EFFECTS OF ESTROGEN OR ESTROGEN PROGESTIN REGIMENS ON HEART-DISEASE RISK-FACTORS IN POSTMENOPAUSAL WOMEN - THE POSTMENOPAUSAL ESTROGEN/PROGESTIN INTERVENTIONS (PEPI) TRIAL/

Objective.-To assess pairwise differences between placebo, unopposed e strogen, and each of three estrogen/progestin regimens on selected hea rt disease risk factors in healthy postmenopausal women. Design.-A 3-y ear, multicenter, randomized, double-blind, placebo-controlled trial. Participants.-A total of 875 healthy postmenopausal women aged 45 to 6 4 years who had no known contraindication to hormone therapy. Interven tion.-Participants were randomly assigned in equal numbers to the foll owing groups: (1) placebo; (2) conjugated equine estrogen (CEE), 0.625 mg/d; (3) CEE, 0.625 mg/d plus cyclic medroxyprogesterone acetate (MP A), 10 mg/d for 12 d/mo; (4) CEE, 0.625 mg/d plus consecutive MPA, 2.5 mg/d; or (5) CEE, 0.625 mg/d plus cyclic micronized progesterone (MP) , 200 mg/d for 12 d/mo. Primary Endpoints.-Four endpoints were chosen to represent four biological systems related to the risk of cardiovasc ular disease: (1) high-density lipoprotein cholesterol (HDL-C), (2) sy stolic blood pressure, (3) serum insulin, and (4) fibrinogen. Analysis .-Analyses presented are by intention to treat. P values for primary e ndpoints are adjusted for multiple comparisons; 95% confidence interva ls around estimated effects were calculated without this adjustment. R esults.-Mean changes in HDL-C segregated treatment regimens into three statistically distinct groups: (1) placebo (decrease of 0.03 mmol/L [ 1.2 mg/dL]); (2) MPA regimens (increases of 0.03 to 0.04 mmol/L [1.2 t o 1.6 mg/dl]); and (3) CEE with cyclic MP (increase of 0.11 mmol/L [4. 1 mg/dL]) and CEE alone (increase of 0.14 mmol/L [5.6 mg/dL]). Active treatments decreased mean low-density lipoprotein cholesterol (0.37 to 0.46 mmol/L [14.5 to 17.7 mg/dL]) and increased mean triglyceride (0. 13 to 0.15 mmol/L [11.4 to 13.7 mg/dL]) compared with placebo. Placebo was associated with a significantly greater increase in mean fibrinog en than any active treatment (0.10 g/L compared with -0.02 to 0.06 g/L ); differences among active treatments were not significant. Systolic blood pressure increased and postchallenge insulin levels decreased du ring the trial, but neither varied significantly by treatment assignme nt. Compared with other active treatments, unopposed estrogen was asso ciated with a significantly increased risk of adenomatous or atypical hyperplasia (34% vs 1%) and of hysterectomy (6% vs 1%). No other adver se effect differed by treatment assignment or hysterectomy status. Con clusions.-Estrogen alone or in combination with a progestin improves l ipoproteins and lowers fibrinogen levels without detectable effects on postchallenge insulin or blood pressure. Unopposed estrogen is the op timal regimen for elevation of HDL-C, but the high rate of endometrial hyperplasia restricts use to women without a uterus. In women with a uterus, CEE with cyclic MP has the most favorable effect on HDL-C and no excess risk of endometrial hyperplasia.