A landmark national study has dealt a heavy blow to the decades-old assumption that women with a uterus stand to benefit from hormone replacement therapy (HRT) during and after menopause. Instead, it found that the combination estrogen-progestin regimen used by millions of middle-aged and older womenan estimated 6 million of them in the United States alonedoes more harm than good.
The study was funded by a National Institutes of Health program called the Womens Health Initiative (WHI). Begun in 1993, it is the first study to put HRT through a placebo-controlled randomized clinical trialthe gold standard for the purposeto examine its risks and benefits in healthy women. Originally scheduled to continue well into 2005, the trial was stopped in early July because, after an average 5.2 years of participant follow-up, 26% more cases of invasive breast cancer were found among those taking the hormone regimen than in women taking a placebo.
The trials 16,608 participants were broadly representative of American hormone therapy users as a whole, explained Marcia Stefanick, Ph.D., of Stanford University, at a news conference held in Washington, D.C., when the studys termination was announced. For one thing, they were healthy, active women who were 50 to 79 years old when they volunteered for the study and "came from a wide variety of backgrounds and circumstances"; about 16% of the participants were minorities, said Stefanick, who chairs the WHI steering committee.
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The trials data showed that increases in the breast cancer rates of the participants on the HRT regimen did not differ by age, ethnicity, or health history. Jacques Rossouw, M.D., WHIs acting director, noted at the news conference that participants on the HRT regimen were at particularly elevated risk if they had used menopausal hormones prior to enrolling in the study. (This was permitted after a 3-month washout period before entering the study.) The implication, he said, is that "the estrogen plus progestin treatment may have a cumulative effect."
The elevation in breast cancer risk did not emerge clearly until several years into the study, which also suggests a cumulative effect. Only after users had been on the hormones for 4 years did the increased risk become evident, and it took another 1.2 years for the trend to become definitive. However, another adverse impact of the regimencardiovascular eventsemerged considerably sooner.
Specifically, the risk of heart attack began to increase in the first year of HRT use in the WHI trial, rose further in the second year, and then persisted. Also in that second year, there were 41% more strokes in the estrogen plus progestin group than in the placebo group, and this increase persisted as well. Moreover, during the first 2 years, the rate of blood clots doubled in the legs of the hormone users and more than doubled in their lungs, a seeming indicator, Rossouw said, that "the process of thrombosis ... may play a role in increasing the risk for heart attack and stroke."
The trial also found that HRT has benefits, albeit fewer than the harms. Compared with the placebo group, the hormone group had a 37% reduction in colorectal cancer risk, a 34% reduction in hip fracture risk, and a 24% reduction in the total risk of fractures. The latter findings, Rossouw noted, provide the first solid evidence of what has previously been taken on faith: that the bone loss prevented by HRT actually translates into fewer broken bones.
Nonetheless, these benefits do not make much of a case for the estrogen-progestin regimen as a hedge against chronic disease, in part because there are alternatives for managing osteoporosis and, more importantly, because fewer women in the WHI trial benefited from the drugs than were harmed by its adverse effects. (See Stat Bite, p. 1118.)
On the other hand, the study found a womans individual risk of being harmed by the estrogen-progestin treatment to be small. The risk of developing breast cancer, for example, was less than one-tenth of 1% per year among those taking the drugs. However, those individual risks add up to eight more breast cancers than otherwise would be expected for every 10,000 women on estrogen and progestin for a year (38 cases per 10,000 women taking HRT, compared with 30 cases per 10,000 women not taking hormones).
Among those same 10,000 women, there would be 7 more cases of heart attack, 8 more cases of stroke, and 18 more cases of blood clots in the lungs and legs each year. The study also found that there would be 6 fewer colon cancers and 5 fewer hip fractures per 10,000 women each year. However, the study was stopped because the serious adverse health events caused by HRT would outnumber those it prevented.
In other words, HRT has not one risk but several, and they run concurrently and thus add up over time. Consequently, given the millions of women who have been on the regimen, it is likelyby conservative estimatesthat many thousands of them have developed or will develop breast cancer or a life-threatening cardiovascular illness as a result.
Although different routes of administration (by skin patch, for example) or lower dose formulations might be more benign, Rossouw cautioned a reporter who asked about them not to count on it. "Until better data are available," he said, "its safest to assume that their risks are more similar than dissimilar to those of the standard dual drug therapy. They (the alternatives) were, after all, designed to achieve the same benefits."
Estrogen-Only Therapy
Would estrogen alonerather than the estrogen-progestin combinationhave fewer adverse effects? Perhaps, but it is not an accepted option for women who still have a uterus because it is known to increase the risk of endometrial cancer (cancer of the uterine lining). Then, too, estrogen without progestinstandard HRT for women who have had a surgical menopausemay prove to have many of the same drawbacks as the dual drug therapy.
Indeed, one week after the combination HRT study was halted, researchers from the National Cancer Institute reported in the Journal of the American Medical Association that long-term use of estrogen-only therapy is associated with an increased risk of ovarian cancer. Although a womans lifetime risk of developing ovarian cancer is relatively low (1.7%), the retrospective cohort study found that women who took estrogen only were 60% more likely to develop ovarian cancer, and the increased risk appeared to accumulate with the number of years a woman took estrogen. Another WHI study, which, like the combination HRT study, is randomized and placebo controlled, is looking at the risks and benefits of estrogen-only therapy in women who have had a prior hysterectomy. However, barring some unforeseen development, it will be another 3 or so years before its results are in.
Studies Continue
During those years, the women who joined the estrogen-progestin trial will no longer be taking their study pills, but the WHI will continue to follow them. This will make it possible to determine the effects over timewhether good, bad, or neutralof discontinuing the regimen and will provide the raw material for further analyses. For example, the data will be combed for the dual hormone regimens impactor lack of iton memory and other cognitive functions and on a number of quality-of-life issues in general.
When finished, Rossouw reported, the total project is expected to have cost about $170 million. The investment should, he and some observers think, quickly pay for itself and then some if for no other reason than that annual sales of the dual hormone therapy have long been in the $1 billion range.
Meanwhile, this study, which was published rapidly with an accompanying editorial in the Journal of the American Medical Association has, understandably, been hailed as a triumph for evidence-based medicine.
The women whose participation made it possible are also being congratulated. Reporters at the press conference were told that the women who volunteered to participate in the trial did so for the benefit of their daughters and granddaughters, as well as countless other women for generations to come.
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