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The Women's Health Initiative Randomized Trial

Garnet L. Anderson, PhD; Howard L. Judd, MD; Andrew M. Kaunitz, MD; David H. Barad, MD, MS; Shirley A. A. Beresford, PhD; Mary Pettinger, MS; James Liu, MD; S. Gene McNeeley, MD; Ana Maria Lopez, MD; for the Women's Health Initiative Investigators

JAMA. 2003;290:1739-1748.

Context  The effects of continuous combined hormone therapy on gynecologic cancers have not been investigated previously in a randomized trial setting.

Objective  To determine the possible associations of estrogen plus progestin on gynecologic cancers and related diagnostic procedures.

Design, Setting, and Participants  Randomized, double-blind, placebo-controlled trial of 16 608 postmenopausal women, who had not had a hysterectomy at baseline and who had been recruited from 40 US clinical centers between September 1993 and October 1998 (average follow-up, 5.6 years).

Intervention  One tablet per day containing 0.625 mg of conjugated equine estrogens plus 2.5 mg of medroxyprogesterone acetate (n = 8506) or placebo (n = 8102).

Main Outcome Measure  Incident invasive cancer of the ovary and endometrium.

Results  In 5.6 years of follow-up, there were 32 cases of invasive ovarian cancer, 58 cases of endometrial cancer, 1 case of nonendometrial uterine cancer, 13 cases of cervical cancer, and 7 cases of other gynecologic cancers. The hazard ratio (HR) for invasive ovarian cancer in women assigned to estrogen plus progestin compared with placebo was 1.58 (95% confidence interval [CI], 0.77-3.24). The HR for endometrial cancer was 0.81 (95% CI, 0.48-1.36). No appreciable differences were found in the distributions of tumor histology, stage, or grade for either cancer site. The incidence of other gynecologic cancers was low and did not differ by randomization assignment. More women taking estrogen plus progestin required endometrial biopsies (33% vs 6%; P<.001).

Conclusions  This randomized trial suggests that continuous combined estrogen plus progestin therapy may increase the risk of ovarian cancer while producing endometrial cancer rates similar to placebo. The increased burden of endometrial biopsies required to assess vaginal bleeding further limits the acceptability of this regimen. These data provide additional support for caution in the use of continuous combined hormones.

Author Affiliations: Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, Wash (Drs Anderson and Beresford and Ms Pettinger); Department of Epidemiology, University of Washington, Seattle (Dr Beresford); Department of Obstetrics and Gynecology, University of California, Los Angeles (Dr Judd); Department of Obstetrics and Gynecology, University of Florida Health Science Center, Jacksonville (Dr Kaunitz); Department of Obstetrics and Gynecology and Women's Health, Albert Einstein College of Medicine, Bronx, NY (Dr Barad); Department of Reproductive Biology, Case Western Reserve University, Cleveland, Ohio (Dr Liu); Department of Obstetrics and Gynecology, Wayne State University, Detroit, Mich (Dr McNeeley); and Department of Internal Medicine, University of Arizona Cancer Center, Tucson (Dr Lopez).

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RELATED LETTERS

Hormone Therapy and Risk of Gynecologic Cancers
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JAMA. 2004;291(1):42.
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Hormone Therapy and Risk of Gynecologic Cancers—Reply
Garnet L. Anderson, Howard L. Judd, Andrew M. Kaunitz, S. Gene McNeeley, David H. Barad, James Liu, Ana Maria Lopez, Shirley A. A. Beresford, and Mary Pettinger
JAMA. 2004;291(1):43.
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JAMA. 2003;290(13):1729-1738.
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