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Estrogen therapy in younger postmenopausal women linked to less plaque in arteries

June 21, 2007

Experts caution that heart disease effects remain unclear

New results from a substudy of the Women's Health Initiative (WHI) Estrogen-Alone Trial show that younger postmenopausal women who take estrogen-alone hormone therapy have significantly less buildup of calcium plaque in their arteries compared to their peers who did not take hormone therapy. Coronary artery calcium is considered a marker for future risk of coronary artery disease.

Results of the WHI Coronary Artery Calcium Study are published in the June 21, 2007, issue of the New England Journal of Medicine. The WHI is sponsored by the National Heart, Lung, and Blood Institute (NHLBI) of the National Institutes of Health.

"These new results offer some reassurance to younger women who have had a hysterectomy and who would like to use hormone therapy on a short-term basis to ease menopausal symptoms," noted Elizabeth G. Nabel, M.D., NHLBI director. "We must emphasize, however, that these findings do not alter the current recommendations that when hormone therapy is used for menopausal symptoms, it should only be taken at the smallest dose and for the shortest time possible, and hormone therapy should never be used to prevent heart disease."

The new findings are from an ancillary study of 1064 women who were 50-59 years of age at the start of the WHI hormone therapy clinical trial. Participants were randomly assigned to either 0.625 milligrams per day of conjugated equine estrogens (Premarin™) or placebo (inactive pill). Participants took assigned medication for an average of nearly seven and one-half years. After slightly more than one year after treatment ended, researchers used computed tomography (CT scan) to measure the level of calcium plaque in the women's coronary arteries. Those who had taken estrogen were 30 to 40 percent less likely to have measurable levels of coronary artery calcium compared to those on placebo.

"Although our findings lend support to the theory that estrogen may slow early stages of plaque build-up in the coronary arteries, estrogen has complex effects and other known risks," said JoAnn Manson, M.D., chief of Preventive Medicine at Harvard's Brigham and Women's Hospital and lead author of the paper. "The results are consistent with our earlier findings that younger women treated with estrogen had a trend toward fewer heart attacks but, for an individual woman, it remains uncertain whether the benefits of estrogen would outweigh the risks. For this reason, estrogen should not be used for the express purpose of preventing cardiovascular disease, but it may be appropriate for the short-term treatment of moderate-to-severe hot flashes or night sweats among recently menopausal women."

In February 2006, WHI researchers reported that among the women in the estrogen-alone trial who were 50-59 years of age at study entry, women in the estrogen group had a non-significant trend towards lower rates of heart attacks compared to the placebo group, and significantly fewer women in the estrogen group required procedures to re-open clogged arteries. There was no suggestion of cardiovascular benefit in women who were 60 years or older.

"Heart attacks are uncommon among younger women, and the more relevant question is about long-term benefit as women grow older," noted Jacques Rossouw, M.D., chief of the NHLBI Women's Health Initiative Branch. "Conducting a clinical trial that would start any form of hormone therapy on postmenopausal women at a younger age and follow them for decades - when they would be more likely to have heart attacks - is not feasible.

"We cannot assume that any possible short-term, cardiovascular benefit from hormone therapy to postmenopausal women in their fifties would extend into older ages if they were to continue using hormones," Rossouw cautioned. "We already know that starting hormone therapy in older women increases their risk of heart disease. And long-term hormone therapy has other risks such as strokes and blood clots, and, with the use of combination therapy, breast cancer."

The WHI is a major, 15-year research program designed to address the most frequent causes of death, disability, and poor quality of life in postmenopausal women: cardiovascular disease, cancer, and osteoporosis. The principal findings from the WHI hormone therapy trials, which studied 27,347 postmenopausal women on estrogen-alone or estrogen plus progestin, found that the overall risks of hormone therapy outweigh the benefits. Both of these trials were stopped early because of increased health risks and failure to prevent heart disease, a key question of the studies. Even though the risks for coronary heart disease were less pronounced in the estrogen alone trial than in the estrogen-plus-progestin trial, both therapies increased the risk of stroke and of blood clots.

Overall, the estrogen-alone study involved 40 clinical centers and 10,739 generally healthy postmenopausal women ages 50-79 who did not have a uterus. The clinical trial was stopped in February 2004 after approximately 7 years of follow up because of increased risk of stroke and no reduction in risk of coronary heart disease. The study also found an increased risk of blood clots.

The estrogen-plus-progestin study (conducted in postmenopausal women with a uterus) was stopped in 2002 due to an increase in breast cancer. Like estrogen-alone, combination hormone therapy was also found to increase the risk of stroke and blood clots regardless of the women's age or time since menopause. Combination therapy was also found to increase the risk of heart disease in the first few years.

All women who wish to lower their risk of heart disease should make healthy lifestyle choices, such as following a diet low in sodium, saturated fat, transfat and cholesterol; maintaining a healthy weight; engaging in regular physical activity; and not smoking. In addition, they should work with their healthcare provider to identify and manage other known risk factors such as high blood pressure, high blood cholesterol, and diabetes.

NIH/National Heart, Lung and Blood Institute