Hot Flash!

A spate of recent studies has linked hormone replacement therapy to a variety of life-threatening side effects, from breast cancer to heart disease. But is this popular therapy for menopausal women as bad as the media makes it out to be? A new report says yes--and no.

Last week, the North American Menopause Society (NAMS) released the results of its thorough examination of hormone replacement in menopausal women. The report clarified how much remains to be learned about this alarming and confusing topic, which has grown even more alarming and confusing over the past 18 months. The experts convened by the NAMS (an organization of researchers who study menopause) reached consensus on some topics--for example, that hormone replacement therapy (HRT) alleviates the uncomfortable and embarrassing hot flashes associated with menopause. But they failed to agree on other issues, such as the appropriate length of treatment. The report concludes with a lengthy list of concerns that require further investigation, a roster that highlights how few firm answers there are to the multitude of questions about HRT.

HRT is an umbrella term that covers a variety of hormone treatments designed to replace the natural sex hormones that wane as a woman ages. Over the past 20 years, these hormone regimens have been widely prescribed not just to treat hot flashes and other symptoms of menopause, but to stave off diseases of aging, including osteoporosis, heart disease, and even dementia. But then studies in the United States and abroad began to uncover associations between HRT and a number of life-threatening disorders. In July 2002, the U.S. National Institutes of Health shut down its Women's Health Initiative (WHI), a large clinical trial of HRT, when the study revealed small increases in the incidences of invasive breast cancer, coronary heart disease, stroke, and pulmonary embolism in women taking Prempro--at that time the most commonly prescribed HRT in the United States. The same group subsequently reported small increases in dementia and memory loss in Prempro users. And last month, the Million Women observational study conducted in the United Kingdom confirmed a link between HRT and small increases in the incidence of breast cancer overall.

The WHI study also revealed some benefit to HRT: Prempro appeared to reduce the risks of hip fracture and colon cancer, for example. But the bad news grabbed the headlines, generating confusion and panic among the 6 million American women who are on HRT--and the millions of women who are trying to make a decision about whether to start it. What these women--and the doctors who treat them--need is a clear explanation of the pros and cons of HRT. Such information would help menopausal women weigh the therapy's risks and benefits and make informed decisions about whether they want to use it.

With its report, the NAMS attempted to bring order to this chaos. However, the researchers who produced the report--some of whom were involved in the WHI and others who were its critics--reached agreement on only a few specific, carefully qualified items. For example, the experts agreed that HRT regimens involving a combination of hormones should not be used to prevent heart disease. Such combination therapies, including Prempro, contain both estrogens and progestins--synthetic hormones that mimic some of the actions of the natural hormone progesterone. Whether estrogen alone might help prevent cardiovascular disease, however, is not yet clear.

The estrogen question is just one item on the report's lengthy "to do" list of research tasks. Additional proposals range from investigating different hormones and HRT formulations to learning, at long last, why hot flashes plague many menopausal women. But the prospects for these research projects are iffy at best, says NAMS Executive Director Wulf H. Utian. "Some of them will get done, and some of them I'd be pessimistic about."

This uncertainty about the future of HRT research is a direct fallout from the negative publicity, which has made women skittish about volunteering for such studies--and funders skittish about supporting them, says Neil MacLusky, scientific director of the Center for Reproductive Science at Columbia University College of Physicians and Surgeons in New York City. "It's a public relations problem," he says. "The data from these trials have been interpreted nonscientifically, and their interpretation has been broadened way beyond the scope of the information actually available." The bad press about the WHI study, for example, has fueled the widespread but erroneous belief that studies have shown that all forms of HRT are always harmful.

The researchers and the media should share the blame for creating these misconceptions about HRT, says Utian. "The way [information] gets presented by the investigators--and sometimes the way it gets interpreted by the media--are grossly exaggerated for effect." For example, the headlines that appeared after the WHI study was terminated said that HRT increases the risk of breast cancer by 26% and the risk of heart disease by 34%. "Of course women went ballistic, because in their minds one in three women is going to get a heart attack and one in four women is going to get breast cancer," says Utian. But in the WHI study, 38 out of 10,000 women taking Prempro developed breast cancer each year, compared to 30 in 10,000 women who did not receive the hormones. Although an increase from 30 to 38 cases does constitute a 26% rise in the number of cancer cases overall, an individual woman's personal risk actually increases from 0.3% (30/10,000) to 0.38% (38 in 10,000).

But bad publicity is not the only problem facing HRT. Critics say that the studies themselves were flawed. The WHI, for example, examined the effects of HRT in women who started the therapy at an average age of 63--well beyond the time when most women commence therapy. "You can't generalize those findings to a 49-year-old," says psychologist Barbara Sherwin of McGill University in Montreal, Canada. Researchers involved in the WHI agree, and so the NAMS report urges additional studies on whether HRT--begun at the onset of menopause--might postpone some of the diseases of aging without promoting cancer or heart disease.

The other problem with the WHI study is that it tested only one combination of hormones, says neuroscientist Bruce McEwen of Rockefeller University in New York City. WHI researchers focused on Prempro because it was by far the most common HRT. But McEwen says they should have tested more natural formulations of female reproductive hormones, such as progesterone and estradiol, the type of estrogen produced by the ovaries. "We need to do more work--not to reject hormone replacement, but to improve it, to make it so it works more like natural hormones," MacLusky says. "That’s the message I hope gets across to the public and the grant-awarding agencies."

The future of HRT research might depend on whether funding agencies get the message. When the WHI study suggested that Prempro increased the risk of memory loss and dementia, the Canadian Institutes of Health Research withdrew their support for MacLusky's studies on whether very low doses of estradiol and progestin can stave off Alzheimer's disease. "All the publicity and the late-night talk shows have created such a negative climate that it's now very difficult to do the research which still absolutely needs to be done," MacLusky laments. And without additional research, the risks and benefits of HRT will remain a mystery, leaving millions of women uncertain about whether these treatments might improve or endanger their health.

Tabitha M. Powledge is a science writer and editor based near Washington, D.C. After the hurricane-induced power failure, she emptied out her fridge and is now undergoing food replacement therapy.