Effect of 11-β-hydroxysteroid dehydrogenase 2 (11-βHSD2) activity on intracellular metabolism of cortisol in a mineralocorticoid target tissue. (A) Normal physiologic conditions. 11-βHSD2 converts cortisol to inactive cortisone, preventing cortisol activation of the mineralocorticoid receptor. (B) In the setting of high circulating concentrations of cortisol (pharmacologic doses), the 11-βHSD2 isoenzyme is overloaded, and cortisol can activate the mineralocorticoid receptor. (C) (Theoretical) Upregulation of 11-βHSD2 activity inactivates cortisol even in pharmacologic doses, allowing aldosterone to exert separate mineralocorticoid action.