Postmenopausal Estrogen/Progestin Interventions - PEPI


The PEPI trial was a prospective, multicenter, randomized, double-blind, placebo-controlled trial, designed to assess pairwise differences between placebo, unopposed estrogen, and each of three estrogen/progestin regimens on selected heart disease risk factors in healthy postmenopausal women.


In healthy postmenopausal women with no contraindication to hormone therapy, estrogen alone or in combination with a progestin would favorably influence cardiovascular risks as measured by their effect on lipid metabolism, blood pressure, carbohydrate metabolism and coagulation/hemostasis.

Study Design

Study Design:

Patients Enrolled: 875
Mean Follow Up: 3 years
Mean Patient Age: 45-64
Female: 100

Patient Populations:

Women aged 45 to 64 years, with or without a uterus were invited to participate in PEPI. Women were required to be naturally or surgically menopausal. Normal baseline results of mammography and endometrial biopsy were required.


Women with severe menopausal symptoms were excluded, as were women who had used estrogens or progestins within 3 months. Women treated with thyroid hormone who had not been taking a stable dose for at least three months and who did not have a normal TSH level were excluded. Other exclusion criteria were serious illness (e.g., myocardial infarction within 6 months, congestive heart failure, stroke, transient ischemic attack) or contraindication to estrogen, including prior breast or endometrial cancer. Laboratory exclusions included LDL-C ≥ 190 mg/dl, triglyceride level ≥ 500 mg/dl, BMI ≥ 40, SBP ≥ 160 mm Hg, DBP ≥ 95 mm Hg, and fasting plasma glucose ≥ 140 mg/dl.

Primary Endpoints:

HDL-C levels, systolic blood pressure, serum insulin, and fibrinogen.

Secondary Endpoints:

Weight and waist-Hip Ratio, adverse effects (endometrial hyperplasia, endometrial cancer, hysterectomies, breast cancer, other cancers, cardiovascular events, thromboembolic events.

Drug/Procedures Used:

Women were randomized to one of the following treatments in 28-day cycles: (1) placebo; (2) Conjugated Equine Estrogen (CEE), 0.625 mg/day; (3) CEE, 0.625 mg/d plus cyclic medroxyprogesterone acetate (MPA), 10 mg/d for 12 d/month; (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. All medications were taken orally. Women were scheduled to be seen at 3, 6, and 12 months and every 6 months thereafter for a total of 3 years. At every visit, a diary of symptoms, bleeding, medication use, and interim illness was reviewed. Unused pills were returned to assess adherence. Blood pressure and weight were measured. Fasting morning blood was obtained for measurements of lipids and lipoproteins at 6 months and at each annual visit. Blood for insulin and glucose, before and after a glucose tolerance test, and for fibrinogen was obtained at years 1 and 3 of the trial. Physical examination, mammography, and endometrial biopsy were performed annually.

Concomitant Medications:


Principal Findings:

875 healthy postmenopausal women were randomized. Each active treatment group was associated with a significantly greater increment in mean HDL-C levels than placebo (Bonferroni p<0.001). The average increases in HDL-C levels were similar in the CCE (5.6 mg/dl) and the CEE plus MP (4.1 mg/dl) groups and were significantly greater compared to the CEE plus cyclic or continuous MPA groups (1.6 mg/dl and 1.2 mg/dl, respectively, Bonferroni p<0.004). LDL-C levels decreased by an average of 15.9 mg/dl and were significantly different from placebo for all active treatment regimens (p<0.001). triglyceride levels increased comparably in all active treatment groups (from a mean of 98.3 mg/dl to 111 mg/dl) and differed significantly from placebo (p<0.001). There were no differences in blood pressure by treatment assignment. Mean changes in 2-hour insulin did not differ significantly by treatment assignment. Two-hour glucose levels increased significantly in women assigned to active treatment (p=0.1). Fasting glucose levels decreased slightly and significantly in all active treatment groups (p=0.03). Women assigned to placebo had greater increases in fibrinogen than women assigned to active treatment (0.10 g/L vs. -0.02 to 0.06 g/L respectively, all Bonferroni p≤0.02). Women assigned to unopposed estrogen had significantly more adenomatous and atypical hyperplasia (p<0.001) and were more likely to have a hysterectomy during the course of the study.


Among healthy postmenopausal women, estrogen alone or in combination with a progestin improves lipoproteins and lowers fibrinogen levels without detectable effects on post challenge insulin or blood pressure. The high rate of endometrial hyperplasia restricts the use of unopposed estrogen to women without a uterus. The study did not assess clinical outcomes but only four end-points that represent biological systems (HDL-C, SBP, serum insulin, and fibrinogen) related to the risk of cardiovascular disease. The results of the PEPI trial should be interpreted in the context of the newer data from the most recent large related trials (the Women’s Health Initiative trial and the Hormone estrogen/Progestin Replacement Study).


“Effects of Estrogen/Progestin Regimens on heart Disease Risk Factors in Postmenopausal Women: The Postmenopausal Estrogen/Progestin Interventions (PEPI) Trial”. The Writing Group for the PEPI Trial. JAMA 1995; 273: 199-208

Keywords: Progesterone, Progestins, Mammography, Medroxyprogesterone Acetate, Lipid Metabolism, Biopsy, Lipoproteins, Women's Health, Risk Factors, Blood Pressure, Insulins, Hemostasis, Hyperplasia, Estrogen Replacement Therapy, Endometrial Hyperplasia, Carbohydrate Metabolism, Glucose Tolerance Test, Postmenopause, Hysterectomy, Fibrinogen, Triglycerides, Fasting

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