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Hormone Replacement: No Simple Answers

By Amy Tsao What's a woman to do? When it comes to hormone replacement therapy (HRT) for women approaching or in menopause, that lament continues to haunt patients, doctors, and researchers alike.

HRT was first called into question in July, 2002, when to the surprise of almost everyone, a broad clinical trial of estrogen-progestin treatment by the National Institutes of Health had to be halted because the therapy seemed to increase a woman's risks of breast cancer and cardiac problems. Since then, confusion has reigned as experts and women's groups have sparred over the meaning of the Women's Health Initiative (WHI) trials.

Previous studies had suggested that a cocktail of estrogen and progestin would have protective effects against cardiovascular disease. Critics suspect that the WHI study came up with such different results partly because they think it was flawed.

Other questions have been raised, too. The WHI trial was part of a broad initiative to examine many aspects of women's health. The widely prescribed HRT Prempro was given to 16,608 women between ages 50 and 79 and compared with a control group that was given a placebo. Since the trial was stopped last summer, details of more possible problems with Prempro have been streaming out.

DEVILISH DETAILS? It seems to increase the risk of Alzheimer's disease and dementia, according to the initial data. And Prempro didn't provide some of the benefits it was expected to: It was of no use in improving sexual satisfaction and had little impact on overall quality of life.

More bad news could be on that way. This fall, details on bone health in the women who took Prempro are expected. Also coming soon is information on whether the drug increases the risk of endometrial, ovarian, and colon cancer.

Most experts consider the WHI trial a warning, even if an ambiguous one. "The study isn't perfect, but it's the best that has ever been conducted," says Diana Zuckerman, president of the National Center for Policy Research for Women & Families. (Funding for the center is provided by the federal government and foundations, Zuckerman says.)

WRONG POPULATION? Still, dissenters argue that more study is needed before premenopausal women give up on HRT completely. The main problem, they say, is that the average age of women in the WHI trial was 63, which is about 12 years past the age that most women begin HRT. This

isn't the relevant population to study, says Frederick Naftolin, director of the Yale University Center for Research. "We haven't learned from these trials the effect of estrogen plus progestin on symptomatic women close to the age of menopause in terms of [prevention of cardiovascular problems]." (Naftolin says he receives funding from the NIH, Wyeth (WYE), Lilly (LLY), Berlex, and Solvay (SVYSY)).

The WHI trial instead proves that women in their mid-60s or older, who may already be at higher risk for heart attacks and other cardiovascular events, have increased risks when taking HRT, Naftolin contends. He points to previous studies that showed HRT use can help cut the incidence of cardiovascular events like heart attacks by 50%.

Other researchers believe HRT shouldn't be written off based on a test of just one drug, Prempro. In January, the Food & Drug Administration ordered manufacturers of all HRT products, not just Prempro, to change their labeling to warn that long-term use could increase certain risks.

NATURAL ALTERNATIVES. It's unwise to deem all formulations of estrogen-progestin therapies equal, some experts contend. "What I think is sad is that we have ignored pharmacological differences [between different kinds of estrogen and progestin] to the detriment of patients," says Dr. Elizabeth Vliet, a Tucson-based women's health and hormones specialist and author of the book It's My Ovaries, Stupid.

Vliet believes there are natural versions of hormones made by a women's ovaries that are chemically different from the estrogens and progestin in Prempro. As a result they often have more favorable effects on women, she says. (Vliet has no financial interest in any products, hormone or otherwise.)

Although a study as large and costly as the WHI report isn't in the cards anytime soon, many are hoping it won't be the last word on HRT. "People have not stopped studying this," says Naftolin, who's seeking funds for HRT studies of cardiovascular effects in women who are closer to their menopause years. "Some [scientists] changed to other fields because they think it's an area under a cloud. It's harder to get subjects to be involved [in research projects], but we really haven't found evidence that we should stop [researching HRT]."

GETTING WHACKED. With HRT's benefits in such doubt, sales of commercial treatments continue to decline dramatically. Wyeth, which is the dominant company in the field, has seen a worse-than-expected drop in sales of Prempro and other HRT products. The number of American women taking some kind of HRT has fallen from 15 million to 9.2 million since the WHI results hit the news, says Victoria Kusiak, vice-president for clinical affairs at Wyeth.

Kusiak figures the decline in HRT sales is leveling off, but analysts expect it to continue. Prempro sales have already dropped from $888 million in 2001 to $637 million in 2002, and Bernstein Research analyst Richard Evan expects that fall an additional 46% this year, to $346 million. Premarin, Wyeth's estrogen, is also getting whacked. Sales climbed 4% to $1.2 billion in 2002, but Evans expects a reversal of 26% this year, to $914 million.

Physicians, perhaps fearful of possible lawsuits, are looking for safe ground. HRT is the single most effective option for treatment of menopausal symptoms such as hot flashes, sleeplessness, and vaginal dryness and burning. For women with severe symptoms, many doctors will likely still prescribe HRT for short periods.

TOUGH CHOICE. Some other treatments under consideration by doctors include so-called selective serotonin reuptake inhibitors, a class of antidepressants that includes Pfizer's (PFE) Zoloft and GlaxoSmithKline's (GSK) Paxil and that is thought to help alleviate menopause symptoms. Low-dose hormones are another option, as are plant estrogens. An herb called black cohosh has also shown some evidence of relieving menopausal symptoms. However, none of these alternatives have gone through rigorous clinical testing.

Researchers are making promising progress. Some companies, including Wyeth, are working on what's known as selective estrogen receptor modulators. Similar to Eli Lilly's Evista, these drugs would be used to treat and prevent osteoporosis but also might help alleviate menopausal symptoms. Several companies are also working on patch, cream, and gel formulations of HRT in various doses, using varying hormones.

To help women understand the issues and options, the FDA recently released a list of guidelines for patients. Ultimately, it's up to each woman to cull through all the conflicting data and opinions and come up with her own personal balance of risk and benefit. However, the evidence -- imperfect as it is -- now suggests that HRT is mainly for those with severe menopausal symptoms. Tsao covers the pharmaceutical and biotechnology industries for BusinessWeek Online in New York

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