For older women, estrogen was a wonder drug. The hormone not only relieved menopausal symptoms such as hot flashes and mood swings, but also prevented bone loss, heart disease and memory problems. Better yet, it endowed many of those who took it with youth and vigor.
At least, that's what everybody thought.
Over the past two years, estrogen's reputation has plummeted. Two large-scale clinical studies by the National Institutes of Health were called off early when researchers decided that hormone replacement therapy increased the risk of stroke and heart disease -- the very ailments it was thought to prevent.
An article in last week's Journal of the American Medical Association confirmed the bad news. The study's leader, National Heart, Lung, and Blood Institute director Dr. Barbara Alving, said hormone replacement therapy (HRT) does not prevent chronic disease, and should only be used for menopausal symptoms on a short-term basis and as a second-line drug for bone loss.
The latest study "is the final nail in the coffin," said Dr. Lori Mosca, director of preventive cardiology at New York Presbyterian Hospital.
So what happened? How could so many scientists and doctors have been so wrong?
Those involved say it was human error: Researchers and practitioners relied on believable but flawed evidence, and put too much faith in appealing but unproven theories.
Critics say other human failings -- greed and naivete -- also played a role. They blame drug companies for overselling hormones and doctors for buying into the hype.
Women have been taking estrogen since the 1930s, when scientists first distilled it from the urine of pregnant mares (which remains a key source). Over the decades, researchers uncovered a mountain of evidence that estrogen could stave off a range of ailments in menopausal women.
"Lots of people were looking at the pill as a fountain of youth," said Garnet Anderson, a biostatistician at the Fred Hutchinson Cancer Research Center in Seattle and a lead investigator in the two halted studies.
But much of the support for HRT's preventative properties came from so-called "observational" evidence. In these studies, scientists compared women who were on HRT with others who weren't. Although seemingly balanced, this research contained a huge flaw, scientists say.
The key problem: Women who take estrogen tend to be significantly healthier than those who don't, even before they start the therapy. On average, they are wealthier, take better care of themselves and are more likely to get early care for medical problems. As a result, positive effects that seem to come from estrogen might actually stem from the overall health disparity between the groups.
The NIH study, known as the Women's Health Initiative (WHI), was set up differently. It was a randomized clinical trial, which is less prone to bias than an observational study.
WHI researchers randomly split a pool of similar subjects into equal groups, then gave estrogen therapy to one and a placebo to the other. This approach ensured that both groups started out equally healthy and allowed scientists to accurately gauge the preventative effects of hormone therapy.
The WHI trial, which included more than 16,000 women, came up with very different results than earlier studies.
In 2002, NIH abruptly ended a portion of the study because the therapy increased risk for strokes, heart attacks and possibly dementia.
This study looked at a combination of estrogen and progestin, another hormone. (Estrogen raises uterine cancer rates; progestin offsets this risk.)
Last month, NIH stopped another segment of the study, this one involving estrogen alone, which is taken by women who have had hysterectomies. The findings showed women on estrogen had a slightly higher risk of stroke.
The negative results -- particularly the 2002 announcement -- startled millions of women, many of whom had been taking estrogen to prevent a variety of ailments. Estrogen use in the United States dropped significantly, from about 15 million women in 2000 to 10 million today, according to a recent study.
Among those cutting back was 49-year-old Linda Vinson, a retired sales manager who lives in Stevenson. She had a hysterectomy in 1998 and has been on estrogen ever since. But she has reduced her dosage by two-thirds. "There's no reason to take a medicine if you don't need it," she said.
The negative results also stunned researchers. "Anybody who's honest will say they were surprised," said Mosca. She thinks the mistake will change the way medical science is practiced. "The great lesson we learned from this is the critical importance of randomized trials in humans," she said.