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Original Contribution JAMA. 1996;275(5):370-375. doi: 10.1001/jama.1996.03530290040035 Effects of Hormone Replacement Therapy
on Endometrial Histology in
Postmenopausal Women
The Postmenopausal Estrogen/Progestin Interventions
(PEPI) Trial
1. Writing Group for the PEPI Trial; 2. Howard L. Judd, MD; 3. Irma Mebane-Sims, PhD; 4. Claudine Legault, PhD; 5. Carol Wasilauskas, MS; 6. Susan Johnson, MD; 7. Maria Merino, MD; 8. Elizabeth Barrett-Connor, MD; 9. Jose Trabal, MD; 10. Valery T. Miller, MD; 11. Vanessa Barnabei, MD; 12. Ginny Levin, MPH.; 13. Trudy Bush, PhD; 14. David Foster, MD; 15. Howard Zacur, MD; 16. J. Donald Woodruff, MD; 17. Marcia Stefanick, PhD; 18. Peter D. Wood, DSc, PhD; 19. Allison Akana, PA; 20. W. Leroy Heinrichs, MD; 21. Katherine O'Hanlan, MD; 22. Howard L. Judd, MD; 23. Richard P. Buyalos, MD; 24. Gail Greendale, MD; 25. Kathy Lozano, RNP; 26. Elizabeth Barrett-Connor, MD; 27. Mary Lou Carrion-Petersen, RN; 28. Carmella Cavero, RN; 29. Robert Langer, MD; 30. Helmut G. Schrott, MD; 31. Jo Ann Benda, MD; 32. Charles deProsse, MD; 33. Deborah Fedderson, RN; 34. Susan R. Johnson, MD; 35. Jose Trabal, MD, MPH; 36. Carl J. Pauerstein, MD; 37. Mohammad M. Ahmad, MD, PhD; 38. Herbert P. Brown, MD; 39. Robert S. Schenken, MD; 40. Mercedes Rodriguez-Sifuentes, RN; 41. Philip T. Valente, MD; 42. Mark Espeland, PhD; 43. H. Bradley Wells, PhD; 44. Kathy Lane; 45. Claudine Legault, PhD; 46. Carol Wasilauskas, MS.; 47. Irma L. Mebane-Sims, PhD; 48. Joseph Kelaghan, MD; 49. Joan McGowan, PhD; 50. Judith Fradkin, MD; 51. Sheryl Sherman, PhD; 52. Maria Merino, MD; 53. Robert Scully, MD 1. 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 2. From The Writing Group for the PEPI Trial. 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.

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