Health Outcomes After Stopping Conjugated Equine Estrogens Among Postmenopausal Women With Prior Hysterectomy: A Randomized Controlled Trial | Acute Coronary Syndromes | 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 Please contact the publisher to request reinstatement.
Anderson GL, Limacher M, Assaf AR,  et al.  Effects of conjugated equine estrogen in postmenopausal women with hysterectomy: the Women's Health Initiative randomized controlled trial.  JAMA. 2004;291(14):1701-171215082697PubMedGoogle ScholarCrossref
The Women's Health Initiative Study Group.  Design of the Women's Health Initiative clinical trial and observational study.  Control Clin Trials. 1998;19(1):61-1099492970PubMedGoogle ScholarCrossref
Curb JD, McTiernan A, Heckbert SR,  et al.  Outcomes ascertainment and adjudication methods in the Women's Health Initiative.  Ann Epidemiol. 2003;13(9):(suppl)  S122-S12814575944PubMedGoogle ScholarCrossref
Heiss G, Wallace R, Anderson GL,  et al.  Health risks and benefits 3 years after stopping randomized treatment with estrogen and progestin.  JAMA. 2008;299(9):1036-104518319414PubMedGoogle ScholarCrossref
Cox DR. Regression analysis and life tables.  J R Stat Soc [Ser A]. 1972;34:187-220Google Scholar
Prentice RL, Caan B, Chlebowski RT,  et al.  Low-fat dietary pattern and risk of invasive breast cancer: the Women's Health Initiative Randomized Controlled Dietary Modification Trial.  JAMA. 2006;295(6):629-64216467232PubMedGoogle ScholarCrossref
Rossouw JE, Prentice RL, Manson JE,  et al.  Postmenopausal hormone therapy and risk of cardiovascular disease by age and years since menopause.  JAMA. 2007;297(13):1465-147717405972PubMedGoogle ScholarCrossref
Stefanick ML, Anderson GL, Margolis KL,  et al.  Effects of conjugated equine estrogens on breast cancer and mammography screening in postmenopausal women with hysterectomy.  JAMA. 2006;295(14):1647-165716609086PubMedGoogle ScholarCrossref
Prentice RL, Chlebowski RT, Stefanick ML,  et al.  Conjugated equine estrogens and breast cancer risk in the Women's Health Initiative clinical trial and observational study.  Am J Epidemiol. 2008;167(12):1407-141518448442PubMedGoogle ScholarCrossref
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(9084):1047-105910213546PubMedGoogle ScholarCrossref
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(24):1589-15937753136PubMedGoogle ScholarCrossref
Beral V.Million Women Study Collaborators.  Breast cancer and hormone-replacement therapy in the Million Women Study.  Lancet. 2003;362(9382):419-42712927427PubMedGoogle ScholarCrossref
Li CI, Malone KE, Porter PL,  et al.  Relationship between long durations and different regimens of hormone therapy and risk of breast cancer.  JAMA. 2003;289(24):3254-326312824206PubMedGoogle ScholarCrossref
Kerlikowske K, Miglioretti DL, Ballard-Barbash R,  et al.  Prognostic characteristics of breast cancer among postmenopausal hormone users in a screened population.  J Clin Oncol. 2003;21(23):4314-432114645420PubMedGoogle ScholarCrossref
Schairer C, Lubin J, Troisi R,  et al.  Menopausal estrogen and estrogen-progestin replacement therapy and breast cancer risk.  JAMA. 2000;283(4):485-49110659874PubMedGoogle ScholarCrossref
Calle EE, Feigelson HS, Hildebrand JS,  et al.  Postmenopausal hormone use and breast cancer associations differ by hormone regimen and histologic subtype.  Cancer. 2009;115(5):936-94519156895PubMedGoogle ScholarCrossref
Chen WY, Manson JE, Hankinson SE,  et al.  Unopposed estrogen therapy and the risk of invasive breast cancer.  Arch Intern Med. 2006;166(9):1027-103216682578PubMedGoogle ScholarCrossref
Beral V, Reeves G, Bull D,  et al.  Breast cancer risk in relation to the interval between menopause and starting hormone therapy.  J Natl Cancer Inst. 2011;103(4):296-30521278356PubMedGoogle ScholarCrossref
Fournier A, Mesrine S, Boutron-Ruault MC, Clavel-Chapelon F. Estrogen-progestin menopausal hormone therapy and breast cancer: does delay from menopause onset to treatment initiation influence risks?  J Clin Oncol. 2009;27(31):5138-514319752341PubMedGoogle ScholarCrossref
Chlebowski RT, Anderson GL. The influence of time from menopause and mammography on hormone therapy-related breast cancer risk assessment.  J Natl Cancer Inst. 2011;103(4):284-28521278357PubMedGoogle ScholarCrossref
McTiernan A, Chlebowski RT, Martin C,  et al.  Conjugated equine estrogen influence on mammographic density in postmenopausal women in a substudy of the Women's Health Initiative randomized trial.  J Clin Oncol. 2009;27(36):6135-614319901118PubMedGoogle ScholarCrossref
Chlebowski RT, Anderson G, Manson JE,  et al.  Estrogen alone in postmenopausal women and breast cancer detection by means of mammography and breast biopsy.  J Clin Oncol. 2010;28(16):2690-269720439627PubMedGoogle ScholarCrossref
Santen RJ, Song RX, Zhang Z,  et al.  Adaptive hypersensitivity to estrogen.  J Steroid Biochem Mol Biol. 2005;95(1-5):155-16516024245PubMedGoogle ScholarCrossref
Jeng MH, Shupnik MA, Bender TP,  et al.  Estrogen receptor expression and function in long-term estrogen-deprived human breast cancer cells.  Endocrinology. 1998;139(10):4164-41749751496PubMedGoogle ScholarCrossref
Ellis MJ, Gao F, Dehdashti F,  et al.  Lower-dose vs high-dose oral estradiol therapy of hormone receptor-positive, aromatase inhibitor-resistant advanced breast cancer.  JAMA. 2009;302(7):774-78019690310PubMedGoogle ScholarCrossref
Dunbier AK, Anderson H, Ghazoui Z,  et al.  Relationship between plasma estradiol levels and estrogen-responsive gene expression in estrogen receptor-positive breast cancer in postmenopausal women.  J Clin Oncol. 2010;28(7):1161-116720124184PubMedGoogle ScholarCrossref
Chlebowski RT, Hendrix SL, Langer RD,  et al.  Influence of estrogen plus progestin on breast cancer and mammography in healthy postmenopausal women.  JAMA. 2003;289(24):3243-325312824205PubMedGoogle ScholarCrossref
Chlebowski RT, Kuller LH, Prentice RL,  et al.  Breast cancer after use of estrogen plus progestin in postmenopausal women.  N Engl J Med. 2009;360(6):573-58719196674PubMedGoogle ScholarCrossref
Chlebowski RT, Anderson GL, Gass M,  et al.  Estrogen plus progestin and breast cancer incidence and mortality in postmenopausal women.  JAMA. 2010;304(15):1684-169220959578PubMedGoogle ScholarCrossref
Greendale GA, Espeland M, Slone S,  et al.  Bone mass response to discontinuation of long-term hormone replacement therapy.  Arch Intern Med. 2002;162(6):665-67211911720PubMedGoogle ScholarCrossref
Yates J, Barrett-Connor E, Barlas S,  et al.  Rapid loss of hip fracture protection after estrogen cessation: evidence from the National Osteoporosis Risk Assessment.  Obstet Gynecol. 2004;103(3):440-44614990403PubMedGoogle ScholarCrossref
Cauley JA, Seeley DG, Ensrud K,  et al.  Estrogen replacement therapy and fractures in older women.  Ann Intern Med. 1995;122(1):9-167985914PubMedGoogle ScholarCrossref
Banks E, Beral V, Reeves G,  et al.  Fracture incidence in relation to the pattern of use of hormone therapy in postmenopausal women.  JAMA. 2004;291(18):2212-222015138243PubMedGoogle ScholarCrossref
Mendelsohn ME, Karas RH. Molecular and cellular basis of cardiovascular gender differences.  Science. 2005;308(5728):1583-158715947175PubMedGoogle ScholarCrossref
Manson JE, Allison MA, Rossouw JE,  et al.  Estrogen therapy and coronary-artery calcification.  N Engl J Med. 2007;356(25):2591-260217582069PubMedGoogle ScholarCrossref
Mikkola TS, Clarkson TB. Estrogen replacement therapy, atherosclerosis, and vascular function.  Cardiovasc Res. 2002;53(3):605-61911861031PubMedGoogle ScholarCrossref
Grodstein F, Clarkson TB, Manson JE. Understanding the divergent data on postmenopausal hormone therapy.  N Engl J Med. 2003;348(7):645-65012584376PubMedGoogle ScholarCrossref
Manson JE, Bassuk SS. Invited commentary: hormone therapy and risk of coronary heart disease why renew the focus on the early years of menopause?  Am J Epidemiol. 2007;166(5):511-51717646204PubMedGoogle ScholarCrossref
Grodstein F, Manson JE, Stampfer MJ. Hormone therapy and coronary heart disease: the role of time since menopause and age at hormone initiation.  J Womens Health (Larchmt). 2006;15(1):35-4416417416PubMedGoogle ScholarCrossref
Hernán MA, Alonso A, Logan R,  et al.  Observational studies analyzed like randomized experiments: an application to postmenopausal hormone therapy and coronary heart disease.  Epidemiology. 2008;19(6):766-77918854702PubMedGoogle ScholarCrossref
Original Contribution
April 6, 2011

Health Outcomes After Stopping Conjugated Equine Estrogens Among Postmenopausal Women With Prior Hysterectomy: A Randomized Controlled Trial

Author Affiliations

Author Affiliations: Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington (Dr LaCroix and Mr Aragaki); Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, Torrance, California (Dr Chlebowski); Division of Preventive Medicine, Brigham and Women's Hospital, Harvard University, Boston, Massachusetts (Dr Manson); Health Science Center, Department of Preventive Medicine, University of Tennessee, Memphis (Dr Johnson); Department of Cardiology, George Washington University, Washington, DC (Dr Martin); Berman Center for Clinical Research, University of Minnesota, Minneapolis (Dr Margolis); Stanford Prevention Research Center, Stanford University School of Medicine, Stanford, California (Dr Stefanick); Health Science Center, University of Texas, San Antonio (Dr Brzyski); John A. Burns School of Medicine, University of Hawaii and Pacific Health Research Institute, Honolulu (Dr Curb); MedStar Research Institute, Hyattsville, Maryland (Dr Howard); Division of Preventive Medicine, University of Alabama, Birmingham (Dr Lewis); and Department of Social and Preventive Medicine, State University of New York, Buffalo (Dr Wactawski-Wende).

JAMA. 2011;305(13):1305-1314. doi:10.1001/jama.2011.382

Context The Women's Health Initiative Estrogen-Alone Trial was stopped early after a mean of 7.1 years of follow-up because of an increased risk of stroke and little likelihood of altering the balance of risk to benefit by the planned trial termination date. Postintervention health outcomes have not been reported.

Objective To examine health outcomes associated with randomization to treatment with conjugated equine estrogens (CEE) among women with prior hysterectomy after a mean of 10.7 years of follow-up through August 2009.

Design, Setting, and Participants The intervention phase was a double-blind, placebo-controlled, randomized clinical trial of 0.625 mg/d of CEE compared with placebo in 10 739 US postmenopausal women aged 50 to 79 years with prior hysterectomy. Follow-up continued after the planned trial completion date among 7645 surviving participants (78%) who provided written consent.

Main Outcome Measures The primary outcomes were coronary heart disease (CHD) and invasive breast cancer. A global index of risks and benefits included these primary outcomes plus stroke, pulmonary embolism, colorectal cancer, hip fracture, and death.

Results The postintervention risk (annualized rate) for CHD among women assigned to CEE was 0.64% compared with 0.67% in the placebo group (hazard ratio [HR], 0.97; 95% confidence interval [CI], 0.75-1.25), 0.26% vs 0.34%, respectively, for breast cancer (HR, 0.75; 95% CI, 0.51-1.09), and 1.47% vs 1.48%, respectively, for total mortality (HR, 1.00; 95% CI, 0.84-1.18). The risk of stroke was no longer elevated during the postintervention follow-up period and was 0.36% among women receiving CEE compared with 0.41% in the placebo group (HR, 0.89; 95% CI, 0.64-1.24), the risk of deep vein thrombosis was lower at 0.17% vs 0.27%, respectively (HR, 0.63; 95% CI, 0.41-0.98), and the risk of hip fracture did not differ significantly and was 0.36% vs 0.28%, respectively (HR, 1.27; 95% CI, 0.88-1.82). Over the entire follow-up, lower breast cancer incidence in the CEE group persisted and was 0.27% compared with 0.35% in the placebo group (HR, 0.77; 95% CI, 0.62-0.95). Health outcomes were more favorable for younger compared with older women for CHD (P = .05 for interaction), total myocardial infarction (P = .007 for interaction), colorectal cancer (P = .04 for interaction), total mortality (P = .04 for interaction), and global index of chronic diseases (P = .009 for interaction).

Conclusions Among postmenopausal women with prior hysterectomy followed up for 10.7 years, CEE use for a median of 5.9 years was not associated with an increased or decreased risk of CHD, deep vein thrombosis, stroke, hip fracture, colorectal cancer, or total mortality. A decreased risk of breast cancer persisted.

Trial Registration Identifier: NCT00000611