Louise A. Brinton^1,*, Britton Trabert¹, Garnet L. Anderson², Roni T. Falk1, Ashley S Felix³, Barbara J. Fuhrman⁴, Margery L. Gass⁵, Lewis H. Kuller⁶, Ruth M. Pfeiffer¹, Thomas E. Rohan⁷, Howard D. Strickler⁷, Xia Xu⁸, and Nicolas Wentzensen¹

¹Division of Cancer Epidemiology and Genetics, National Cancer Institute

²Division of Public Health Sciences, Fred Hutchinson Cancer Research Center

³Epidemiology, Ohio State University

⁴Department of Epidemiology, University of Arkansas for Medical Sciences

⁵Women's Health Institute, Cleveland Clinic

⁶Department of Epidemiology, University of Pittsburgh

⁷Department of Epidemiology and Population Health, Albert Einstein College of Medicine

⁸Cancer Research Technology Program, Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research

Corresponding Author:
Louise A. Brinton, Division of Cancer Epidemiology and Genetics, National Cancer Institute, 9609 Medical Center Dr, Room 7E-102, MSC 9774, Bethesda, MD, 20892-9774, United States. E-mail: brintonl@exchange.nih.gov

Background: Although endometrial cancer is clearly influenced by hormonal factors, few epidemiologic studies have investigated the role of endogenous estrogens or especially estrogen metabolites. Methods: We conducted a nested case-control study within the Women's Health Initiative Observational Study (WHI-OS), a cohort of 93,676 postmenopausal women recruited between 1993-1998. Using baseline serum samples from women who were non-current hormone users with intact uteri, we measured 15 estrogens/estrogen metabolites via HPLC-MS/MS among 313 incident endometrial cancer cases (271 Type I, 42 Type II) and 354 matched controls, deriving adjusted odds ratios (OR) and 95% confidence intervals (CIs) for overall and subtype-specific endometrial cancer risk. Results: Parent estrogens (estrone and estradiol) were positively related to endometrial cancer risk, with the highest risk observed for unconjugated estradiol (OR 5th vs. 1st quintile=6.19, 95% CI 2.95-13.03, ptrend=0.0001). Nearly all metabolites were significantly associated with elevated risks, with some attenuation after adjustment for unconjugated estradiol (residual risks of 2-3-fold). Body mass index (kg/m2, BMI) relations were somewhat reduced after adjustment for estrogen levels. The association with unconjugated estradiol was stronger for Type I than II tumors (phet=0.01). Conclusions: Parent estrogens as well as individual metabolites appeared to exert generalized uterotropic activity, particularly for type I tumors. The effects of obesity on risk were only partially explained by estrogens. Impact: These findings enhance our understanding of estrogen mechanisms involved in endometrial carcinogenesis but also highlight the need for studying additional markers that may underlie the effects on risk of certain risk factors, e.g., obesity.