate from heart disease

Breast: Estrogen stimulates breast-cell growth and increases cancer rates in long-term users

Bones: The hormone inhibits cells that eat away bone and so prevents osteoporosis

Uterus: Estrogen promotes growth of cells in the lining, increasing the risk of cancer

Women benefit from estrogen therapy if they . . .

Have high blood pressure Are obese Smoke Have high cholesterol levels

They may not benefit if . . .

Their mother or sister had breast cancer They have had benign breast tumors They menstruated early They had a first full-term pregnancy late in life or are childless