Cortisol, a steroid hormone produced by the adrenal cortex, exerts its actions primarily through the glucocorticoid receptor. The glucocorticoid receptor regulates gene transcription by binding to glucocorticoid response elements (GREs) near the basal promoters of cortisol-regulated genes. In the absence of hormone, the glucocorticoid receptor resides in the cytoplasm complexed with chaperone proteins. Upon cortisol binding, the chaperone proteins dissociate, allowing the cortisol-glucocorticoid receptor complex to rapidly translocate into the nucleus. Inside the nucleus, the complex dimerizes and recruits coactivator proteins and general transcription factors, leading to increased or decreased transcription of targeted genes. Additionally, the glucocorticoid receptor can interact with other transcription factors, such as the proinflammatory nuclear factor κB, to inhibit their ability to activate gene expression.

Cortisol, often referred to as a "stress hormone," has a wide range of physiological actions. It helps maintain blood glucose levels, central nervous system function, and cardiovascular function during fasting. During periods of stress, cortisol increases blood glucose at the expense of muscle protein. Furthermore, cortisol plays a crucial role in protecting the body from excessive inflammatory and immune responses. It also inhibits reproductive function to redirect energy towards coping with stress. Additionally, cortisol affects various tissues and systems, including bone, skin, connective tissue, the gastrointestinal tract, and the developing fetus, independent of its stress-related functions. One important aspect of cortisol metabolism is the conversion of cortisol to cortisone by the enzyme 11β-hydroxysteroid dehydrogenase type 2 (11β-HSD2) in target cells of aldosterone. This conversion prevents cortisol from binding to the mineralocorticoid receptor, avoiding inappropriate mineralocorticoid actions. Interestingly, the inactivation of cortisol by 11β-HSD2 is reversible, as cortisone can be converted back to cortisol by another enzyme, 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1), in tissues expressing the glucocorticoid receptor.

Overall, cortisol, through its mechanism of action and physiological effects, plays a crucial role in regulating various aspects of metabolism, stress response, and tissue function.
•Fig. 43.9 A,Reaction1,catalyzedbyCYP11A1,inmakingcortisol.B,Reactions2a/bandreactions3a/b,involvingCYP17(17-hydroxylasefunction)and3β-hydroxysteroiddehydrogenase(3β-HSD),inmakingcortisol.ThisfigureshowstheΔ5versusΔ4pathway.
•Fig. 43.9, cont’d C,Reactions4and5,involvingCYP21BandCYP11B1,inwhichthelasttwostepsincortisolsynthesisarecarriedout.Alsoshownistheminorpathwayleadingtocorticosteronesynthesisinthezonafasciculata.(ModifiedfromWhiteBA,PorterfieldSP.Endocrine and Reproductive Physiology.
4thed.Philadelphia:Mosby;2013.) target cells of aldosterone (see below). The conversion of cortisol to cortisone prevents the binding of cortisol to the MR and having inappropriate mineralocorticoid actions on these cells. Inactivation of cortisol by 11β-HSD2 is reversible in that another enzyme, 11β-HSD1, converts cortisone back to cortisol. This conversion occurs in tissues expressing the glucocorticoid receptor (GR), including liver, adipose tissue, and the CNS, as well as in skin.
Mechanism of Action of Cortisol
Cortisol acts primarily through the glucocorticoid receptor, which regulates gene transcription (see ). In the absence of hormone, the GR resides in the cytoplasm in a stable complex with several molecular chaperones, including heat shock proteins and cyclophilins. Cortisol-GR binding promotes dissociation of the chaperone proteins, followed by: aAllvaluesarerelativetotheglucocorticoidandmineralocorticoidpotenciesofcortisol,whichhaveeachbeenarbitrarilysetat1.0.Cortisolactuallyhasonly1/500thepotencyofthenaturalmineralocorticoidaldosterone.
1.
rapid translocation of the cortisol-GR complex into the nucleus, 2.
dimerization and binding to glucocorticoid response elements (GREs, both “positive” GREs and “negative” GREs) near the basal promoters of cortisol-regulated genes, and 3.
recruitment of coactivator proteins and assembly of general transcription factors leading to increased or decreased transcription of the targeted genes.
In some cases the GR interacts with other transcription factors, such as the proinflammatory nuclear factor (NF)κB transcription factor, and interferes with their ability to activate gene expression.
Physiological Actions of Cortisol
Cortisol has a broad range of actions and is often characterized as a “stress hormone.” In general, cortisol maintains blood glucose levels, CNS function, and cardiovascular function during fasting and increases blood glucose during stress at the expense of muscle protein. Cortisol protects the body against the self-injurious effects of unbridled inflammatory and immune responses. Cortisol also partitions energy to cope with stress by inhibiting reproductive function. As stated later, cortisol has several other effects on bone, skin, connective tissue, the GI tract, and the developing fetus that are independent of its stress-related functions.
As the term glucocorticoid implies, cortisol is a steroid hormone from the adrenal cortex that regulates blood glucose. It increases blood glucose by stimulating gluconeogenesis (