Endogenous sex hormones, aromatase activity and lung cancer risk in postmenopausal never‐smoking women

Although reproductive factors have been repeatedly associated with lung cancer risk, no study to date has directly evaluated the relationship with endogenous sex hormones nor with aromatase activity in postmenopausal never‐smoking women. A case‐control study of 397 incident lung cancer cases and their individually matched controls, nested within the Shanghai Women's Health Study, was conducted among postmenopausal women who were lifetime never smokers. Prediagnostic concentrations of sex hormones was quantitated using LC‐MS/MS assays in plasma. The product‐substrate molar ratio of estrone to androstenedione was used as an index of aromatase activity (IAA). Multivariable conditional logistic regression models were used to calculate odds ratios (ORs) for lung cancer. Baseline concentrations of estradiol, free testosterone and IAA were inversely associated with subsequent risk of lung cancer in multivariable‐adjusted models. When further adjusted for body mass index, the inverse association with estradiol was attenuated and no longer statistically significant, but the association with free testosterone and IAA remained. In analyses confined to participants having never used menopausal hormone therapy in 376 case‐control pairs, the inverse association with free testosterone and IAA was slightly strengthened. OR for the highest vs the lowest quartile of free testosterone was 0.55 (95% CI = 0.34‐0.90; Ptrend = .03), and the corresponding OR for IAA was 0.57 (95% CI = 0.34‐0.96; Ptrend = .04). Our study, for the first time, suggests that higher levels of circulating free testosterone and estimated aromatase activity may be associated with lower lung cancer risk in postmenopausal never‐smoking women. What's new? Reproductive factors have been repeatedly associated with lung cancer risk in epidemiological studies. However, no study to date has prospectively evaluated the association between endogenous sex hormones and lung cancer risk in postmenopausal never‐smoking women. In this nested case‐control study, the authors found that higher baseline levels of circulating free testosterone may be associated with lower risk of lung cancer in postmenopausal never‐smoking women. A similar association was found with aromatase activity, which is primarily responsible for the catalysis of estrogen production in postmenopausal women. The findings may point to novel mechanisms of lung cancer in never‐smoking women.