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 Web of Science (627)  • Contact me when this article is cited  Related Content  • Related letters  • Related articles  • Similar articles in JAMA  Topic Collections  • Oncology  • Breast Cancer  • Radiologic Imaging  • Women's Health  • Menopause  • Randomized Controlled Trial  • Mammography  • Alert me on articles by topic  Social Bookmarking   What's this?

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).

CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    Twitter     What's this?

RELATED LETTERS

Effects of Conjugated Equine Estrogen in Postmenopausal Women With Hysterectomy: The Women's Health Initiative Randomized Controlled Trial
The Women's Health Initiative Steering Committee
JAMA. 2004;291(14):1701-1712.
ABSTRACT | FULL TEXT  

Effects of Estrogen-Only Treatment in Postmenopausal Women
Carlo Campagnoli, Chiara Abbà, Simona Ambroggio, and Clementina Peris
JAMA. 2004;292(6):684.
EXTRACT | FULL TEXT  

Effects of Estrogen-Only Treatment in Postmenopausal Women—Reply
Garnet L. Anderson
JAMA. 2004;292(6):685-686.
EXTRACT | FULL TEXT  

RELATED ARTICLES

Relationship Between Long Durations and Different Regimens of Hormone Therapy and Risk of Breast Cancer
Christopher I. Li, Kathleen E. Malone, Peggy L. Porter, Noel S. Weiss, Mei-Tzu C. Tang, Kara L. Cushing-Haugen, and Janet R. Daling
JAMA. 2003;289(24):3254-3263.
ABSTRACT | FULL TEXT  

Combined Hormone Therapy and Breast Cancer: A Single-Edged Sword
Peter H. Gann and Monica Morrow
JAMA. 2003;289(24):3304-3306.
EXTRACT | FULL TEXT  

THIS ARTICLE HAS BEEN CITED BY OTHER ARTICLES

Update: A 55-Year-Old Woman With Osteopenia
Mattson-DiCecca et al.
JAMA 2009;302:2023-2024.
FULL TEXT  

Rates of Atypical Ductal Hyperplasia Have Declined with Less Use of Postmenopausal Hormone Treatment: Findings from the Breast Cancer Surveillance Consortium
Menes et al.
Cancer Epidemiol. Biomarkers Prev. 2009;18:2822-2828.
ABSTRACT | FULL TEXT  

Estrogen-Progestagen Menopausal Hormone Therapy and Breast Cancer: Does Delay From Menopause Onset to Treatment Initiation Influence Risks?
Fournier et al.
JCO 2009;27:5138-5143.
ABSTRACT | FULL TEXT  

Combined Hormone Therapy at Menopause and Breast Cancer: A Warning--Short-Term Use Increases Risk
Bernstein
JCO 2009;27:5116-5119.
FULL TEXT  

Variation in the FGFR2 Gene and the Effects of Postmenopausal Hormone Therapy on Invasive Breast Cancer
Prentice et al.
Cancer Epidemiol. Biomarkers Prev. 2009;18:3079-3085.
ABSTRACT | FULL TEXT  

Salivary Sex Hormone Measurement in a National, Population-Based Study of Older Adults
Gavrilova and Lindau
J Gerontol B Psychol Sci Soc Sci 2009;64B:i94-i105.
ABSTRACT | FULL TEXT  

New-Onset Breast Tenderness After Initiation of Estrogen Plus Progestin Therapy and Breast Cancer Risk
Crandall et al.
Arch Intern Med 2009;169:1684-1691.
ABSTRACT | FULL TEXT  

Breast Cancer Patients Unknowingly Dosing Themselves With Estrogen by Using Topical Moisturizers
Olson et al.
JCO 2009;27:e103-e104.
FULL TEXT  

Efficacy, Safety, and Tolerability of Low-Dose Hormone Therapy in Managing Menopausal Symptoms
Langer
J Am Board Fam Med 2009;22:563-573.
ABSTRACT | FULL TEXT  

Regulation of thrombospondin-1 by natural and synthetic progestins in human breast cancer cells
Hyder et al.
Endocr Relat Cancer 2009;16:809-817.
ABSTRACT | FULL TEXT  

Progesterone Increases Rat Neural Progenitor Cell Cycle Gene Expression and Proliferation Via Extracellularly Regulated Kinase and Progesterone Receptor Membrane Components 1 and 2
Liu et al.
Endocrinology 2009;150:3186-3196.
ABSTRACT | FULL TEXT  

Endometrium protection and acceptability of nasally administered continuously combined hormone therapy: a multicentre, multinational, double-blind trial in post-menopausal women evaluating three regimens of 17{beta}-estradiol and norethisterone when compared with an orally administered 17{beta}-estradiol norethisterone regimen
Rozenberg et al.
Hum Reprod 2009;24:1739-1747.
ABSTRACT | FULL TEXT  

Benefits and Risks of Postmenopausal Hormone Therapy When It Is Initiated Soon After Menopause
Prentice et al.
Am J Epidemiol 2009;170:12-23.
ABSTRACT | FULL TEXT  

Cancer Prevention: From 1727 to Milestones of the Past 100 Years
Lippman and Hawk
Cancer Res. 2009;69:5269-5284.
ABSTRACT | FULL TEXT  

Hormone Therapy Use May Explain Recent Results Regarding Tumor Regression
Weedon-Fekjaer et al.
Arch Intern Med 2009;169:996-997.
FULL TEXT  

Drospirenone in HRT?
DTB 2009;47:41-44.
ABSTRACT | FULL TEXT  

Menopausal Hormone Therapy and Risk of Clinical Breast Cancer Subtypes
Slanger et al.
Cancer Epidemiol. Biomarkers Prev. 2009;18:1188-1196.
ABSTRACT | FULL TEXT  

RE: "ESTROGEN PLUS PROGESTIN THERAPY AND BREAST CANCER IN RECENTLY POSTMENOPAUSAL WOMEN"
Langer
Am J Epidemiol 2009;169:784-785.
FULL TEXT  

Cost-effectiveness of hormone replacement therapy for menopausal symptoms in the UK
Lekander et al.
Menopause Int 2009;15:19-25.
ABSTRACT | FULL TEXT  

Regression of progestin-accelerated 7,12-dimethylbenz[a]anthracene-induced mammary tumors in Sprague-Dawley rats by p53 reactivation and induction of massive apoptosis: a pilot study
Benakanakere et al.
Endocr Relat Cancer 2009;16:85-98.
ABSTRACT | FULL TEXT  

Breast Cancer after Use of Estrogen plus Progestin in Postmenopausal Women
Chlebowski et al.
NEJM 2009;360:573-587.
ABSTRACT | FULL TEXT  

Glycodelin in reproductive endocrinology and hormone-related cancer
Seppala et al.
Eur J Endocrinol 2009;160:121-133.
ABSTRACT | FULL TEXT  

Prospective cohort study of soy food intake and colorectal cancer risk in women
Yang et al.
Am. J. Clin. Nutr. 2009;89:577-583.
ABSTRACT | FULL TEXT  

Limited evidence for a protective effect of unopposed oestrogen therapy for osteoarthritis of the hip: a systematic review
de Klerk et al.
Rheumatology (Oxford) 2009;48:104-112.
ABSTRACT | FULL TEXT  

Insulin, Insulin-Like Growth Factor-I, and Risk of Breast Cancer in Postmenopausal Women
Gunter et al.
JNCI J Natl Cancer Inst 2009;101:48-60.
ABSTRACT | FULL TEXT  

Radiation Therapy for Early-Stage Breast Cancer after Breast-Conserving Surgery
Buchholz
NEJM 2009;360:63-70.
FULL TEXT  

Images, femininity and cancer: an analysis of an international patient education programme
Phillips
Health (London) 2009;13:67-85.
ABSTRACT  

Reassessing Benefits and Risks of Hormone Therapy
Gass et al.
AMERICAN JOURNAL OF LIFESTYLE MEDICINE 2009;3:29-43.
ABSTRACT  

Obesity, Mammography Use and Accuracy, and Advanced Breast Cancer Risk
Kerlikowske et al.
JNCI J Natl Cancer Inst 2008;100:1724-1733.
ABSTRACT | FULL TEXT  

Approach to the Patient with Menopausal Symptoms
Martin and Manson
J. Clin. Endocrinol. Metab. 2008;93:4567-4575.
ABSTRACT | FULL TEXT  

The Mammary Glands of Macaques
Cline and Wood
Toxicol Pathol 2008;36:130S-141S.
ABSTRACT | FULL TEXT  

The Natural History of Invasive Breast Cancers Detected by Screening Mammography
Zahl et al.
Arch Intern Med 2008;168:2311-2316.
ABSTRACT | FULL TEXT  

Menopausal Hormone Therapy and Breast Cancer Risk in the NIH-AARP Diet and Health Study Cohort
Brinton et al.
Cancer Epidemiol. Biomarkers Prev. 2008;17:3150-3160.
ABSTRACT | FULL TEXT  

Metabolic Profiling and Cytochrome P450 Reaction Phenotyping of Medroxyprogesterone Acetate
Zhang et al.
Drug Metab. Dispos. 2008;36:2292-2298.
ABSTRACT | FULL TEXT  

Using Mammographic Density to Improve Breast Cancer Screening Outcomes
Kavanagh et al.
Cancer Epidemiol. Biomarkers Prev. 2008;17:2818-2824.
ABSTRACT | FULL TEXT  

Conjugated Equine Estrogens and Colorectal Cancer Incidence and Survival: The Women's Health Initiative Randomized Clinical Trial
Ritenbaugh et al.
Cancer Epidemiol. Biomarkers Prev. 2008;17:2609-2618.
ABSTRACT | FULL TEXT  

Hormone Therapy and the Risk of Breast Cancer in BRCA1 Mutation Carriers
Eisen et al.
JNCI J Natl Cancer Inst 2008;100:1361-1367.
ABSTRACT | FULL TEXT  

Menopausal Hormone Therapy in BRCA1 Mutation Carriers: Uncertainty and Caution
Chlebowski and Prentice
JNCI J Natl Cancer Inst 2008;100:1341-1343.
FULL TEXT  

Metabolism, Distribution, and Excretion of a Next Generation Selective Estrogen Receptor Modulator, Lasofoxifene, in Rats and Monkeys
Prakash et al.
Drug Metab. Dispos. 2008;36:1753-1769.
ABSTRACT | FULL TEXT  

Estrogen plus Progestin and Risk of Benign Proliferative Breast Disease
Rohan et al.
Cancer Epidemiol. Biomarkers Prev. 2008;17:2337-2343.
ABSTRACT | FULL TEXT  

Progesterone Receptor-B Regulation of Insulin-Like Growth Factor-Stimulated Cell Migration in Breast Cancer Cells via Insulin Receptor Substrate-2
Ibrahim et al.
Mol Cancer Res 2008;6:1491-1498.
ABSTRACT | FULL TEXT  

The effect of mifepristone on breast cell proliferation in premenopausal women evaluated through fine needle aspiration cytology
Engman et al.
Hum Reprod 2008;23:2072-2079.
ABSTRACT | FULL TEXT  

Progesterone Receptor Inhibits Aromatase and Inflammatory Response Pathways in Breast Cancer Cells via Ligand-Dependent and Ligand-Independent Mechanisms
Hardy et al.
Mol. Endocrinol. 2008;22:1812-1824.
ABSTRACT | FULL TEXT  

Risk Factors for the Incidence of Breast Cancer: Do They Affect Survival From the Disease?
Barnett et al.
JCO 2008;26:3310-3316.
ABSTRACT | FULL TEXT  

Polymorphisms in Genes Involved in Sex Hormone Metabolism, Estrogen Plus Progestin Hormone Therapy Use, and Risk of Postmenopausal Breast Cancer
Diergaarde et al.
Cancer Epidemiol. Biomarkers Prev. 2008;17:1751-1759.
ABSTRACT | FULL TEXT  

Disposition of Lasofoxifene, a Next-Generation Selective Estrogen Receptor Modulator, in Healthy Male Subjects
Prakash et al.
Drug Metab. Dispos. 2008;36:1218-1226.
ABSTRACT | FULL TEXT  

Colorectal Cancer in Women After Stopping Postmenopausal Hormone Therapy--Reply
Chlebowski
JAMA 2008;299:2744-2745.
FULL TEXT  

The Rise of Raloxifene and the Fall of Invasive Breast Cancer
Jordan
JNCI J Natl Cancer Inst 2008;100:831-833.
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;167:1407-1415.
ABSTRACT | FULL TEXT  

HABITS trial results confirmed in two-year follow-up
Brown
Menopause Int 2008;14:48-51.
FULL TEXT  

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

Estrogen Receptor-Negative Breast Cancer Is Less Likely to Arise among Lipophilic Statin Users
Kumar et al.
Cancer Epidemiol. Biomarkers Prev. 2008;17:1028-1033.
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  

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  

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 | FULL TEXT  

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;357:509-513.
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