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Experimental and clinical evidence suggests that 16α-hydroxylated estrogen metabolites, biologically strong estrogens, are associated with breast cancer risk, while 2-hydroxylated metabolites, with lower estrogenic activity, are weakly related to this disease. This study analyzes the association of breast cancer risk with estrogen metabolism, expressed as the ratio of 2-hydroxyestrone to 16α-hydroxyestrone, in a prospective nested case-control study. Between 1987 and 1992, 10,786 women (ages 35–69 years) were recruited to a prospective study on breast cancer in Italy, the “Hormones and Diet in the Etiology of Breast Cancer” (ORDET) study. Women with a history of cancer and women on hormone therapy were excluded at baseline. At recruitment, overnight urine was collected from all participants and stored at −80°C. After an average of 5.5 years of follow-up, 144 breast cancer cases and four matched controls for each case were identified among the participants of the cohort. Among premenopausal women, a higher ratio of 2-hydroxyestrone to 16α-hydroxyestrone at baseline was associated with a reduced risk of breast cancer: women in the highest quintile of the ratio had an adjusted odds ratio (OR) for breast cancer of 0.58 [95% confidence interval (CI) = 0.25−1.34]. The corresponding adjusted OR in postmenopausal women was 1.29 (95% CI = 0.53–3.10). Results of this prospective study support the hypothesis that the estrogen metabolism pathway favoring 2-hydroxylation over 16α-hydroxylation is associated with a reduced risk of invasive breast cancer risk in premenopausal women.