Medical Examiner

Hormonal Imbalances

Why were all those women taking hormones in the first place?

Illustration by Robert Neubecker

How could so many doctors get it so wrong for so long?

This week the Women’s Health Initiative, sponsored by the National Institutes of Health, suddenly pulled the plug three years early on part of its massive study seeking to determine whether hormone replacement therapy for healthy, older women could prevent major chronic illnesses. For years now, women have been told that staying on hormones for the entirety of their post-menopausal lives would keep them living as long as the biblical Sarah while looking as gorgeous as Gwyneth Paltrow. But five years after taking hormones, a small but statistically significant number of women in the study were getting breast cancer, making the researchers conclude it was unethical to continue. In addition, the study revealed that women on HRT, in contrast with those taking a placebo, had more blood clots, strokes, and heart attacks. All this outweighed a corresponding reduction among participants in fractures and colon cancer.

These findings contradicted almost all medical expectations and call into question literally stacks of previous studies. After all, the pharmaceutical manufacturer Wyeth hadn’t provided its drug gratis in the hope that the results would sink its stock price. Most people believed the HRT question was essentially settled; this latest study would offer the final proof. But with an editorial in the Journal of the American Medical Association announcing “Do not use estrogen/progestin to prevent chronic disease,” long-vilified hormone skeptics scored a big win this week.

None of these skeptics is more prominent, less surprised, or has been more attacked than Dr. Susan Love, a researcher, medical activist, and former breast cancer surgeon at Harvard and UCLA. In her 1997 best seller, Dr. Susan Love’s Hormone Book,and in op-eds and speeches, Love has argued for years that routinely prescribing hormones for older women amounts to a conspiracy between Big Medicine and Big Pharmaceuticals to turn a natural process—menopause—into a disease. As she writes in her book, even the phrase “hormone replacement therapy” implies “that you’ve lost something you should get back.” As a consequence, Love had been treated by much of the medical establishment as a dangerous New Age nut who’d forgotten to get out of the menstrual hut in time to take her own estrogen. On the side of the Bigs were seemingly persuasive studies showing that taking HRT was one of the best things older women could do to prevent their number one cause of death: heart disease.

But Love was unconvinced by the supposedly miraculous effect of HRT on the heart and more concerned about the possible devastating effect on the breast. For one thing, most of the studies that showed heart benefits also showed some degree of increase in breast cancer. The heart benefits of such studies were seen to trump the breast cancer risks because heart disease overall kills many more women (a fact Love got wrong in her book). But as she presciently wrote five years ago:

Is it possible that … we will put millions of women on HRT to prevent heart disease and then the Women’s Health Initiative will show that it doesn’t work or, even worse, that the resulting increase in breast cancer is higher than we thought? It certainly is possible and some such as myself think it is even likely.

Love turned out to be right, because she pointed out an essential flaw in the many studies that had found that HRT protects the heart. One of the best known was the Nurses’ Health Study, a huge investigation done at Harvard. The study tracked women’s behavior—did they or did they not decide to take hormones?—and correlated it with their likelihood of contracting subsequent disease. This observational study found that hormone users had about a 50 percent reduction in fatal heart disease (and an increased risk of breast cancer that was, as noted, deemed worth the heart benefits).

But it turns out—and Love called this—finding that taking HRT tends to result in women getting less heart disease is like finding that dating Donald Trump tends to result in women’s hair turning blond. All that was really “proved” in this study was that generally healthy women chose to take hormones in the first place. If you were the type of woman who went to the doctor to get the hormones and faithfully took them, you were also likely to be the type of woman who ate nutritiously, exercised, watched your blood pressure and cholesterol. And it showed that healthy women generally stay healthier than unhealthy ones.

The recommendation to get on hormones and stay there for life was founded on similarly observational studies of voluntary behavior. The Women’s Health Initiative is seen as definitive (and different) because as a clinical trial it took two large matching groups of women from the general population and assigned one group to take the hormones, the other to take a placebo, and watched to see what happened.

There were other ways the hormone-using women may have skewed the results of the earlier observational studies. One was, as Love points out, that because of conflicting data over the decades, until recently women at high risk for heart disease were often not prescribed HRT, just as women at high risk of breast cancer were discouraged from using it. This meant that it’s likely that women at lower risk for these diseases ended up being put on hormones in the first place. That self-selected sampling may have helped overestimate the beneficial effect of hormones on the heart since those most likely to get heart disease weren’t in the hormone-taking group, just as it may have underestimated the deleterious effect of hormones on the breast, because women at high risk of breast cancer were also excluded.

Dr. Deborah Grady, a researcher at the medical school at the University of California San Francisco, has become an estrogen apostate. In 1992 she co-wrote treatment guidelines encouraging widespread, long-term prescription of hormones for prevention of heart disease. This week she told the New York Times of those same hormones pills, “This is a dangerous drug,” and encouraged women to get off HRT. What happened in between? She became co-leader of a large clinical trial, the Heart and Estrogen/Progestin Replacement Study, that was only recently completed. Like the Women’s Health Initiative, Grady’s study was designed to compare two groups of rigorously selected women, in this case to see if older women who already had heart disease did better with hormone treatment or a placebo.

Grady’s expectation was that HERS would give definitive proof to the assumption behind hormone recommendation. But in the first 18 months of this study, 50 percent more of the women on the hormones had heart problems than the control group. So confounding were the results that the researchers had the pills tested to make sure they hadn’t been mixed up, Grady told the Journal of the American Medical Association. At the end of the more than six-year study, there was no difference in the heart problems between the two groups. The women being “treated” were no healthier than the women receiving the placebo.

Love says there was a question lurking in the stacks of all those observational studies: Did hormones make you healthy or did healthier women take hormones? Both HERS and the Women’s Health Initiative study have shown the answer is the latter.

While one part of the Women’s Health Initiative has been terminated, another part—the long-term health effects of estrogen alone on women who have had hysterectomies—will continue. (The hormone progestin is added to estrogen in HRT for women who have their uteruses in order to prevent cancer of the uterine lining.) To date, participants in that part of the study have not shown an increase in breast cancer. The hormone opponents say just wait. Research shows, says Love, that estrogen alone seems less damaging to the breast than the hormone combination. But she doesn’t believe it’s benign. Let this study run long enough, she says, and there will likely be more bad news for the advocates of hormones.