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…Back to Menopause
At about this time, Seaman says, New York gynecologist Robert Wilson was writing about hormones for a different use. In 1966, he published his best seller, Feminine Forever, in which he claimed that estrogen supplements might keep women forever young. This sparked the term "estrogen replacement" (ERT) therapy, in which postmenopausal women would simply "replace" what they had lost with time and therefore maintain their femininity. Drug companies such as Wyeth-Ayerst, looking for new markets for their estrogen-based drugs, seized the idea. By 1975, Seaman says, Wyeth-Ayerst's Premarin (which is formulated from the urine of pregnant mares, hence the drug's name), became the fifth-leading prescription drug in the United States.

Corfman tells an anecdote about Premarin. "It's an old drug that goes back to the '40s," he says. Apparently chemists had to formulate a heavy varnish coating to keep the pills from dissolving too soon in the stomach. Otherwise, "when a woman burped, she might detect what the drug was made of," Corfman says.

With promises of relief from menopausal symptoms (see sidebar) and a fountain of youth to boot, menopausal women began taking pills and suffering fewer hot flashes, crying jags, and other symptoms.

Then a glitch occurred. Two major studies, published in 1975 in the New England Journal of Medicine (NEJM), confirmed that estrogen supplements could increase by 14 times a woman's risk of cancer of the lining of the uterus–the same cancer that had killed Seaman's aunt 16 years earlier. Drug sales fell. In response, Seaman explains, physicians and pharmaceutical companies crafted another strategy–combining estrogen with another hormone, progesterone, thus producing what is now known as "hormone replacement therapy" (HRT). Progesterone generates a menstrual period and thereby counters the increased cancer risk of estrogen supplementation used alone.

By the 1980s, Seaman says, doctors were singing the praises of hormones for postmenopausal women. Based on a dozen studies that showed the benefits of HRT, physicians, backed by drug companies, advocated that it would also lower the risk of heart disease, osteoporosis, and potentially Alzheimer's disease. The companies did receive approval from the FDA to promote HRT for the prevention of osteoporosis, as well as menopausal symptoms, Seaman says, but never for the prevention of heart disease, stroke, or Alzheimer's.

One NEJM study, conducted on 122,000 nurses and published in 1985, showed that estrogen could halve the risk of heart disease. Yet, in that same issue, a second equally powerful study predicted that hormones would increase, and, in fact, double a postmenopausal woman's risk of heart disease, particularly among women who smoked.

The latter, however, was "the road not taken," says medical oncologist Rowan Chlebowski of the Harbor UCLA Research and Education Institute in Torrance, California.

Seaman says it was no mystery; drug companies and the medical community suppressed the negative in favor of the positive results. Em-ploying what Seaman views as "science by press release," Wyeth-Ayerst, backed by other HRT providers, asked the FDA in 1990 to approve Premarin as a preventer of heart disease. The NWHN objected to the request, pointing to the negative studies, including those demonstrating that estrogen-related drugs could aggravate the risk of breast cancer.

Whether pro or con, the studies at this point were less than state-of-the-art. In what scientists called "observational" trials, tens of thousands of women had chosen to take hormones (or not) on their own and then report on their health in surveys. This approach, taken for both NEJM trials, was far from the gold standard, because other factors could have skewed the results–some women taking hormones might have fared better at the end of the study for reasons other than the drugs.

Despite this weakness, says Seaman, an advisory committee for the FDA voted to change Premarin's label to add claims of protection against heart disease. The FDA, nudged along by Corfman, then did a rare thing: it overrode its own committee's recommendation and asked for a stronger study–a double-blind, placebo-controlled, clinical trial.

Not long afterward, the NIH started the Women's Health Initiative (WHI), a large clinical trial on women's health that involved approximately 16,600 postmenopausal women randomly assigned to take either sugar pills or the most widely prescribed estrogen and progesterone combination, Prempro. This was by far the largest drug study of this type ever undertaken. Presumably confident of a positive outcome, Wyeth provided pills for the trial for free.

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