Introduction: Breast cancer is frequently a hormonally dependent cancer, and associations of circulating estrogens and androgens with subsequent breast cancer risk are well established in postmenopausal women. Associations of serum estrogens and androgens with breast cancer risk in premenopausal women are less well studied. The objective of this study was to determine whether estradiol and testosterone levels in serum collected before menopause are associated with subsequent breast cancer risk. Methods: We conducted a prospective case-control study of 266 participants who were registered in the Columbia, Missouri, Serum Bank and not using exogenous hormones at the time of blood collection. Each of 98 insitu or invasive breast cancer cases with prediagnostic serum collected before menopause was matched to two controls by age, date, menstrual cycle day, and time of day of blood collection. Estradiol and testosterone concentrations were quantified by using specific radioimmunoassays, and sex hormone-binding globulin (SHBG) was quantified with a chemiluminescent immunoassay to allow calculation of the non-SHBG bound hormone fractions. Data were analyzed by using conditional logistic regression. All tests of statistical significance were two-sided. Results: Serum testosterone was strongly and significantly associated with breast cancer risk. The relative odds (OR) for increasing quartiles of total testosterone were 1.0, 2.1 (95% confidence interval (CI) 0.9 to 4.8), 1.5 (95% CI, 0.6 to 3.4), and 3.3 (95% CI, 1.5 to 7.5, P_trend = 0.006). Comparable ORs for the non-SHBG bound fraction of testosterone that is bioavailable were 1.0, 1.7 (95% CI, 0.7 to 4.2), 1.7 (95% CI, 0.7 to 4.0), and 4.2 (95% CI, 1.6 to 10.9, P_trend = 0.002). Total and non-SHBG-bound estradiol were not associated with breast cancer, but extreme variation in levels across the menstrual cycle coupled with relatively small numbers, particularly for analyses stratified by cycle phase, limited the power to detect associations. Conclusions: Results suggest that premenopausal women with elevated serum testosterone levels are at an increased risk of breast cancer.

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