Analgesic Use and Patterns of Estrogen Metabolism in Premenopausal Women

Analgesic use has been hypothesized to reduce the risk of some cancers, with inverse associations between analgesics and colon cancer, and suggestive inverse associations for breast cancer. Estrogen metabolites (EM) have genotoxic and estrogenic potential; genotoxicity may differ by hydroxylation pathway. Analgesic use may impact patterns of estrogen metabolism; effects of analgesics on disease risk could be mediated through these patterns. We conducted a cross-sectional study among 603 premenopausal women in the Nurses' Health Study II. Frequency of aspirin, non-aspirin nonsteroidal anti-inflammatory drugs (NSAIDs), and acetaminophen use was reported via questionnaire; average frequency in 1997 and 1999 was calculated. Women provided urine samples between 1996 and 1999, collected during the mid-luteal phase of the menstrual cycle. Urinary EM were quantified using high-performance liquid chromatography-tandem mass spectrometry. We observed no association between analgesic use and estradiol, estrone, or specific pathways of estrogen metabolism. Women reporting more frequent aspirin use had lower methylated 2-catechols (e.g., 2-hydroxyestrone-3-methyl ether, 2+ days/week vs. non-use: 0.95 vs. 1.21 pmol/mg creatinine; p (difference) = 0.01, p (trend) = 0.07). Non-aspirin NSAID use was positively associated with 17-epiestriol (4+ days/week vs. non-use: 2.48 vs. 1.52 pmol/mg creatinine; p (difference) = 0.01, p (trend) = 0.11). Acetaminophen use was positively associated with total EM (2+ days/week vs. non-use: 236 vs. 198 pmol/mg creatinine; p (difference) = 0.02, p (trend) = 0.11), 2-hydroxyestrone-3-methyl ether (1.6 vs. 1.1 pmol/mg creatinine; p (difference) < 0.01, p (trend) = 0.02), and 16 alpha-hydroxyestrone (17 vs. 12 pmol/mg creatinine; p (difference) = 0.01, p (trend) = 0.05). This study provides the first assessment of analgesic use and patterns of estrogen metabolism in women. While we observed some associations between analgesics and individual EM, no clear patterns emerged.