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Hormone Replacement Therapy: The Whole Story

"I couldn't go without it — I have a lot of flashes if I don't take it," says Shirley Waddell, 59, of Jonesville, N.C.

She's talking about the hormone medication she's been taking for the past 20 or so years. The drug, Premarin 625, replaces the estrogen that her body stopped making after she had a partial hysterectomy, which throws a woman, ready or not, right into menopause.

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"I just feel better when I take it," she said. About one-fourth of postmenopausal women in the United States are on hormone replacement therapy (HRT). (Postmenopausal is the term doctors use to refer to the entire remainder of a woman's life after she ceases menstruating.) Most women take it for the same reason that Waddell does — to stop the hot flashes that often begin right before menopause and can continue for years afterward. (They take either estrogen or estrogen with a synthetic progesterone called progestin to protect against uterine — or endometrial — cancer.)

Estrogen also helps prevent other symptoms of menopause, such as vaginal dryness. Plus — and this is a big plus for many women — it lowers the risk of developing brittle, easily breakable bones, or osteoporosis. Another reason doctors have encouraged the use of estrogen is to protect women against heart disease, the leading cause of death in postmenopausal women. Early studies suggested that taking estrogen after menopause would decrease the likelihood that a woman will suffer a heart attack.

New Research Reverses Assumptions

But Waddell's experience is one reason doctors are now questioning that claim, and again questioning whether the benefits of estrogen outweigh its risks, particularly the risk of breast cancer. Waddell has heart disease. She had a heart attack in 1991, and in 1998 she underwent a procedure to open up a clogged artery that was restricting blood flow to her heart. Over the past three years she participated in a large study examining the long-held belief that taking estrogen reduces heart disease.

In the study, researchers gave women who already had heart disease either estrogen or inactive "placebo" pills. They didn't tell the women which medication they were on. At the beginning and end of the study, they took angiograms, a type of X-ray picture, of the women's arteries.

The angiograms revealed that estrogen failed to improve the atherosclerosis, or plaque buildup in the arteries that blocks the flow of blood and is a major cause of heart attack and stroke, reported David M. Herrington, M.D., and colleagues in the August 24, 2000, New England Journal of Medicine.

These results suggest that women who already have heart disease "should not use estrogen replacement with an expectation of cardiovascular benefit," Herrington and colleagues wrote. Not everyone agrees with the team's conclusions.

The women in the study began hormone replacement an average of 23 years after their periods stopped. Estrogen "may not protect against secondary events when initiated so long after menopause," Elizabeth G. Nabel, M.D., of the National Heart, Lung, and Blood Institute in Bethesda, Md., wrote in an editorial accompanying Herrington's report.

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Also, estrogen may "alter the biology of the vessel wall" in ways that lower the risk of having a heart attack but don't show up on an angiogram, she wrote. However, in another large study of women with heart disease, the participants assigned to take estrogen were more likely than placebo recipients to have a heart attack soon after beginning the study, researchers reported in the March 3, 1999, Journal of the American Medical Association. And, the estrogen didn't help with their atherosclerosis.

Even in the Women's Health Initiative, a large, ongoing trial of women free of heart disease, the participants assigned to estrogen were having slightly more heart attacks, strokes and blood clots during the first two years of the study than were placebo recipients.

Herrington and other doctors still think estrogen may help healthy women's hearts stay healthy. "There's reason to be hopeful that that may be true," said Herrington.

Reason for Optimism?

Estrogen looks like a likely crusader for the heart because taking it improves cholesterol scores. It also improves the relationship between "good" HDL cholesterol and "bad" LDL cholesterol, lowers blood pressure, increases the body's sensitivity to insulin, boosts the functioning of cells that line arteries, and increases blood flow to the heart, studies show.

Also, it appears to be estrogen that protects premenopausal women from heart attacks at the time men, who produce only a small amount of estrogen, begin to have their hearts fail. As women reach menopause, around age 51, however, their estrogen levels crash and their rate of heart attacks soar — matching men's by the time women are 65.

Another big reason doctors have viewed estrogen as the heart's superwoman: Healthy women, with no predisposing cardiovascular problems, who take estrogen are much less likely than nonusers to have heart attacks, about 30 observational studies have shown.

But these studies reveal only that women who take estrogen have lower rates of heart attacks, not that the hormone medication protected them, explains Jacques Rossouw, M.D., of the National Institutes of Health in Bethesda, Md. He's acting director of the large Women's Health Initiative study. In those earlier observational studies, researchers followed women who had chosen either to take the drug or to not use it. The researchers didn't assign the medication or a placebo to similar groups of women, as they would in a "clinical" trial.

Indeed, women who opt for estrogen tend to be healthier than nonusers even before starting the drug. Also, women who actually take the medication regularly are "doing a bunch of other things that are keeping them healthy," Rossouw said. They eat a good diet, exercise and watch their weight. Many women, who are prescribed estrogen, never fill their first prescription or they don't stay on the drug for longer than a year, studies show.

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When scientists began designing the Women's Health Initiative, other researchers "didn't even think we should examine the cardiac question," said Rossouw, because they were convinced of estrogen's benefit to the heart. Now many doctors eagerly await the study's findings, due out in 2005.

Take an Accounting

Women need to know whether or not estrogen helps the heart, so they can write an accurate list of its pros and cons before deciding whether or not to use it. The drug helps reduce osteoporosis, and that's high on many women's list of concerns. No one wants to end up with a broken hip or hunched over in pain. But the drug also comes with serious risks and side effects.

In some women, estrogen causes menstrual — like bleeding, headaches, nausea, vaginal discharge, fluid retention, swollen breasts, weight gain, breast tenderness, depression, or blood clots. Because of such side effects, doctors often advise women who have high blood pressure, diabetes, liver disease, blood-clotting disorders, seizures, migraine headaches, gall-bladder disease, or a history of cancer to stay off the medication.

Daughters of mothers who took DES (diethylstilbestrol) during pregnancy are also advised against it. Taking estrogen for more than five to 10 years may increase the risk of developing breast cancer by 40 percent, recent studies show. However, it's not just taking estrogen medication that ups the odds of cancer. A woman's likelihood of getting breast cancer increases two to three percent every year prior to menopause, because of the estrogen her body produces naturally, Rossouw noted.

Early studies suggested that taking progesterone with estrogen throughout the month, instead of for just part of the month, eliminates the breast cancer risk. Whether this is true "remains unresolved," Louise A. Brinton, Ph.D., and Catherine Schairer, Ph.D., from the National Cancer Institute in Bethesda, Md., wrote in the August 9, 2000, Journal of the American Medical Association (JAMA). More researchers need to look into this question, the team notes.

But two studies published in early 2000 pointed out that combining synthetic progesterone with estrogen as hormone replacement therapy for menopausal women actually increased the risk of breast cancer, particularly in thin women thought to be at lower risk for the disease. In the study reported in JAMA in January 2000, the risk of breast cancer was 40 percent higher in women taking combination HRT than in women who had never used hormones. Another study reported in the Feb. 16, 2000, Journal of the National Cancer Institute reached the same conclusions.

What's the Alternative to Hormone Replacement Therapy?

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The cancer statistics, plus the new research on estrogen and the heart, are giving some women "more motivation to say 'well, maybe I don't really need this,'" said Tori Hudson, N.D., a naturopathic physician in Portland, Ore., who specializes in menopause. She recommends that women find alternatives to the traditional menopause medications.

Diane Lehman of McLean, Va., has tried estrogen three or four times, but it always made her feel "weird," she said. "I just know my body doesn't like this stuff." Some women, like Melissa Herman of Bethesda, Md., check out the pros and cons of estrogen and decide to avoid it completely, despite pressure from their doctors to do otherwise. When Herman went through menopause at age 50, her symptoms were mild and no one recommended estrogen medication.

Now at age 59, she's being "bombarded by all this stuff about taking hormones," she said. "My doctor had me frightened that I'd fall over jogging if I didn't take estrogen." But her fear of cancer overrules her concern about osteoporosis. Instead of taking estrogen, she runs, eats a good diet and takes vitamins.

But none of the cardiac research or breast cancer alarms have changed Shirley Waddell's mind. She's staying on the medication. She gets a mammogram every year to screen for breast cancer. She's confident that the estrogen is preventing her from developing osteoporosis, which runs in her family.

Women need to make up their own minds about estrogen, doctors and patients say. "I make decisions for me, and I think all women should make their own decisions," Herman said. "Every woman needs to determine what her benefits and risks are."

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