Although elevated circulating estrogens are associated with increased postmenopausal breast cancer risk, less is known regarding the role of estrogen metabolism in breast carcinogenesis. We conducted a case–cohort study within the Breast and Bone Follow-up to the Fracture Intervention Trial to assess serum estrogens and estrogen metabolites (EMs) in 407 incident breast cancer cases diagnosed during follow-up and a subcohort of 496 women. In 1992–93, women completed a baseline questionnaire and provided blood samples. Hazard ratios (HRs) and 95% confidence intervals (CIs), adjusted for geography and trial participation status, were estimated using Cox proportional hazard regression. Serum concentrations of EMs were measured by liquid chromatography–tandem mass spectrometry. EMs (quintiles, Q) were analyzed individually, as metabolic pathways (C-2, -4 or -16) and as ratios. Elevated circulating estradiol was associated with increased breast cancer risk (HR _Q5vsQ1 = 1.86; 95% CI: 1.19–2.90; P trend = 0.04). An elevated ratio of the 2-hydroxylation pathway (HR _Q5vsQ1 = 0.69; 95% CI: 0.46–1.05; P trend = 0.01) and 4-hydroxylation pathway (HR _Q5vsQ1 = 0.61; 95% CI: 0.40–0.93; P trend = 0.004) to parent estrogens (estradiol and estrone) was inversely associated with risk. A higher ratio of the 2/16-hydroxylation pathways was associated with reduced risk (HR _Q5vsQ1 = 0.60; 95% CI: 0.40–0.90; P trend = 0.002). Increased 2- or 4-hydroxylation of parent estrogens may lower risk of postmenopausal breast cancer. Analyses of metabolic pathways may help elucidate the role of estrogen metabolism in breast carcinogenesis.

R and 15 urinary estrogens and estrogen metabolites (EM) among postmenopausal controls from a population-based breast cancer case-control study conducted in Poland (2000–2003). Methods Postmenopausal women (N = 542) were ages 40 to 72 yr and not currently using hormone therapy. Accelerometers, worn for 7 d, were used to derive measures of average activity (counts per day) and sedentary behavior (<100 counts per minute per day). Estrogen metabolites were measured in 12-h urine samples using liquid chromatography-tandem mass spectrometry. Estrogen metabolites were analyzed individually, in metabolic pathways (C-2, -4, or -16), and as ratios relative to parent estrogens. Geometric means of estrogen metabolites by tertiles of accelerometer-measures, adjusted for age and body mass, were computed using linear models. Results High activity was associated with lower levels of estrone and estradiol (P trend = 0.01), whereas increased sedentary time was positively associated with these parent estrogens (P trend = 0.04). Inverse associations were observed between high activity and 2-methoxyestradiol, 4-methoxyestradiol, 17-epiestriol, and 16-epiestriol (P trend = 0.03). Sedentary time was positively associated with methylated catechols in the 2- and 4-hydroxylation pathways (P trend ≤ 0.04). Women in the highest tertile of activity had increased hydroxylation at the C-2, -4, and -16 sites relative to parent estrogens (P trend ≤ 0.02), whereas increased sedentary time was associated with a lower 16-pathway/parent estrogen ratio (P trend = 0.01). Conclusions Higher activity was associated with lower urinary estrogens, possibly through increased estrogen hydroxylation and subsequent metabolism, whereas sedentary behavior may reduce metabolism....

Phthalates, plasticizers ubiquitous in household and personal care products, have been associated with metabolic disturbances. Despite the noted racial differences in phthalate exposure and the prevalence of metabolic syndrome (MetS), it remains unclear whether associations between phthalate metabolites and MetS vary by race and sex. A cross-sectional analysis was conducted among 10,017 adults from the National Health and Nutritional Examination Survey (2005–2014). Prevalence odds ratios (POR) and 95% confidence intervals (CIs) were estimated for the association between 11 urinary phthalate metabolites and MetS using weighted sex and race stratified multivariable logistic regression. Higher MCOP levels were significantly associated with increased odds of MetS among women but not men, and only remained significant among White women (POR _{Q4 vs. Q1} = 1.68, 95% CI: 1.24, 2.29; p-trend = 0.001). Similarly, the inverse association observed with MEHP among women, persisted among White women only (POR _{Q4 vs. Q1} = 0.53, 95% CI: 0.35, 0.80; p-trend = 0.003). However, ΣDEHP metabolites were associated with increased odds of MetS only among men, and this finding was limited to White men (POR _{Q4 vs. Q1} = 1.54, 95% CI: 1.01, 2.35; p-trend = 0.06). Among Black men, an inverse association was observed with higher MEP levels (POR _{Q4 vs. Q1} = 0.43, 95% CI: 0.24, 0.77; p-trend = 0.01). The findings suggest differential associations between phthalate metabolites and MetS by sex and race/ethnicity.