It was back in 1966 that Robert Wilson, MD, a Brooklyn gynecologist, published his best-selling book, Feminine Forever, and declared that taking estrogen was a postmenopausal woman's best chance to lead a healthy, happy, and sexually active life. In the ensuing decade, prescriptions for the hormone almost doubled. But then came evidence that taking estrogen could lead to uterine cancer, and prescriptions dropped off dramatically.

Hormone therapy regained its popularity, however, after the discovery that adding progestin headed off the risk of uterine cancer. In the early 1980s, scientists began to focus on how estrogen could protect women's bones against osteoporosis. By the '90s, research seemed to confirm its long-suspected link to preventing heart disease, at which point the American Heart Association and the American College of Physicians came onboard. Once again, hormone therapy looked like a smart idea.

But in 2002, the Women's Health Initiative caused scientific whiplash. According to its findings, the hormone pills in question—Prempro, the most popular brand of estrogen and progestin—not only failed to protect against heart disease but actually raised the risk. Crunching the data, the researchers projected that among 10,000 women taking these hormones for a year, compared with a placebo, there would be seven more cases of coronary heart disease, eight more cases of stroke, and 18 more cases of blood clots. "There was much rending of clothes and gnashing of teeth when this study came out, because the results were very unexpected," says Nanette Santoro, MD, director of reproductive endocrinology and infertility at Albert Einstein College of Medicine, in the Bronx.

Less shocking but more unnerving for many: Among 10,000 women on Prempro, there would also be eight additional cases of invasive breast cancer. (The fact that there was a lower risk of colorectal cancer and hip fractures got lost in the shuffle.)

The WHI findings made major headlines and were particularly scary to the public, given that researchers stopped the study three years early to protect participants' health. Women by the millions threw out their hormone pills. And seven years later, many are still wary. "I can understand the mistrust," says Carla Lupi, MD, an assistant professor of clinical obstetrics and gynecology at the University of Miami Miller School of Medicine. "These women grew up being told that hormone therapy was the greatest thing since sliced bread, only to wake up and be told that there actually are some risks."

Unfortunately, scientists have yet to unearth a more effective remedy than estrogen, and that may reflect what's been a relatively narrow approach to the profound mind-body shifts that occur during menopause. "All of this focus on estrogen may be a bit misplaced," says Lisa Sanders, MD, clinical instructor at Yale University School of Medicine. "Women exist in an incredibly complicated hormonal milieu during menopause. Estrogen declines, but so does testosterone, which is why libido goes down. We're also losing hormones that we really don't know much about, and we haven't asked the questions."

The fact is, however, researchers do know a lot more about hormone therapy today. Since the WHI shake-up, they have begun to explore—and shed light on—how the formulation and timing of HT may lower its risks and improve its benefits. And the result is a more nuanced knowledge of how the treatment might be most safely applied. 

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