BACKGROUND: Circulating estrogens and androgens are important factors in the development of various female cancers. Caffeine intake may decrease risk of breast and ovarian cancer, although the data are not entirely consistent. Whether or not caffeine affects cancer risk by altering sex hormone levels is currently unknown. METHODS: We examined the relationship of caffeine, coffee, decaffeinated coffee, and tea with plasma concentrations of estrogens, androgens, progesterone, prolactin, and sex hormone-binding globulin (SHBG) in 524 premenopausal and 713 postmenopausal women from the Nurses' Health Study (NHS) and NHSII. RESULTS: In premenopausal women, caffeine intake was inversely associated with luteal total and free estradiol, and positively associated with luteal progesterone levels (P-trend = .02, .01, .03, respectively). Coffee intake was significantly associated with lower luteal total and free estradiol levels, but not luteal progesterone levels (P-trend = .007, .004, .20, respectively). Among the postmenopausal women, there was a positive association between caffeine and coffee intake and SHBG levels (P-trend = .03 and .06, respectively). No significant associations were detected with the other hormones. CONCLUSIONS: Data from this cross-sectional study suggest that caffeine may alter circulating levels of luteal estrogens and SHBG, representing possible mechanisms by which coffee or caffeine may be associated with pre- and postmenopausal malignancies, respectively. Future studies evaluating how caffeine-mediated alterations in sex hormones and binding protein levels affect the risk of female cancers are warranted. (c) 2009 American Cancer Society.