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Cortisol Metabolism in Healthy Young Adults: Sexual Dimorphism in Activities of A-Ring Reductases, but not 11ß-Hydroxysteroid Dehydrogenases¹

University of Edinburgh, Endocrinology Unit, Department of Medical Sciences, Western General Hospital, Edinburgh, United Kingdom EH4 2XU

Address all correspondence and requests for reprints to: Dr. Brian R. Walker, University of Edinburgh, Endocrinology Unit, Department of Medical Sciences, Western General Hospital, Edinburgh, United Kingdom EH4 2XU. E-mail: b.walker{at}ed.ac.uk

Cortisol is metabolized irreversibly by A-ring reductases (5- and 5ß-reductases) and reversibly (to cortisone) by 11ß-hydroxysteroid dehydrogenases (11ßHSDs). In rats, estradiol down-regulates 11ßHSD1 expression. In humans, ratios of urinary cortisol/cortisone metabolites differ in men and women. In this study, urinary cortisol metabolites and hepatic 11ßHSD1 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 µg 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 5-tetrahydrocortisol, 1811 (interquartile range, 1391–2300) µg/day in menstrual phase vs. 2723 (interquartile range, 2454–3154) in men (P = 0.01); 5ß-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 11ßHSD1. This difference is not influenced acutely by gonadal steroids. 11ßHSD1 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.

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