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February 7, 1996, Vol 275, No. 5 >
ARTICLE | February 7, 1996

Effects of Hormone Replacement Therapy on Endometrial Histology in Postmenopausal Women: Title and subTitle BreakThe Postmenopausal Estrogen/Progestin Interventions (PEPI) Trial FREE

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
[+] Author Affiliations

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).


JAMA. 1996;275(5):370-375. doi:10.1001/jama.1996.03530290040035
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References

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)

REFERENCES

1 +
Smith DC, Prentice R, Thompson DJ, Herrmann WL.  Association of exogenous estrogen and endometrial carcinoma. N Engl J Med . 1975;;293:1164-1167.
2 +
Ziel HK, Hinkle WD.  Increased risk of endometrial carcinoma among users of conjugated estrogens. N Engl J Med . 1975;;293:1167-1170.
3 +
Mack TM, Pike MC, Henderson BE, et al.  Estrogens and endometrial cancer in a retirement community. N Engl J Med . 1976;;294:1262-1267.
4 +
Hulka BS, Fowler WC, Kaufman DG, et al.  Estrogen and endometrial cancer: cases and two control groups from North Carolina. Am J Obstet Gynecol . 1980;;137:92-101.
5 +
Shapiro S, Kelly JP, Rosenberg L, et al.  Risk of localized and widespread endometrial cancer in relation to recent and discontinued use of conjugated estrogens. N Engl J Med . 1985;;313:969-972.
6 +
Henderson BE.  The cancer question: an overview of recent epidemiologic and retrospective data. Am J Obstet Gynecol . 1989;;161:1859-1864.
7 +
Persson I, Adami HO, Bergkvist L, et al.  Risk of endometrial cancer after treatment with oestrogens alone or in conjunction with progestogens: results of a prospective study. BMJ . 1989;;298:147-151.
8 +
Voigt LF, Weiss NS, Chu J, et al.  Progestogen supplementation of exogenous oestrogens and risk of endometrial cancer. Lancet . 1991;;338:274-277.
9 +
Brinton LA, Hoover RN, and The Endometrial Cancer Collaborative Group.  Estrogen replacement therapy and endometrial cancer risk: unresolved issues. Obstet Gynecol . 1993;;81:265-271.
10 +
Schiff I, Sela HK, Cramer D, et al.  Endometrial hyperplasia in women on cyclic or continuous estrogen regimens. Fertil Steril . 1982;;37:79-82.
11 +
Gelfand MM, Ferenczy A.  A prospective 1-year study of estrogen and progestin in postmenopausal women: effects on the endometrium. Obstet Gynecol . 1989;;74:398-402.
12 +
Woodruff JD, Pickar JH.  Incidence of endometrial hyperplasia in postmenopausal women taking conjugated estrogens (Premarin) with medroxyprogesterone acetate or conjugated estrogens alone. Am J Obstet Gynecol . 1994;;170:1213-1223.
13 +
The Writing Group for the PEPI Trial.  Effects of estrogen or estrogen/progestin regimens on heart disease risk factors in postmenopausal women: The Postmenopausal Estrogen/Progestin Interventions (PEPI) Trial. JAMA . 1995;;273:199-208.
14 +
The Writing Group for the PEPI Trial.  The Postmenopausal Estrogen/Progestin Interventions (PEPI) Trial: rationale, design and conduct (I). J Controlled Clin Trials . 1995;;16( (suppl) ):3S-19S.
15 +
The Writing Group for the PEPI Trial.  The Postmenopausal Estrogen/Progestin Interventions (PEPI) Trial: the recruitment of postmenopausal women (II). J Controlled Clin Trials . 1995;;16( (suppl) )20S-35S.
16 +
The Writing Group for the PEPI Trial.  The Postmenopausal Estrogen/Progestin Interventions (PEPI) Trial: physical and laboratory measurements (III). J Controlled Clin Trials . 1995;;16( (suppl) ):36S-53S.
17 +
The Writing Group for the PEPI Trial.  The Postmenopausal Estrogen/Progestin Interventions (PEPI) Trial: baseline characteristics of participants (IV). J Controlled Clin Trials . 1995;;16( (suppl) ):54S-72S.
18 +
Hendrickson M, Kempson R. Major Problems in Pathology . Philadelphia, Pa: WB Saunders; 1980;;12: 285-318. Major Problems in Pathology series.
19 +
Bush TL.  Noncontraeeptive estrogen use and risk of cardiovascular disease: an overview and critique of the literature.  In: Korenmann SG, ed. The Menopause: Biological and Clinical Consequences of Ovarian Failure: Evolution and Management . Norwell, Mass: Sereno Symposia; 1990;:211-224.
20 +
Stampfer MJ, Colditz GA.  Estrogen replacement and coronary heart disease: a quantitative assessment of the epidemiologie evidence. Prev Med . 1991;; 20:47-63.
21 +
Grady D, Rubin SM, Petitti DB, et al.  Hormone therapy to prevent disease and prolong Ufe in postmenopausal women. Ann Intern Med . 1992;;117:1016-1037.
22 +
Kennedy DL, Baum C, Forbes MB.  Noncontraception estrogens and progestins: use patterns over time. Obstet Gynecol . 1985;;65:441-446.
23 +
Gibbons WE, Moyer DL, Lobo RA, Roy S, Mishell DR Jr.  Biochemical and histologie effects of sequential estrogen/progestin therapy on the endometrium of postmenopausal women. Am J Obstet Gynecol . 1986;;154:456-461.
24 +
Sturdee DW, Wade-Evans T, Paterson MEL, Thorn M, Studd JWW.  Relations between bleeding pattern, endometrium histology and estrogen treatment in menopausal women. BMJ . 1978;;1:1575-1577.
25 +
Weinstein L.  Efficacy of a continuous estrogen-progestin regimen in the menopausal patient. 06stet Gynecol . 1987;;69:929-932.
26 +
Moorjani S, Dupont A, Labrie F, et al.  Changes in plasma lipoprotein and apolipoprotein composition in relation to oral versus percutaneous administration of estrogen alone or in cyclic association with utrogestan in menopausal women. J Clin Endocrinol Metabol . 1991;;73:373-379.
27 +
Jensen J, Riis BJ, Strom V, Nilas L, Christiansen C.  Long-term effects of percutaneous estrogens and oral progesterone on serum lipoproteins in postmenopausal women. Am J Obstet Gynecol . 1987;;156:66-71.
28 +
Gusberg SB.  Precursors of corpus carcinoma: estrogens and adenomatous hyperplasia. Am J Obstet Gynecol . 1947;;54:905-927.
29 +
Hall KV.  Irregular hyperplasia of the endometrium. Acta Obstet Gynecol Scand . 1957;;36:306-321.
30 +
Campbell PE, Barter RA.  The significance of atypical endometrial hyperplasia. J Obstet Gynecol Br Commonw . 1961;;68:668-672.
31 +
Wentz WB.  Treatment of persistent endometrial hyperplasia with progestin. Am J Obstet Gynecol . 1966;;96:999-1004.
32 +
Sherman AI, Brown S.  The precursors of endometrial carcinoma. Am J Obstet Gynecol . 1979;;135: 947-956.
33 +
Thorn M, Whit PJ, Williams RM, et al.  Prevention and treatment of endometrial disease in climacteric women receiving oestrogen therapy. Lancet . 1978;;1:455-457.
34 +
 metrial carcinoma. Am J Obstet Gynecol . 1979;;135:947-956.

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1 +
Smith DC, Prentice R, Thompson DJ, Herrmann WL.  Association of exogenous estrogen and endometrial carcinoma. N Engl J Med . 1975;;293:1164-1167.
2 +
Ziel HK, Hinkle WD.  Increased risk of endometrial carcinoma among users of conjugated estrogens. N Engl J Med . 1975;;293:1167-1170.
3 +
Mack TM, Pike MC, Henderson BE, et al.  Estrogens and endometrial cancer in a retirement community. N Engl J Med . 1976;;294:1262-1267.
4 +
Hulka BS, Fowler WC, Kaufman DG, et al.  Estrogen and endometrial cancer: cases and two control groups from North Carolina. Am J Obstet Gynecol . 1980;;137:92-101.
5 +
Shapiro S, Kelly JP, Rosenberg L, et al.  Risk of localized and widespread endometrial cancer in relation to recent and discontinued use of conjugated estrogens. N Engl J Med . 1985;;313:969-972.
6 +
Henderson BE.  The cancer question: an overview of recent epidemiologic and retrospective data. Am J Obstet Gynecol . 1989;;161:1859-1864.
7 +
Persson I, Adami HO, Bergkvist L, et al.  Risk of endometrial cancer after treatment with oestrogens alone or in conjunction with progestogens: results of a prospective study. BMJ . 1989;;298:147-151.
8 +
Voigt LF, Weiss NS, Chu J, et al.  Progestogen supplementation of exogenous oestrogens and risk of endometrial cancer. Lancet . 1991;;338:274-277.
9 +
Brinton LA, Hoover RN, and The Endometrial Cancer Collaborative Group.  Estrogen replacement therapy and endometrial cancer risk: unresolved issues. Obstet Gynecol . 1993;;81:265-271.
10 +
Schiff I, Sela HK, Cramer D, et al.  Endometrial hyperplasia in women on cyclic or continuous estrogen regimens. Fertil Steril . 1982;;37:79-82.
11 +
Gelfand MM, Ferenczy A.  A prospective 1-year study of estrogen and progestin in postmenopausal women: effects on the endometrium. Obstet Gynecol . 1989;;74:398-402.
12 +
Woodruff JD, Pickar JH.  Incidence of endometrial hyperplasia in postmenopausal women taking conjugated estrogens (Premarin) with medroxyprogesterone acetate or conjugated estrogens alone. Am J Obstet Gynecol . 1994;;170:1213-1223.
13 +
The Writing Group for the PEPI Trial.  Effects of estrogen or estrogen/progestin regimens on heart disease risk factors in postmenopausal women: The Postmenopausal Estrogen/Progestin Interventions (PEPI) Trial. JAMA . 1995;;273:199-208.
14 +
The Writing Group for the PEPI Trial.  The Postmenopausal Estrogen/Progestin Interventions (PEPI) Trial: rationale, design and conduct (I). J Controlled Clin Trials . 1995;;16( (suppl) ):3S-19S.
15 +
The Writing Group for the PEPI Trial.  The Postmenopausal Estrogen/Progestin Interventions (PEPI) Trial: the recruitment of postmenopausal women (II). J Controlled Clin Trials . 1995;;16( (suppl) )20S-35S.
16 +
The Writing Group for the PEPI Trial.  The Postmenopausal Estrogen/Progestin Interventions (PEPI) Trial: physical and laboratory measurements (III). J Controlled Clin Trials . 1995;;16( (suppl) ):36S-53S.
17 +
The Writing Group for the PEPI Trial.  The Postmenopausal Estrogen/Progestin Interventions (PEPI) Trial: baseline characteristics of participants (IV). J Controlled Clin Trials . 1995;;16( (suppl) ):54S-72S.
18 +
Hendrickson M, Kempson R. Major Problems in Pathology . Philadelphia, Pa: WB Saunders; 1980;;12: 285-318. Major Problems in Pathology series.
19 +
Bush TL.  Noncontraeeptive estrogen use and risk of cardiovascular disease: an overview and critique of the literature.  In: Korenmann SG, ed. The Menopause: Biological and Clinical Consequences of Ovarian Failure: Evolution and Management . Norwell, Mass: Sereno Symposia; 1990;:211-224.
20 +
Stampfer MJ, Colditz GA.  Estrogen replacement and coronary heart disease: a quantitative assessment of the epidemiologie evidence. Prev Med . 1991;; 20:47-63.
21 +
Grady D, Rubin SM, Petitti DB, et al.  Hormone therapy to prevent disease and prolong Ufe in postmenopausal women. Ann Intern Med . 1992;;117:1016-1037.
22 +
Kennedy DL, Baum C, Forbes MB.  Noncontraception estrogens and progestins: use patterns over time. Obstet Gynecol . 1985;;65:441-446.
23 +
Gibbons WE, Moyer DL, Lobo RA, Roy S, Mishell DR Jr.  Biochemical and histologie effects of sequential estrogen/progestin therapy on the endometrium of postmenopausal women. Am J Obstet Gynecol . 1986;;154:456-461.
24 +
Sturdee DW, Wade-Evans T, Paterson MEL, Thorn M, Studd JWW.  Relations between bleeding pattern, endometrium histology and estrogen treatment in menopausal women. BMJ . 1978;;1:1575-1577.
25 +
Weinstein L.  Efficacy of a continuous estrogen-progestin regimen in the menopausal patient. 06stet Gynecol . 1987;;69:929-932.
26 +
Moorjani S, Dupont A, Labrie F, et al.  Changes in plasma lipoprotein and apolipoprotein composition in relation to oral versus percutaneous administration of estrogen alone or in cyclic association with utrogestan in menopausal women. J Clin Endocrinol Metabol . 1991;;73:373-379.
27 +
Jensen J, Riis BJ, Strom V, Nilas L, Christiansen C.  Long-term effects of percutaneous estrogens and oral progesterone on serum lipoproteins in postmenopausal women. Am J Obstet Gynecol . 1987;;156:66-71.
28 +
Gusberg SB.  Precursors of corpus carcinoma: estrogens and adenomatous hyperplasia. Am J Obstet Gynecol . 1947;;54:905-927.
29 +
Hall KV.  Irregular hyperplasia of the endometrium. Acta Obstet Gynecol Scand . 1957;;36:306-321.
30 +
Campbell PE, Barter RA.  The significance of atypical endometrial hyperplasia. J Obstet Gynecol Br Commonw . 1961;;68:668-672.
31 +
Wentz WB.  Treatment of persistent endometrial hyperplasia with progestin. Am J Obstet Gynecol . 1966;;96:999-1004.
32 +
Sherman AI, Brown S.  The precursors of endometrial carcinoma. Am J Obstet Gynecol . 1979;;135: 947-956.
33 +
Thorn M, Whit PJ, Williams RM, et al.  Prevention and treatment of endometrial disease in climacteric women receiving oestrogen therapy. Lancet . 1978;;1:455-457.
34 +
 metrial carcinoma. Am J Obstet Gynecol . 1979;;135:947-956.

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