THE ESTROGEN DILEMMA

By Claudia Wallis

On Feb. 13, 1963, a new patient strode into the office of New York City gynecologist Robert A. Wilson. To Wilson, she was nothing less than a revelation or, to be more precise, a walking, talking confirmation of his most deeply held medical convictions. Wilson was a leading proponent of treating menopausal women with the female hormone estrogen. He was convinced that, given early enough and continued throughout life, hormone treatment could actually prevent what he called the "staggering catastrophe" of menopause and the "fast and painful aging process" that attended it.

Wilson's new patient, "Mrs. P.G.," as he later called her, said she was 52 years old, but her body told another story. "Her breasts were supple and firm, her carriage erect; she had good general muscle tone, no dryness of the mucous membranes and no visible genital atrophy. Above all," Wilson noted, "her skin was smooth and pliant as a girl's." When asked about menopause, she laughed and replied, "I assure you, Dr. Wilson, I have never yet missed a period. I'm so regular, astronomers could use me for timing the moon."

Pressed for her secret, the youthful matron eventually revealed she had been taking birth-control pills, containing estrogen and a second female hormone, progesterone. That was the very formula Wilson had developed as a means not only to treat menopausal complaints but also to forestall the aging process. Mrs. P.G. was a lush exemplar of his notion that "menopause is unnecessary. It can be prevented entirely."

Three years later, in a hugely successful book, Feminine Forever, Wilson announced the good news to all womankind. "For the first time in history," he wrote, "women may share the promise of tomorrow as biological equals of men ... Thanks to hormone therapy, they may look forward to prolonged well-being and extended youth."

Estrogen is indeed the closest thing in modern medicine to an elixir of youth -- a drug that slows the ravages of time for women. It is already the No. 1 prescription drug in America, and it is about to hit its demographic sweet spot: the millions of baby boomers now experiencing their first hot flashes. What Wilson didn't appreciate, but what today's women should know, is that, like every other magic potion, this one has a dark side. To gain the full benefits of estrogen, a woman must take it not only at menopause but also for decades afterward. It means a lifetime of drug taking and possible side effects that include an increased risk of several forms of cancer. That danger was underscored last week by a report in the New England Journal of Medicine reaffirming the long-suspected link between estrogen-replacement therapy and breast cancer. Weighing such risks against the truly marvelous benefits of estrogen may be the most difficult health decision a woman can make. And there's no avoiding it.

As research reveals the pros and cons of estrogen, the therapy's popularity has flowed and ebbed like some sort of national hormonal cycle. Wilson's book did wonders for the sale of Premarin (a form of estrogen made from -- and named for -- a pregnant mare's urine). But estrogen use plummeted after 1975, when studies revealed that women taking the hormone had up to a 14-fold increased risk of uterine cancer. Reports of a 30% increased risk of breast cancer scared away many others.

Today estrogen in its various forms -- pills, patches and creams -- is flowing as never before. Cancer risks have been diminished, doctors believe, by lowering the dosages used in hormone-replacement therapy (HRT). The risk of uterine cancer, in particular, can be virtually eliminated, experts say, by adding synthetic progesterone (progestin) to the estrogen prescription, either combined in one capsule or as a separate pill. Meanwhile a raft of studies showing new and unexpected benefits has propelled medical enthusiasm for the treatment to huge, if not quite Wilsonian, proportions. Estrogen, it seems, can prevent or slow many of the ravages of aging, including:

Menopausal miseries. The oldest and most familiar use of HRT is to relieve the hot flashes, night sweats, vaginal dryness and other symptoms of estrogen "withdrawal" that occur around menopause, when the ovaries produce less and less estrogen.

Heart disease. Several studies, including the famous Nurses Health Study that followed 120,000 nurses for more than 10 years, have found that postmenopausal women on estrogen have about half the incidence of heart disease of those who don't take hormones. HRT seems to improve a woman's ratio of good cholesterol (HDL) to bad cholesterol (LDL) and also maintains the pliability of the blood vessels, lessening the risk of blockage.

Osteoporosis. Estrogen is the most effective means of preventing the thinning of bones that makes older women so vulnerable to fractures. Studies have shown that it cuts the risk of hip fractures up to 50% if treatment begins at menopause. And new evidence suggests that it could help prevent devastating fractures even when treatment begins at 70 or older.

Mental deterioration. Several small trials have indicated that estrogen improves memory for postmenopausal women. And a tantalizing study, reported in 1993, found that HRT enhanced the mental function of women with mild to moderate symptoms of Alzheimer's disease.

Colon cancer. A large study released in April found that estrogen users had a 29% lower risk of dying from colon cancer than nonusers. For those on estrogen more than 10 years, the risk was 55% lower.

Aging skin. HRT seems to help preserve skin elasticity, much as Wilson boasted. It helps maintain the collagen that keeps skin looking plumped up and moist.

Given all this, it's no wonder doctors are handing out estrogen prescriptions with almost gleeful enthusiasm. According to researchers at the Food and Drug Administration, estrogen prescriptions in the U.S. more than doubled between 1982 and 1992. About a quarter of U.S. women at or past menopause -- roughly 10 million -- take the hormone, making estrogen a billion-dollar business. As baby boomers approach menopause, those numbers will skyrocket.

While gynecologists acknowledge that there are risks to estrogen therapy, they tend to emphasize the pluses. "The benefits of HRT will outweigh the risks for most women," says Dr. William Andrews, former president of the American College of Obstetrics and Gynecology. "Eight times as many women die of heart attacks as die of breast cancer."

Still, the specter of cancer continues to haunt HRT. With last week's New England Journal report, hope faded that progestin would offer estrogen users protection against breast cancer, as it does against uterine cancer. In fact, it appears that the combined hormones may put women at a higher risk for breast cancer than estrogen alone. This bad news came in the wake of an alarming report in May suggesting that long-term use of estrogen heightens the risk of fatal ovarian cancer.

Even before these disturbing reports appeared, American women were distinctly less exuberant about estrogen than their doctors. A 1987 survey showed that 20% of women given a prescription for estrogen never even fill it. Of those who do begin taking the hormone, a third stop within nine months, and more than half quit within one year. Many others go on and off HRT. Some do it because they don't feel quite right on the medication, some because they hate taking drugs, many because they worry about cancer. "I feel like a guinea pig," complains a 52-year-old woman attending a women's discussion group in Minnesota. "In 10 years we'll all be saying 'We should have been on hormones!' or 'Damn it, why did we take those things?' "

For many women there is something fundamentally disturbing about turning a natural event like menopause into a disease that demands decades of medication. And there's something spooky about continuing to have monthly bleeding at age 60, a fairly common consequence of some types of hormone therapy. "Why fight vainly to remain in a stage of life you can't be in anymore, instead of enjoying the stage you are in?" asks Dr. Nada Stotland, 51, an HRT dropout. Stotland, a psychiatrist at the University of Chicago, says she is "extra skeptical, because there are powerful forces that aim one toward prescribed hormones, but there is no profit motive in not prescribing something."

Breast-cancer specialist Dr. Susan Love shares her skepticism: "Many gynecologists are handing out these hormones like M&M's," she says. No matter how beneficial estrogen may seem, no drug treatment comes without drawbacks. In biology as in business, notes the Los Angeles oncologist, "there's no free lunch."

THE POWER HORMONE

To understand the risks and wonders of estrogen therapy, it helps to know something about the hormone's natural role in the body. Estrogen is powerful stuff. Receptors for the hormone are found in some 300 different tissues, from brain to bone to liver. This means that in one way or another, all these tissues respond to the presence of estrogen. Some, including tissues in the urinogenital tract, the blood vessels, the skin and the breasts, require estrogen to maintain their tone and flexibility.

Estrogen levels begin to rise in girls as early as age 8 in response to a symphony of signals that stir sexual development. The hypothalamus, in the brain, acts as the maestro, spurring the pituitary to release hormones, which in turn prompt the ovaries to churn out estrogen. By age 11 or 12, production of estrogen and other hormones by the ovaries is sufficient to trigger the development of the breasts, growth of underarm and pubic hair, and the beginning of menstruation. But because these hormones influence so many tissues, they incite all sorts of adolescent mayhem: oilier hair and blemished skin, lurching moodiness, a growing interest in sex, and sometimes severe menstrual cramps.

In many ways, menopause is a mirror image of this process. Just as estrogen rises gradually in childhood, so it begins to wane some 25 years later, starting in the early 30s. The effects of the decline are rarely noticeable -- except in decreasing fertility -- until the early 40s, when women enter the transitional period known as perimenopause. Menstruation becomes less regular, the skin becomes dryer, hair turns more brittle and sparser under the arms and between the legs. Some women feel a loss of libido, and many suffer fluctuations in mood analogous to those that afflict adolescents.

IS IT HOT IN HERE?

As estrogen levels drop during perimenopause, the hypothalamus sends out more and more hormonal signals in a desperate attempt to get the ovaries to make more estrogen. But the aging eggs in ovaries respond erratically, explains endocrinologist Lila Nachtigall of New York University. As a result, "estrogen levels can fluctuate from low to high, day by day, and that can drive you crazy."

Since the hypothalamus is also the body's thermostat, its overactivity triggers the famous hot flashes of menopause, described by one sufferer as "a blowtorch aimed right at your face." According to current theory, this may be caused by the hypothalamus' release of an adrenaline-like substance that revs up the metabolism. The same mechanism may cause heart palpitations and nighttime sweating so intense that it can soak through the sheets.

About 85% of women experience some symptoms around menopause, lasting up to five years. At a round-table discussion sponsored by the pharmaceutical company Ciba-Geigy, a group of eight women described their tribulations with an extraordinary mix of candor, desperation and humor. (The women, most of whom do not take estrogen, agreed to be identified by their first names only.)

Sonia, 48, has "terrible" headaches and wakes up in the middle of the night with hot flashes: "I have to keep a cold washcloth on my night table; I put it on the back of my neck." Marguerite, 43, said she is so irritable before her period that she has taken to warning her officemates, "Next week's the week." For Susan, 48, "vaginal dryness is the worst," and beginning at 41, she was bothered by the unpredictability of her menstrual cycle: "My period would last 10 days, 12 days, 14 days. Then it would be six weeks, three weeks, two weeks."

More alarming is the gushing bleeding some of the women have experienced, the result, in many cases, of missed hormonal signals and a loss of uterine muscle tone. "Sometimes when I'm at the office and I stand up, the blood is dripping down my leg," said Marian, 45. "What the hell is going on? Am I hemorrhaging?" And a few women complained about bladder-control problems. Joked Marian: "Don't tell me I'm going to replace tampons with Depends!"

Not every woman will feel the symptoms so intensely. Heavy women tend to have an advantage at menopause, since fat cells manufacture a form of estrogen called estrone. Some lucky women, regardless of weight, simply churn out more estrone once estrogen from the ovaries shuts off.

Personal circumstances may matter as much as chemistry. The decline in estrogen often coincides with many life changes. "Your children grow up and move away. You don't look as gorgeous as you used to, and your husband leaves you for a younger woman. These things may leave you vulnerable to depression," says Dr. Stotland of the University of Chicago. "The more a woman feels valued in her life, the less likely she is to have emotional symptoms at menopause. Working women tend to do better than women who stay home."

Women are often shocked when menopausal symptoms strike in the early 40s. The average age of menopause, after all, is 51. Most know little about perimenopause, and their doctors aren't much help. A Gallup poll of women ages 45 to 60 conducted last year found that only 44% were satisfied with the information they received from their doctors about menopause. Until recently, doctors "simply weren't aware of perimenopause," admits endocrinologist Howard Zacur of Johns Hopkins Hospital in Baltimore. "Changes in the cycle at this time of life were misinterpreted and misdiagnosed."

Even now, the odd bleeding patterns of perimenopause are often attributed to fibroid tumors (which may or may not be a factor). Because their symptoms have been poorly understood, many women have undergone unnecessary hysterectomies and D&Cs (dilatation and curettage), a procedure that scrapes away the uterine lining. Roughly 1 out of 4 U.S. women is thrown into "surgical menopause" by the removal of her uterus and ovaries instead of hitting menopause naturally.

HERE, HAVE SOME HORMONES

The best therapy for perimenopause is "knowing what it is," says Harvard gynecologist Alan Altman. Exercise, a proper diet and not smoking can also help. (Women who smoke reach menopause an average of two years earlier than nonsmokers.) For 85% of women, the symptoms will stop within one year of their final period. But for those who are in too much misery to wait it out, estrogen can do wonders.

Patricia Thomas, 56, of Baltimore suffered nearly five years with hot flashes, night sweats and sleeplessness. Estrogen completely halted her symptoms and made her feel "wonderful." Barbara Williams, 47, of Chicago was so irritable, she says, that "my family would hate to see me coming home from work." An estrogen patch (plus progesterone pills) evened out her moods. HRT can sometimes alleviate vaguer woes -- the generalized achiness that some women feel and a sense of mental fogging. There is a "euphoric effect or general improvement in mental state," says Cleveland endocrinologist Wulf Utian, co-founder of the North American Menopause Society.

But Utian is quick to point out that not every woman should take estrogen. It is not advisable for those with a history or a high risk of breast or uterine cancer. Nor is it recommended for women with clotting problems.

Besides, some women feel lousy on hormones. And many are distressed to find they gain weight (though it's unclear that estrogen is really to blame). When Lynn Schleeter, 44, of New Brighton, Minnesota, was taking estrogen and progesterone, "I was so lethargic, I couldn't walk around the block." She feels more energetic now that she has thrown away her estrogen patch and switched to a regimen of exercise, vitamins and calcium supplements (to fight osteoporosis).

Progesterone pills can be particularly hard to tolerate. Progestin is always prescribed along with estrogen for women with an intact uterus. While estrogen prompts the uterine lining to thicken, progestin signals it to stop growing and slough off; this artificial menstrual cycle seems to prevent endometrial cancer. But progestin often causes cramps, irritability and other PMS-like problems. In her 1991 book on menopause, The Silent Passage, Gail Sheehy tells how estrogen highs and progestin lows made her feel as though her body was "at war with itself for half of every month."

ESTROGEN FOREVER?

Once the storms of perimenopause have cleared, many women see little reason to remain on estrogen. Some enter a period of well-being, famously dubbed "post-menopausal zest" by anthropologist Margaret Mead. In her latest book, New Passages, Sheehy calls this the "pits to peak phenomenon": Women emerge from the morass of menopause with "a greater sense of well-being than any other stage of their lives."

Yet, no matter how marvelous such women may feel, the prevailing medical view is that most should stay on estrogen for the long haul. Unnatural as that sounds, doctors argue that life after menopause is itself somewhat unnatural. "As women have lived increasingly longer lives, they are facing problems their grandmothers never faced," says Dr. Charles Hammond, chairman of obstetrics and gynecology at Duke University Medical Center. "At the turn of the century, women died soon after their ovaries quit." Now they live to face heart disease, osteoporosis, increased fractures -- problems that may be prevented in part by taking estrogen.

Unfortunately, estrogen works its preventive wonders only if taken for many years -- the longer, the better. To prevent osteoporosis, for instance, a woman must use estrogen continuously for at least seven years, according to recent data from the Framingham study in Boston. Currently, 95% of women on HRT take it for three years or less -- "not long enough to get any positive effects on their bones," says Dr. John Gallagher, an endocrinologist at Creighton University in Omaha, Nebraska.

Similarly, researchers studying estrogen and heart disease see the greatest benefits in long-term use. Estrogen helps keep levels of LDL cholesterol low and HDL cholesterol high, which is one reason pre-menopausal women have a much lower rate of heart disease than their male peers. Without HRT, a woman's risk of a heart attack rises to match that of men within 15 years of menopause. Estrogen also acts directly on blood vessels, causing them to dilate slightly so that blood flow improves, says Dr. Roger Blumenthal of Johns Hopkins Hospital. But these benefits disappear as soon as the patient stops taking hormones.

Given all this, it seems logical to recommend HRT for postmenopausal women with high cholesterol levels or other warning signs of heart disease. Indeed, Blumenthal considers HRT "a first-line therapy" for such women. Likewise, it is now standard practice to give estrogen to women with a high risk of osteoporosis -- approximately 1 in 3 U.S. women. Gallagher recommends routine bone-density tests to assess bone condition and at least 10 years of estrogen, beginning at menopause, for those with fragile bones.

While such recommendations are based on the best available research, experts, if pressed, will admit that the research is woefully inadequate. Most of the controlled studies on estrogen therapy have been short-term and can shed no light on long-term risks. "I think the currently available data are extrapolated to excess with respect to heart disease," complains cardiologist David Herrington of Bowman Gray School of Medicine in Winston-Salem, North Carolina.

What does emerge from the longer-term data is that prolonged use of estrogen appears to increase the risk of breast cancer and other malignancies. And the longer estrogen is taken, the greater the risks. For instance, a study of 240,000 women sponsored by the American Cancer Society found that those who took estrogen for at least six years had a 40% increased risk of fatal ovarian cancer. For those taking estrogen for 11 or more years, the increase jumped to 70%.

There may be other risks and other advantages of HRT, but what doctors know is limited by the type of research that has been done. Instead of setting up a group of women on HRT and a carefully matched control group that does not take hormones, studies like the Nurses trial simply look at populations of women who made their own choice whether to take estrogen. "The problem with this," explains Dr. Susan Love, "is that women who take hormones go to doctors more, eat well, exercise and are in better health generally than women who don't take hormones." Thus it is hard to tell whether their lower rates of heart disease or colon cancer or fractures reflect HRT or these other healthy habits.

The good news is that a well-designed, long-term study of HRT is finally under way. Last year, in an attempt to redress a historic shortfall in research on women's health, the National Institutes of Health launched the $628 million Women's Health Initiative. In the HRT portion of the study, which will involve 27,500 women, half will be randomly assigned to HRT, half to a placebo. Researchers will follow the women for at least eight years and compare rates of heart disease, osteoporosis, breast cancer and other ailments. When the results are reported, doctors and patients may finally have some clear picture of the risks and benefits of long-term HRT. Alas, that won't be until 2005.

In the meantime, women are faced with a tough choice. Dr. Isaac Schiff, chief of obstetrics and gynecology at Massachusetts General Hospital, puts it with refreshing bluntness: "Basically, you're presenting women with the possibility of increasing the risk of getting breast cancer at age 60 in order to prevent a heart attack at age 70 and a hip fracture at age 80. How can you make that decision for a patient?"

Those who don't like that choice may want to examine the alternatives. There are other ways to fight osteoporosis and heart disease: don't smoke; get regular exercise that is both weight bearing (to prevent bone loss) and aerobic (to condition the cardiovascular system); eat a diet rich in calcium and low in fat. And, of course, there are other drugs for heart disease and several promising new ones in the pipeline for osteoporosis. Many of the "alternative" practitioners around the country are suggesting that women seek estrogen from dietary sources. In Los Angeles and Boston, Mexican yams have become all the rage among women of a certain age. Yams contain a weak form of estrogen. San Francisco nutritionist Linda Ojeda, author of Menopause Without Medicine, advocates soybeans, which contain a natural progesterone as well as estrogen. The low rate of menopausal complaints among Japanese women may be due in part to their consumption of tofu, she suggests. To relieve hot flashes, Ojeda recommends 6Eoz. of tofu four times a week, 800 units of vitamin E daily, plus a few other herbs and vitamins. "Why not start with the least invasive products first? If you have a cold, you start with chicken soup and garlic."

In the final analysis, the decision about estrogen is a highly individual one. It should depend on a woman's assessment of her own health; her family history of cancer, heart disease and osteoporosis; and even on personal philosophy. "I have a hunch that I'll remain on HRT for the rest of my life," says Frida, a Chicago-area college instructor in her early 70s, who feels that estrogen gives her "more energy" and a more youthful appearance. But for Joan Israel, 64, a clinical social worker in Franklin, Michigan, fear of cancer was a deciding factor against estrogen. "So what if you get wrinkles or a little flabby, as long as you are basically healthy?"

As is so often the case in modern medicine, the most a patient can ask of her doctor is to lay out the risks, the benefits and the honest fact that the data are inadequate, and then let her make the choice.

--Reported by Wendy Cole/Chicago, Alice Park/New York and Martha Smilgis/Los Angeles

With reporting by WENDY COLE/CHICAGO, ALICE PARK/NEW YORK AND MARTHA SMILGIS/LOS ANGELES