Postmenopausal Estrogen/Progestin Interventions (PEPI)
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.
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.
Study Design
Allocation: Randomized, Control: Placebo Control, Masking: Double-Blind, Primary Purpose: Prevention
Conditions
Bone Diseases
Intervention
estrogens, conjugated, medroxyprogesterone, progesterone, estrogen replacement therapy
Status
Completed
Source
National Heart, Lung, and Blood Institute (NHLBI)
Results (where available)
Links
- Source: http://clinicaltrials.gov/show/NCT00000466
- Information obtained from ClinicalTrials.gov on July 15, 2010
Medical and Biotech [MESH] Definitions
Estrogen Replacement Therapy
The use of hormonal agents with estrogen-like activity in postmenopausal or other estrogen-deficient women to alleviate effects of hormone deficiency, such as vasomotor symptoms, DYSPAREUNIA, and progressive development of OSTEOPOROSIS. This may also include the use of progestational agents in combination therapy.
Receptors, Progesterone
Specific proteins found in or on cells of progesterone target tissues that specifically combine with progesterone. The cytosol progesterone-receptor complex then associates with the nucleic acids to initiate protein synthesis. There are two kinds of progesterone receptors, A and B. Both are induced by estrogen and have short half-lives.
Estrogens, Esterified (usp)
A pharmaceutical preparation containing a mixture of esterified estrogens derived from estrogen sulfates, principally from ESTRONE sulfate. Esterified estrogen content should be 75-85% of the estrone sulfate and 6-15% of the EQUILIN sulfate.
Estrogens, Conjugated (usp)
A pharmaceutical preparation containing a mixture of water-soluble, conjugated estrogens derived wholly or in part from URINE of pregnant mares or synthetically from ESTRONE and EQUILIN. It contains a sodium-salt mixture of estrone sulfate (52-62%) and equilin sulfate (22-30%) with a total of the two between 80-88%. Other concomitant conjugates include 17-alpha-dihydroequilin, 17-alpha-estradiol, and 17-beta-dihydroequilin. The potency of the preparation is expressed in terms of an equivalent quantity of sodium estrone sulfate.
Receptors, Estrogen
Cytoplasmic proteins that bind estrogens and migrate to the nucleus where they regulate DNA transcription. Evaluation of the state of estrogen receptors in breast cancer patients has become clinically important.
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PubMed Articles
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