Endometrial carcinoma risks among menopausal estrogen plus progestin and unopposed estrogen users in a cohort of postmenopausal women

Background: Because unopposed estrogen substantially increases endometrial carcinoma risk, estrogen plus progestin is one menopausal hormone therapy formulation for women who have not had a hysterectomy. However, endometrial carcinoma risks among estrogen plus progestin users and among former unopposed estrogen users are not firmly established. Methods: We evaluated endometrial carcinoma risks associated with estrogen plus progestin and unopposed estrogen therapies in 30,379 postmenopausal Breast Cancer Detection Demonstration Project follow-up study participants. We ascertained hormone therapy use and other risk factors during telephone interviews and mailed questionnaires between 1979 and 1998. We identified 541 endometrial carcinomas via self-report, medical records, the National Death Index, and state cancer registries. Poisson regression generated time-dependent rate ratios (RR) and 95% confidence intervals (95% CI). Results: Endometrial carcinoma was significantly associated with estrogen plus progestin only use (n = 68 cancers; RR, 2.6; 95% CI, 1.9-3.5), including both sequential (progestin <15 days per cycle; n = 32 cancers; RR, 3.0; 95% CI, 2.0-4.6) and continuous (progestin at least 15 days per cycle; n = 15 cancers; RR, 2.3; 95% CI, 1.3-4.0) regimens. The RR increased by 0.38 (95% CI, 0.20-0.64) per year of estrogen plus progestin use, and RRs increased with increasing duration of use for both regimens. The strong association with unopposed estrogen use declined after cessation but remained significantly elevated >10 years after last use (RR, 1.5; 95% CI, 1.0-2.1). Conclusions: Both estrogen plus progestin regimens significantly increased endometrial carcinoma risk in this study. Risks among unopposed estrogen users remained elevated long after last use. The prospect that all estrogen plus progestin regimens increase endometrial carcinoma risk deserves continued research.