Postmenopausal Estrogen/Progestin Interventions (PEPI)
Condition: Bone Diseases; Cardiovascular Diseases; Coronary Disease; Diabetes Mellitus; Heart Diseases; Hypercholesterolemia; Hypertension; Myocardial Ischemia; Osteoporosis; Thrombosis; Postmenopause
MeSH terms: Osteoporosis; Bone Diseases; Cardiovascular Diseases; Heart Diseases; Thrombosis; Coronary Disease; Myocardial Ischemia; Hypercholesterolemia; Ischemia
Study type: Interventional
Phase: Phase 3

Summary: 
      To assess the effects of various postmenopausal estrogen replacement therapies on selected
      cardiovascular risk factors, including high density lipoprotein cholesterol, systolic blood
      pressure, fibrinogen, and insulin and on osteoporosis risk factors. Conducted in
      collaboration with the National Institute of Child Health and Human Development, the National
      Institute of Arthritis and Musculoskeletal and Skin Diseases, The National Institute of
      Diabetes and Digestive and Kidney Diseases, and the National Institute on Aging. The extended
      follow-up is for 3 years focusing on endometrium and breast evaluation.
    

Detailed description: 
      BACKGROUND:

      The life expectancy of American women is 78 years. More than one-third of those years are
      postmenopausal, during which time the risk of coronary heart disease is increased. The
      current United States estimate of more than 40 million women over the age of 50 indicates a
      large segment of the population at increased risk for coronary heart disease. Heart disease
      accounts for a third of all deaths in 50-69 year old women. In 1978, for example,
      approximately 66,000 of the 210,000 deaths in women 50-69 were attributed to heart disease.

      Premenopausal women have a lower rate of ischemic heart disease compared to men of similar
      age. Surgically induced or natural early menopause increases the risk of ischemic heart
      disease. These facts have focused interest on estrogens as possible mediators of the
      beneficial effects, and pointed to the need for further study of their relationship to
      atherosclerosis risk factors.

      Estimates from the Lipid Research Clinics Program indicate estrogen use in approximately one
      third of postmenopausal women. Analysis of Lipid Research Clinics data confirmed that
      administration of estrogens results in lower plasma low density lipoprotein levels and
      elevated plasma high density lipoprotein levels. Thus, the ratio of high density
      lipoprotein/low density lipoprotein levels is substantially increased. Given the inverse
      relationship between high density lipoprotein levels and coronary heart disease risk, this
      effect of estrogens on the plasma lipoproteins could be expected to further reduce coronary
      heart disease risk in women.

      Although the bulk of currently available evidence suggests benefit, some controversy
      concerning the effects of postmenopausal estrogens on morbidity and mortality from coronary
      heart disease persists. Analysis of the Lipid Research Clinics Follow-up Study population
      indicated a potentially profound beneficial effect of postmenopausal estrogen use. Mortality
      from all causes decreased considerably in postmenopausal estrogen users, and the effect was
      most pronounced in hysterectomized and oophorectomized women. Similar results have been
      observed for cardiovascular deaths. These benefits appeared to be mediated by the higher high
      density lipoprotein levels associated with postmenopausal estrogen use. Framingham data are
      the primary sources reporting possible detrimental effects of postmenopausal estrogen use on
      cardiovascular morbidity; mortality from all cause and cardiovascular disease was not
      reported to vary by use.

      NHLBI convened a Trans-NIH Estrogen Working Group to make recommendations to NHLBI on the
      feasibility of undertaking a clinical trial of the effects of postmenopausal estrogen use on
      cardiovascular disease mortality. The Working Group identified a number of important research
      questions which needed to be answered to elucidate the effects of postmenopausal estrogen use
      on risk factors for cardiovascular disease and osteoporosis. This initiative was the result
      of the Working Group's deliberations and recommendations.

      DESIGN NARRATIVE:

      There were seven clinical centers and a coordinating center in this randomized, double-blind
      clinical trial. The women were allocated to one of five treatment arms: placebo; conjugated
      equine estrogen (CEE), 0.625 milligrams per day; conjugated equine estrogen, 0.625 milligrams
      per day plus cyclic medroxyprogesterone acetate (MPA), 10 milligrams per day for 12 days per
      month; CEE, 0.625 milligrams per day plus consecutive MPA, 2.5 milligrams per day; CEE, 0.625
      milligrams per day plus cyclic micronized progesterone (MP), 200 milligrams per day for 12
      days a month. The four primary endpoints were chosen to represent four biological systems
      related to the risk of cardiovascular disease and included high density lipoprotein
      cholesterol (HDL-C), systolic blood pressure, serum insulin, and fibrinogen. Recruitment
      began in October 1989 and ended in February 1991. Baseline data collected included blood
      pressure, resting heart rate, weight, waist/hip ratios and endometrial biopsy. Laboratory
      evaluations included lipid panel, high density lipoprotein cholesterol, insulin and glucose,
      bone density, fibrinogen, and in three clinics, additional hemostasis factors, renin
      substrate, plasma renin activity, aldosterone, and oral post-heparin lipase activity. All
      women underwent an endometrial aspiration biopsy at baseline and annually thereafter.
      Additional biopsy specimens were obtained if there was noncyclic endometrial bleeding. All
      women also had baseline and annual mammograms. Other data were collected on quality of life,
      exercise, diet, alcohol use, and smoking. Participants were followed at three, six and twelve
      months post-randomization, and at six month intervals thereafter for three years. Post-trial
      analyses of existing data sets were funded for three years by the cooperative agreement
      mechanism beginning August 1, 1994. A three-year safety follow-up funded through the contract
      mechanism began in 1994. It included three annual visits at which endometrial biopsies,
      mammograms, and some limited health information were obtained.

      The study completion date listed in this record was obtained from the "End Date" entered in
      the Protocol Registration and Results System (PRS) record.
    

Intervention name(s): estrogens, conjugated; medroxyprogesterone; progesterone; estrogen replacement therapy
Intervention type(s): Drug; Drug; Drug; Drug
Intervention MeSH terms: Medroxyprogesterone Acetate; Medroxyprogesterone; Progesterone; Estrogens, Conjugated (USP); Estrogens
Allocation: Randomized
Masking: Double
Primary purpose: Prevention