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By Sally Squires
Washington Post Staff Writer
Tuesday, June 4, 2002

Recent research has cast critical new light on estrogen replacement therapy, which over the past few decades has been prescribed to one in three menopausal women seeking relief from hot flashes, vaginal dryness and bone loss. Given the treatment's purported extra benefits, ranging from heart health to improved mood, the decision to take estrogen was often easy.

But that common practice is now being called into question. First came a study casting doubt on the ability of estrogen to prevent and treat heart disease. Other research questioned whether estrogen helps protect against Alzheimer's disease. As continuing research clarifies estrogen's corresponding risks, women and their doctors are looking with new urgency at the question of how -- and whether -- to treat symptoms of menopause.

"Women come into my office these days, and look me straight in the eye, and say, 'Are you for or against estrogen?' " says Wolf Utian, executive director of the North American Menopause Society (NAMS) and a consultant to the Cleveland Clinic. "It's like saying, 'Are you a Republican or a Democrat?' I'm not for or against estrogen replacement therapy. It's just one of the tools that I have at my disposal."

Scientists say it will be years before the answers about the true value and risks of estrogen replacement therapy are sorted out. But the thinking behind the long-term use of hormones at menopause is this: Since estrogen and other key hormones, including androgens, decline at the so-called change of life, replacing them can help manage symptoms (hot flashes, vaginal dryness, decline of libido) and help protect against bone loss and a myriad of other problems.

Of course, no drug comes without potential risks. Estrogen seems to increase the risk of breast and uterine cancer and is linked with an increased risk of blood clots and stroke.

At issue is not just whether to give hormone replacement, but for how long and to whom. While some women have taken estrogen for decades, such long-term use is linked with the greatest risk. Yet recent studies show that those who use estrogen for five years or less seem to have little or no change in their overall risk of death.

Even when more is known about the risks and benefits of estrogen, what proves effective in large population studies may not be the best choice for an individual. This is why doctors recommend that any treatment for menopause is the result of a woman's personal decision made in consultation with her physician. "What has become very clear with this whole area of menopause," says Utian, "is that it is one thing to speak about group studies and outcomes and quite a different thing to speak about an individual."

As the debate rages, however, there is also strong scientific consensus that estrogen remains the treatment of choice for three leading concerns related to menopause: hot flashes (experienced at some point by about 85 percent of menopausal women), vaginal dryness (a problem for 70 to 80 percent of women at some time) and loss of bone density (experienced by about 50 percent of women).

Study after study shows that for these concerns "hormone replacement therapy is by far the best option," says JoAnn Pinkerton, director of the University of Virginia's Women's Place Mid-Life Health Center in Charlottesville.

Within a week of their beginning estrogen, Pinkerton typically sees a reduction in the number and severity of hot flashes in her patients. By six weeks, hot flashes are usually completely suppressed, enabling women to break "the cascade of hot flashes, insomnia and night sweats that lead to fatigue, irritability and depressive symptoms," she says.

That's good news for the one in every three women who experience hot flashes severe enough to interfere with their daily lives. But for the rest -- and for those who have a history of breast cancer in their families or are at increased risk of heart disease themselves -- the question of estrogen replacement "is a very different issue," says physician Florence Haseltine, director of the Center for Population Research at the National Institute of Child Health and Human Development (NICHD) and co-editor of the Journal of Women's Health.

In fact, the most recent results suggest that estrogen, which has long been thought to protect against heart disease, may actually increase the risk of heart attack and stroke in the first few years of hormone replacement treatment, especially among those who already have high blood pressure, diabetes or elevated cholesterol levels. And always factored into the estrogen dilemma is the question of breast cancer.

How real is the increased risk of breast cancer for women taking replacement hormones? It depends how you look at the numbers. Over a 10-year period, "there is about a 30 percent increase in breast cancer with estrogen replacement," says Edward Klaiber, author of "Hormones and the Mind: A Woman's Guide to Enhancing Mood, Memory and Sexual Vitality" (Quill; $13.95). "That sounds horrendous."

Statistically, however, it works out like this, Klaiber says: About four in every 100 women who do not take estrogen will develop breast cancer between the ages of 50 and 60. With estrogen there will be an additional 1.2 cases of breast cancer per 100 women -- a statistically significant number to researchers, but not a huge elevation in the overall risk for a specific individual. "I don't think that we as doctors have gotten this point across very well," Klaiber says.

Maybe -- at first -- try none of the above, say experts, who caution against being too quick to "medicalize" menopause. "We have tried to turn menopause into a disease so we can sell women as much as we can," says Utian of NAMS. "Menopause is a normal event that takes place in every woman's life cycle," not a "disease" that necessarily requires a medical response.

Better, experts say, to start with low-cost, risk-free lifestyle changes. Yes, those same healthy eating habits and regular exercise that can battle expanding midlife waistlines and reduce disease risk are also important for reducing hot flashes and coping with other concerns of menopause.

"Women who are having things like hot flashes or complaining of fatigue and irritability and memory disturbances, symptoms that are blamed on menopause but are not necessarily part of it, those people who change their diet and lifestyle can actually see benefits," Utian says.

About half of women 50 to 70 years old already have the so-called metabolic syndrome, according to David Heber, director of the Center for Human Nutrition at the University of California, Los Angeles (UCLA). "This pre-diabetic state is characterized by high blood pressure, elevated blood fats, including cholesterol, high blood sugar, insulin resistance and abdominal fat that gives women with the condition a waist circumference of 35 inches or greater," he says, and sets the stage for heart disease and stroke.

Losing weight and getting daily activity can help drop the risk of developing full-blown diabetes by as much as 65 percent, as demonstrated by the federally funded Diabetes Prevention Program last year. That in turn reduces the risk of heart disease without the uncertainties of taking estrogen.

Trimming pounds can also help slow the precipitous decline in estrogen that seems to occur in overweight women and may exacerbate some symptoms of menopause. That's because blood estrogen levels tend to be higher in pre-menopausal obese and overweight women, due to overproduction of the hormone by fat cells.

There's evidence to suggest those elevated levels of estrogen plummet more sharply at menopause, resulting in more hot flashes and making the passage through midlife a little rockier for overweight women. Plus, being overweight can add snoring and sleep apnea to a woman's list of sleep disturbances.

"For women looking to reduce post-menopausal symptoms," Heber says, "diet, exercise and adopting a healthy lifestyle looks very effective." And "there is no risk associated with any of them."

Interest in soy as a remedy for menopause symptoms stems from population studies in China and Japan, where soy is a significant part of the diet and only 15 percent of menopausal women report hot flashes.

Rates of breast cancer are also lower in Asia than in the United States. In Asia, however, women consume soy throughout their lives, including at puberty, a critical time for breast development. "If we start consuming soy at age 40 or 50, is it too late" to get the benefits, asks Fredi Kronenberg, director of the Rosenthal Center for Alternative/Complementary Medicine at Columbia University in New York. "That is something that we're trying to get a handle on."

As promising as soy may sound, results from scientific studies are mixed. The evidence for the heart-protective benefits of soy is compelling enough that the Food and Drug Administration (FDA) allows the products carry a health claim. In fact, a year-long FDA review in 1999 found that 25 milligrams a day of soy protein -- combined with a diet low in saturated fat and cholesterol -- may reduce the risk of heart disease.

Of course, most women don't turn to soy for its heart benefits, but rather for other symptoms, including hot flashes. Whether soy can help in other areas of menopause is also under debate. "Studies show that soy does not affect the vagina at all," Heber says. That means it's unlikely to help with vaginal dryness -- or the accompanying yeast infections that plague many women at midlife.

On the other hand, 12 clinical trials "suggest that soy may take the edge off of hot flashes for some women," Kronenberg says. "But it's nothing near what estrogen does." So it may help women who are slightly bothered by hot flashes, but it probably won't do much for those whose lives are disrupted by this sudden profuse sweating and heart palpitations.

Also unclear is whether the beneficial effects on hot flashes are due to soy itself or to a placebo effect. Soy products "work to some degree in about 40 percent of women -- about the same as placebo," says Utian.

As consumers gobble everything from soy-fortified cereals to soy burgers, many are ingesting high amounts of soy -- more than the 50 to 100 milligrams of soy isoflavones typically consumed daily by consumers in Asia. "People are now taking soy in every persuasion, plus there is hidden soy in food, like fillers in meatballs," Kronenberg says. "We are doing a natural experiment on ourselves. A lot of women are taking soy and herbs. Are they acting synergistically?"

Yet another unanswered question. One thing certain is that soy can interact with drugs, including estrogen. Klaiber tells of treating a woman with hormone replacement therapy who did remarkably well for about a year.

"She felt like she had her life back," he recalls. Then, she phoned to complain that all her symptoms had suddenly returned.

Klaiber asked her to take a blood test for estrogen and found that her levels were very low -- inconsistent with the estrogen replacement. Then one of the woman's friends called, complaining of the same thing. Again, blood tests confirmed a low estrogen level. Klaiber reviewed what the women were eating and discovered the cause: "They had a special on soy milk at the supermarket and they were both drinking a lot of it," he says. "Once they stopped, their estrogen levels rose again and they were fine."

Just another illustration, he says, "that we need a lot more information about what is going on here." And just another reason why most experts urge women to limit soy to food and avoid supplements, which can provide very high doses of soy.

"Look, the Japanese eat 50 to 100 grams of soy, which contains about 50 to 100 milligrams of soy isoflavones per day," notes Heber. "There are soy supplements here that have 50 milligrams in a single pill. We Americans are famous for popping too many pills and can easily get into pharmacological levels of soy."

Okay, but what of other herbal supplements -- including black cohosh and St. John's wort -- now marketed to menopausal women?

"We're doing a study now of black cohosh to see if it works" for hot flashes and other signs of menopause, says Columbia University's Kronenberg. A plant native to the East Coast and used by Native Americans, black cohosh has been sold in Europe for more than 50 years. (The best known black cohosh product in the United States is Remifemin, sold over-the-counter as a dietary supplement.) Studies show that black cohosh may provide relief to about 40 percent of women who take it -- roughly the same as placebo.

Black cohosh "contains no phytoestrogens and it may be acting by a mechanism that is different than estrogen," Kronenberg says. "It may be a natural selective estrogen receptor modulator [similar to tamoxifen and raloxifene]."

It seems to work slowly, however, requiring at least four to six weeks of use before providing any relief. "After a month, patients said that they felt nothing," Kronenberg says. "But by the end of two months, it was helping them."

At the University of Virginia, Pinkerton recommends the herbal tea valerian to some of her menopausal patients who have trouble sleeping. "They try it at night before going to bed, or take up a Thermos to put by their bedside so that when they wake up they can drink it," she says. "It may have a mildly sedative effect."

The point, however, is that "people have to know how to use these things," Kronenberg says. "They have to understand that these herbals can work differently than hard-hitting drugs."

Absolutely, the experts say, and in some cases they may be preferable to estrogen, particularly as a protection against heart disease.

If cholesterol levels soar or diabetes surfaces or blood pressure rises during menopause, estrogen is not the drug of choice. "You need to take care of the disease that you've got," says NICHD's Haseltine. "If you've got heart disease, you should be treating that as a serious illness. Don't rely on estrogens or anything else to take care of it."

That means using a combination of medicine and diet to control blood pressure and blood sugar and to lower cholesterol. Not only are statin drugs "more effective than estrogen at lowering cholesterol, Pinkerton notes, but "they are proven prevention for heart attacks."

A study released Monday in the journal Circulation also reported that women with heart disease who take statins, with or without estrogen, have a reduced risk of heart attacks and deaths from cardiovascular causes. And there's new evidence to suggest that statins may protect against Alzheimer's disease.

Similarly, studies now show that the so-called designer estrogens, tamoxifen and raloxifene, may be a good alternative to standard estrogen for women with a history of breast cancer or at increased risk for the disease. Unlike standard estrogen, these drugs target only certain organs in the body, and seem to provide some of the benefits of estrogen -- such as protecting bone -- with less risk of breast cancer. In fact, tamoxifen is used help prevent recurrence of breast cancer.

It may also help prevent the disease. In 1998, a large national study showed that tamoxifen cut the incidence of invasive breast cancer by 49 percent in a group of women at moderately increased risk of the disease. Among women 50 to 59 years of age, the study found that just three in every 1,000 who took tamoxifen developed invasive breast cancer annually compared to six in every 1,000 of those who did not take the drug.

Studies hint that tamoxifen and raloxifene may offer some heart disease protection, because they lower levels of blood fats. But like estrogen, these newer medications hike the odds of developing blood clots and suffering a stroke. And there are downsides: Tamoxifen and raloxifene can produce hot flashes. Tamoxifen increases the risk of endometrial cancer.

Raloxifene is also now an option for women interested in protecting their bones. "It is effective at preventing back fractures," Pinkerton says. "And we know that raloxifene may prevent breast cancer in women with osteoporosis." Whether it will also help prevent breast cancer in other women is expected to be answered by a major clinical study that will be completed in several years.

Calcitonin and the bisphosphonates -- Fosamax and Actinel -- provide other choices for women concerned primarily with preventing or slowing osteoporosis. Calcitonin comes in a nasal spray and an injection and costs about $33 month -- about $10 more than estrogen. Fosamax and Actinel are now available in weekly doses. Their drawback: cost and some inconvenience.

"Women are going to spend a lot more money on these other drugs," says Haseltine, who takes estrogen replacement therapy herself. (A month's supply runs about $60.) And because both Fosamax and Actinel can damage the esophagus, women must remain upright for half an hour after taking the drugs. "They're a bear to take," Haseltine says.

The good news: Osteoporosis only affects about 25 percent of menopausal women. Bone scans and blood tests can help pinpoint which women are losing bone the fastest and are the best candidates for treatment, but experts also say that calcium, vitamin D and exercise are good strategies for everyone as they age.

For hot flashes, doctors now prescribe tiny doses of antidepressant drugs. There are estrogen-containing creams, pills and rings to help with vaginal dryness. But for many women, even these symptoms are temporary.

"Women are telling us that menopause is not a bad time of their lives," Utian says. "They say, 'I'm enjoying my life more at this stage more than I ever have."

All good signs, the experts say, that menopause is not the change of life, but a change of life.

"People have been trying to convince us that menopause is a hormone deficiency . . . that you have to replace," says UCLA's Heber. "In fact, it's just a natural change in physiology."