This proposal contains plans for a Stanford Clinical Center to participate with six other centers and a Coordinating Center in the operation of the Postmenopausal EStrogen/Progestin Interventions (PEPI) program. This is a collaborative randomized clinical study, in a total of about 1050 recently menopausal women, of the effects of various estrogen replacement therapies upon risk factors for cardiovascular disease (in particular, plasma lipoproteins and related entities) and osteoporosis, and upon endometrial status. The trial will last for five years, including three years of interventions, and a final protocol will be developed by the study Steering Committee. The Stanford PEPI will contribute approximately 150 perimenopausal women aged 45-55 with an intact uterus, who have no prior history of estrogen treatment or of major systemic disease. Suitable, consenting participants will be randomized in a double-blind manner, in the Stanford proposed design, into one of six estrogen treatment groups and two placebo-control groups. Measurements of the cholesterol content of plasma lipoproteins and high-density lipoprotein subfractions, apolipoproteins A-I and B, post-heparin lipases, bone densities, blood pressure, endometrial status (biopsy), gallbladder status (ultrasonography), and a variety of behavioral parameters, and probably many other health-related variables, will be made by standardized procedures at baseline and after three months, one year, two years, and three years of drug/placebo therapy. Women will be seen at the clinic at three- month intervals to monitor adherence and to dispense pills or transdermal patches, according to treatment group. Major issues of cardiovascular and bone disease risk to be studied, each related to important therapeutic decisions which must be made every day by practicing physicians, include: the beneficial effect of estrogens on the lipoprotein and osteoporosis risk profile; the deleterious effect of estrogens on endometrial hyperplasia; the negative effects of progestins on the lipoprotein and osteoporosis profile, despite their preventive effect on endometrial hyperplasia; and issues of acceptability and compliance by women of optimal treatments, identified by multi-risk analysis. These are major public health concerns which urgently need resolution.