Hormones, Heart, and Cancer

How women use postmenopausal hormones was forever changed about six years ago by the Women's Health Initiative. Rather than seeing hormone replacement as the answer to all female problems of middle age and beyond, doctors now typically prescribe combined estrogen-progestin therapy case by case, in the lowest possible dose for the shortest duration of time, and mainly in that subset of women who cannot otherwise control the debilitating symptoms of menopause. The practice shift came almost overnight, with the WHI findings that combined hormones appear to raise the risk of invasive breast cancer, and increase, at least a little—not decrease—the risk of heart attacks, stroke, and thromboembolism.

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Now, three years after thousands of WHI women stopped their pills cold turkey, a follow-up study published today in the Journal of the American Medical Association reinforces the merit of the 2002 findings. The good news is that the small increase in risk of heart attacks, stroke, and clots in the lung, and the significant increase in clots deep the legs, vanished after stopping the estrogen-progestin pill. On the other hand, the small increased risk of breast cancer among those who had used hormones persisted. Along with this, the women who discontinued drugs lost the protective benefit of the hormones on the risk of bone fractures and colon cancer.

What came as a surprise to researchers this time was an overall increase in cancer risk of 24 percent among those who had taken the estrogen-progestin combination—a risk that was not seen while the women were taking the drugs. But it's important to note that for this broader cancer risk, no one particular cancer showed statistical significance. Before getting too exercised over these new cancer findings, women must realize that this is an aging population of women (many are in their 80s), and new cancer events will continue to increase over time.

Marcia Stefanick, Ph.D. and professor of medicine at Stanford University who chairs the WHI steering committee, says that the 15 percent increased risk in mortality (in which cancer is the major cause of death) among the hormone users—also seen only in the 2.4-year follow-up period—is not conclusive, and she points out that very few deaths were from breast cancer. "It's very important that we continue to follow these women to see if this trend is real," Stefanick cautions. She notes that mortality trend differences are still quite small in absolute terms and might disappear as time goes on. It will take more analysis and follow-up to sort out the effect of hormones on both cancer and mortality, which WHI researchers are now doing.

On the brighter side, Yale gynecologist and hormone researcher Hugh S. Taylor says that, overall, the disappearance of any added cardiovascular risk after stopping the combined hormone treatment should be reassuring to women. He says that, spurred on by the WHI findings, the current practice of using lower doses for shorter times and only in those women who have debilitating symptoms has become the right one. He also stresses that some women do have severe symptoms, in which surges of adrenalin, flushing, anxiety, and disordered sleep can devastate their personal lives and their careers. To them, the small risks that are now becoming clearer may be worth the benefit to their quality of life. Taylor is rightly concerned about sensationalizing risks that are not statistically significant and instilling fear in women who are previous hormone users.

What the follow-up study says for sure, however, is that most deaths in the under-80 population were caused by cancer—not heart disease or stroke—and this is so whether or not women were on hormones. And lung cancer, not breast cancer, accounts for most of the WHI cancer deaths. Why not? Half of the women enrolled in this hormone study are present or former smokers. Beyond hormones, this follow-up carries a strong message for women: Pay attention to prevention and early detection of cancer. That means a healthy lifestyle, a good diet, annual mammograms, and a renewed crusade against smoking.