Abstract A53: Estrogen metabolism in relation to the risk of aggressive prostate cancer
Authors: Black Amanda , Pinsky Paul F. , Grubb Robert L. , Falk Roni T. , Hsing Ann W. , Chu Lisa W. , Meyer Tamra E. , Veenstra Tim , Xu Xia , Yu Kai , Brinton Louise A. , Hoover Robert N. , Cook Michael B. 
Published: May 2019

Abstract
Introduction and Objective: Existing epidemiologic data do not support an association between circulating levels of sex steroid hormones and risk of prostate cancer. Although it has been suggested that the combined action of androgens and estrogens'specifically their balance'may play a key role in prostate carcinogenesis, epidemiologic studies to evaluate this hypothesis are sparse, have assessed a limited number of sex steroid hormones, and have provided inconsistent results. We investigated associations between serum sex hormones'with a particular focus on estrogen metabolites'and risk of aggressive prostate cancer.
Study Population, Design and Methods: In a case-control study nested within the Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Trial, we measured 15 parent serum estrogens (estrone and estradiol) and estrogen metabolites, including those in the C-2, -4, or 16 hydroxylation pathways, using a liquid chromatography-tandem mass spectrometry (LC/MS/MS) assay. Cases (n=195) were defined as non-Hispanic white men diagnosed with aggressive prostate cancer (stage III or IV and/or Gleason ≥7) between and 1994 and 2009 who were 55–70 years at diagnosis. Controls (n=195) were non-Hispanic white men who were free from prostate cancer for the duration of follow-up and frequency-matched to cases by age at study entry (5-yr intervals), time since baseline screen (1-yr time windows) and year of blood draw. Only cases and controls included in a previous study that measured serum androgens and sex-hormone binding globulin (SHBG) were eligible. Logistic regression models were used to estimate odds ratios (OR) and 95% confidence intervals (95%CI).
Results: Individual parent estrogens and individual estrogen metabolites were unrelated to risk of aggressive prostate cancer; with the exception of a non-linear inverse relationship between cancer and levels of methylated catechols, namely 2- and 4-methoxyestrone. However, there was an increased risk of aggressive prostate cancer associated with an increasing ratio of 2:16 hydroxyestrone (fourth vs. first quartile: OR 2.44, 95% CI 1.34–4.45, p trend=0.001) and a strong trend of decreasing prostate cancer risk with an increasing ratio of estradiol to testosterone (fourth vs. first quartile: OR 0.27, 95% CI 0.12–0.59, p trend=0.003).
Conclusion: We observed a strong protective effect of higher serum estradiol to testosterone levels in relation to risk of aggressive prostate cancer. Men with higher concentrations of methylated catechols in the 2- and 4-hydroxylation pathway may have a reduced risk of aggressive prostate cancer, while those with higher ratios of 2:16 hydroxyestrone may be at increased risk. These findings suggest a role for sex steroid hormone metabolism in prostate carcinogenesis.
Citation Format: Amanda Black, Paul F. Pinsky, Robert L. Grubb, III, Roni T. Falk, Ann W. Hsing, Lisa W. Chu, Tamra E. Meyer, Tim Veenstra, Xia Xu, Kai Yu, Louise A. Brinton, Robert N. Hoover, Michael B. Cook. Estrogen metabolism in relation to the risk of aggressive prostate cancer. [abstract]. In: Proceedings of the Twelfth Annual AACR International Conference on Frontiers in Cancer Prevention Research; 2013 Oct 27-30; National Harbor, MD. Philadelphia (PA): AACR; Can Prev Res 2013;6(11 Suppl): Abstract nr A53.