Background: Prospective studies have consistently found that postmenopausal breast cancer risk increases with circulating estrogens; however, findings from studies of estrogens and mammographic 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 regression models were 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 of most individual estrogens and metabolites were not associated with MD; however, across the interdecile range of the ratio of parent estrogens (estrone and estradiol) to their metabolites, 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-, and 16-hydroxylation pathways to the parent estrogens, MD declined by 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
