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Progestin use did not attenuate the cardiovascular protective effects of postmenopausal estrogen therapy

ACP J Club. 1997 Jan-Feb;126:22. doi:10.7326/ACPJC-1997-126-1-022

Source Citation

Grodstein F, Stampfer MJ, Manson JE, et al. Postmenopausal estrogen and progestin use and the risk of cardiovascular disease. N Engl J Med. 1996 Aug 15;335:453-61.



To determine the association between estrogen alone or combined with progestin and cardiovascular disease in postmenopausal women.


Population-based cohort study of women (Nurses' Health Study), with a follow-up of ≤ 16 years.


United States.


59 337 postmenopausal nurses were enrolled in 1976 when they were between the ages of 30 and 55 years. Exclusion criteria were stroke, myocardial infarction (MI), angina, or cancer at baseline or at the start of each 2-year period. Follow-up data to 1992 were available in > 90% of the cohort.

Assessment of risk factors

Questionnaires were sent every 2 years and medical records were obtained to gather data on cardiovascular risk factors and other serious illnesses. Hormone use was ascertained at baseline and updated every 2 years. Hormone use was categorized as never used, used in the past, and currently used.

Main outcome measures

Major coronary heart disease (non-fatal MI and death from coronary disease), total stroke (fatal and nonfatal stroke, ischemic stroke, and subarachnoid hemorrhage), and coronary surgery or angioplasty.

Main results

584 nonfatal MIs, 186 deaths from coronary disease, 572 strokes (285 ischemic events, 155 subarachnoid hemorrhages, and 132 other or unspecified types), and 553 instances of coronary surgery or angioplasty occurred. Multivariate analysis was done to adjust for age, time interval, age at menopause, body mass index, diabetes, high blood pressure, high cholesterol levels, cigarette smoking, past oral contraceptive use, parental history of MI before 60 years of age, and type of menopause. Compared with women who had never used postmenopausal hormones, women who currently used estrogen alone or combined with progestin had a reduced risk for major coronary disease (relative risk [RR] for estrogen alone, 0.60, 95% CI 0.43 to 0.83; RR for combined estrogen and progestin 0.39, CI 0.19 to 0.78). Total stroke occurrence did not increase with use of estrogen alone (RR 1.27, CI 0.95 to 1.69) or with estrogen and progestin (RR 1.09, CI 0.66 to 1.80). When the estrogen dose was taken into account, only the 0.625-mg dose reduced the risk for coronary heart disease (RR 0.53, CI 0.36 to 0.78). The beneficial effect was no longer significant 3 years after estrogen use was discontinued.


In postmenopausal women, major coronary events were reduced by current use of estrogen alone or with progestin. Neither regimen resulted in an increase in strokes.

Source of funding: National Institutes of Health.

For article reprint: Dr. F. Grodstein, Channing Laboratory, 181 Longwood Avenue, Boston, MA 02115, USA. FAX 617-731-1541.


Much of the data regarding the risks and benefits of hormone replacement therapy were generated from women who had used estrogen alone. Because unopposed estrogen causes endometrial cancer, most women who use replacement hormones now also take progestins. Because progestins raise low-density lipoprotein cholesterol and decrease high-density lipoprotein cholesterol, the cardioprotective effect of the combined regimen has been questioned.

The new data from the Harvard Nurses' Health Study help to confirm what had been previously suspected: The protective effects of estrogen against coronary artery disease are preserved when progestins are added. Although this effect was only significant for the 0.625-mg dose of conjugated estrogen, the 0.3-mg dose (RR 0.57, CI 0.28 to 1.16) and the 1.25-mg dose (RR 0.82, CI 0.51 to 1.33) may also be cardioprotective. A decrease in cardiac events appears to be the most important benefit of estrogens in terms of overall reduction of morbidity and mortality, but the decrease in osteoporosis is also important (1).

Combined hormone replacement therapy did not protect against stroke. At the lower doses of 0.3 and 0.625 mg/d, it also did not increase risk. However, a trend toward increased risk was seen for cerebrovascular events at doses of conjugated estrogen of ≥ 1.25 mg (RR 1.86, CI 0.59 to 5.90). This finding, and the increased risk for stroke at contraceptive doses of estrogen (approximately 6 times more potent than 0.625 mg of conjugated estrogen), suggest that the effect of estrogen on cerebrovascular disease varies with dose.

This study adds cardioprotection to the potential benefits of combined hormone replacement therapy (1). The small increase in risk for breast cancer after 5 years of combined (or estrogen only) therapy, the patient's health status, and her preferences are other important factors in considering this treatment.

Margretta Diemer, MD
Walter Reed Army Medical CenterWashington, DC, USA

Margretta Diemer, MD
Walter Reed Army Medical Center
Washington, DC, USA


1. Grady D, Rubin SM, Petti DB, et al. Hormone therapy to prevent disease and prolong life in postmenopausal women. Ann Intern Med. 1992;117:1016-37.