Variation in urinary estrogen levels according to breast parenchymal texture in postmenopausal women

Background: Estrogen levels and breast parenchymal texture are both risk factors for breast cancer, but the relationship between the two is incompletely understood. This study evaluated associations between urinary estrogens, their metabolites, and parenchymal texture features in postmenopausal women to clarify how hormonal pathways contribute to radiomic breast tissue characteristics. Methods: Urinary concentrations of estradiol, estrone, and 13 estrogen metabolites were quantified using liquid chromatography/tandem mass spectrometry (LC-MS/MS) and standardized to urinary creatinine levels (pmol/mg creatinine) among 294 postmenopausal women undergoing screening mammography at the University of North Carolina between 2020 and 2022. Women who were using menopausal hormones, oral contraceptives, or chemoprevention, or who had breast implants were excluded. An automated radiomic pipeline was used to quantify 344 parenchymal texture features from bilateral mammograms. Features were harmonized using ComBat to reduce batch effects. Principal components analysis and unsupervised clustering of features were used to define texture groups. Multinomial regression was used to assess associations between texture groups and estrogen levels, with and without adjustment for age and body mass index (BMI). Results: Participants had a median age of 64 years (IQR: 59-71), a median BMI of 28 kg/m2 (IQR: 24-33), and a median total estrogen level of 20.9 pmol/mg creatinine. Participants clustered into three groups (Group 1: n=120, Group 2: n=154, Group 3: n=21). In the unadjusted analysis, Group 1 had lower levels of all parent estrogens and metabolites compared with Group 2, including lower levels of estrone (beta =-0.046, p=0.04), 2-hydroxyestrone (beta=-0.064, p=0.03), 16-epiestriol (beta=-0.177, p = 0.03), and 17-epiestriol (beta=-0.449, p=0.02). Differences in some, but not all, metabolites were attenuated after adjustment. In contrast, there was no consistent difference in estrogens between Group 3 and Group 2 in unadjusted or adjusted analyses. Conclusion: For some postmenopausal women, estrogen metabolism, particularly through the 2- and 16-hydroxylation pathways, was associated with distinct mammographic parenchymal texture profiles. Identification of texture patterns linked to specific hormonal profiles may help explain the biological factors that shape breast composition and inform strategies for prevention of hormonally driven breast cancers.