Hutch News Stories

New figures in the HRT equation

New Women's Health Initiative studies link ovarian-cancer risks and bone benefits to HRT
Drs. Andrea LaCroix and Garnet Anderson
Drs. Andrea LaCroix (right) and Garnet Anderson, investigators in the Women's Health Initiative, and colleagues found that despite new bone-benefit data, combination-hormone therapy still poses risks for women. Photo by Todd McNaught Photo by Todd McNaught

Two new reports from the Women's Health Initiative (WHI) suggest that combination-hormone-replacement therapy for postmenopausal women may increase their risk of ovarian cancer and decrease their risk of endometrial cancer and bone fractures, though the health risks of the drugs continue to outweigh benefits. Public Health Sciences Division researchers contributed to both studies, which appear in the Oct. 1 issue of the Journal of the American Medical Association (JAMA).

Dr. Garnet Anderson, co-principal investigator of the WHI coordinating center, led an analysis that found that after more than five years of follow-up, estrogen plus progestin increased ovarian cancer rates by 58 percent, although because of the small overall number of cancers that occurred, the increase was not statistically significant. The researchers, including PHS co-authors Dr. Shirley Beresford and Mary Pettinger, also found that combination-hormone therapy decreased rates of endometrial cancer, which affects the lining of the uterus, by 19 percent.

"The existing literature on hormone therapy and ovarian cancer from observational studies is somewhat mixed, with most larger studies pointing to an increased risk with estrogen," Anderson said. "Continuous combined estrogen plus progestin has not previously been linked to ovarian-cancer risk but the data to address this question are very sparse. The WHI provides a unique opportunity to look at this relationship in a randomized, double-blind, placebo-controlled trial that is therefore free of most biases that may influence other study results.

"Nevertheless, the small number of ovarian cancers observed (32 total) means we cannot rule out the possibility that this is a chance finding. What is clear is that this form of hormone therapy does not offer significant hope for prevention of ovarian cancer and hence it does not add anything positive to the risk/benefit profile of combined hormones. Hopefully other studies will help us sort out whether the increased risk is real."

The findings emerged from ongoing analysis of a long-term randomized study of hormone use in postmenopausal women, which was halted last year after evidence emerged that estrogen-plus-progestin therapy was associated with an increased risk of breast cancer, stroke and heart disease.

Risky benefits

The WHI trial involved 16,608 postmenopausal women who had not had a hysterectomy. The women were randomized into two groups ? one that received a placebo and the other a single daily tablet of Prempro, the most commonly prescribed form of combination-hormone therapy. Women who had a prior hysterectomy were randomized to a parallel trial of estrogen alone, which is continuing until 2005.

In 5.6 years of follow-up, the rate of ovarian cancer in women who took a placebo was 27 per 100,000 women per year. With estrogen-plus-progestin use, this rate was increased to 42 cancers in 100,000 women per year. The authors concluded that even if the observed effect is real, ovarian cancer remains a rare disease in women taking these hormones.

Though combined hormones have a slightly protective effect on endometrial cancer, this therapy does not completely prevent the disease. In addition, because women who take the therapy commonly experience vaginal bleeding, women who took continuous combined hormones were subjected to more endometrial biopsies and vaginal ultrasounds. They also were more frequently found to have mild abnormalities in routine Pap smears, a screening test for cervical cancer.

In a second JAMA paper, WHI researchers, including Dr. Andrea LaCroix and Mary Pettinger, report the updated, final analysis of fracture risk and bone density in women who took part in the combination-hormone-therapy randomized trial.

In July 2002, the researchers found that for women randomized to the estrogen-plus-progestin group, hip and clinical vertebral fractures were significantly reduced by 34 percent and total bone fractures by 24 percent.

In the updated analysis, which was led by Dr. Jane Cauley at the University of Pittsburgh, 11.1 percent of women in the placebo group experienced a fracture compared to 8.6 percent of women in the estrogen-plus-progestin group during the follow-up period of 5.6 years, which amounts to a 33 percent reduction of risk associated with hormone use. The combination-hormone therapy also showed consistent positive effects on hip and lumbar spine bone-mineral density.

"Although it seems like we've known about the benefits of estrogen on the bone forever, this is really the first large randomized controlled trial that has been done to determine if combined-hormone therapy reduces the risk of hip and other osteoporotic fractures," LaCroix said. "What is remarkable about the WHI findings is that estrogen plus progestin reduced rates of hip and other fractures profoundly among women who were healthy and predominantly not at high risk of fracture. No other osteoporosis medication has been shown to have such an effect.

"Unfortunately, that benefit has so many risky strings attached that the use of combined-hormone therapy for widespread fracture prevention is not a viable public-health recommendation."

Study continues

Established in 1991 by the National Institutes of Health and funded by the National Heart, Lung and Blood Institute along with private donations to Fred Hutchinson, the WHI is a 15-year, multi-million-dollar study. Nationwide, more than 160,000 women and 40 clinical centers are involved, including one in Seattle that is run jointly by Fred Hutchinson and the University of Washington and coordinated through the PHS division by Dr. Ross Prentice, principal investigator.

The WHI is the largest-ever women's health study and seeks to find ways to prevent cardiovascular disease, osteoporosis and cancer, all of which have a significant impact on women's health.

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