Glucocorticoid metabolism. The secretion of glucocorticoids by the adrenal gland is regulated by the HPA axis via secretion of ACTH. The main plasma cortisol (F) is protein bound with 4–5% free fraction. The plasma cortisone (E) is in the free unbound form. The equilibrium of cortisol and cortisone between the plasma and tissues are illustrated with the dotted bidirectional arrows. Tissue-specific GC metabolism are also depicted. GCs are metabolized primarily in liver and the metabolites are excreted in the urine. Only tissues relevant to the Metabolic Syndrome are shown. THE, tetrahydrocortisone; THF, tetrahydrocortisol.