This Article  • References  • Full text PDF  • Send to a friend  • Save in My Folder  • Save to citation manager  • Permissions  Citing Articles  • Citation map  • Citing articles on HighWire  • Contact me when this article is cited  Related Content  • Similar articles in JAMA  Social Bookmarking   What's this?

The Postmenopausal Estrogen/Progestin Interventions (PEPI) Trial

Writing Group for the PEPI Trial; Howard L. Judd, MD; Irma Mebane-Sims, PhD; Claudine Legault, PhD; Carol Wasilauskas, MS; Susan Johnson, MD; Maria Merino, MD; Elizabeth Barrett-Connor, MD; Jose Trabal, MD; Valery T. Miller, MD; Vanessa Barnabei, MD; Ginny Levin, MPH.; Trudy Bush, PhD; David Foster, MD; Howard Zacur, MD; J. Donald Woodruff, MD; Marcia Stefanick, PhD; Peter D. Wood, DSc, PhD; Allison Akana, PA; W. Leroy Heinrichs, MD; Katherine O'Hanlan, MD; Howard L. Judd, MD; Richard P. Buyalos, MD; Gail Greendale, MD; Kathy Lozano, RNP; Elizabeth Barrett-Connor, MD; Mary Lou Carrion-Petersen, RN; Carmella Cavero, RN; Robert Langer, MD; Helmut G. Schrott, MD; Jo Ann Benda, MD; Charles deProsse, MD; Deborah Fedderson, RN; Susan R. Johnson, MD; Jose Trabal, MD, MPH; Carl J. Pauerstein, MD; Mohammad M. Ahmad, MD, PhD; Herbert P. Brown, MD; Robert S. Schenken, MD; Mercedes Rodriguez-Sifuentes, RN; Philip T. Valente, MD; Mark Espeland, PhD; H. Bradley Wells, PhD; Kathy Lane; Claudine Legault, PhD; Carol Wasilauskas, MS.; Irma L. Mebane-Sims, PhD; Joseph Kelaghan, MD; Joan McGowan, PhD; Judith Fradkin, MD; Sheryl Sherman, PhD; Maria Merino, MD; Robert Scully, MD

JAMA. 1996;275(5):370-375.

Abstract
Objective.
—To report the histological findings of the endometrium of postmenopausal women who were randomized to receive placebo, estrogen only, or one of three estrogen plus progestin (E+P) regimens in the Postmenopausal Estrogen/ Progestin Interventions (PEPI) Trial.

Design.
—A 3-year multicenter, randomized, double-masked, placebo-controlled trial.

Participants
—A total of 596 postmenopausal women aged 45 through 64 years without contraindication to hormone therapy.

Intervention.
—Participants were randomized and stratified in equal numbers to one of the following treatments in 28-day cycles: placebo, 0.625 mg/d of conjugated equine estrogens (CEE), 0.625 mg/d of CEE plus 10 mg/d of medroxyprogesterone acetate (MPA) for the first 12 days, 0.625 mg/d of CEE plus 2.5 mg/d of MPA, or 0.625 mg/d of CEE plus 200 mg/d of micronized progesterone (MP) for the first 12 days.

Outcome Measure.
—Histology of endometrium collected at baseline, annual, or unscheduled visits by biopsy, curettage, or hysterectomy.

Analysis.
—Intention to treat.

Results.
—During follow-up women assigned to estrogen alone were more likely to develop simple (cystic), complex (adenomatous), or atypical hyperplasia than those given placebo (27.7% vs 0.8%, 22.7% vs 0.8%, and 11.8% vs 0%, respectively) for the same types of hyperplasia (P<.001). Participants administered one of the three E+P regimens had similar rates of hyperplasia as those given placebo (P=.16). The occurrence of hyperplasia was distributed evenly across the 3 years of the trial. Women taking estrogens alone also had more unscheduled biopsies (66.4% vs 8.4%; P<.001) and curettages (17.6% vs 0.8%; P<.001) than women receiving placebo. The number of surgical procedures was similar for women receiving placebo and women receiving the E+P regimens (P=.38). Of the 45 women with complex (adenomatous) or atypical hyperplasia, study medications were discontinued in all, and the biopsy results of 34 (94%) of 36 women with hyperplasia reverted to normal with progestin therapy. The remainder had dilatation and curettage (n=2) or hysterectomy with (n=2) or without (n=6) prior medical therapy, or refused further biopsies (n=1). One woman developed adenocarcinoma of the endometrium while receiving placebo.

Conclusions.
—At a dosage of 0.625 mg, the daily administration of CEE enhanced the development of endometrial hyperplasia. Combining CEE with cyclic or continuous MPA or cyclic MP protected the endometrium from hyperplastic changes associated with estrogen-only therapy.

(JAMA. 1996;275:370-375)

Author Affiliations
principal investigator; The Johns Hopkins University, Baltimore; Stanford University, Palo Alto, Calif; University of California, Los Angeles; The University of California, San Diego; The University of Iowa, Iowa City; The University of Texas Health Science Center, San Antonio

From The Writing Group for the PEPI Trial.

Footnotes
A list of the members of The Writing Group for the PEPI Trial appears at the end of this article.

Dr Judd has received honoraria from Wyeth-Ayerst Laboratories, Philadelphia, Pa, producers of Premarin.

Reprint requests to National Heart, Lung, and Blood Institute, National Institutes of Health, 2 Rockledge Centre, Suite 10193, 6701 Rockledge Dr, MSC 7956, Bethesda, MD 20892-7956 (Irma Mebane-Sims, PhD).

CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    Twitter     What's this?

THIS ARTICLE HAS BEEN CITED BY OTHER ARTICLES

Endometrium protection and acceptability of nasally administered continuously combined hormone therapy: a multicentre, multinational, double-blind trial in post-menopausal women evaluating three regimens of 17{beta}-estradiol and norethisterone when compared with an orally administered 17{beta}-estradiol norethisterone regimen
Rozenberg et al.
Hum Reprod 2009;24:1739-1747.
ABSTRACT | FULL TEXT  

Dehydroepiandrosterone replacement therapy in older adults: 1- and 2-y effects on bone
Weiss et al.
Am. J. Clin. Nutr. 2009;89:1459-1467.
ABSTRACT | FULL TEXT  

Primary Ovarian Insufficiency
Nelson
NEJM 2009;360:606-614.
FULL TEXT  

Hormone-dependent effects of FGFR2 and MAP3K1 in breast cancer susceptibility in a population-based sample of post-menopausal African-American and European-American women
Rebbeck et al.
Carcinogenesis 2009;30:269-274.
ABSTRACT | FULL TEXT  

A multi-center, randomized, double blind placebo-controlled trial of estrogens to prevent Alzheimer's disease and loss of memory in women: design and baseline characteristics
Sano et al.
Clin Trials 2008;5:523-533.
ABSTRACT  

Conjugated Equine Estrogens and Colorectal Cancer Incidence and Survival: The Women's Health Initiative Randomized Clinical Trial
Ritenbaugh et al.
Cancer Epidemiol. Biomarkers Prev. 2008;17:2609-2618.
ABSTRACT | FULL TEXT  

Risk of Complex and Atypical Endometrial Hyperplasia in Relation to Anthropometric Measures and Reproductive History
Epplein et al.
Am J Epidemiol 2008;168:563-570.
ABSTRACT | FULL TEXT  

Estrogen plus Progestin and Risk of Benign Proliferative Breast Disease
Rohan et al.
Cancer Epidemiol. Biomarkers Prev. 2008;17:2337-2343.
ABSTRACT | FULL TEXT  

Progestin Treatment Induces Apoptosis and Modulates Transforming Growth Factor-{beta} in the Uterine Endometrium
Rodriguez et al.
Cancer Epidemiol. Biomarkers Prev. 2008;17:578-584.
ABSTRACT | FULL TEXT  

Pharmacogenetic Modulation of Combined Hormone Replacement Therapy by Progesterone-Metabolism Genotypes in Postmenopausal Breast Cancer Risk
Rebbeck et al.
Am J Epidemiol 2007;166:1392-1399.
ABSTRACT | FULL TEXT  

Progesterone receptor modulators and the endometrium: changes and consequences
Horne and Blithe
Hum Reprod Update 2007;13:567-580.
ABSTRACT | FULL TEXT  

Hormone therapy in menopausal women with cognitive complaints: A randomized, double-blind trial
Maki et al.
Neurology 2007;69:1322-1330.
ABSTRACT | FULL TEXT  

Endometrial bleeding
The ESHRE Capri Workshop Group
Hum Reprod Update 2007;13:421-431.
ABSTRACT | FULL TEXT  

Novel Perspectives for Progesterone in Hormone Replacement Therapy, with Special Reference to the Nervous System
Schumacher et al.
Endocr. Rev. 2007;28:387-439.
ABSTRACT | FULL TEXT  

Management of Menopausal Symptoms
Grady
NEJM 2006;355:2338-2347.
FULL TEXT  

Case-Control Study of Postmenopausal Hormone Replacement Therapy and Endometrial Cancer
Strom et al.
Am J Epidemiol 2006;164:775-786.
ABSTRACT | FULL TEXT  

Molecular and Pathologic Aspects of Endometrial Carcinogenesis
Hecht and Mutter
JCO 2006;24:4783-4791.
ABSTRACT | FULL TEXT  

Estrogen sulfation genes, hormone replacement therapy, and endometrial cancer risk.
Rebbeck et al.
JNCI J Natl Cancer Inst 2006;98:1311-1320.
ABSTRACT | FULL TEXT  

Regression of Latent Endometrial Precancers by Progestin Infiltrated Intrauterine Device
Orbo et al.
Cancer Res. 2006;66:5613-5617.
ABSTRACT | FULL TEXT  

Combined Analysis of Women's Health Initiative Observational and Clinical Trial Data on Postmenopausal Hormone Treatment and Cardiovascular Disease
Prentice et al.
Am J Epidemiol 2006;163:589-599.
ABSTRACT | FULL TEXT  

Levonorgestrel intrauterine system (LNG-IUS) with conjugated oral equine estrogen: a successful regimen for HRT in perimenopausal women
Hampton et al.
Hum Reprod 2005;20:2653-2660.
ABSTRACT | FULL TEXT  

Combined Postmenopausal Hormone Therapy and Cardiovascular Disease: Toward Resolving the Discrepancy between Observational Studies and the Women's Health Initiative Clinical Trial
Prentice et al.
Am J Epidemiol 2005;162:404-414.
ABSTRACT | FULL TEXT  

Endometrial Carcinoma Risks among Menopausal Estrogen plus Progestin and Unopposed Estrogen Users in a Cohort of Postmenopausal Women
Lacey et al.
Cancer Epidemiol. Biomarkers Prev. 2005;14:1724-1731.
ABSTRACT | FULL TEXT  

Breast and Uterine Effects of Soy Isoflavones and Conjugated Equine Estrogens in Postmenopausal Female Monkeys
Wood et al.
J. Clin. Endocrinol. Metab. 2004;89:3462-3468.
ABSTRACT | FULL TEXT  

Medroxyprogesterone Acetate Antagonizes the Effects of Estrogen Treatment on Social and Sexual Behavior in Female Macaques
Pazol et al.
J. Clin. Endocrinol. Metab. 2004;89:2998-3006.
ABSTRACT | FULL TEXT  

The WHI Estrogen-Alone Trial--Do Things Look Any Better?
Hulley and Grady
JAMA 2004;291:1769-1771.
FULL TEXT  

Effects of Estrogen Plus Progestin on Gynecologic Cancers and Associated Diagnostic Procedures: The Women's Health Initiative Randomized Trial
Anderson et al.
JAMA 2003;290:1739-1748.
ABSTRACT | FULL TEXT  

Randomized, double-blind, multicenter trial comparing two doses of arzoxifene (LY353381) in hormone-sensitive advanced or metastatic breast cancer patients
Baselga et al.
Ann Oncol 2003;14:1383-1390.
ABSTRACT | FULL TEXT  

Effects of Estrogen plus Progestin on Health-Related Quality of Life
Hays et al.
NEJM 2003;348:1839-1854.
ABSTRACT | FULL TEXT  

Comparing Therapies for Postmenopausal Osteoporosis Prevention and Treatment
Eichner et al.
The Annals of Pharmacotherapy 2003;37:711-724.
ABSTRACT | FULL TEXT  

Mutagenic events induced by 4-hydroxyequilin in supF shuttle vector plasmid propagated in human cells
Yasui et al.
Carcinogenesis 2003;24:911-917.
ABSTRACT | FULL TEXT  

Risks and benefits of hormone replacement therapy: The evidence speaks
Humphries and Gill
CMAJ 2003;168:1001-1010.
ABSTRACT | FULL TEXT  

Continuous combined hormone replacement therapy and endometrial hyperplasia
Archer
BMJ 2002;325:231-232.
FULL TEXT  

Effect on endometrium of long term treatment with continuous combined oestrogen-progestogen replacement therapy: follow up study
Wells et al.
BMJ 2002;325:239-239.
ABSTRACT | FULL TEXT  

Risks and Benefits of Estrogen Plus Progestin in Healthy Postmenopausal Women: Principal Results From the Women's Health Initiative Randomized Controlled Trial
Writing Group for the Women's Health Initiative In
JAMA 2002;288:321-333.
ABSTRACT | FULL TEXT  

Estrogen Replacement Therapy and Risk of Ovarian Cancer
Noller
JAMA 2002;288:368-369.
FULL TEXT  

Bone Mass Response to Discontinuation of Long-term Hormone Replacement Therapy: Results From the Postmenopausal Estrogen/Progestin Interventions (PEPI) Safety Follow-up Study
Greendale et al.
Arch Intern Med 2002;162:665-672.
ABSTRACT | FULL TEXT  

Endometrial Cancer: Hormonal Factors, the Perimenopausal ""Window of Risk,"" and Isoflavones
Hale et al.
J. Clin. Endocrinol. Metab. 2002;87:3-15.
ABSTRACT | FULL TEXT  

Hormone replacement therapy and the endometrium
Feeley and Wells
J. Clin. Pathol. 2001;54:435-440.
ABSTRACT | FULL TEXT  

Estrogen Replacement Therapy and Ovarian Cancer Mortality in a Large Prospective Study of US Women
Rodriguez et al.
JAMA 2001;285:1460-1465.
ABSTRACT | FULL TEXT  

How Many Women Lose Bone Mineral Density While Taking Hormone Replacement Therapy?: Results From the Postmenopausal Estrogen/Progestin Interventions Trial
Greendale et al.
Arch Intern Med 2000;160:3065-3071.
ABSTRACT | FULL TEXT  

Aortic Plaque Size and Endometrial Response in Cholesterol-Fed Rabbits Treated With Estrogen Plus Continuous or Sequential Progestin
Brehme et al.
Arterioscler. Thromb. Vasc. Bio. 1999;19:1930-1937.
ABSTRACT | FULL TEXT  

American Society of Clinical Oncology Technology Assessment on Breast Cancer Risk Reduction Strategies: Tamoxifen and Raloxifene
Chlebowski et al.
JCO 1999;17:1939-1939.
ABSTRACT | FULL TEXT  

Strategies for Individualizing Patient Decisions About Hormone Therapy
Col et al.
J. Clin. Endocrinol. Metab. 1999;84:1799-1802.
FULL TEXT  

Endometrial Evaluation in Menopausal Women
JWatch Women's Health 1999;1999:21-21.
FULL TEXT  

Modulation of Coronary Vascular Resistance in Female Rabbits by Estrogen and Progesterone
Gorodeski et al.
Reproductive Sciences 1998;5:197-202.
ABSTRACT  

Coronary Artery Disease in Women: A Historical Perspective
Thomas and Braus
Arch Intern Med 1998;158:333-337.
ABSTRACT | FULL TEXT  

Transvaginal Ultrasonography Compared with Endometrial Biopsy for the Detection of Endometrial Disease
Langer et al.
NEJM 1997;337:1792-1798.
ABSTRACT | FULL TEXT  

Low-Dose Esterified Estrogen Therapy: Effects on Bone, Plasma Estradiol Concentrations, Endometrium, and Lipid Levels
Genant et al.
Arch Intern Med 1997;157:2609-2615.
ABSTRACT  

A Comparison of Estrogen Replacement, Pravastatin, and Combined Treatment for the Management of Hypercholesterolemia in Postmenopausal Women
Davidson et al.
Arch Intern Med 1997;157:1186-1192.
ABSTRACT  

Patient-Specific Decisions About Hormone Replacement Therapy in Postmenopausal Women
Col et al.
JAMA 1997;277:1140-1147.
ABSTRACT  

Boning Up on Estrogen: New Options, New Concerns
Insogna et al.
JAMA 1996;276:1430-1432.
ABSTRACT  

Estrogen Replacement Therapy and Endometrial Hyperplasia
Subbiah
JAMA 1996;275:1880-1880.
ABSTRACT  

Estrogen Replacement Therapy and Endometrial Hyperplasia
Tsang
JAMA 1996;275:1880-1880.
ABSTRACT  

ADDING PROGESTIN TO ERT PROTECTS THE UTERUS
JWatch General 1996;1996:3-3.
FULL TEXT