English: Regulation of glucocorticoid (GC) levels in blood and tissues. Circulating GC levels are tightly regulated by negative feedback inhibition at the hypothalamic-pituitary-adrenal (HPA) axis. Active GCs (cortisol in humans, corticosterone in rodents) circulate mostly bound to CBG (corticosteroid binding globulin) such that only ~4% are free to enter tissues. The inactive GCs (cortisone, 11-dehydrocorticosterone) the products of 11β-HSD2 metabolism mainly in kidney, circulates unbound to plasma proteins so all are available to enter tissues. Once inside the cell, there is another level of control by the presence of 11β-HSD1 (found in specific cells in the adult brain such as in hippocampus and cortex and other tissues such as liver and adipose). 11β-HSD1 regenerates active GCs from their inactive forms thereby effectively amplifying intracellular GC levels before they bind to MR and/or GR (depending on brain region). The activated receptors then translocate into the nucleus to activate the transcription of target genes.