Epidemiological study of urinary 6 beta-hydroxycortisol to cortisol ratiosand breast cancer risk

The ratio of urinary 6 beta -hydroxycortisol:cortisol is a measure of the a ctivity of cytochrome p450 3A4 (CYP3A4), CYP3A4 catalyzes the formation of the genotoxic estrogen, 16 alpha -hydroxyestrone. It is also involved in th e activation of many other mammary carcinogens, such as the polycyclic arom atic hydrocarbons and heterocyclic amines, We evaluated the association bet ween urinary cortisol ratios and breast cancer risk in a subgroup of women who participated in a population-based case-control study in Shanghai, Over night urine samples from 246 case-control pairs were assayed for 6 beta -hy droxycortisol (6 beta -OHC) to cortisol, The urine samples from all of the breast cancer patients were collected before any chemotherapy or radiothera py. In-person interviews were conducted to obtain comprehensive information on dietary habits, reproductive history, and other lifestyle factors. The median levels of 6 beta -OHC:cortisol ratios were 2,61 in cases and 2.16 in controls, a 20.8% difference (P < 0,001), The case-control difference was Larger in women over 45 years of age (31.3% difference; P < 0.001) than you nger women (6.0%; P = 0,45), After adjusting for confounding variables, the risks of breast cancer were increased from 1.0 (reference) to 1.6 [95% con fidence interval (CI), 0,9-3,1], 2.2 (95% CI, 1,1-4,2), and 3.7 (95% CI, 1. 9-7.4; P for trend, <0.001) with increasing levels of 6<beta>-OHC:cortisol ratios. The positive association was more pronounced among older women (>45 years) than among younger women (1;45 years). The adjusted odds ratios ass ociated with the highest cortisol ratio were 6.0 (95% CI, 2.21-6.1) among o lder women and 2.2 (95%CI, 0.8-6.1) among younger women. The association of the 6 beta -OHC:cortisol ratio was stronger among older women who had a hi gh body mass index, late age at menopause, and early age at menarche (facto rs related to high endogenous estrogen exposure) than those who did not hav e these factors. These findings are consistent with the role of CYP3A4 in e strogen and carcinogen metabolism and suggest that high CYP3A4 activity may be a risk factor for breast cancer risk.