Research Article Estrogen Metabolism and Mammographic Density in Postmenopausal Women: A Cross-Sectional Study

Background: Prospective studies have consistently found that postmenopausal breast cancer risk increases with circulating estrogens; however, findings from studies of estrogens andmammographic density (MD), an intermediate marker of breast cancer risk, have been inconsistent. We investigated the cross-sectional associations of urinary estrogens, and their 2-, 4-, and 16-hydroxylated metabolites with MD. Methods: Postmenopausal women without breast cancer (n 194), ages 48 to 82 years, and reporting no current menopausal hormone therapy use were enrolled at a clinic in Western NY in 2005. Urinary estrogens and estrogen metabolites were measured using mass spectrometry. Percent MD and dense area (cm2) were measured using computer-assisted analyses of digitized films. Linear regressionmodelswere used to estimate associations of log-transformed estrogen measures with MD while adjusting for age, body mass index (BMI), parity, and past hormone therapy use. Results:Urinary concentrations ofmost individual estrogens andmetaboliteswere not associatedwithMD; however, across the interdecile rangeof the ratio of parent estrogens (estrone andestradiol) to theirmetabolites, MD increased by 6.8 percentage points (P 0.02) and dense area increased by 10.3 cm2 (P 0.03). Across the interdecile ranges of the ratios of 2-, 4-, and16-hydroxylationpathways to theparent estrogens,MDdeclinedby 6.2 (P 0.03), 6.4 (P 0.04), and 5.7 (P 0.05) percentage points, respectively. All associations remained apparent in models without adjustment for BMI. Conclusion: In this study of postmenopausal women, less extensive hydroxylation of parent estrogens was associated with higher MD. Impact: Hydroxylation of estrogens may modulate postmenopausal breast cancer risk through a pathway involving MD. Cancer Epidemiol Biomarkers Prev; 21(9); 1582–91. 2012 AACR