Scientists Are Sharply Divided Over Hormone Therapy for Menopausal Women

By Anita Slomski
Special to The Washington Post
Tuesday, May 12, 2009

On July 9, 2002, investigators in charge of the Women's Health Initiative, the largest, most ambitious examination of menopausal women, abruptly stopped one part of the study three years ahead of schedule. They took this unusual step after finding that a routinely prescribed combination of two hormones, estrogen and progestin, was making many women more susceptible to heart attack, stroke, breast cancer and blood clots.

At that time, 40 percent of menopausal women in the United States were receiving hormone therapy, largely to protect them from cardiovascular disease. But when the results came out, Isaac Schiff, chief of Massachusetts General Hospital's Vincent Obstetrics and Gynecology Service and editor of the journal Menopause, gave some blunt advice: "If you're taking hormone therapy to protect your heart, get off the drugs now."

Millions of women did, including those whose primary motivation was to relieve the distressing symptoms -- from hot flashes and night sweats to reduced libido -- that afflict 80 percent of women entering menopause. Within a year, U.S. prescriptions for Prempro, the combination drug tested in the WHI trial, had plummeted and researchers in Australia, Britain and New Zealand had canceled a major hormone therapy trial that was about to begin.

That sudden shift in attitudes toward hormone replacement therapy was only the latest pendulum swing that has made it so tricky for women to figure out what to do.

"In the early 1970s, estrogen was considered the fountain of youth, but by the middle of that decade, it had been identified as a cause of endometrial cancer," says Schiff. "Then we added progestin to estrogen because it protected against endometrial cancer, and hormone therapy was terrific again. Through the 1980s and '90s, people thought it would prevent all sorts of diseases, including colon cancer, even though there was a suspicion it might cause breast cancer. Finally, the WHI threw cold water on hormone therapy. I'm not aware of any other medications for which advice has swung back and forth so strongly and so often."

Once again scientists are sharply divided over whether, and to what degree, hormone therapy should be rehabilitated. In the seven years since the WHI dropped its bombshell, the study's results have been endlessly analyzed, with detractors wondering how a single randomized, controlled trial, even one as mammoth as this, could have negated dozens of observational and epidemiological studies that showed estrogen reduced women's heart disease risk by as much as 50 percent.

"A misunderstanding of the WHI results has turned off so many women and their physicians from hormone therapy," laments Frederick Naftolin, director of reproductive biology research and co-director of menopause medicine at New York University School of Medicine. "And there may be a price to pay. Women may die prematurely from heart disease and suffer unnecessarily from fractures or diabetes because they or their doctors didn't want to consider estrogen."

A Matter of Timing?

Naftolin and other estrogen researchers have become interested in a "timing hypothesis": that if hormones are prescribed promptly at menopause, they'll have the beneficial effect the WHI study seemed to disprove. These scientists fault the WHI for enrolling women who were many years past menopause, whereas the earlier observational studies that showed positive heart effects from hormone therapy used newly menopausal women.

"The women in the earlier research took hormone therapy when they started experiencing symptoms of menopause," says S. Mitchell Harman, director and president of Kronos Longevity Research Institute, a sponsor of one of two randomized controlled trials testing the timing hypothesis. "In the U.S., that's at age 51, on average. But the women in WHI had an average age of 63 -- 12 years past the onset of menopause -- when they started taking these drugs."

Other scientists consider the WHI findings definitive and use lipid-lowering statins to curb women's cardiovascular risks and bisphosphonates to slow the development of osteoporosis, another condition that accelerates after menopause. But additional research and further shifts in the advice for women seem almost inevitable.

Estrogen is one of several chemicals secreted by a woman's endocrine glands, principally the ovaries, starting in puberty. Because estrogen is essential to readying the body for pregnancy, its production falls off when ovulation stops. But it also has a profound effect on other parts of a woman's body, from the heart and the brain to the blood vessels, the liver, the urinary tract and the digestive system. It keeps skin smooth and promotes cell growth that keeps bones strong and breasts firm.

All those benefits cease when a woman's ovaries virtually end the output of estrogen. "The transformation, within a few years, of a formerly pleasant, energetic woman into a dull-minded but sharp-tongued caricature of her former self is one of the saddest of human spectacles," wrote gynecologist Robert Wilson in his 1966 bestseller, "Feminine Forever." Today those words sound shockingly impolitic, but no one questions the profound nature of menopausal changes.

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