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James V. Lacey, Jr, PhD; Pamela J. Mink, PhD; Jay H. Lubin, PhD; Mark E. Sherman, MD; Rebecca Troisi, ScD; Patricia Hartge, ScD; Arthur Schatzkin, MD, DrPH; Catherine Schairer, PhD

JAMA. 2002;288:334-341.

Context  The association between menopausal hormone replacement therapy and ovarian cancer is unclear.

Objective  To determine whether hormone replacement therapy using estrogen only, estrogen-progestin only, or both estrogen only and estrogen-progestin increases ovarian cancer risk.

Design  A 1979-1998 cohort study of former participants in the Breast Cancer Detection Demonstration Project, a nationwide breast cancer screening program.

Setting  Twenty-nine US clinical centers.

Participants  A total of 44 241 postmenopausal women (mean age at start of follow-up, 56.6 years).

Main Outcome Measure  Incident ovarian cancer.

Results  We identified 329 women who developed ovarian cancer during follow-up. In time-dependent analyses adjusted for age, menopause type, and oral contraceptive use, ever use of estrogen only was significantly associated with ovarian cancer (rate ratio [RR], 1.6; 95% confidence interval [CI], 1.2-2.0). Increasing duration of estrogen-only use was significantly associated with ovarian cancer: RRs for 10 to 19 years and 20 or more years were 1.8 (95% CI, 1.1-3.0) and 3.2 (95% CI, 1.7-5.7), respectively (P value for trend <.001), and we observed a 7% (95% CI, 2%-13%) increase in RR per year of use. We observed significantly elevated RRs with increasing duration of estrogen-only use across all strata of other ovarian cancer risk factors, including women with hysterectomy. The RR for estrogen-progestin use after prior estrogen-only use was 1.5 (95% CI, 0.91-2.4), but the RR for estrogen-progestin–only use was 1.1 (95% CI, 0.64-1.7). The RRs for less than 2 years and 2 or more years of estrogen-progestin–only use were 1.6 (95% CI, 0.78-3.3) and 0.80 (95% CI, 0.35-1.8), respectively, and there was no evidence of a duration response (P value for trend = .30).

Conclusion  Women who used estrogen-only replacement therapy, particularly for 10 or more years, were at significantly increased risk of ovarian cancer in this study. Women who used short-term estrogen-progestin–only replacement therapy were not at increased risk, but risk associated with short-term and longer-term estrogen-progestin replacement therapy warrants further investigation.

Author Affiliations: Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, Md.

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RELATED LETTER

Estrogen Replacement Therapy and Risk of Ovarian Cancer in Postmenopausal Women
Kenneth Burry, Joanna M. Cain, Lucy Gilbert, Srinivasan Krishnamurthy, Seang Lin Tan, Eduardo L. Franco, James V. Lacey, Jr, Pamela J. Mink, Jay H. Lubin, Mark E. Sherman, Rebecca Troisi, Patricia Hartge, Arthur Schatzkin, and Catherine Schairer
JAMA. 2002;288(20):2538-2539.
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