Risks and Benefits of Estrogen Plus Progestin in Healthy Postmenopausal Women: Principal Results From the Women's Health Initiative Randomized Controlled Trial | Breast Cancer | JAMA | JAMA Network
[Skip to Navigation]
Access to paid content on this site is currently suspended due to excessive activity being detected from your IP address 34.239.150.57. Please contact the publisher to request reinstatement.
1.
The Women's Health Initiative Study Group.  Design of the Women's Health Initiative clinical trial and observational study.  Control Clin Trials.1998;19:61-109.Google Scholar
2.
Stampfer M, Colditz G. Estrogen replacement therapy and coronary heart disease: a quantitative assessment of the epidemiologic evidence.  Prev Med.1991;20:47-63.Google Scholar
3.
Grady D, Rueben SB, Pettiti DB.  et al.  Hormone therapy to prevent disease and prolong life in postmenopausal women.  Ann Intern Med.1992;117:1016-1037.Google Scholar
4.
Rijpkema AH, van der Sanden AA, Ruijs AH. Effects of postmenopausal estrogen-progesterone therapy on serum lipids and lipoproteins: a review.  Maturitas.1990;12:259-285.Google Scholar
5.
Adams MR, Kaplan JR, Manuck SB.  et al.  Inhibition of coronary artery atherosclerosis by 17-beta estradiol in ovariectomized monkeys: lack of an effect of added progesterone.  Arteriosclerosis.1990;10:1051-1057.Google Scholar
6.
Weiss NS, Ure CL, Ballard JH, Williams AR, Daling JR. Decreased risk of fractures of the hip and lower forearm with postmenopausal use of estrogen.  N Engl J Med.1980;303:1195-1198.Google Scholar
7.
Genant HK, Baylink DJ, Gallagher JC, Harris ST, Steiger P, Herber M. Effect of estrone sulfate on postmenopausal bone loss.  Obstet Gynecol.1990;76:579-584.Google Scholar
8.
Steinberg KA, Thacker SB, Smith SJ.  et al.  A meta-analysis of the effect of estrogen replacement therapy on the risk of breast cancer.  JAMA.1991;265:1985-1990.Google Scholar
9.
Gerhardsson de VM, London S. Reproductive factors, exogenous female hormones, and colorectal cancer by subsite.  Cancer Causes Control.1992;3:355-360.Google Scholar
10.
Hulley S, Grady D, Bush T.  et al.  Randomized trial of estrogen plus progestin for secondary prevention of coronary heart disease in postmenopausal women.  JAMA.1998;280:605-613.Google Scholar
11.
Grodstein F, Manson JE, Stampfer MJ. Postmenopausal hormone use and secondary prevention of coronary events in the Nurses' Health Study.  Ann Intern Med.2001;135:1-8.Google Scholar
12.
Alexander KP, Newby LK, Hellkamp AS.  et al.  Initiation of hormone replacement therapy after acute myocardial infarction is associated with more cardiac events during follow-up.  J Am Coll Cardiol.2001;38:1-7.Google Scholar
13.
Heckbert SR, Kaplan RC, Weiss NS.  et al.  Risk of recurrent coronary events in relation to use and recent initiation of postmenopausal hormone therapy.  Arch Intern Med.2001;161:1709-1173.Google Scholar
14.
Grodstein F, Manson JE, Colditz GA, Willit WC, Speizer FE, Stampfer MJ. A prospective, observational study of postmenopausal hormone therapy and primary prevention of cardiovascular disease.  Ann Intern Med.2000;133:933-941.Google Scholar
15.
The Writing Group for the PEPI Trial.  Effects of hormone replacement therapy on endometrial histology in postmenopausal women: the Postmenopausal Estrogen/Progestin Interventions (PEPI) Trial.  JAMA.1996;275:370-375.Google Scholar
16.
Ives DG, Fitzpatrick AL, Bild DE.  et al.  Surveillance and ascertainment of cardiovascular events: the Cardiovascular Health Study.  Ann Epidemiol.1995;5:275-285.Google Scholar
17.
Cox DR. Regression analysis and life tables.  J R Stat Soc.1972;34:187-220.Google Scholar
18.
O'Brien PC, Fleming RT. A multiple testing procedure for clinical trials.  Biometrics.1979;35:549-556.Google Scholar
19.
Freedman LS, Anderson G, Kipnis V.  et al.  Approaches to monitoring the results of long-term disease prevention trials: examples from the Women's Health Initiative.  Control Clin Trials.1996;17:509-525.Google Scholar
20.
Gail MH, Brinton LA, Byar DP.  et al.  Projecting individualized probabilities of developing breast cancer for white females who are being examined annually.  J Natl Cancer Inst.1989;81:1879-1886.Google Scholar
21.
Pilon D, Castilloux AM, Lelorier J. Estrogen replacement therapy: determinants of persistence with treatment.  Obstet Gynecol.2001;97:97-100.Google Scholar
22.
Writing Group for the PEPI Trial.  Effects of estrogen or estrogen/progestin regimens on heart disease risk factors in postmenopausal women.  JAMA.1995;273:199-208.Google Scholar
23.
Herrington DM, Reboussin DM, Brosnihan KB.  et al.  Effects of estrogen replacement on the progression of coronary artery atherosclerosis.  N Engl J Med.2000;343:522-529.Google Scholar
24.
Schulman SP, Thiemann DR, Ouyang P.  et al.  Effects of acute hormone therapy on recurrent ischemia in postmenopausal women with unstable angina.  J Am Coll Cardiol.2002;39:231-237.Google Scholar
25.
Grady D, Herrington D, Bittner V.  et al. for the HERS Research Group.  Cardiovascular disease outcomes during 6.8 years of hormone therapy: Heart and Estrogen/progestin Replacement Study Follow-up (HERS II).  JAMA.2002;288:49-57.Google Scholar
26.
Simon JA, Hsia J, Cauley JA.  et al.  Postmenopausal hormone therapy and risk of stroke: the Heart and Estrogen-progestin Replacement Study (HERS).  Circulation.2001;103:638-642.Google Scholar
27.
Viscoli CM, Brass LM, Kernan WN, Sarrel PM, Suissa S, Horwitz RI. A clinical trial of estrogen-replacement therapy after ischemic stroke.  N Engl J Med.2001;345:1243-1249.Google Scholar
28.
Hodis HN, Mack WJ, Lobo RA.  et al.  Estrogen in the prevention of atherosclerosis: a randomized, double-blind controlled trial.  Ann Intern Med.2001;135:939-953.Google Scholar
29.
Angerer P, Stork S, Kothny W, Schmitt P, von Schacky C. Effect of oral postmenopausal hormone replacement on progression of atherosclerosis: a randomized, controlled trial.  Arterioscler Thromb Vasc Biol.2001;21:262-268.Google Scholar
30.
Castellsague J, Perez Gutthann S, Garcia Rodriguez LA. Recent epidemiological studies of the association between hormone replacement therapy and venous thromboembolism: a review.  Drug Saf.1998;18:117-123.Google Scholar
31.
Grady D, Wenger NK, Herrington D.  et al.  Postmenopausal hormone therapy increases risk for venous thromboembolic disease: the Heart and Estrogen/progestin Replacement Study.  Ann Intern Med.2000;132:689-696.Google Scholar
32.
Collaborative Group on Hormonal Factors in Breast Cancer.  Breast cancer and hormone replacement therapy: collaborative reanalysis of data from 51 epidemiological studies of 52,705 women with breast cancer and 108,411 women without breast cancer.  Lancet.1997;350:1047-1059.Google Scholar
33.
Hulley S, Furberg C, Barrett-Connor E.  et al. for the HERS Research Group.  Noncardiovascular disease outcomes during 6.8 years of hormone therapy: Heart and Estrogen/progestin Replacement Study Follow-up (HERS II).  JAMA.2002;288:58-66.Google Scholar
34.
Schairer C, Lubin J, Troisi R, Sturgeon S, Brinton L, Hoover R. Menopausal estrogen and estrogen-progestin replacement therapy and breast cancer risk.  JAMA.2000;283:485-491.Google Scholar
35.
Ross RK, Paganini-Hill A, Wan PC, Pike MC. Effect of hormone replacement therapy on breast cancer risk: estrogen versus estrogen plus progestin.  J Natl Cancer Inst.2000;92:328-332.Google Scholar
36.
Colditz GA, Hankinson SE, Hunter DJ.  et al.  The use of estrogens and progestins and the risk of breast cancer in postmenopausal women.  N Engl J Med.1995;332:1589-1593.Google Scholar
37.
Magnusson C, Baron JA, Correia N, Bergstrom R, Adami H-O, Persson I. Breast-cancer risk following long-term oestrogen and oestrogen-progestin-replacement therapy.  Int J Cancer.1999;81:339-344.Google Scholar
38.
Greendale GA, Reboussin BA, Sie A.  et al.  Effects of estrogen and estrogen-progestin on mammographic parenchymal density.  Ann Intern Med.1999;130:262-269.Google Scholar
39.
Grodstein F, Newcomb PA, Stampfer MJ. Postmenopausal hormone therapy and the risk of colorectal cancer: a review and meta-analysis.  Am J Med.1999;106:574-582.Google Scholar
40.
Vickers MR, Meade TW, Wilkes HC. Hormone replacement therapy and cardiovascular disease: the case for a randomized controlled trial.  Ciba Found Symp.1995;191:150-160.Google Scholar
41.
Torgerson DJ, Bell-Seyer SE. Hormone replacement therapy and prevention of nonvertebral fractures: a meta-analysis of randomized trials.  JAMA.2001;285:2891-2897.Google Scholar
42.
Writing Group for the PEPI Trial.  Effects of hormone therapy on bone mineral density: results from the Postmenopausal Estrogen/Progestin Interventions (PEPI) Trial.  JAMA.1996;275:1389-1396.Google Scholar
43.
Mosca L, Collins P, Herrington DM.  et al.  Hormone replacement therapy and cardiovascular disease: a statement for healthcare professionals from the American Heart Association.  Circulation.2001;104:499-503.Google Scholar
Original Contribution
July 17, 2002

Risks and Benefits of Estrogen Plus Progestin in Healthy Postmenopausal Women: Principal Results From the Women's Health Initiative Randomized Controlled Trial

Author Affiliations

Writing Group for the Women's Health Initiative Investigators: Jacques E. Rossouw, MBChB, MD, National Heart, Lung, and Blood Institute, Bethesda, Md; Garnet L. Anderson, PhD, Ross L. Prentice, PhD, Andrea Z. LaCroix, PhD, and Charles Kooperberg, PhD, Fred Hutchinson Cancer Research Center, Seattle, Wash; Marcia L. Stefanick, PhD, Stanford University Clinical Center, Stanford, Calif; Rebecca D. Jackson, MD, Ohio State University Clinical Center, Columbus; Shirley A. A. Beresford, PhD, Fred Hutchinson Cancer Research Center, Seattle, Wash; Barbara V. Howard, PhD, MedStar Research Institute, Washington, DC; Karen C. Johnson, MD, MPH, University of Tennessee, Memphis; Jane Morley Kotchen, MD, Medical College of Wisconsin, Milwaukee; Judith Ockene, PhD, University of Massachusetts Medical School, Worcester.

JAMA. 2002;288(3):321-333. doi:10.1001/jama.288.3.321
Abstract

Context Despite decades of accumulated observational evidence, the balance of risks and benefits for hormone use in healthy postmenopausal women remains uncertain.

Objective To assess the major health benefits and risks of the most commonly used combined hormone preparation in the United States.

Design Estrogen plus progestin component of the Women's Health Initiative, a randomized controlled primary prevention trial (planned duration, 8.5 years) in which 16608 postmenopausal women aged 50-79 years with an intact uterus at baseline were recruited by 40 US clinical centers in 1993-1998.

Interventions Participants received conjugated equine estrogens, 0.625 mg/d, plus medroxyprogesterone acetate, 2.5 mg/d, in 1 tablet (n = 8506) or placebo (n = 8102).

Main Outcomes Measures The primary outcome was coronary heart disease (CHD) (nonfatal myocardial infarction and CHD death), with invasive breast cancer as the primary adverse outcome. A global index summarizing the balance of risks and benefits included the 2 primary outcomes plus stroke, pulmonary embolism (PE), endometrial cancer, colorectal cancer, hip fracture, and death due to other causes.

Results On May 31, 2002, after a mean of 5.2 years of follow-up, the data and safety monitoring board recommended stopping the trial of estrogen plus progestin vs placebo because the test statistic for invasive breast cancer exceeded the stopping boundary for this adverse effect and the global index statistic supported risks exceeding benefits. This report includes data on the major clinical outcomes through April 30, 2002. Estimated hazard ratios (HRs) (nominal 95% confidence intervals [CIs]) were as follows: CHD, 1.29 (1.02-1.63) with 286 cases; breast cancer, 1.26 (1.00-1.59) with 290 cases; stroke, 1.41 (1.07-1.85) with 212 cases; PE, 2.13 (1.39-3.25) with 101 cases; colorectal cancer, 0.63 (0.43-0.92) with 112 cases; endometrial cancer, 0.83 (0.47-1.47) with 47 cases; hip fracture, 0.66 (0.45-0.98) with 106 cases; and death due to other causes, 0.92 (0.74-1.14) with 331 cases. Corresponding HRs (nominal 95% CIs) for composite outcomes were 1.22 (1.09-1.36) for total cardiovascular disease (arterial and venous disease), 1.03 (0.90-1.17) for total cancer, 0.76 (0.69-0.85) for combined fractures, 0.98 (0.82-1.18) for total mortality, and 1.15 (1.03-1.28) for the global index. Absolute excess risks per 10 000 person-years attributable to estrogen plus progestin were 7 more CHD events, 8 more strokes, 8 more PEs, and 8 more invasive breast cancers, while absolute risk reductions per 10 000 person-years were 6 fewer colorectal cancers and 5 fewer hip fractures. The absolute excess risk of events included in the global index was 19 per 10 000 person-years.

Conclusions Overall health risks exceeded benefits from use of combined estrogen plus progestin for an average 5.2-year follow-up among healthy postmenopausal US women. All-cause mortality was not affected during the trial. The risk-benefit profile found in this trial is not consistent with the requirements for a viable intervention for primary prevention of chronic diseases, and the results indicate that this regimen should not be initiated or continued for primary prevention of CHD.

×