This Article  • Full text  • PDF  • Send to a friend  • Save in My Folder  • Save to citation manager  • Permissions  Citing Articles  • Citation map  • Citing articles on HighWire  • Citing articles on ISI (486)  • Contact me when this article is cited  Related Content  • Similar articles in JAMA  Topic Collections  • Menopause  • Randomized Controlled Trial  • Oncology  • Breast Cancer  • Mammography  • Alert me on articles by topic

The Women's Health Initiative Randomized Trial

Rowan T. Chlebowski, MD, PhD; Susan L. Hendrix, DO; Robert D. Langer, MD, MPH; Marcia L. Stefanick, PhD; Margery Gass, MD; Dorothy Lane, MD, MPH; Rebecca J. Rodabough, MS; Mary Ann Gilligan, MD, MPH; Michele G. Cyr, MD; Cynthia A. Thomson, PhD, RD; Janardan Khandekar, MD; Helen Petrovitch, MD; Anne McTiernan, MD , PhD; for the WHI Investigators

JAMA. 2003;289:3243-3253.

Context  The Women's Health Initiative trial of combined estrogen plus progestin was stopped early when overall health risks, including invasive breast cancer, exceeded benefits. Outstanding issues not previously addressed include characteristics of breast cancers observed among women using hormones and whether diagnosis may be influenced by hormone effects on mammography.

Objective  To determine the relationship among estrogen plus progestin use, breast cancer characteristics, and mammography recommendations.

Design, Setting, and Participants  Following a comprehensive breast cancer risk assessment, 16 608 postmenopausal women aged 50 to 79 years with an intact uterus were randomly assigned to receive combined conjugated equine estrogens (0.625 mg/d) plus medroxyprogesterone acetate (2.5 mg/d) or placebo from 1993 to 1998 at 40 clinical centers. Screening mammography and clinical breast examinations were performed at baseline and yearly thereafter.

Main Outcome Measures  Breast cancer number and characteristics, and frequency of abnormal mammograms by estrogen plus progestin exposure.

Results  In intent-to-treat analyses, estrogen plus progestin increased total (245 vs 185 cases; hazard ratio [HR], 1.24; weighted P<.001) and invasive (199 vs 150 cases; HR, 1.24; weighted P = .003) breast cancers compared with placebo. The invasive breast cancers diagnosed in the estrogen plus progestin group were similar in histology and grade but were larger (mean [SD], 1.7 cm [1.1] vs 1.5 cm [0.9], respectively; P = .04) and were at more advanced stage (regional/metastatic 25.4% vs 16.0%, respectively; P = .04) compared with those diagnosed in the placebo group. After 1 year, the percentage of women with abnormal mammograms was substantially greater in the estrogen plus progestin group (716 [9.4%] of 7656) compared with placebo group (398 [5.4%] of 7310; P<.001), a pattern which continued for the study duration.

Conclusions  Relatively short-term combined estrogen plus progestin use increases incident breast cancers, which are diagnosed at a more advanced stage compared with placebo use, and also substantially increases the percentage of women with abnormal mammograms. These results suggest estrogen plus progestin may stimulate breast cancer growth and hinder breast cancer diagnosis.

Author Affiliations: Harbor-UCLA Research and Education Institute, Torrance, Calif (Dr Chlebowski); Wayne State University, Detroit, Mich (Dr Hendrix); University of California San Diego School of Medicine, La Jolla (Dr Langer); Department of Medicine, Stanford University, Palo Alto, Calif (Dr Stefanick); Department of Obstetrics and Gynecology, University of Cincinnati College of Medicine, Cincinnati, Ohio (Dr Gass); Department of Preventive Medicine, State University of New York, Stony Brook (Dr Lane); Fred Hutchinson Cancer Research Center, Seattle, Wash (Ms Rodabough); Department of Medicine, Medical College of Wisconsin, Milwaukee (Dr Gilligan); Department of Medicine, Brown Medical School, Providence, RI (Dr Cyr); University of Arizona, Tucson (Dr Thomson); Department of Medicine, Evanston Northwestern Healthcare, Evanston, Ill (Dr Khandekar); Department of Geriatrics and Medicine, John A. Burns School of Medicine, Honolulu, Hawaii (Dr Petrovitch); and Fred Hutchinson Cancer Research Center, Seattle, Wash (Dr McTiernan).

THIS ARTICLE HAS BEEN CITED BY OTHER ARTICLES

Estrogen Plus Progestin Therapy and Breast Cancer in Recently Postmenopausal Women
Prentice et al.
Am J Epidemiol 2008;167:1207-1216.
ABSTRACT | FULL TEXT  

Changes in breast cancer incidence and mortality in middle-aged and elderly women in 28 countries with Caucasian majority populations
Hery et al.
Ann Oncol 2008;19:1009-1018.
ABSTRACT | FULL TEXT  

Age-specific Trends in Mammographic Density: The Minnesota Breast Cancer Family Study
Kelemen et al.
Am J Epidemiol 2008;167:1027-1036.
ABSTRACT | FULL TEXT  

Conjugated Equine Estrogens and Breast Cancer Risk in the Women's Health Initiative Clinical Trial and Observational Study
Prentice et al.
Am J Epidemiol 2008;0:kwn090v1-kwn090.
ABSTRACT | FULL TEXT  

Increased Risk of Recurrence After Hormone Replacement Therapy in Breast Cancer Survivors
Holmberg et al.
JNCI J Natl Cancer Inst 2008;100:475-482.
ABSTRACT | FULL TEXT  

Impact of Estrogen Deprivation on Gene Expression Profiles of Normal Postmenopausal Breast Tissue In vivo
Kendall et al.
Cancer Epidemiol. Biomarkers Prev. 2008;17:855-863.
ABSTRACT | FULL TEXT  

The Medical Management of Menopause: To Treat or Not To Treat?
BARLOW
Ann. N. Y. Acad. Sci. 2008;1127:134-139.
ABSTRACT | FULL TEXT  

Progesterone Receptor Rapid Signaling Mediates Serine 345 Phosphorylation and Tethering to Specificity Protein 1 Transcription Factors
Faivre et al.
Mol. Endocrinol. 2008;22:823-837.
ABSTRACT | FULL TEXT  

Prediagnostic Use of Hormone Therapy and Mortality After Breast Cancer
Newcomb et al.
Cancer Epidemiol. Biomarkers Prev. 2008;17:864-871.
ABSTRACT | FULL TEXT  

Use of Different Postmenopausal Hormone Therapies and Risk of Histology- and Hormone Receptor-Defined Invasive Breast Cancer
Fournier et al.
JCO 2008;26:1260-1268.
ABSTRACT | FULL TEXT  

Health Risks and Benefits 3 Years After Stopping Randomized Treatment With Estrogen and Progestin
Heiss et al.
JAMA 2008;299:1036-1045.
ABSTRACT | FULL TEXT  

Hormone Therapy, Dilemmas, Medical Decisions.
Schulkin
J Law Med Ethics 2008;36:73-88.
 

Estrogen Plus Progestin and Breast Cancer Detection by Means of Mammography and Breast Biopsy
Chlebowski et al.
Arch Intern Med 2008;168:370-377.
ABSTRACT | FULL TEXT  

Relationship between Menopausal Hormone Therapy and Risk of Ductal, Lobular, and Ductal-Lobular Breast Carcinomas
Li et al.
Cancer Epidemiol. Biomarkers Prev. 2008;17:43-50.
ABSTRACT | FULL TEXT  

Long-Term Treatment of Transsexuals with Cross-Sex Hormones: Extensive Personal Experience
Gooren et al.
J. Clin. Endocrinol. Metab. 2008;93:19-25.
ABSTRACT | FULL TEXT  

Phosphorylation-Dependent Antagonism of Sumoylation Derepresses Progesterone Receptor Action in Breast Cancer Cells
Daniel et al.
Mol. Endocrinol. 2007;21:2890-2906.
ABSTRACT | FULL TEXT  

Estrogen Receptors in BRCA1-Mutant Breast Cancer: Now You See Them, Now You Don't
Jordan
JNCI J Natl Cancer Inst 2007;99:1655-1657.
FULL TEXT  

Progestin-Dependent Progression of Human Breast Tumor Xenografts: A Novel Model for Evaluating Antitumor Therapeutics
Liang et al.
Cancer Res. 2007;67:9929-9936.
ABSTRACT | FULL TEXT  

Mammary Gland Development in Early Pubertal Female Macaques
Wood et al.
Toxicol Pathol 2007;35:793-803.
ABSTRACT  

Relationship Between Epidemiologic Risk Factors and Breast Cancer Recurrence
Brewster et al.
JCO 2007;25:4438-4444.
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  

Randomized Dose-Ranging Trial of Tamoxifen at Low Doses in Hormone Replacement Therapy Users
Decensi et al.
JCO 2007;25:4201-4209.
ABSTRACT | FULL TEXT  

Progestins Reinitiate Cell Cycle Progression in Antiestrogen-Arrested Breast Cancer Cells through the B-Isoform of Progesterone Receptor
McGowan et al.
Cancer Res. 2007;67:8942-8951.
ABSTRACT | FULL TEXT  

Hormones and Breast Cancer: What's the Story?
Brinton and Lacey
Cancer Epidemiol. Biomarkers Prev. 2007;16:1697-1699.
FULL TEXT  

A decline in breast-cancer incidence.
Bluming et al.
NEJM 2007;357:509-510.
FULL TEXT  

Management of cardiovascular risk in the peri-menopausal woman: a consensus statement of European cardiologists and gynaecologists
Collins et al.
Eur Heart J 2007;28:2028-2040.
ABSTRACT | FULL TEXT  

Endogenous Hormone Levels, Mammographic Density, and Subsequent Risk of Breast Cancer in Postmenopausal Women
Tamimi et al.
JNCI J Natl Cancer Inst 2007;99:1178-1187.
ABSTRACT | FULL TEXT  

Breast Cancer Trends: A Marriage Between Clinical Trial Evidence and Epidemiology
Berry and Ravdin
JNCI J Natl Cancer Inst 2007;99:1139-1141.
FULL TEXT  

Disruption of androgen receptor signaling by synthetic progestins may increase risk of developing breast cancer
Birrell et al.
FASEB J. 2007;21:2285-2293.
ABSTRACT | FULL TEXT  

Effect of Tibolone on Breast Cancer Cell Proliferation in Postmenopausal ER+ Patients: Results from STEM Trial
Kubista et al.
Clin. Cancer Res. 2007;13:4185-4190.
ABSTRACT | FULL TEXT  

Critical assessment of new risk factors for breast cancer: considerations for development of an improved risk prediction model
Santen et al.
Endocr Relat Cancer 2007;14:169-187.
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  

Progestin Effects on Breast Cancer Cell Proliferation, Proteases Activation, and in Vivo Development of Metastatic Phenotype All Depend on Progesterone Receptor Capacity to Activate Cytoplasmic Signaling Pathways
Carnevale et al.
Mol. Endocrinol. 2007;21:1335-1358.
ABSTRACT | FULL TEXT  

Age and Menopausal Effects of Hormonal Birth Control and Hormone Replacement Therapy in Relation to Breast Cancer Risk
Shantakumar et al.
Am J Epidemiol 2007;165:1187-1198.
ABSTRACT | FULL TEXT  

Postmenopausal Hormone Therapy and Changes in Mammographic Density
van Duijnhoven et al.
JCO 2007;25:1323-1328.
ABSTRACT | FULL TEXT  

Managing the menopause
Roberts
BMJ 2007;334:736-741.
FULL TEXT  

Endometrial Effects of Tibolone
Archer et al.
J. Clin. Endocrinol. Metab. 2007;92:911-918.
ABSTRACT | FULL TEXT  

Type and Duration of Exogenous Hormone Use A3ects Breast Cancer Histology
Kumar et al.
Ann. Surg. Oncol. 2007;14:695-703.
ABSTRACT | FULL TEXT  

The Role of Extranuclear Signaling Actions of Progesterone Receptor in Mediating Progesterone Regulation of Gene Expression and the Cell Cycle
Boonyaratanakornkit et al.
Mol. Endocrinol. 2007;21:359-375.
ABSTRACT | FULL TEXT  

Selective Activation of Estrogen Receptor-{beta} Transcriptional Pathways by an Herbal Extract
Cvoro et al.
Endocrinology 2007;148:538-547.
ABSTRACT | FULL TEXT  

Safety of hormone therapy after breast cancer: a qualitative systematic review
Antoine et al.
Hum Reprod 2007;22:616-622.
ABSTRACT | FULL TEXT  

Progesterone Receptors Upregulate Wnt-1 To Induce Epidermal Growth Factor Receptor Transactivation and c-Src-Dependent Sustained Activation of Erk1/2 Mitogen-Activated Protein Kinase in Breast Cancer Cells
Faivre and Lange
Mol. Cell. Biol. 2007;27:466-480.
ABSTRACT | FULL TEXT  

Ligand-Selective Interdomain Conformations of Estrogen Receptor-{alpha}
Padron et al.
Mol. Endocrinol. 2007;21:49-61.
ABSTRACT | FULL TEXT  

Risk Factors for Hormone Receptor-Defined Breast Cancer in Postmenopausal Women
Rosenberg et al.
Cancer Epidemiol. Biomarkers Prev. 2006;15:2482-2488.
ABSTRACT | FULL TEXT  

Hormones and Breast Cancer: Should Practice Be Changed?
Collins
Obstet Gynecol 2006;108:1352-1353.
FULL TEXT  

Breast Cancer Risk in Postmenopausal Women Using Estrogen-Only Therapy
Lyytinen et al.
Obstet Gynecol 2006;108:1354-1360.
ABSTRACT | FULL TEXT  

Risk of Brain Tumors Associated with Exposure to Exogenous Female Sex Hormones
Wigertz et al.
Am J Epidemiol 2006;164:629-636.
ABSTRACT | FULL TEXT  

Mammographic Density: Use in Risk Assessment and as a Biomarker in Prevention Trials
Fabian and Kimler
J. Nutr. 2006;136:2705S-2708S.
FULL TEXT  

Prospective breast cancer risk prediction model for women undergoing screening mammography.
Barlow et al.
JNCI J Natl Cancer Inst 2006;98:1204-1214.
ABSTRACT | FULL TEXT  

Sex-steroid regulation of vascular endothelial growth factor in breast cancer.
Hyder
Endocr Relat Cancer 2006;13:667-687.
ABSTRACT | FULL TEXT  

Risk-benefit profiles of raloxifene for women.
Stefanick
NEJM 2006;355:190-192.
FULL TEXT  

Adult weight change and risk of postmenopausal breast cancer.
Eliassen et al.
JAMA 2006;296:193-201.
ABSTRACT | FULL TEXT  

IDENTIFICATION OF HUMAN HEPATIC CYTOCHROME P450 ENZYMES INVOLVED IN THE METABOLISM OF 8-PRENYLNARINGENIN AND ISOXANTHOHUMOL FROM HOPS (HUMULUS LUPULUS L.)
Guo et al.
Drug Metab. Dispos. 2006;34:1152-1159.
ABSTRACT | FULL TEXT  

Aspects of the design and analysis of high-dimensional SNP studies for disease risk estimation
Prentice and QI
Biostatistics 2006;7:339-354.
ABSTRACT | FULL TEXT  

HRT, osteoporosis and regulatory authorities Quis custodiet ipsos custodes?
Stevenson and on behalf of the International Consensus Group on
Hum Reprod 2006;21:1668-1671.
ABSTRACT | FULL TEXT  

Risk Factors for the Incidence of Endometrial Cancer according to the Aggressiveness of Disease
Weiss et al.
Am J Epidemiol 2006;164:56-62.
ABSTRACT | FULL TEXT  

Natural and Synthetic Progestins Accelerate 7,12-Dimethylbenz[a]Anthracene-Initiated Mammary Tumors and Increase Angiogenesis in Sprague-Dawley Rats.
Benakanakere et al.
Clin. Cancer Res. 2006;12:4062-4071.
ABSTRACT | FULL TEXT  

Endocrine Regulation of HOX Genes
Daftary and Taylor
Endocr. Rev. 2006;27:331-355.
ABSTRACT | FULL TEXT  

The WHI and the Postmenopausal Woman: No Magic Bullet
JWatch Women's Health 2006;2006:1-1.
FULL TEXT  

Relationship between Established Breast Cancer Risk Factors and Risk of Seven Different Histologic Types of Invasive Breast Cancer.
Li et al.
Cancer Epidemiol. Biomarkers Prev. 2006;15:946-954.
ABSTRACT | FULL TEXT  

Mammographic density as a surrogate marker for the effects of hormone therapy on risk of breast cancer.
Boyd et al.
Cancer Epidemiol. Biomarkers Prev. 2006;15:961-966.
ABSTRACT | FULL TEXT  

Potentially inappropriate prescribing for elderly patients in 2 outpatient settings.
Maio et al.
American Journal of Medical Quality 2006;21:162-168.
ABSTRACT  

Trends in breast cancer by race and ethnicity: update 2006.
Smigal et al.
CA Cancer J Clin 2006;56:168-183.
ABSTRACT | FULL TEXT  

Effects of Conjugated Equine Estrogens on Breast Cancer and Mammography Screening in Postmenopausal Women With Hysterectomy
Stefanick et al.
JAMA 2006;295:1647-1657.
ABSTRACT | FULL TEXT  

A prospective study of female hormone use and breast cancer among black women.
Rosenberg et al.
Arch Intern Med 2006;166:760-765.
ABSTRACT | FULL TEXT  

Influence of Estrogen Receptor {alpha} and Progesterone Receptor Polymorphisms on the Effects of Hormone Therapy on Mammographic Density.
van Duijnhoven et al.
Cancer Epidemiol. Biomarkers Prev. 2006;15:462-467.
ABSTRACT | FULL TEXT  

Medroxyprogesterone acetate binds the glucocorticoid receptor to stimulate {alpha}-ENaC and sgk1 expression in renal collecting duct epithelia
Thomas et al.
Am. J. Physiol. Renal Physiol. 2006;290:F306-F312.
ABSTRACT | FULL TEXT  

Reform of Drug Regulation -- Beyond an Independent Drug-Safety Board
Ray and Stein
NEJM 2006;354:194-201.
FULL TEXT  

Postmenopausal serum androgens, oestrogens and breast cancer risk: the European prospective investigation into cancer and nutrition
Kaaks et al.
Endocr Relat Cancer 2005;12:1071-1082.
ABSTRACT | FULL TEXT  

Dose and duration of hormone use: understanding the effects of combined menopausal hormones on breast cancer better, 1976-2004
McPherson and Mant
J. Epidemiol. Community Health 2005;59:1078-1079.
FULL TEXT  

Effect of Short-Term Hormone Replacement Therapy on Breast Cancer Risk Reduction After Bilateral Prophylactic Oophorectomy in BRCA1 and BRCA2 Mutation Carriers: The PROSE Study Group
Rebbeck et al.
JCO 2005;23:7804-7810.
ABSTRACT | FULL TEXT  

Breast cancer risk with postmenopausal hormonal treatment
Collins et al.
Hum Reprod Update 2005;11:545-560.
ABSTRACT | FULL TEXT  

Changes in Women's Use of Hormones After the Women's Health Initiative Estrogen and Progestin Trial by Race, Education, and Income
Wei et al.
J Natl Cancer Inst Monogr 2005;2005:106-112.
ABSTRACT | FULL TEXT  

Estrogen-Plus-Progestin Use and Mammographic Density in Postmenopausal Women: Women's Health Initiative Randomized Trial
McTiernan et al.
JNCI J Natl Cancer Inst 2005;97:1366-1376.
ABSTRACT | FULL TEXT  

Premalignant and In Situ Breast Disease: Biology and Clinical Implications
Arpino et al.
ANN INTERN MED 2005;143:446-457.
ABSTRACT | FULL TEXT  

Decreased Androgen Receptor Levels and Receptor Function in Breast Cancer Contribute to the Failure of Response to Medroxyprogesterone Acetate
Buchanan et al.
Cancer Res. 2005;65:8487-8496.
ABSTRACT | FULL TEXT  

Hormone replacement therapy and breast cancer: estimate of risk
Coombs et al.
BMJ 2005;331:347-349.
FULL TEXT  

Proliferation of Endothelial and Tumor Epithelial Cells by Progestin-Induced Vascular Endothelial Growth Factor from Human Breast Cancer Cells: Paracrine and Autocrine Effects
Liang and Hyder
Endocrinology 2005;146:3632-3641.
ABSTRACT | FULL TEXT  

Hormone replacement therapy: pathobiological aspects of hormone-sensitive cancers in women relevant to epidemiological studies on HRT: a mini-review
Dietel et al.
Hum Reprod 2005;20:2052-2060.
ABSTRACT | FULL TEXT  

Breast cancer incidence, case-fatality and breast cancer mortality in Danish women using hormone replacement therapy--a prospective observational study
Stahlberg et al.
Int J Epidemiol 2005;34:931-935.
FULL TEXT  

Benign Breast Disease and the Risk of Breast Cancer
Hartmann et al.
NEJM 2005;353:229-237.
ABSTRACT | FULL TEXT  

The structural basis of androgen receptor activation: Intramolecular and intermolecular amino-carboxy interactions
Schaufele et al.
Proc. Natl. Acad. Sci. USA 2005;102:9802-9807.
ABSTRACT | FULL TEXT  

Premature ovarian failure
Goswami and Conway
Hum Reprod Update 2005;11:391-410.
ABSTRACT | FULL TEXT  

Estrogen and Raloxifene, a Selective Estrogen Receptor Modulator, Ameliorate Renal Damage in db/db Mice
Chin et al.
Am. J. Pathol. 2005;166:1629-1636.
ABSTRACT | FULL TEXT  

Serum Sex Steroids in Premenopausal Women and Breast Cancer Risk Within the European Prospective Investigation into Cancer and Nutrition (EPIC)
Kaaks et al.
JNCI J Natl Cancer Inst 2005;97:755-765.
ABSTRACT | FULL TEXT  

Medroxyprogesterone Acetate and Metastases: Of Mice and (wo)Men
Jordan
JNCI J Natl Cancer Inst 2005;97:619-621.
FULL TEXT  

Postmenopausal hormone therapy: from monkey glands to transdermal patches
Davis et al.
J Endocrinol 2005;185:207-222.
ABSTRACT | FULL TEXT  

Menopause, micronutrients, and hormone therapy
Wylie-Rosett
Am. J. Clin. Nutr. 2005;81:1223S-1231S.
ABSTRACT | FULL TEXT  

Transdermal Drug Delivery: Clinical Considerations for the Obstetrician-Gynecologist
Potts and Lobo
Obstet Gynecol 2005;105:953-961.
ABSTRACT | FULL TEXT  

Reduction in mortality from breast cancer: Fall in use of hormones could have reduced breast cancer mortality
Grant
BMJ 2005;330:1024-1024.
FULL TEXT