December 2001

From University of Southern California

Estrogen holds promise as preventive therapy for cardiovascular disease

Taking estrogen appears to reverse thickening in the arteries of healthy, postmenopausal women, according to a study by researchers at the USC Atherosclerosis Research Unit.

Atherosclerosis—accumulation of plaque in the arteries—decreased in women using unopposed estrogen therapy in the trial, according to Howard Hodis, M.D., principal investigator and associate professor of medicine and preventive medicine at the Keck School of Medicine of USC. The article appears in the Dec. 4 issue of the Annals of Internal Medicine.

The study is the first randomized controlled trial to test estrogen’s effectiveness in preventing atherosclerosis progression in women with no existing heart trouble. Atherosclerosis is the major contributor to life-threatening events, accounting for more than 1.5 million heart attacks and 600,000 strokes every year in the United States, Hodis says, and is the number one cause of death in women.

Women’s own estrogen helps protect them from cardiovascular disease during youth, but as women pass through menopause, that protection evaporates—and the risk mounts for heart attacks or strokes.

"If you can reduce the progress of atherosclerosis, though, that change translates into a reduced risk for heart attacks or strokes," Hodis says. "The idea is to reach women early in menopause, to prevent those cardiovascular events that commonly occur later."

Called the Estrogen in the Prevention of Atherosclerosis Trial (EPAT) the study monitored how much artery walls thickened over two years in 222 healthy postmenopausal women who took unopposed estrogen or a placebo.

Women on estrogen therapy saw their atherosclerosis rate decrease by .0017 millimeters (mm) per year over two years, while artery wall thickness increased by .0036 mm per year over two years in women who took a placebo.

As a guideline, Hodis says, an increase of .033 mm per year translates to a two-to-three-fold increase in risk of events such as heart attacks, and a starting thickness of .8 mm or greater also puts an individual at high risk.

The EPAT trial is one of a number of studies in postmenopausal women to examine the interaction between hormone replacement therapy and cardiovascular disease. Some recent widely publicized studies showed little benefit in using estrogen, but those studies were done in women with existing cardiovascular disease. EPAT participants were free from heart disease and began the estrogen replacement therapy at a younger age than women in previous trials, Hodis notes.

Also, EPAT investigators could compare women who used cholesterol-lowering drugs against women who did not take such medication. Besides taking estrogen or a placebo, all women who started the trial with levels of 160 or higher of low-density lipoprotein (often called LDL or "bad" cholesterol) were put on a cholesterol-lowering medication.

Among the group of women who took no cholesterol-lowering medications in EPAT, those on estrogen therapy had .0147 mm per year slower atherosclerosis progression than those who took a placebo.

Interestingly, women who received both estrogen and cholesterol-lowering drugs had about the same decrease in atherosclerosis progression as women who took cholesterol-lowering drugs alone.

Researchers do not know why the combination of estrogen and cholesterol-lowering drugs does not result in even further atherosclerosis improvement. "But the effects of lipid-lowering drugs are quite powerful," Hodis says. "You’re probably not seeing any effect above that."

Hodis notes that use of unopposed estrogen generally is restricted to postmenopausal women who have had a hysterectomy. Physicians usually recommend that other postmenopausal women use hormone replacement therapy pairing estrogen with progestin instead, to reduce uterine cancer risk. Women considering the therapies should speak with their physician.

Studies are unclear on whether estrogen-and-progestin hormone therapy offers cardiovascular effects similar to unopposed estrogen. The Atherosclerosis Research Unit recently completed the WELL-HART Study, which tested the effects of such therapy in women with existing heart disease, and researchers plan to examine its effects in healthy women as well.

Scientists have a few ideas about how estrogen deters atherosclerosis in healthy women, but the exact mechanism is unknown. A variety of factors, including the amount and type of fat in the diet, blood cholesterol levels, exercise habits, smoking and heredity, contribute to atherosclerosis progression.

Howard N. Hodis, Wendy J. Mack, Roger A. Lobo, Donna Shoupe, Alex Sevanian, Peter R. Mahrer, Robert H. Selzer, Chao-ran Liu, Ci-hua Liu, and Stanley P. Azen. "Estrogen in the Prevention of Atherosclerosis," Annals of Internal Medicine, Dec. 4, 2001, Vol. 135, No. 11.











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