Women approaching their middle years have plenty to cope with, and now they face a new twist on an old medical dilemma: Should they take hormones as they approach menopause because recent findings suggest that estrogen replacement therapy (ERT) may protect some older women from fatal heart attacks?

Sounds good, but the estrogen story is already so complicated that the news about a possible heart disease prevention is just the latest chapter in a long-running debate on the risks and benefits of ERT -- or HRT (hormone replacement therapy) when progestin is included. Moreover, it may mean that many more women will make crucial decisions about ERT without, many specialists believe, adequate information.

The issue has come to a head because the Food and Drug Administration is currently considering a request by Wyeth-Ayerst, the manufacturers of Premarin, the most commonly prescribed oral estrogen product, to permit promotion of the drug for prevention of heart disease at least for those women who have had hysterectomies and no longer have a uterus. The request follows a recommendation by an FDA advisory committee that there is enough evidence of a heart disease benefit to justify the new use. But not everyone agrees that the benefit has been conclusively demonstrated -- or that long-term use of ERT is safe.

In the past, the use of estrogens in post-menopausal women was linked to increased rates of uterine cancer. There are also disturbing hints that current dosages of replacement hormones over many years might increase the risk of breast cancer as well.

The decline of natural estrogens in a woman's body as she ages produces the cluster of symptoms known as the menopause. It is characterized principally by cessation of menstrual periods (and loss of fertility) and sometimes accompanied by mood swings, sleep disorders, vaginal dryness and hot flashes. These symptoms are by no means universal. Many are transitory and mild, requiring little special treatment.

Still, some women suffer terribly, and hormone replacement, it was discovered almost 50 years ago, can ease these conditions.

Moreover, as some specialists have unkindly noted, nature has little interest in keeping a female alive much beyond her childbearing years. So a lot of other things related to hormone levels start happening at or after menopause. Bones begin to thin. In some women, this leads to osteoporosis and hip and spinal fractures. The rate of heart attacks, almost unheard-of in younger women, starts inching up to the same level as that for men. All in all, heart disease becomes the No. 1 killer of women, with some 250,000 deaths a year, outnumbering all cancers in women combined.

In the 1940s, it was discovered that Premarin, estrogens derived from (and named for) the urine of a pregnant mare, could ease the hot flashes of menopause. The drug was promoted to the medical profession and to women in general as a means of staying young, and it was prescribed in relatively large doses to millions of women. Then, it was found to protect bone density and its use peaked in the 1960s and '70s, even though its formal approval for osteoporosis prevention came only last year.

But as its usage soared, so did the incidence of cancer of the uterus and of pre-cancerous conditions in the lining of the uterus. Eventually, specialists found that adding another hormone -- progestin -- to the estrogen therapy, protected the uterus and did not affect the benefit to bone density.

For women entering menopause who have not had hysterectomies, estrogen at lower doses than had been prescribed in the '40s and '50s, along with progestin during part of the monthly cycle, has become a standard therapy. Between 5 and 9 million women in this country are on a regimen that includes Premarin.

Now, however, comes another source of concern: It seems that progestin may block some of the heart benefits of estrogen, and there is some suspicion that progestin also may increase the risk of breast cancer.

The bottom line for women who have had hysterectomies is that ERT does ease the transient symptoms of menopause; yes, it does protect bone density; perhaps long-term use cuts deaths from heart attacks, and perhaps long-term use increases the risk of breast cancer.

Elizabeth Barrett-Connor of the departments of epidemiology and of family and community medicine at the University of California, San Diego, told the FDA advisory committee, "I would not make a blanket recommendation at any age to any woman. It depends on how she feels, what she's concerned about, what is her quality of life, her own risks and benefits, her own particular anxieties" and, in the end, what she and her doctor conclude.

At a National Institutes of Health symposium in May and at the FDA Advisory Committee public hearing a month later, scientists offered conflicting views of some 30 studies on the beneficial link between estrogen and heart disease. For the FDA committee, the evidence was convincing. It concluded that "the cardiovascular benefits of estrogen replacement therapy with Premarin in women without a uterus may outweigh the possible risks, considering the individual patient's risk for various estrogen-related diseases and conditions."

There are an estimated 6 million women who have had hysterectomies who are not currently using Premarin. Of the 35 million U.S. women 50 and older, almost 40 percent will have, or have had, hysterectomies by age 60.

Studies of groups of women at or after menopause were cited as evidence that the heart benefit effect exists:

Johns Hopkins epidemiologist Trudy L. Bush, at the May meeting, described a study she co-authored of 2,270 white women between the ages of 40 and 69 in 10 U.S. centers. Estrogen tended to lower total cholesterol, raise levels of HDLs (high-density lipoproteins, the good kind) and lower levels of LDLs (low-density lipoproteins, the bad kind). What turned out in the first 8.5 years to be about a 30-50 percent reduction in heart-attack deaths for estrogen users has held up in the 15-year follow-up, which is not yet published, she said.

Barrett-Connor, a co-author of the lipid study, said at the FDA hearing that the women who used Premarin were also less likely to smoke, were thinner and better educated than the non-users -- variables, she noted, that could affect the findings. For example, a thin woman is more prone to symptoms of menopause, including osteoporosis, and might have chosen ERT for those reasons. But thin women who don't smoke are less likely to have heart problems, even without ERT.

Gary L. Friedman of Kaiser Permanente in Los Angeles, who analyzed the 30 studies that were under review, found that virtually all of them showed heart benefits for estrogen. But, he noted, "although the case for estrogen is strong, it is not open and shut."

The biggest problem with these studies, he said, is that they are "observational" and that the participants selected themselves to participate.

As Cynthia Pearson explained in opposing approval of the new use for Premarin on behalf of the National Women's Health Network: One study found that users of estrogens, as compared with non-users, had lower mortality not only from heart disease but also as a result of accidents, suicide and homicide. She wondered, "Does that mean that we can conclude that estrogen use protects one from being murdered?"

Even those who testified at the request of the company, including Barrett-Connor, indicated that without clinical trials comparable to the heart disease prevention aspirin studies in men, and without some more studies of the risks of ERT over time, it would be premature to recommend estrogens for all women.

Barrett-Connor was recently in Bethesda to explore with NIH specialists the possibility of setting up such trials. She said, "Whenever you're talking about preventing a disease, you have to be very sure you're not causing another one."

More Information

Meanwhile, PEPI, (Postmenopausal Estrogen/Progestin Interventions), a national trial sponsored by the National Institutes of Health, is getting underway. It will determine the effectiveness of ERT/HRT on heart disease risk factors but will not examine the effects of long-term usage. In the Washington area, the trial is at George Washington University Medical Center. For information, call 676-5150.