In obesity, urinary cortisol excretion is enhanced but plasma cortisol levels are elevated, suggesting that metabolic clearance of cortisol is increased. Cortisol is metabolised in liver and fat by A-ring reductases but also regenerated from inactive cortisone in liver, fat, and skeletal muscle by 11β-reductase. These enzymes are regulated by estrogen. This study addressed whether there are differences in cortisol metabolism in obesity, and whether these differences are estrogen dependent.

31 men and 37 post-menopausal women (9 on estrogen replacement therapy) aged 47–53 y supplied 24 h urine for gas chromatograph/mass spectrometry. Total cortisol metabolite excretion was higher in men than women, but weakly related to indices of obesity. By contrast, metabolism of cortisol favoured 5α- rather than 5β-reduction in obese men and obese women, and favoured cortisol rather than cortisone in obese men. In women compared with men ratio sof 5α-/5β-reduced and cortisol/cortisone metabolites were also higher but these variables were not affected by estrogen replacement therapy.

We conclude that in obesity, inactivation of cortisol by 5α-reductase is enhanced but this is offset by impaired metabolism of cortisol by 5β-reductase in women and enhanced conversion of cortisone to cortisol by 11β-reductase in men. These observations suggest that cortisol clearance is altered in obesity, and this may account for activation of the hypothalamic-pituitary-adrenal axis. Moreover, these data predict that obese subjects will have higher concentrations of cortisol in key target tissues including liver and visceral fat. This may contribute to the adverse metabolic consequences of obesity.