Finken M J, Andrews R C, Andrew R, Walker B R
University of Edinburgh, Department of Medical Sciences, Western General Hospital, United Kingdom.
J Clin Endocrinol Metab. 1999 Sep;84(9):3316-21. doi: 10.1210/jcem.84.9.6009.
Cortisol is metabolized irreversibly by A-ring reductases (5alpha- and 5beta-reductases) and reversibly (to cortisone) by 11beta-hydroxysteroid dehydrogenases (11betaHSDs). In rats, estradiol down-regulates 11betaHSD1 expression. In humans, ratios of urinary cortisol/cortisone metabolites differ in men and women. In this study, urinary cortisol metabolites and hepatic 11betaHSD1 activity were measured in healthy young men and women at different phases of the menstrual cycle. Ten men and 10 women with regular menstrual cycles collected a 24-h urine sample, took 250 microg oral dexamethasone at 2300 h, took 25 mg oral cortisone at 0900 h (after fasting), and had blood sampled for plasma cortisol estimation over the subsequent 150 min. Women repeated the tests in random order in menstrual, follicular, and luteal phases. Women excreted disproportionately less A-ring-reduced metabolites of cortisol [median 5alpha-tetrahydrocortisol, 1811 (interquartile range, 1391-2300) microg/day in menstrual phase vs. 2723 (interquartile range, 2454-3154) in men (P = 0.01); 5beta-tetrahydrocortisol, 1600 (interquartile range, 1419-1968) vs. 2197 (interquartile range, 1748-2995; P = 0.03)] but similar amounts of cortisol, cortisone, and tetrahydrocortisone. Analogous differences were observed in urinary excretion of androgen metabolites. Conversion of cortisone to cortisol on hepatic first pass metabolism was not different (peak plasma cortisol, 733 +/- 60 nmol/L in women vs. 684 +/- 53 nmol/L in men; mean +/- SEM; P = 0.55). There were no differences in cortisol or androgen metabolism between phases of the menstrual cycle. We conclude that sexual dimorphism in cortisol metabolite excretion is attributable to less A-ring reduction of cortisol in women, rather than less reactivation of cortisone to cortisol by 11betaHSD1. This difference is not influenced acutely by gonadal steroids. 11BetaHSD1 has been suggested to modulate insulin sensitivity and body fat distribution, but caution must be exercised in extrapolating inferences about its regulation from rodents to man. A-Ring reductases may have an equally important influence on metabolic clearance of cortisol and intracellular cortisol concentrations.
皮质醇可被A环还原酶（5α-和5β-还原酶）不可逆地代谢，并被11β-羟基类固醇脱氢酶（11βHSDs）可逆地（转化为可的松）代谢。在大鼠中，雌二醇下调11βHSD1的表达。在人类中，尿皮质醇/可的松代谢物的比率在男性和女性中有所不同。在本研究中，测量了健康年轻男性和女性在月经周期不同阶段的尿皮质醇代谢物和肝脏11βHSD1活性。10名月经周期规律的男性和10名女性收集了24小时尿液样本，于23:00口服250微克地塞米松，于09:00（禁食后）口服25毫克可的松，并在随后的150分钟内采集血样以测定血浆皮质醇。女性在月经周期的月经期、卵泡期和黄体期以随机顺序重复这些测试。女性排泄的皮质醇A环还原代谢物明显较少[月经期5α-四氢皮质醇中位数为1811（四分位间距，1391 - 2300）微克/天，男性为2723（四分位间距，2454 - 3154）（P = 0.01）；5β-四氢皮质醇，1600（四分位间距，1419 - 1968）对2197（四分位间距，1748 - 2995；P = 0.03）]，但皮质醇、可的松和四氢可的松的排泄量相似。在雄激素代谢物的尿排泄中也观察到类似差异。肝脏首过代谢时可的松向皮质醇的转化没有差异（女性血浆皮质醇峰值为733±60纳摩尔/升，男性为684±53纳摩尔/升；均值±标准误；P = 0.55）。月经周期各阶段之间的皮质醇或雄激素代谢没有差异。我们得出结论，皮质醇代谢物排泄的性别差异归因于女性皮质醇的A环还原较少，而非11βHSD1将可的松再激活为皮质醇的能力较低。这种差异不受性腺类固醇的急性影响。有人提出11βHSD1可调节胰岛素敏感性和体脂分布，但在将关于其调节的推论从啮齿动物外推至人类时必须谨慎。A环还原酶可能对皮质醇的代谢清除和细胞内皮质醇浓度有同样重要的影响。
