Under physiological conditions, the production of cortisol is tightly regulated by the so-called hypothalamuspituitary- adrenal (HPA) axis (Figure 1a). Adrenocorticotropin (ACTH) producing cells in the anterior pituitary lobe respond to the hypothalamic corticotropin-releasing hormone (CRH) by increasing the transcription of the pro-opiomelanocortin (POMC) gene. POMC is further processed by prohormone convertases that cleave the POMC molecule into various molecules, e.g. ACTH and α-melanocyte stimulating hormone ¹ ¯ ³. By binding to its receptor (the melanocortin type 2 receptor; MC2R), ACTH induces the expression of several steroidogenic enzymes in the zona fasciculata of the adrenal cortex that are required for the biosynthesis of cortisol, including CYP17A1 and CYP11B1 4. MC2R activation also triggers phosphorylation of the steroidogenic acute regulatory protein (STAR), which facilitates cholesterol transport over the mitochondrial inner membrane. Consequently, the production rate of cortisol will increase.

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Goodlife Healthcare b.v., Ipsen Farmaceutica b.v., Jurriaanse Stichting, Merck, Pfizer b.v. and NovoNordisk
L.J. Hofland (Leo)
Erasmus University Rotterdam
Erasmus MC: University Medical Center Rotterdam