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Lipidomics Gateway (28 March 2012) [doi:10.1038/lipidmaps.2012.7]

Elevated levels of cortisol are designed to help the body respond to danger, but chronic exposure to this glucocorticoid can have detrimental effects.

Dubbed 'the stress hormone', the glucocorticoid cortisol is involved in the 'fight or flight' response. Although the threats faced by our prehistoric ancestors differ from today's stresses, the primary physiological effects — increased blood pressure, increased blood sugar levels and suppression of the immune system — are ultimately the same, and are designed to improve our chances of survival.

In response to the pituitary hormone adrenocorticotropic hormone (ACTH), the secretion of which is, in turn, induced by corticotropin-releasing hormone released from the hypothalamus, cells in the zona fasciculata of the adrenal cortex secrete cortisol. ACTH enhances transcription of the steroidogenic acute regulatory protein, which mediates the transfer of mobilized cholesterol from the outer to the inner mitochondrial membrane. Here, cleavage of the side chain, catalyzed by cytochrome P450 monooxygenase (CYP)11A, converts cholesterol to pregnenolone, which is subsequently hydroxylated by CYP17 to 17α-hydroxypregnenolone prior to the formation of 17α-hydroxyprogesterone by 3β-hydroxysteroid dehydrogenase. CYP21 and 11β-hydroxylase catalyze the conversion to 11-deoxycortisol and, subsequently, cortisol 1 .

In the absence of stress and other factors that can influence the levels of cortisol (such as laughing or sleep deprivation), the secretion of this steroid hormone follows a diurnal pattern: high levels in the morning rapidly decline towards midday and then more gradually throughout the remainder of the day. The vast majority of cortisol in the blood is bound to carrier proteins, predominantly corticosteroid-binding globulin (also known as transcortin), but also serum albumin. Cortisol can diffuse easily through the plasma membrane and once inside the cell binds to, and activates, the glucocorticoid receptor in the cytoplasm, inducing biological responses via transactivation or transrepression by binding to glucocorticoid response elements 2 .

The structure of cortisol (systematic name 11β,17,21-trihydroxypregn-4-ene-3,20-dione). Visit cortisol in the LIPID MAPS structure database for more molecular information.

One of the primary functions of cortisol is to increase the availability of fuel substrates, which it does by stimulating gluconeogenesis and mobilizing free fatty acids and amino acids from endogenous stores 3 . Indeed, the use of the name 'glucocorticoid' stemmed from the ability of adrenocortical extracts to increase blood sugar concentrations. Cortisol also increases blood pressure 3 . In response to stress/danger, energy resources are directed to essential functions, and cortisol is known to suppress the immune system by inhibiting pro-inflammatory and antiviral immune responses 4 . This response also operates when inflammation reaches dangerously high levels, and is the basis for the use of cortisol as an immunosuppressive agent — hydrocortisone — for the treatment of anaphylaxis, eczema and many other inflammatory conditions. Continual cortisol secretion and immune suppression, in response to chronic stress, however, is likely to have detrimental effects 4 .

Katrin Legg

- Copyright © 2012 Nature Publishing Group, a division of Macmillan Publishers Limited; used with permission


  1. Miller, W.L. & Bose, H.S. Early steps in steroidogenesis: intracellular cholesterol trafficking.

    J. Lipid Res. 52, 2111-2135 (2011). doi:10.1194/jlr.R016675

  2. Zanchi, N.E. et al. Glucocorticoids: extensive physiological actions modulated through multiple mechanisms of gene regulation.

    J. Cell. Physiol. 224, 311-315 (2010). doi:10.1002/jcp.22141

  3. Arlt, W. & Stewart, P.M. Adrenal corticosteroid biosynthesis, metabolism, and action.

    Endocrinol. Metab. Clin. North Am. 34, 293-313 (2005). doi:10.1016/j.ecl.2005.01.002

  4. Zen, M. et al. The kaleidoscope of glucorticoid effects on immune system.

    Autoimmun. Rev. 10, 305-310 (2011). doi:10.1016/j.autrev.2010.11.009

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