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Am Fam Physician. 2001;64(3):504-506

The apparent cardiovascular benefits of hormone use play a significant role in decisions about the use of hormone replacement therapy (HRT) in healthy postmenopausal women. Although data seem to confirm a long-term coronary benefit, some results are equivocal.

The Heart and Estrogen/progestin Replacement Study and the Nurses' Health Study showed an increased risk for coronary events in women with existing heart disease who are given hormone replacement therapy. A report from the Women's Health Initiative, a randomized, clinical trial of hormone therapy for primary prevention of cardiovascular disease, has also suggested an elevated risk in healthy women. The use of lower dosages than the standard daily dose of 0.625 mg of oral conjugated estrogen seems to reduce the risk of thromboembolism and decrease endometrial hyperplasia. The relation between low-dose estrogen and primary prevention of heart disease and stroke remains unclear. Grodstein and associates followed women taking daily doses of estrogen of less than 0.625 mg in the ongoing Nurses' Health Study.

Episodes of major coronary events, including nonfatal myocardial infarctions and coronary deaths, and strokes were tabulated among more than 70,000 study participants who were followed for up to 20 years. Current use of hormone therapy was associated with an age-adjusted relative risk of major coronary event of 0.54. Little association was found between current use of hormone therapy and risk of stroke. The relative risk of major coronary disease was similar in women taking 0.625 mg and 0.3 mg of estrogen daily. The risk of stroke, however, was increased among women taking the higher estrogen dose. The overall risk of combined cardiovascular disease (major coronary heart disease plus stroke) was reduced more among women taking 0.3 mg of estrogen daily than among those taking the higher daily dose. The reduction in coronary heart disease risk was similar among women taking oral conjugated estrogen alone and those taking estrogen plus progestin. However, a higher risk of stroke was found among women taking estrogen combined with progestin than among those taking estrogen alone. Combining heart disease and stroke end points, a 25 percent reduced risk for cardiovascular disease was found among current users of estrogen alone, but little relation was seen between current use of combined hormone therapy and cardiovascular disease.

In this large, observational, prospective study, the risk of major coronary events appeared to substantially decrease among current users of hormone therapy. A modest increase in stroke risk was found among women taking 0.625 mg or more of conjugated estrogen daily and in those taking estrogen plusprogestin.

The authors conclude that hormone therapy may be associated with coronary benefit and that low dosages of estrogen as well as estrogen combined with progestin may be equally effective in providing these benefits. The risk of stroke, however, is increased with hormone use, and hormone therapy appears to be related to increased risk of breast cancer.

In an editorial in the same journal, Grady and Hulley comment on observational studies. The lack of dose-response or duration-response effects of estrogen use do not support the premise that hormone replacement therapy prevents coronary heart disease. Several randomized, blinded, placebo-controlled studies have found no benefit from postmenopausal hormone therapy in secondary prevention of coronary disease. The Women's Health Initiative, currently in about the third year of a planned nine-year treatment period, is looking at hormone therapy in women without coronary disease. The preliminary results are demonstrating an increased risk of coronary events among the hormone-treated women in the first two years of the trial. The increased risk was seen in women taking unopposed estrogen and those taking estrogen and progestin. Grady and Hulley conclude that despite strong observational evidence from the Nurses' Health Study and others, the results of three recent trials are disappointing and imply that more supportive evidence is needed from randomized trials before hormone therapy is recommended for the prevention of coronary disease in postmenopausal women.

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Copyright © 2001 by the American Academy of Family Physicians.

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