Cortisol exposure and sensitivity in health and disease

Cortisol, the main glucocorticoid (GC) in man, is produced by the adrenal glands and its secretion is under control of the Hypothalamic-Pituitary-Adrenal (HPA) axis. Activation of the HPA-axis begins with the release of corticotrophinreleasing hormone (CRH) from neurons in the paraventricular nucleus (PVN) of the hypothalamus (1). CRH is released in the hypophysial-portal circulation and binds to the type 1 corticotrophin releasing hormone receptors (CRH-R1) on the anterior pituitary corticotroph cells. This stimulates the biosynthesis and secretion of adrenocorticotropic hormone (ACTH) (2). This hormone is produced by cleavage of pro-opiomelanocortin (POMC). ACTH is released in the peripheral circulation and stimulates glucocorticoid production by the zona fasciculate cells of the adrenal cortex, by binding to the type 2 melanocortin receptor (MC2-R). Binding of ACTH to its receptor results in elevated intracellular levels of cyclic AMP (cAMP), which ultimately leads to activation of steroidogenic enzymes, which are required for the cortisol synthesis from cholesterol (3-4). There are three regulatory mechanisms of cortisol secretion, namely 1) the inhibition of ACTH and CRH production by cortisol itself (negative feedback), 2) the circadian rhythm of ACTH and cortisol secretion and 3) the response to stress of the HPA-axis. A simplified version of the HPA-axis is shown in figure 1.