NEWS

Few Alternatives As HRT `Fountain of Youth' Runs Dry

James Schultz

Once touted as the preferred means of banishing the worst ravages of menopause, hormone therapy—often referred to as hormone replacement therapy (HRT)—has fallen on hard times. Within the past 2 years, several major studies have revealed that, outside of reducing menopausal symptoms, HRT conveys more risk than benefit in terms of disease prevention.

The latest setback came in late June, with the publication of results from the Women's Health Initiative (WHI) Memory Study in the Journal of the American Medical Association. According to the study, the routine use of estrogen-alone HRT among older women could lead to a greater risk of developing dementia, including Alzheimer's disease, compared with women who do not use any menopausal hormone therapy. In the wake of the report, Judith A. Salerno, M.D., deputy director of the National Institute on Aging, urged women to "follow the Food and Drug Administration's recommendation that those who want to... control their menopausal symptoms should use [estrogen] at the lowest effective dose for the shortest time necessary."

Despite the popularity of herbal and other remedies, effective, medically vetted replacements to counter the worst effects of menopause have yet to debut. "We thought hormone therapy was the fountain of youth," said Jennifer Hays, Ph.D., director of the Center for Women's Health at the Baylor College of Medicine in Houston. "It was not. It's very good for vaginal tissue. But it's not good for other systems in the body."

Hays was one of several presenters at this year's annual meeting of the American Society of Clinical Oncology (ASCO) who discussed the effect of recent studies of HRT on clinical practice. The most recent data comes from the WHI, which was the first to put HRT through a placebo-controlled, randomized clinical trial to assess the risks and benefits of long-term administration in healthy women. Originally scheduled to continue well into 2005, the arm of the trial looking at combination estrogen–progesterone was stopped by early July 2002 when researchers found an increased risk of breast cancer, along with increased risks of heart disease, stroke, and blood clots, and determined that these risks outweighed the benefits of reduced risks of hip fracture and colorectal cancer.

The estrogen-only arm of the study was halted at the end of February because of an elevated risk of stroke among women taking the drug. They also found that estrogen-only HRT had no effect on coronary heart disease risk, nor did it have a clear impact on the risk of breast or colorectal cancer, although the risk of hip and other fractures was reduced.

Another recent study that has unveiled adverse risk increases among HRT users is a Swedish trial called HABITS (Hormonal Replacement Therapy After Breast Cancer: Is It Safe?), run by Lars Holmberg in Uppsala, Sweden. HABITS was among several studies originally designed to assess the efficacy of HRT among breast cancer survivors. The trial was stopped in December 2003—3 years ahead of schedule—because of an unacceptably high risk of recurrent breast cancer.

By the time the study was halted, 434 breast cancer survivors had been enrolled and randomly assigned to an HRT group or a non-HRT group. Those who took HRT were further subdivided to receive estrogen only, continuous estrogen–progesterone, or sequential estrogen–progesterone. In the median 2-year follow-up period, trial organizers discovered 26 new breast cancers, five deaths, and eight serious adverse events. In the non-HRT arm, there were only seven cases of breast cancer, four deaths, and four adverse events.

"To me, it's fascinating that after all these years of using hormone replacement therapy with what would seem to have been some pretty good observational studies, we've had this big wake-up call," said Kathleen Pritchard, M.D., a breast cancer expert and professor of medicine at the Toronto-Sunnybrook Regional Cancer Centre in Toronto. "In randomized trials, which are the most appropriate and robust design, the results weren't what we thought. It's clear that combined HRT is associated with increased rate of breast cancer events. It doesn't seem useful, at least in the combined form, in reducing cardiovascular or cognitive events."



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Dr. Kathleen Pritchard

 

Immediately following the termination of the WHI's combination HRT trial, there was a 66% drop in women taking estrogen-plus-progesterone and a 33% drop in women taking estrogen only, Hays said. The latest findings from the estrogen-only trial may spur additional declines, as the word spreads and women elect not to pursue estrogen and/or progesterone courses to relieve menopausal difficulties.

"The crux of the problem right now for many women is how to balance quality-of-life needs with adverse outcomes," Hays said. "Twenty-five percent will remain asymptomatic. Others are miserable into their 70s. I would love to see research on safer hormones and on better alternatives."

Antidepressants may be of value, as may taking estrogen alone in small subdermal doses that would bypass the liver and thus reduce the threat of blood clots. Aerobic exercise and yoga both appear to have some benefit, reducing the incidence and severity of hot flashes. Select plants and herbs may help as well. But these alternatives, although enthusiastically embraced by some, have yet to be scheduled for assessment in any large-scale clinical trial.

"What can we do for the [menopausal] patient with a previous diagnosis of breast cancer, or any kind of cancer? What we do for those who are cancer free: dress in layers and carry a fan," Pritchard said. "Seriously, though, I think we need to maximize the alternative approaches we have. They need to be put forward strongly."



             
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