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A cancer preventive // a cause of cancer // the fountain of youth // a heart attack in a pill // a relationship saver // a stroke stoker // a treatment on which the jury is still out.

Yes. No. Maybe.

by Anita Slomski // Photographs By Ramona Rosales // Spring 2009
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hormone replacement therapy

On July 9, 2002, investigators in charge of the Women’s Health Initiative, the largest, most ambitious examination of menopausal women, abruptly stopped one arm of the study three years ahead of schedule. They and the National Institutes of Health, which provided funding, also took the unusual step of releasing preliminary trial results to the public. At the time, two out of five menopausal women in the United States were receiving hormone therapy, largely to protect them from cardiovascular disease. But the results of the WHI study’s randomized clinical trial demonstrated that the routinely prescribed combination of two hormones, estrogen and progestin, was actually making many women more susceptible to heart attack, stroke, breast cancer and blood clots. That day, when reporters asked Isaac Schiff, chief of the Vincent OB/GYN Service at the Massachusetts General Hospital and editor of the journal Menopause, what women should do in light of the findings, his advice was clear: “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 four out of five women entering menopause. Within a year, U.S. prescriptions of Prempro, the combination drug tested in the WHI trial, had plummeted 52%, and researchers in Australia, Britain and New Zealand had canceled a major hormone therapy trial that was about to begin.

That sudden shift was only the latest and most dramatic change in the prevailing attitude toward hormone therapy. Several times during its 80-year history, physicians and their patients have alternately embraced and rejected this approach to supplementing the ovaries’ production of estrogen, which falls off drastically at menopause. “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 clinical 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%. “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.”

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—a demographic that didn’t match the newly menopausal participants in previous observational studies that had shown a positive cardiac effect from hormone therapy. “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 new 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. “With evolution of the data since WHI, it is clear that hormone therapy still hasn’t been given the scientific justice it deserves,” says Howard N. Hodis, director of the atherosclerosis research unit at the University of Southern California.

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Hormone Therapy’s Moving Target


For nearly 100 years, different opinions on hormone replacement therapy have caused its use to ebb and flow.

The Cancer Question

There’s little doubt that hormone therapy affects a woman’s risk of malignancies. But that’s where the clarity ends.

New Fuel for the Hormone Therapy Debate

Attitudes towards hormone therapy have shifted toward a more nuanced approach.


“Can Menopausal Hormone Therapy Prevent Coronary Heart Disease?” by Eliot A. Brinton, Howard N. Hodis, George R. Merriam, S. Mitchell Harman and Frederick Naftolin, Trends in Endocrinology & Metabolism, August 2008. The authors make the case for the timing hypothesis, citing meta-analyses of randomized trials that show cardioprotective effects of hormone therapy in women younger than 60.

Hot Flashes, Hormones, and Your Health: Breakthrough Findings to Help You Sail Through Menopause, by JoAnn E. Manson with Shari S. Bassuk (McGraw Hill, 2007). The consumer-oriented title belies a serious approach to the topic: Manson, a Women’s Health Initiative investigator, interprets the confounding results of the trial.

The Estrogen Elixir: A History of Hormone Replacement Therapy in America, by Elizabeth Siegel Watkins (The Johns Hopkins University Press, 2007). Watkins artfully tells the fascinating story of hormone therapy, which was influenced as much by science as it was by the rise of feminism and the medicalization of menopause.

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