NEWS

NIH Workshop Tries to Create Consensus on HRT Use

Judith Randal

A little of the dust has settled since the July 9 news about the use of combined hormone replacement therapy (HRT) during and after menopause: Long-term use may increase a woman’s chances of becoming chronically ill. (See News, August 7, p. 1116.)

But that has not dampened interest in the landmark study that yielded those results—a 16,608-woman randomized trial that was funded by the National Institutes of Health as part of its Women’s Health Initiative (WHI). The trial pitted Prempro (a combined estrogen-progestin pill made by Wyeth) against a placebo. When NIH held a workshop on its campus in October in reaction to the study, some 500 scientists, clinicians, women’s health advocates, regulatory officials and others showed up to discuss its ramifications.

(The workshop dealt only with issues raised by the WHI’s Prempro trial, which enrolled women with a uterus. A second WHI study of estrogen replacement therapy is ongoing for women who have had a hysterectomy.)

A concern that several attendees voiced was that the average age of the women in the trial was 63—much higher than the average age of a woman going through menopause. Gynecologists in the audience, in particular, seized on this to allege that the older-than-average mean age could have caused the study to overstate the cardiovascular risks that HRT posed, and thus, they asserted, unfairly damage the therapy’s previous reputation as being good for women’s hearts. In fact, the allegation—common in gynecologic circles—stemmed from an apparent misperception: that women younger than age 60 were underrepresented in the trial.

Actually, the study enrolled roughly equal numbers of women in their 50s, 60s, and 70s. As importantly, the size of the trial was large enough to allow for an analysis of the outcome data by decade of life.

In none of the three age groups, it turned out, was the presumed cardioprotective effect of HRT confirmed, and in all age groups, the hormone users—regardless of race or health history—had more heart attacks, strokes, and blood clots than the controls as well as more breast cancer. The controls, to be sure, had more fractures and more cases of colon cancer than the hormone users, but on balance the non-users still had fewer serious adverse health effects.

A number of the workshop’s presenters, like Marcia Stefanick, Ph.D., of Stanford University, made a point of telling the workshop attendees that the study had shown that an individual woman’s absolute risk of injury from estrogen-progestin HRT is low. On the other hand, said Stefanick, who is an WHI principal investigator, "if the benefit [of estrogen-progestin HRT] was as great as the medical community had been led to believe, the women in the control group should have been at a considerable disadvantage ... ." In fact, the study showed that the women in the placebo group were better off without the hormone therapy.



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Dr. Marcia Stefanick

 
HRT won U.S. Food and Drug Administration approval for the relief of hot flashes and certain other menopausal symptoms in 1942, and nothing that does the job as well has come along in the 60 years since. Therefore, many physicians are inclined, despite the WHI findings, to prescribe the hormones for however long it takes—usually a year or two, but sometimes longer—for a patient’s menopausal symptoms to subside on their own.

Doctors do so, however, on the assumption that, because the typical woman entering menopause is in her early 50s, she is least likely to be harmed by the hormones. But Marian Limacher, M.D., a WHI investigator at the University of Florida College of Medicine in Gainesville, warned the workshop that to believe that assumption is, in effect, to ignore the trial’s results.

For one thing, she noted, it was the women ages 50 to 59, the trial’s youngest cohort, who had the greatest degree of excess relative risk compared with their age-matched controls. For another, the study also found that the rate of adverse cardiovascular events (heart attack, stroke, and blood clots) rose within 1 to 2 years of starting menopausal hormone use—well within the time span that hot flashes often persist. (By contrast, the excess risk of invasive breast cancer began to appear about four years after the initiation of menopausal hormone use.)

There was much talk at the workshop about identifying subgroups of women who could confidently be expected to be spared HRT’s detrimental effects, enabling them to use it with impunity at menopause. WHI investigators hope that further analysis of the trial data will be a step toward making it possible to individualize the regimen. But Deborah Grady, M.D., an epidemiologist at the University of California at San Francisco, is reserving judgment on that score. "The dilemma now," she told the conference, "is ...[that we have no way to tell] who’s at too much risk to take hormone replacement therapy."

Some at the workshop maintained that lower oral doses of estrogen and progestin or dose delivery by skin patch or vaginally could be expected to be safer than and at least as effective as the regimen used in the trial, and that other options—such as 17-beta estradiol instead of the conjugated equine estrogen in Prempro as well as a different form of progesterone—might also alter the outcome. These hypotheses, however, are unproven.

In fact, there are other combination HRT products that have FDA approval for the relief of menopausal symptoms in addition to Prempro. The obvious question, therefore, is how they stack up against the Wyeth product, especially in terms of safety. However, Janet Woodcock, M.D., who heads the FDA’s Center for Drug Evaluation and Research, said that the information that could answer this question does not exist because the ingredients of the alternative products differ in key ways from those in Prempro. For example, Prempro contains medroxyprogesterone acetate, a synthetic hormone. The other products are compounded with different and often natural forms of progesterone.

The reality, in other words, is that no matter what the potential pharmaceutical alternatives to Prempro—whether or not they are already on the market—each of them would likely have to be put through a large and lengthy controlled trial to prove long-term safety. Also a concern voiced at the workshop is that further menopausal hormone trials may present such vexing ethical and practical problems that they could be difficult and perhaps impossible to mount.

Indeed, just that sort of handwriting seemed already to be on the wall when news came from London during the NIH workshop that an English HRT trial very similar to the WHI trial had just been cancelled. Although difficulty in recruiting enough women for the trial was not the only reason Britain’s Medical Research Council called off its $32 million study, it was surely one of them.

Meanwhile, the U.S. Preventive Services Task Force, a group of independent experts that exists to advise the federal government on health matters, has issued a guideline that "recommends against" the use of dual hormone therapy for the prevention of chronic disease.

Similarly, other expert groups have cautioned that if the therapy is used to combat menopausal symptoms, it should be prescribed at the lowest effective dose for the shortest possible time. There is, besides, a school of thought that says that menopausal women with a uterus should seriously consider foregoing the hormones unless their symptoms are severely incapacitating them.

But perhaps the workshop’s most heartfelt words about HRT were spoken by Susan Hendrix, D.O. "Women are more than just their hormones," said Hendrix, a WHI investigator at Wayne State University in Detroit. "It’s important to realize that we can’t take a pill for the rest of our lives to make us young again. ... Disappointing, but true. That was the message of this (the WHI) trial."



             
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