The Hormone Conundrum
An abrupt end to a major menopause study leaves women as confused as ever
Seven years ago, Mary Lazarus read an ad in her local paper asking for volunteers for a clinical trial of hormone replacement therapy. It was part of the federally funded Women's Health Initiative, and the scientists were looking for postmenopausal women at least 50 years old. "I wanted to do it," says Lazarus, of Millbrae, Calif. "There was so little information on women's health." So she signed up.
Lazarus was just 50 at that time, but she had been taking estrogen since her hysterectomy at age 46. Her gynecologist prescribed the pills to relieve her severe hot flashes and night sweats. To be included in the landmark, 161,000-woman WHI study, she had to go cold turkey for several months to wash her body clean of estrogen. "I got all my symptoms back," she says, but it was a price she was willing to pay for potential payoff ahead.
Those hopes all but came to an end last week when Lazarus opened a letter from officials at the National Institutes of Health. The letter said they were prematurely stopping the estrogen study, which had enrolled 11,000 women. "We have stopped the study in the interest of safety of the study participants," said Barbara Alving, director of the WHI, at a briefing last week. The NIH believes that, based on the data so far, estrogen does not provide the reduction in heart disease that was anticipated and hoped for. Indeed, estrogen therapy is apparently increasing some health risks, especially the risk for stroke. The study did not increase the chance of heart disease or breast cancer, though a separate study revealed a trend toward increased risk of cognitive impairment and dementia. The actual data will be released in April.
This was the second bombshell from the WHI in its long-awaited review of hormone therapy, once believed to be a cure-all for aging women. The first exploded in July 2002, when the NIH stopped the combined estrogen plus progestin trial--the treatment most commonly used by menopausal women who have not had a hysterectomy. The end came after a mountain of data revealed that women on HRT had more invasive breast cancers, heart disease, strokes, and blood clots. That study's positive findings--a reduction in hip fractures and colorectal cancer--did not outweigh the added harm. A New England Journal of Medicine report last week contained a mixed message about HRT and colorectal cancer risk, while another report--showing twice the risk of dementia in the HRT group--cast an even darker shadow over the whole idea of hormone therapy for women. Before the WHI, observational studies of women choosing to take estrogen (usually alone, later combined with progestin) appeared to show that hormones were a fountain of youth. Indeed, hormone pills were credited with reducing heart disease, bone fractures, atherosclerosis, and overall mortality, including deaths from seemingly unrelated causes like accidents and homicide. Hormones were also said to improve mood, skin, hair, sex drive, concentration, and memory. These studies often conflicted on the possibility that estrogen increased the risk of cancer and stroke.
Not surprisingly, estrogen use skyrocketed through the 1970s, until researchers documented that women taking estrogen had four or more times the risk of developing endometrial cancer compared with those who did not use the drug. Estrogen use plummeted until doctors began prescribing another hormone, progestin, to be taken in combination with estrogen. The idea was to mimic women's natural hormonal cycles and eliminate the endometrial cancer risk. By 1999, an estimated 15 million women had prescriptions for hormones.
The WHI study changed all that. Today, according to Wyeth, the company that makes the two bestselling hormone pills, about 8.5 million women use some type of hormone therapy. The vast majority take estrogen, not estrogen plus progestin, and nearly half use Wyeth's Premarin. Clearly, the results of the estrogen-only trial are exceedingly relevant.
The problem is that nobody knows what the results are yet. So stopping the estrogen study is causing a firestorm among researchers. The WHI's Data Safety and Monitoring Board, a group of outside experts in the safety of clinical trials, advised stopping the earlier trial because the data clearly showed the drugs were causing more harm than benefit to women. The safety "boundary" was crossed when a steep increase in invasive breast cancers became evident within five years. "For the estrogen and progestin trial, we basically laid out everything for the world," says Marcia Stefanick, professor of medicine at Stanford University, a lead WHI investigator. But she questions whether the same consensus existed for stopping the estrogen study last week.
The WHI's Alving concedes it did not. No safety boundary was crossed, she says, and indeed the board was divided over stopping the trial. Some members favored sending a letter to the participants describing the stroke risk and allowing the women to decide for themselves whether to continue. That's the route Sharon Lubbers, 60, of Portland, Ore., would have preferred: "Here you are, participating with a long-term commitment. You've invested seven years. I think it would have been better if we had been notified of the results and given the option to continue." She joined the study because she wants her two daughters and six granddaughters to have more information than she had, and she's disappointed it has ended early. "Are they really going to get all the answers they need?" she wonders.
Alving and other officials say yes and that another year of follow-up would not have changed their conclusions. "If you're driving a car and you come to a cliff, do you keep driving and go over the edge?" Alving asks. "This trial was clearly headed to a boundary."
Jacques Rossouw, WHI's project officer, believes strokes were the critical issue. "Stroke is extremely serious. This was a trial to show benefit, and benefit was predicated on a reduction in heart attack. If there is none, and with an increased risk of stroke, then it's important." Though no firm statistics are yet available on the number or the severity of unexpected strokes, WHI officials say there were about as many as in the earlier trial--or eight extra strokes per 10,000 women. That translates to about 6,800 excess strokes per year.
The most intriguing question raised but not answered in the trial is whether estrogen increases breast cancer risk as much as combined HRT. WHI officials say there appeared to be no increase in breast cancer in the seven years of the trial. But some investigators aren't so sure. Stanford's Stefanick believes the different characteristics of the women in the two studies--weight and age, for example--might be obscuring the results. For example, several separate studies have shown that hormones increase breast cancer risk more for thin women as compared with overweight women, presumably because heavier women make more natural estrogen in their fat cells. So the effect of added estrogen in pill form may be less noticeable in terms of increasing breast cancer risk. Says Rossouw: "We're hypothesizing now; this is not known. But it's also possible that the body's own estrogen is a more powerful cancer producer than estrogen pills." He speculates further: "The result may be a `tamoxifenlike effect.' That's how tamoxifen works to retard breast cancer--it binds to the receptors and blocks the body's own estrogen." Investigators will analyze the results in a variety of ways to consider the weight of participants. "It's also possible," Rossouw adds, "that we haven't gone long enough to find the breast cancers."
Then why stop now? Elizabeth Barrett-Connor, a member of the safety monitoring board, believes the answer lies, in part, with the wrath expressed by physicians and drug manufacturers when the earlier HRT study was stopped. "For WHI 1," says Barrett-Connor, professor and chair of the Department of Family and Preventive Medicine, at the University of California-San Diego School of Medicine, "participants were told, a paper was done, physicians were blind-sided, but you could answer the questions." In an attempt to avoid physicians' angry reaction, everyone has been told the study is stopping, but there is no paper and no way to answer the many questions raised. "I expect many of the main purveyors of hormones will like this better," Barrett-Connor adds, "because they have more opportunity to discuss and debate unhampered by the real numbers."
Even when the real numbers are released in April, they'll be preliminary. New interpretations of the earlier HRT trial, published since the July 2002 cancellation, have changed investigators' view about HRT's impact on breast and colon cancer. There was, for instance, a 24 percent increase in breast cancer in women taking combination HRT, compared with those on the placebo. Nearly twice as many women on HRT had abnormal mammograms; increased breast density caused by HRT may explain that difference. What's newly discovered is that the cancers in women on HRT were larger, more advanced, and more likely to involve lymph nodes, leading to speculation that HRT use might result in a less favorable breast cancer prognosis.
Similarly, scientists are revising their interpretations of colon cancer results. One clear benefit seems to be a 44 percent reduction in colorectal cancers, the second leading cause of cancer death in the United States. However, Rowan Chlebowski, a WHI investigator from the Harbor-UCLA Research and Education Institute, recently found that the cancers in the hormone group were more serious: Many involved the lymph nodes--a sign that the cancer had already spread. "Though the numbers are small, these represent terminal cancer," says Chlebowski. While fewer cancers were diagnosed in the HRT group, slightly more women died of them than in the placebo group. In fact, both types of cancers were strikingly similar in HRT users, Chlebowski adds. "The data are consistent with a delay in diagnosis of two of the three most common cancers in postmenopausal women--colon and breast cancer." The final analysis of the results from both trials may not be available for several years.
Last week, Stanford researchers told Mary Lazarus she was among the WHI participants taking estrogen, not the placebo. She feels sad that the trial is over, and just a little nervous waiting for the results. "Still," she says, "I'm glad I did it. I always knew there were risks."
Focusing on Women's Health
The federally funded Women's Health Initiative is one of the largest health studies ever launched. Started in 1991, it eventually enrolled more than 160,000 women. The second and last hormone therapy component was canceled last week owing to concerns about health risks, but these components are still ongoing:
Diet. Researchers are following more than 48,000 women to see the effects of a low-fat, high-carbohydrate diet on breast and colon cancer and heart disease.
Supplements. This study of approximately 45,000 women focuses on the effects of calcium and vitamin D on hip fractures and colon cancer.
Observational study. This long-term study of 93,676 women includes regular health questionnaires as well as blood and genetic work. The goal is to refine current understanding of known disease risks and identify new risks, including genetic markers.
This story appears in the March 15, 2004 print edition of U.S. News & World Report.