Experts consider HT for younger women

After the release of the July 2002 Women's Health Initiative findings, many women chose to abandon their hormone pills, and many physicians decided to offer other options.

Still, questions not answered by the large randomized controlled trial persist. Most notably, what might the effect of hormone therapy be on the overall health of women who were younger than most of those who participated in the trial?

"The best studies we have on the effect of hormone therapy on cardiovascular disease are from the WHI studies," said Marilyn Schapira, MD, MPH, associate professor of internal medicine at the Medical College of Wisconsin in Milwaukee. "But it was not as revealing with regards to the effects on younger women."

Specifically, WHI participants had an average age of 63 and were several years past menopause. This variable leads some experts to theorize that women in their late 40s and early 50s could reap the cardiovascular benefits that the older women didn't by taking the hormones closer to menopause, before heart disease takes hold.

"When you look at the rest of the body of science, there is a biological plausibility for the theory that started early or right at the time of menopause, there may be some preventive role," said Wulf Utian, MD, PhD, executive director of the North American Menopause Society.

Sorting through data, debate

Researchers have been picking apart the WHI data and that of other studies in a search of clues to determine if changes in dosage or initiation age could salvage the previous promise that hormone therapy could do more than just alleviate menopause symptoms, at least for some women. It's also been the subject of numerous academic papers.

A meta-analysis published in the July 2004 issue of the Journal of General Internal Medicine pooled data from randomized controlled trials of hormone therapy since 1966 and suggested that women younger than age 60 who took hormones had a 39% reduction in total mortality compared to women of a similar age who did not take the drug. No such reduction was seen among those who were older.

"People are starting to look at the data objectively and figure out what we really are supposed to be doing with hormone replacement," said Shelley Salpeter, MD, lead author and clinical professor of medicine at Stanford University School of Medicine. She is also planning additional meta-analyses to investigate the effect on metabolic syndrome and factors related to the development of heart disease.

In the research arena, there are also efforts to replicate the WHI, this time studying a younger cohort on a smaller scale. The Phoenix-based Kronos Longevity Research Institute, a nonprofit group focusing on translational research, announced the selection of eight study centers for its Kronos Early Estrogen Prevention Study, KEEPS, in April 2004. The study will randomize women in transition to receive various combinations of oral or transdermal hormones or placebo and use various imaging strategies to track the development of heart disease.

There are many physicians, however, who are critical of such efforts. Experts point out that the WHI, which involved more than 161,000 women and cost millions, is unlikely to be repeated with a younger study group because the cost is simply too great. Some also question the wisdom of doing a trial when the earlier trial showed the intervention to fail in another age group.

"There's a desire of the health field to understand the effects and risks in younger women, but given our findings in older women, I'm not sure it's worth the resources to conduct another trial, and I'm not sure that ethically one can justify conducting a trial," Dr. Schapira said. "We may just have to accept some uncertainty."

The JGIMstudy also received sharp criticism in a review published in the February issue of Evidence Based Medicine. Commentary authors suggested that the meta-analysis conclusion was a chance finding rather than one worth pursuing.

"This paper was low quality and is not a reason to change any of the recommendations to come out of the WHI," said Bruce Psaty, MD, PhD, an author of the commentary and professor of medicine and epidemiology at the University of Washington School of Medicine, Seattle.

Advocates of hormone therapy's possible additional benefits recognize that there is not yet enough science to actually prescribe it for anything beyond symptom relief at the lowest dose for the shortest duration, an approach in accordance with the recommendations from most medical societies, including the American Medical Association. Rather, this line of research might make this age group more comfortable about taking it.

But the continuing controversy over hormone therapy for younger women highlights one of medicine's great divides. Some doctors readily discarded hormones for all but those who needed symptom relief. Others cling to their unfulfilled promise.

"The Women's Health Initiative is a randomized trial, and you can't ignore it," said Isaac Schiff, MD, chief of obstetrics and gynecology at Massachusetts General Hospital in Boston and chair of the hormone therapy committee of the American College of Obstetricians and Gynecologists. "It's a very emotional subject, but there's no right answer. Because there's no right answer, you have people who are good people but interpret the data in different ways."

The WHI might never provide needed answers about younger women -- no matter how the data are crunched. But the study is expected to produce more findings related to older women. The trial will continue to follow women in both the estrogen-plus-progestin and the estrogen-only branches until 2010. Additional results from parts of the trial examining dietary and other lifestyle interventions are expected before the end of this year.

"The results that we found in the WHI really pertain to that group of women who were studied," said Barbara Alving, MD, WHI director and deputy director of the National Heart Lung and Blood Institute. "The WHI studies are not perfect, but they're going to be the best studies we're ever going to have."