View source for Cortisol

{{Distinguish2|[[cortisone]], a similar compound with a similar name, genesis, and function}}
{{Copyedit|date=March 2010}}
{{Cleanup-jargon|date=March 2010}}
{{Expert-subject|Pharmacology|date=July 2010}}
{{drugbox
| Watchedfields = changed
| verifiedrevid = 322155817
| IUPAC_name = (11β)-11,17,21-trihydroxypregn-4-ene-3,20-dione
| image = Cortisol2.svg
| image2 = Cortisol-3D-balls.png
| width = 225
| InChI = 1/C21H30O5/c1-19-7-5-13(23)9-12(19)3-4-14-15-6-8-21(26,17(25)11-22)20(15,2)10-16(24)18(14)19/h9,14-16,18,22,24,26H,3-8,10-11H2,1-2H3/t14-,15-,16-,18+,19-,20-,21-/m0/s1
| smiles = O=C4\C=C2/[C@]([C@H]1[C@@H](O)C[C@@]3([C@@](O)(C(=O)CO)CC[C@H]3[C@@H]1CC2)C)(C)CC4
| InChIKey = JYGXADMDTFJGBT-VWUMJDOOBO
| CAS_number = 50-23-7
|    CASNo_Ref = {{cascite}}
| ChemSpiderID = 5551
| ATC_prefix = H02
| ATC_suffix = AB09
| ATC_supplemental = (and others)
| PubChem = 5754
| DrugBank =
| chemical_formula =
| C=21 | H=30 | O=5
| molecular_weight = 362.460
| bioavailability =
| protein_bound =
| metabolism =
| elimination_half-life =
| pregnancy_category = C
| legal_status = Rx Only (U.S.) (excluding 1-2% strength topical)
| routes_of_administration = Oral tablets, intravenously, topical
}}

'''Cortisol''', also known as '''hydrocortisone''', is a [[corticosteroid|steroid]] [[hormone]] or [[glucocorticoid]] produced by the [[adrenal gland]].<ref name="themedicalbiochemistrypage.org">http://themedicalbiochemistrypage.org/images/adrenalsteroidsynthesis.jpg</ref> It is released in response to [[stress (medicine)|stress]], and to a low level of blood glucocorticoids. Its primary functions are to increase [[blood sugar]] through gluconeogenesis, suppress the immune system, and aid in fat, protein, and carbohydrate metabolism.<ref>First Aid USMLE Step 1 2009, Tao Le et al.</ref> It also decreases bone formation. Various synthetic forms of cortisol are used to treat a variety of different illnesses.

== Physiology ==
=== Production & release ===

Cortisol is produced by the [[zona fasciculata]] of the [[adrenal cortex]], which is one of two parts of the [[adrenal gland]].<ref name="themedicalbiochemistrypage.org"/>

It is released in response to [[stress (medicine)|stress]], or to a low level of blood glucocorticoids, and this release is controlled by the [[hypothalamus]], a part of the brain.The secretion of [[Corticotropin-releasing hormone|corticotropin-releasing hormone (CRH)]] by the hypothalamus triggers pituitary secretion of adrenal corticotrophic hormone ([[ACTH]]); ACTH is carried by the blood to the adrenal cortex where it triggers glucocorticoid secretion.

=== Patterns and rhythms of release ===

The amount of cortisol hormone present in the [[blood]] undergoes [[wiktionary:diurnal|diurnal]] variation, with the highest levels present in the early morning (approximately 8am), and the lowest levels present around 12-4am, or 3–5 hours after the onset of [[sleep]]. Information about the [[Circadian rhythm|light/dark cycle]] is transmitted from the [[retina]] to the paired [[suprachiasmatic nuclei]] in the [[hypothalamus]]. The pattern is not present at birth (estimates of when it starts vary from two weeks to 9 months).<ref>{{Cite journal|author=de Weerth C, Zijl R, Buitelaar J |title=Development of cortisol circadian rhythm in infancy |journal=Early Hum Dev |volume=73 |issue=1-2 |pages=39–52 |year=2003 |pmid=12932892 |doi=10.1016/S0378-3782(03)00074-4}}</ref>

Changed patterns of serum cortisol levels have been observed in connection with abnormal [[ACTH]] levels, [[clinical depression]], [[stress (psychology)|psychological stress]], and such physiological stressors such as [[hypoglycemia]], illness, [[fever]], trauma, [[surgery]], [[fear]], [[pain]], physical exertion or extremes of [[temperature]]. Cortisol levels may also be different for people with [[autism]] or [[Asperger's syndrome]].<ref>{{Cite news| url=http://news.bbc.co.uk/2/hi/health/7976489.stm | work=BBC News | title=Asperger's stress hormone 'link' | date=2009-04-02 | accessdate=2010-04-30}}</ref>

There is also significant individual variation, although a given person tends to have consistent rhythms.

===Normal Level (Baseline cortisol)===

These levels from different labs or hospitals around the world are examples of early morning cortisol levels, ideally around 9am. They are also the equivalent to a random morning cortisol level. (Wording indicating the nature of the test levels below is that of the originating lab or hospital.) <ref name="cortisol">[http://www.addisons-network.co.uk/ad_tests.html], Tests in Addisons</ref>

    * Australia:
          o Baseline: 200-650nmol/L (nanomoles/litre)
    * USA:
          o AM level: 4.0-22.0µg/dl (micrograms/decilitre)
          o PM level: 3.0-17.0µg/dl
    * UK:
          o Hospital #1: Basal cortisol level >150nmol/L.
          o Hospital #2: Cortisol reference range at 9am 200-600nmol/L.

Note:
Whilst no direct conversion factor can be given for correlation of µg/dl against nmol/L. in respect of plasma or serum cortisol estimations, an approximation can be gained by applying a factor of 29.8; thus 10µg/dl is very approximately equal to 298nmol/dl.

=== Effects ===
{{Incoherent|date=March 2010}}
{{Technical|section=Effects|date=September 2010}}
{{See also|Glucocorticoid#Therapeutic use}}

Following stressful events, cortisol, like other [[glucocorticoid]] agents, has widespread effects which help restore [[homeostasis]]. Although cortisol secretion in response to stress is a [[endogenous|natural]] function, prolonged cortisol secretion due to [[chronic stress]] could result in significant physiological changes.<ref>{{Cite web|url=http://stress.about.com/od/stresshealth/a/cortisol.htm |title=Cortisol and Stress: How Cortisol Affects Your Body, and How To Stay Healthy in the Face of Stress |publisher=Stress.about.com |date= |accessdate=2010-06-14}}</ref>

;Insulin:
Cortisol counteracts [[insulin]], contributing to hyperglycemia via stimulation of hepatic [[gluconeogenesis]]<ref name="brown"/> and inhibition of the peripheral utilization of glucose<ref name="brown">{{Cite book|first=Dave D. Brown|title=USMLE Step 1 Secrets|year=2003 |page=63}}</ref> by decreasing the translocation of [[glucose transporter]]s to the cell membrane,<ref>{{Cite book|last=King|first= Michael W.|title=Lange Q&A USMLE Step 1|edition=Sixth|page=82|isbn=0071445781|year=2005|publisher=McGraw-Hill, Medical Pub. Division|location=New York}}</ref> especially [[GLUT4]].<ref>{{cite pmid|17426391}}</ref> However cortisol increases [[glycogen]] synthesis ([[glycogenesis]]) in the [[liver]].<ref>Baynes, J., Dominiczak, M., Medical Biochemistry. Elsevier Limited; Third Edition (2009). ISBN 978-0-323-05371-6.</ref> Permissive effect of cortisol on insulin action on liver glycogenesis is observed in hepatocyte culture in laboratory, although the mechanism is unknown.

;Collagen:
In laboratory rats, cortisol-induced collagen loss in the skin is ten times greater than any other tissue.<ref>{{Cite journal|author=Houck JC, Sharma VK, Patel YM, Gladner JA |title=Induction of collagenolytic and proteolytic activities by anti-inflammatoes this by inhibiting collagen formation, decreasing amino acid uptake by muscle, and inhibiting protein synthesis.}}</ref><ref>Manchester, K.L., “Sites of Hormonal Regulation of Protein Metabolism. p. 229”, Mammalian Protein [Munro, H.N., Ed.]. Academic Press, New York. On p273.</ref> Cortisol (as opticortinol) may inversely inhibit [[IgA]] precursor cells in the intestines of calves.<ref>{{Cite journal|author=Husband AJ, Brandon MR, Lascelles AK |title=The effect of corticosteroid on absorption and endogenous production of immunoglobulins in calves |journal=Aust J Exp Biol Med Sci |volume=51 |issue=5 |pages=707–10 |year=1973 |month=October |pmid=4207041 |doi= 10.1038/icb.1973.67|url=}}</ref> Cortisol also inhibits IgA in serum, as it does [[IgM]], but is not shown to inhibit [[IgE]].<ref>{{Cite journal|author=Posey WC, Nelson HS, Branch B, Pearlman DS |title=The effects of acute corticosteroid therapy for asthma on serum immunoglobulin levels |journal=J. Allergy Clin. Immunol. |volume=62 |issue=6 |pages=340–8 |year=1978 |month=December |pmid=712020 |doi= 10.1016/0091-6749(78)90134-3|url=}}</ref>

;Gastric and renal secretion:
Cortisol stimulates gastric acid secretion.<ref>Soffer, L.J.; Dorfman, R.I.; Gabrilove, J.L,.  “The Human Adrenal Gland”. Febiger, Phil.</ref> Cortisol's only direct effect on the hydrogen ion excretion of the kidneys is to stimulate excretion of ammonium ion by inactivation of renal glutaminase enzyme.<ref>Kokshchuk, G.I.; Pakhmurnyi, B.A. (1979) “Role of Glucocorticoids in Regulation of the Acid-Excreting Function of the Kidneys”. Fiziol. Z H SSR I.M.I.M. Sechenova 65: 751,.</ref> Net chloride secretion in the intestines is inversely decreased by cortisol in vitro ([[methylprednisolone]]).<ref>{{Cite journal|author=Tai YH, Decker RA, Marnane WG, Charney AN, Donowitz M |title=Effects of methylprednisolone on electrolyte transport by in vitro rat ileum |journal=Am. J. Physiol. |volume=240 |issue=5 |pages=G365–70 |year=1981 |month=May |pmid=6112881 |doi= |url=}}</ref>{{Dn}}

;Sodium:
Cortisol inhibits sodium loss through the small intestine of mammals.<ref name="pmid7323700">{{Cite journal|author=Sandle GI, Keir MJ, Record CO |title=The effect of hydrocortisone on the transport of water, sodium, and glucose in the jejunum. Perfusion studies in normal subjects and patients with coeliac disease |journal=Scand. J. Gastroenterol. |volume=16 |issue=5 |pages=667–71 |year=1981 |pmid=7323700 |doi= 10.3109/00365528109182028|url=}}</ref> Sodium depletion, however, does not affect cortisol,<ref>{{Cite journal|author=Mason PA, Fraser R, Morton JJ, Semple PF, Wilson A |title=The effect of sodium deprivation and of angiotensin II infusion on the peripheral plasma concentrations of 18-hydroxycorticosterone, aldosterone and other corticosteroids in man |journal=J. Steroid Biochem. |volume=8 |issue=8 |pages=799–804 |year=1977 |month=August |pmid=592808 |doi= 10.1016/0022-4731(77)90086-3|url=}}</ref> so cortisol cannot be used to regulate serum sodium. Cortisol's purpose may originally have been to transport sodium; this hypothesis is supported by the fact that freshwater fish utilize cortisol to stimulate sodium inward, while saltwater fish have a cortisol-based system for expelling excess sodium.<ref>Gorbman, A.; Dickhoff, W.W.; Vigna, S.R.; Clark, N.B.; Muller, A.F,.  “Comparative Endocrinology”.  John Wiley and Sons, New York.</ref>{{Dn}}

;Potassium:
Sodium load augments the intense potassium excretion by cortisol, and [[corticosterone]] is comparable to cortisol in this case.<ref>Muller AF Oconnor CM, ed. (1958) “An International Symposium on Aldosterone”, page 58. Little Brown & Co.</ref> In order for potassium to move out of the cell, cortisol moves in an equal number of sodium ions.<ref>{{Cite journal|author=KNIGHT RP, KORNFELD DS, GLASER GH, BONDY PK |title=Effects of intravenous hydrocortisone on electrolytes of serum and urine in man |journal=J. Clin. Endocrinol. Metab. |volume=15 |issue=2 |pages=176–81 |year=1955 |month=February |pmid=13233328 |doi= 10.1210/jcem-15-2-176|url=}}</ref> It can be seen that this should make [[pH]] regulation much easier, unlike the normal potassium deficiency situation in which about 2 sodium ions move in for each 3 potassium ions that move out, which is closer to the [[deoxycorticosterone]] effect. Nevertheless, cortisol consistently causes [[alkalosis]] of the serum, while in a deficiency pH does not change. Perhaps this may be for the purpose of bringing serum pH to a value most optimum for some of the immune enzymes during infection in those times when cortisol declines. Potassium is also blocked from loss in the kidneys directly somewhat by decline of cortisol (9 alpha fluorohydrocortisone).<ref>{{Cite journal|author=BARGER AC, BERLIN RD, TULENKO JF |title=Infusion of aldosterone, 9-alpha-fluorohydrocortisone and antidiuretic hormone into the renal artery of normal and adrenalectomized, unanesthetized dogs: effect on electrolyte and water excretion |journal=Endocrinology |volume=62 |issue=6 |pages=804–15 |year=1958 |month=June |pmid=13548099 |doi= 10.1210/endo-62-6-804|url=}}</ref>

;Water:
Cortisol also acts as an anti-diuretic hormone. Half the intestinal diuresis is so controlled.<ref name="pmid7323700"/> Kidney diuresis is also controlled by cortisol in dogs. The decline in water excretion upon decline of cortisol (dexamethasone) in dogs is probably due to inverse stimulation of  [[antidiuretic hormone]] (ADH or [[arginine vasopressin]]), the inverse stimulation of which is not overridden by water loading.<ref>{{Cite journal|author=Boykin J, DeTorrenté A, Erickson A, Robertson G, Schrier RW |title=Role of plasma vasopressin in impaired water excretion of glucocorticoid deficiency |journal=J. Clin. Invest. |volume=62 |issue=4 |pages=738–44 |year=1978 |month=October |pmid=701472 |pmc=371824 |doi=10.1172/JCI109184 |url=}}</ref> Humans also use this mechanism<ref>Dingman, J.F.; Gonzalez-Auvert Ahmed, A.B.J.; Akinura, A. (1965) “Antidiuretic Hormone in Adrenal Insufficiency”. Journal of Clinical Investigation 44: 1041,.</ref> and other different animal mechanisms operate in the same direction.{{dn}}

;Copper:
It is probable that increasing copper availability for immune purposes is the reason many copper enzymes are stimulated to an extent which is often 50% of their total potential by cortisol.<ref>Weber, C.E (1984). “Copper Response to Rheumatoid Arthritis”. Medical Hypotheses 15: 333-348, on p337,.</ref> This includes lysyl oxidase, an enzyme which is used to cross link collagen and [[elastin]].<ref>Weber, C.E. (1984) “Copper Response to Rheumatoid Arthritis”. Medical Hypotheses 15: 333,.on p334.</ref> Particularly valuable for immunity is the stimulation of superoxide dismutase by cortisol<ref>Flohe, L.; Beckman, R.; Giertz, H.; Loschen, G.  “Oxygen Centered Free Radicals as Mediators of Inflammation. p. 405”, Oxidative Stress (Sies H, ed) Academic Press, New York.</ref> since this copper enzyme is almost certainly used by the body to permit superoxide to poison bacteria. Cortisol causes an inverse four- or fivefold decrease of [[metallothionein]], a copper storage protein, in mice<ref>{{Cite journal|author=Piletz JE, Herschman HR |title=Hepatic metallothionein synthesis in neonatal Mottled-Brindled mutant mice |journal=Biochem. Genet. |volume=21 |issue=5-6 |pages=465–75 |year=1983 |month=June |pmid=6870774 |doi= 10.1007/BF00484439|url=}}</ref> (however rodents do not synthesize cortisol themselves). This may be to furnish more copper for ceruloplasmin synthesis or release of free copper. Cortisol has an opposite effect on alpha [[aminoisobuteric acid]] than on the other amino acids.<ref>Chambers, J.W.; Georg, R.H. and Bass, A.D. (1965) “Effect of Hydrocortisone and Insulin on Uptake of Alpha Aminoisobutyric Acid by Isolated Perfused Rat Liver”. Mol. Pharmacol. 1: 66,.</ref> If alpha aminoisobuteric acid is used to transport copper through the cell wall, this anomaly would possibly be explained.

;Immune system:
Cortisol can weaken the activity of the [[immune system]]. Cortisol prevents proliferation of T-cells by rendering the [[interleukin-2]] producer [[T-cell]]s unresponsive to [[interleukin-1]] (IL-1), and unable to produce the T-cell growth factor.<ref>{{Cite journal|author=Palacios R., Sugawara I. |title=Hydrocortisone abrogates proliferation of T cells in autologous mixed lymphocyte reaction by rendering the interleukin-2 Producer T cells unresponsive to interleukin-1 and unable to synthesize the T-cell growth factor |journal=Scand J Immunol |volume=15 |issue=1 |pages=25–31 |year=1982 |pmid=6461917 |doi=10.1111/j.1365-3083.1982.tb00618.x}}</ref> Cortisol also has a negative feedback effect on interleukin-1.<ref name="Besedovsky, H.O. 1984 p. 200">Besedovsky, H.O.; Del Rey, A.; Sorkin, E. (1984) "Integration of Activated Immune Cell Products in Immune Endocrine Feedback Circuits." p. 200 in Leukocytes and Host Defense Vol. 5 [Oppenheim, J.J.; Jacobs, D.M., eds].  Alan R. Liss, New York,.</ref> IL-1 must be especially useful in combating some diseases; however, [[endotoxin]] bacteria have gained an advantage by forcing the [[hypothalamus]] to increase cortisol levels via forcing secretion of [[Corticotropin-releasing hormone|CRH]] hormone, thus antagonizing IL-1 in this case. The suppressor cells are not affected by [[glucosteroid response-modifying factor]] (GRMF),<ref name="pmid6228602">{{Cite journal|author=Fairchild SS, Shannon K, Kwan E, Mishell RI |title=T cell-derived glucosteroid response-modifying factor (GRMFT): a unique lymphokine made by normal T lymphocytes and a T cell hybridoma |journal=J. Immunol. |volume=132 |issue=2 |pages=821–7 |year=1984 |month=February |pmid=6228602 |doi= |url=}}</ref> so that the effective set point for the immune cells may be even higher than the set point for physiological processes. It reflects [[leukocyte]] redistribution to lymph nodes, [[bone marrow]], and [[skin]]. Acute administration of [[corticosterone]] (the endogenous Type I and Type II receptor agonist), or [[RU28362]] (a specific Type II receptor agonist), to adrenalectomized animals induced changes in [[leukocyte distribution]]. Natural killer cells are not affected by cortisol.<ref>{{Cite journal|author=Onsrud M, Thorsby E |title=Influence of in vivo hydrocortisone on some human blood lymphocyte subpopulations. I. Effect on natural killer cell activity |journal=Scand. J. Immunol. |volume=13 |issue=6 |pages=573–9 |year=1981 |pmid=7313552 |doi= |url=}}</ref>

;Bone metabolism:
It lowers [[bone]] formation thus favoring development of osteoporosis in the long term. Cortisol moves [[potassium]] out of cells in exchange for an equal number of [[sodium]] ions as mentioned above.<ref>{{Cite journal|author=Knight, R.P., Jr. Kornfield, D.S. Glaser, G.H. Bondy, P.K. |title=Effects of intravenous hydrocortisone on electrolytes of serum and urine in man |journal=J Clin Endocrinol Metab |volume=15 |issue=2 |pages=176–81 |year=1955 |pmid=13233328 |doi=10.1210/jcem-15-2-176}}</ref> This can cause a major problem with the [[hyperkalemia]] of [[metabolic shock]] from surgery. Cortisol reduces [[calcium]] absorption in the intestine.<ref>{{Cite journal|author=Shultz TD, Bollman S, Kumar R |title=Decreased intestinal calcium absorption in vivo and normal brush border membrane vesicle calcium uptake in cortisol-treated chickens: evidence for dissociation of calcium absorption from brush border vesicle uptake |journal=Proc. Natl. Acad. Sci. U.S.A. |volume=79 |issue=11 |pages=3542–6 |year=1982 |month=June |pmid=6954501 |pmc=346457 |doi= 10.1073/pnas.79.11.3542|url=}}</ref>

;Memory:
It cooperates with [[epinephrine]] (adrenaline) to create [[memories]] of short-term emotional events; this is the proposed mechanism for storage of [[flash bulb memories]], and may originate as a means to remember what to avoid in the future. However, long-term exposure to cortisol results in damage to cells in the [[hippocampus]].<ref>{{Cite journal|author=Mc Auley MM, Kenny RA, Kirkwood TT, Wilkinson DD, Jones JJ, Miller VM |title=A Mathematical Model of aging-related and cortisol induced hippocampal dysfunction |journal=BMC Neurosci |volume=10 |issue=1 |page=26 |year=2009 |month=March |pmid=19320982 |doi=10.1186/1471-2202-10-26 |url= |pmc=2680862}}</ref> This damage results in impaired learning.

;Additional effects:
* It increases [[blood pressure]] by increasing the sensitivity of the vasculature to [[epinephrine]] and [[norepinephrine]].  In the absence of cortisol, widespread [[vasodilation]] occurs. {{Citation needed|date=July 2010}}

* It inhibits the secretion of [[corticotropin-releasing hormone]] (CRH), resulting in [[negative feedback|feedback inhibition]] of [[ACTH]] (Adrenocorticotropic hormone or corticotropin) secretion. Some researchers believe that this normal feedback system may become dysregulated when animals are exposed to chronic stress.{{Clarify|date=March 2010}}{{Citation needed|date=July 2010}}

* It allows for the kidneys to produce [[Hypotonicity|hypotonic]] urine. {{Citation needed|date=July 2010}}

* It shuts down the reproductive system, resulting in an increase for the chance of miscarriage and, in some cases, temporary  infertility.  Fertility returns after cortisol levels are reduced back to normal levels.<ref>An Introduction to Behavioral Endocrinology, Randy J Nelson, 3rd edition, Sinauer</ref>

* It has anti-inflammatory effects by reducing [[histamine]] secretion and stabilizing [[lysosome|lysosomal]] membranes.  The stabilization of lysosomal membranes prevents their rupture, thereby preventing damage to healthy tissues. {{Citation needed|date=July 2010}}

* It stimulates hepatic [[detoxification]] by inducing tryptophan oxygenase (to reduce [[serotonin]] levels in the brain), glutamine synthase (reduce [[glutamate]] and [[ammonia]] levels in the brain), cytochrome P-450 hemoprotein (mobilizes [[arachidonic acid]]), and [[metallothionein]] (reduces [[heavy metals]] in the body). {{Citation needed|date=July 2010}}

* In addition to the effects caused by cortisol binding to the [[glucocorticoid receptor]], because of its molecular similarity to [[aldosterone]], it also binds to the [[mineralocorticoid receptor]]. Aldosterone and cortisol have similar affinity for the mineralocorticoid receptor however, glucocorticoids circulate at roughly 100 times the level of mineralocorticoids. An enzyme exists in mineralocorticoid target tissues to prevent overstimulation by glucocorticoids and allow selective mineralocorticoid action. This enzyme, 11-beta hydroxysteroid dehydrogenase type II (Protein:HSD11B2), catalyzes the deactivation of glucocorticoids to 11-dehydro metabolites.{{Clarify|date=March 2010}}{{Citation needed|date=July 2010}}

* There are potential links between cortisol, appetite and obesity<ref>{{Cite web|url=http://www.unm.edu/~lkravitz/Article%20folder/stresscortisol.html |title=Stress Cortisol Connection |publisher=Unm.edu |date= |accessdate=2010-06-14}}</ref>{{Specify|date=March 2010}}.

=== Binding ===

Most serum cortisol, all but about 4%, is bound to proteins including [[Transcortin|corticosteroid binding globulin]] ('''CBG'''), and [[serum albumin]]. Only free cortisol is available to receptors. {{Citation needed|date=July 2010}}

=== Regulation ===

The primary control of cortisol is the [[pituitary]] gland peptide, adrenocorticotropic hormone ([[ACTH]]). ACTH probably controls cortisol by controlling movement of calcium into the cortisol secreting target cells.<ref>Davies E. Keyon, C.J.; Fraser, R. (1985) "The role of calcium ions in the mechanism of ACTH stimulation of cortisol synthesis." Steroids 45: 557.</ref> ACTH is in turn controlled by the hypothalamic peptide, [[corticotropin releasing hormone]] (CRH), which is under nervous control. CRH acts synergistically with [[arginine vasopressin]], [[angiotensin II]], and [[epinephrine]].<ref>{{Cite journal|author=Plotsky PM, Otto S, Sapolsky RM |title=Inhibition of immunoreactive corticotropin-releasing factor secretion into the hypophysial-portal circulation by delayed glucocorticoid feedback |journal=Endocrinology |volume=119 |issue=3 |pages=1126–30 |year=1986 |month=September |pmid=3015567 |doi= 10.1210/endo-119-3-1126|url=}}</ref>  When activated macrophages start to secrete [[interleukin-1]] (IL-1), which synergistically with CRH increases ACTH,<ref name="Besedovsky, H.O. 1984 p. 200"/> [[T-cells]] also secrete glucosteroid response modifying factor (GRMF or GAF) as well as IL-1, both of which increase the amount of cortisol required to inhibit almost all the immune cells.<ref name="pmid6228602"/>  Thus immune cells take over their own regulation, but at a higher cortisol set point. Even so, the rise of cortisol in diarrheic calves is minimal over healthy calves and drops below with time.<ref>Dvorak, M.; "Plasma 17-Hydroxycorticosteroid Levels in
Healthy and Diarrheic Calves." British Veterinarian Journal  127: 372, 1971.</ref> The cells do not lose all of the fight or flight override because of interleukin-1's synergism with CRH. Cortisol even has a negative feedback effect on interleukin-1 <ref>Besedovsky, H.O.; Del Rey, A.; Sorkin, E. (1984) "Integration
of Activated Immune Cell Products in Immune Endocrine Feedback Circuits." p. 200 in Leukocytes and Host Defense Vol. 5 [Oppenheim, J.J.; Jacobs, D.M., eds].  Alan R. Liss, New York,.</ref> which must be especially useful for those diseases which gain an advantage by forcing the [[hypothalamus]] to secrete too much CRH, such as the [[endotoxin]] bacteria..The suppressor immune cells are not affected by GRMF,<ref name="pmid6228602"/> so that the effective set point for the immune cells may be even higher than the set point for physiological processes. GRMF (called GAF in this reference) primarily affects the liver rather than the kidneys for some physiological processes.<ref>{{Cite journal|author=Stith RD, McCallum RE |title=General effect of endotoxin on glucocorticoid receptors in mammalian tissues |journal=Circ. Shock |volume=18 |issue=4 |pages=301–9 |year=1986 |pmid=3084123 |doi= |url=}}</ref>

A high potassium media, which stimulates aldosterone secretion in vitro, also stimulates cortisol secretion from the [[fasciculata]] zone of dog adrenals <ref>Mikosha, A.S.; Pushkarov, I.S.; Chelnakova, I.S.;
Remennikov, G.Y.A. (1991) “Potassium Aided Regulation of Hormone Biosynthesis in Adrenals of Guinea Pigs Under Action of Dihydropyridines: Possible Mechanisms of Changes in Steroidogenesis Induced by 1,4, Dihydropyridines in Dispersed Adrenocorticytes.” Fiziol. [Kiev] 37: 60,.</ref> unlike [[corticosterone]], upon which potassium has no effect.<ref>{{Cite journal|author=Mendelsohn FA, Mackie C |title=Relation of intracellular K+ and steroidogenesis in isolated adrenal zona glomerulosa and fasciculata cells |journal=Clin Sci Mol Med |volume=49 |issue=1 |pages=13–26 |year=1975 |month=July |pmid=168026 |doi= |url=}}</ref>  Potassium loading increases ACTH and cortisol in people also.<ref>{{Cite journal|author=Ueda Y, Honda M, Tsuchiya M, ''et al.'' |title=Response of plasma ACTH and adrenocortical hormones to potassium loading in essential hypertension |journal=Jpn. Circ. J. |volume=46 |issue=4 |pages=317–22 |year=1982 |month=April |pmid=6283190 |doi= |url=}}</ref>  This is no doubt the reason why a potassium deficiency causes cortisol to decline (as just mentioned) and why a potassium deficiency causes a decrease in conversion of 11deoxycortisol to cortisol.<ref>Bauman K Muller J 1972 “Effect of potassium on the final status of aldosterone biosynthesis in the rat. I 18-hydroxylation and 18hydroxy dehydrogenation. II beta-hydroxylation.” Acta Endocrin. Copenh. 69; I 701-717, II 718-730.</ref>  This probably contributes to the pain in rheumatoid arthritis since cell potassium is always low in that disease <ref>LaCelle PL et al. (1964) “An investigation of total body potassium in patients with rheumatoid arthritis.” Proceedings of the Annual Meeting of the American Rheumatism Association, Arthritis and Rheumatism 7; 321.</ref>

==== Factors generally reducing cortisol levels ====

* [[Magnesium]] supplementation decreases serum cortisol levels after aerobic exercise,<ref>{{cite pmid|6527092}}</ref><ref>{{cite pmid|9794094}}</ref> but not in resistance training.<ref>{{cite doi|10.1186/1550-2783-1-2-12}}</ref>
* [[Omega 3]] fatty acids, in a dose dependent manner (but not significantly),<ref>{{cite pmid|1832814}}</ref> can lower cortisol release influenced by mental stress<ref>{{cite pmid|12909818}}</ref> by suppressing the synthesis of [[interleukin]]-1 and 6 and enhance the synthesis of interleukin-2, where the former promote higher [[Corticotropin-releasing hormone|CRH]] release. [[Omega 6]] fatty acids, on the other hand, acts inversely on interleukin synthesis.{{Citation needed|date=March 2009}}
* [[Music therapy]] can reduce cortisol levels in certain situations.<ref>{{cite pmid|15086180}}</ref>
* [[Massage therapy]] can reduce cortisol.<ref>{{cite pmid|16162447}}</ref>
* [[Sexual intercourse]] can reduce cortisol levels.
* Laughing and the experience of humour can lower cortisol levels.<ref>{{Cite web|url=http://www.fasebj.org/cgi/content/meeting_abstract/22/1_MeetingAbstracts/946.11 |title=Cortisol and Catecholamine stress hormone decrease is associated with the behavior of perceptual anticipation of mirthful laughter | authors Berk et al. 22 (1): 946.11 |publisher=The FASEB Journal |date= |accessdate=2010-06-14}}</ref>
* Soy derived [[Phosphatidylserine]] interacts with cortisol but the right dosage is still unclear.<ref>{{cite pmid|15512856}}</ref><ref>{{Cite journal|author=Starks MA, Starks SL, Kingsley M, Purpura M, Jäger R |title=The effects of phosphatidylserine on endocrine response to moderate intensity exercise |journal=J Int Soc Sports Nutr |volume=5 |issue= |page=11 |year=2008 |pmid=18662395 |pmc=2503954 |doi=10.1186/1550-2783-5-11 |url=}}</ref>
* [[Vitamin C]] may slightly blunt cortisol release in response to a mental stressor.<ref>[http://www.psychologytoday.com/articles/pto-20030425-000001.html Vitamin C: Stress Buster] Psychology today</ref>
* [[Black tea]] may speed up recovery from a high cortisol condition.<ref>{{Cite news| url=http://news.bbc.co.uk/2/hi/health/5405686.stm | work=BBC News | title=Black tea 'soothes away stress' | date=2006-10-04 | accessdate=2010-04-30}}</ref><ref>{{Cite web|url=http://www.springerlink.com/content/m226111566k24u65/ |title=Journal Article |publisher=SpringerLink |date= |accessdate=2010-06-14}}</ref>

==== Factors generally increasing cortisol levels ====

* [[Caffeine]] may increase cortisol levels.<ref>{{Cite journal|author=Lovallo WR, Farag NH, Vincent AS, Thomas TL, Wilson MF |title=Cortisol responses to mental stress, exercise, and meals following caffeine intake in men and women |journal=Pharmacol. Biochem. Behav. |volume=83 |issue=3 |pages=441–7 |year=2006 |month=March |pmid=16631247 |pmc=2249754 |doi=10.1016/j.pbb.2006.03.005 |url=}}</ref>
* [[Sleep deprivation]] increases cortisol levels.<ref>{{Cite web|url=http://cat.inist.fr/?aModele=afficheN&cpsidt=2068517 |title=Sleep loss results in an elevation of cortisol levels the next evening |publisher=Cat.inist.fr |date= |accessdate=2010-06-14}}</ref>
* Intense (high [[VO2 max]]) or prolonged [[physical exercise]] stimulate cortisol release in order to increase [[gluconeogenesis]] and maintain blood glucose.<ref>{{Cite journal|author=Robson PJ, Blannin AK, Walsh NP, Castell LM, Gleeson M |title=Effects of exercise intensity, duration and recovery on in vitro neutrophil function in male athletes |journal=Int J Sports Med |volume=20 |issue=2 |pages=128–35 |year=1999 |month=February |pmid=10190775 |doi= 10.1055/s-2007-971106|url=}}</ref> Proper nutrition<ref>{{cite pmid|16572599}}</ref> and high-level conditioning<ref>{{Cite journal|author=Kraemer WJ, Spiering BA, Volek JS, ''et al.'' |title=Recovery from a national collegiate athletic association division I football game: muscle damage and hormonal status |journal=J Strength Cond Res |volume=23 |issue=1 |pages=2–10 |year=2009 |month=January |pmid=19077734 |doi=10.1519/JSC.0b013e31819306f2 |url= |doi_brokendate=2010-01-03}}</ref> can help stabilize cortisol release.
* Val/Val variation of the [[BDNF]] gene in men, and the Val/Met variation in women is associated with increased salivary cortisol in a stressful situation.<ref>{{cite pmid|18990498}}</ref>
* [[Hypoestrogenism]] and [[melatonin]] supplementation increases cortisol levels in postmenopausal women.<ref>{{cite pmid|9181519}}</ref>
* [[Burnout (psychology)|Burnout]] is associated with higher cortisol levels.<ref>{{cite doi|10.1016/j.psyneuen.2009.02.015}}</ref>
* Severe trauma or stress events can elevate cortisol levels in the blood for prolonged periods.<ref>{{Cite book|first= Sareen Annora Stepnick Gropper,Jack L. Smith,James L. Groff|title=Advanced Nutrition and Human Metabolism |year=2008|page=247}}</ref>
* Subcutaneous adipose tissue regenerates cortisol from [[cortisone]].<ref>{{Cite web|url=http://diabetes.diabetesjournals.org/cgi/content/abstract/58/1/46 |title=Cortisol Release From Adipose Tissue by 11β-Hydroxysteroid Dehydrogenase Type 1 in Humans |publisher=Diabetes.diabetesjournals.org |date=2008-10-13 |accessdate=2010-06-14}}</ref>
* [[Anorexia nervosa]] may be associated with increased cortisol levels.<ref>{{Cite web|url=http://www.ajcn.org/cgi/content/abstract/ajcn.2008.26958v1 |title=Body composition changes in female adolescents with anorexia nervosa | authors = Haas et al., 10.3945/ajcn.2008.26958 |doi=10.3945/ajcn.2008.26958 |publisher=American Journal of Clinical Nutrition |date= |accessdate=2010-06-14}}</ref>
* The [[serotonin]] receptor gene [[5-HT2C receptor|5HTR2C]] is associated with increased cortisol production in men.<ref>{{Cite web|url=http://www.dukehealth.org/HealthLibrary/News/new_clues_about_genetic_influence_of_stress_on_men_s_health |title=New Clues about Genetic Influence of Stress on Men’s Health |publisher=Dukehealth.org |date= |accessdate=2010-06-14}}</ref>
* Some formulations of [[combined oral contraceptive pill]]s increase cortisol levels in young women who perform whole-body resistance exercise training.<ref>{{Cite web|url=http://sciencenews.org/view/generic/id/43210/title/Science_%2B_the_Public__Birth_control_pills_can_limit_muscle-training_gains |title=Birth control pills can limit muscle-training gains |publisher=Sciencenews.org |date= |accessdate=2010-06-14}}</ref>
* [[Commuting]] increases cortisol levels, related to the length of the trip, the amount of effort involved and the predictability of the trip<ref>{{Cite web|url=http://www.utrc2.org/research/assets/74/commuterstress2-report1.pdf |title=The Impact of Mode and Mode Transfer on Commuter Stress, The Montclair Connection|format=PDF |date= |accessdate=2010-06-14}}</ref>

== Clinical chemistry ==

* '''Hypercortisolism''': Excessive levels of cortisol in the blood.
* '''Hypocortisolism''' ([[adrenal insufficiency]]): Insufficient levels of cortisol in the blood.

The relationship between cortisol and ACTH, and some consequent conditions, are as follows:

{| class="wikitable"
|+ THE DISORDERS OF CORTISOL SECRETION<!-- -->
|-
|
|
! colspan=2|Plasma ACTH
|-
|
|
! style="text-align:center;"| <big>↓</big>
! style="text-align:center;"| <big>↑</big>
|-
! rowspan=2|Plasma Cortisol
! style="text-align:center;"| <big>↑</big>
| Primary hypercortisolism ([[Cushing's syndrome]])
| Secondary hypercortisolism (pituitary or ectopic tumor, [[Cushing's disease]], [[pseudo-Cushing's syndrome]])
|-
! style="text-align:center;"| <big>↓</big>
| Secondary hypocortisolism (pituitary tumor, [[Sheehan's syndrome]])
| Primary hypocortisolism ([[Addison's disease]], [[Nelson's syndrome]])
|}

A 2010 study has found that serum cortisol predicts increased cardiovascular mortality in patients with acute coronary syndrome.<ref>{{Cite web|url=http://www.endocrine-abstracts.org/ea/0022/ea0022OC4.6.htm |title=Serum cortisol predicts increased cardiovascular mortality in patients with acute coronary syndrome |publisher=Endocrine-abstracts.org |date= |accessdate=2010-06-14}}</ref><ref>{{cite doi|10.1530/eje.1.01959}}</ref>

== Pharmacology ==

Hydrocortisone is the pharmaceutical term for cortisol used for oral administration, intravenous injection, or topical application. It is used as an [[immunosuppressive drug]], given by injection in the treatment of severe allergic reactions such as [[anaphylaxis]] and [[angioedema]], in place of [[prednisolone]] in patients who need steroid treatment but cannot take oral medication, and peri-operatively in patients on long-term steroid treatment to prevent an [[Addison's disease|Addisonian crisis]].  It may be used topically for allergic rashes, [[eczema]], [[psoriasis]] and certain other inflammatory skin conditions.  It may also be injected into inflamed joints resulting from diseases such as [[gout]].

Compared to [[prednisolone]], hydrocortisone is about 1/4 the strength for the [[anti-inflammatory]] effect, while [[dexamethasone]] is about 40 times as strong as hydrocortisone {{Citation needed|date=July 2010}}. For side effects, see [[corticosteroid]] and [[prednisolone]].

Hydrocortisone creams and ointments are available without prescription in strengths ranging from 0.05% to 2.5%, depending on local regulations, with stronger forms available with prescriptions only.
Covering the skin after application increases the absorption and effect.  Such enhancement is sometimes prescribed, but otherwise should be avoided to prevent over-dosing and systemic impacts.

Advertising for the dietary supplement [[CortiSlim]] originally (and falsely) claimed that it contributed to weight loss by blocking cortisol. The manufacturer was fined $12 million by the [[Federal Trade Commission]] in 2007 for [[false advertising]], and no longer claims in their marketing that CortiSlim is a cortisol [[Receptor antagonist|antagonist]].<ref name=Iwata>{{Cite news|author=Iwata, Edward |title=Diet pill sellers fined $25M |url=http://www.usatoday.com/news/washington/2007-01-04-weight-loss-pills_x.htm |work=[[USA Today]] |date=January 5, 2007 |accessdate=2008-10-26}}</ref>

== Biochemistry ==
=== Biosynthesis ===
[[File:Steroidogenesis.svg|thumb|right|400px|[[Steroidogenesis]], showing cortisol at right.]]

Cortisol is synthesized from [[cholesterol]]. The synthesis takes place in the ''[[zona fasciculata]]'' of the [[adrenal cortex|cortex of the adrenal glands]]. (The name ''cortisol'' comes from ''cortex''.) While the adrenal cortex also produces [[aldosterone]] (in the ''zona glomerulosa'') and some [[sex hormone]]s (in the ''zona reticularis''), cortisol is its main secretion. The medulla of the adrenal gland lies under the cortex and mainly secretes the catecholamines, adrenaline (epinephrine) and noradrenaline (norepinephrine) under sympathetic stimulation.

The synthesis of cortisol in the adrenal gland is stimulated by the [[anterior pituitary|anterior lobe]] of the [[pituitary gland]] with [[adrenocorticotropic hormone]] (ACTH); production of ACTH is in turn stimulated by [[corticotropin-releasing hormone]] (CRH), released by the [[hypothalamus]]. ACTH increases the concentration of cholesterol in the inner mitochondrial membrane (via regulation of STAR (steroidogenic acute regulatory) protein). ACTH also stimulates the main rate-limiting step in cortisol synthesis where cholesterol is converted to pregnenolone, catalyzed by Cytochrome P450SCC ([[side chain cleavage enzyme]]).<ref>[http://www.endocrine-source.com/adrenal/adrenal5/ch01s02.html Mechanism of ACTH action on adrenal cortical cells] Andrew N. Margioris, M.D., and Christos Tsatsanis, Ph.D. Updated: December 4, 2006</ref>

=== Metabolism ===

Cortisol is metabolized by the [[11-beta hydroxysteroid dehydrogenase]] system (11-beta HSD), which consists of two enzymes: [[11-beta HSD1]] and [[11-beta HSD2]].
* ''11-beta HSD1'' utilizes the cofactor NADPH to convert biologically inert [[cortisone]] to biologically active cortisol.
* ''11-beta HSD2'' utilizes the cofactor NAD+ to convert cortisol to cortisone.

Overall the net effect is that 11-beta HSD1 serves to increase the local concentrations of biologically active cortisol in a given tissue, while 11-beta HSD2 serves to decrease the local concentrations of biologically active cortisol.

Cortisol is also metabolized into [[5-alpha tetrahydrocortisol]] (5-alpha THF) and [[5-beta tetrahydrocortisol]] (5-beta THF), reactions for which [[5-alpha reductase]] and [[5-beta reductase]] are the [[Rate-determining step|rate-limiting factors]], respectively. 5-beta reductase is also the rate-limiting factor in the conversion of cortisone to [[tetrahydrocortisone]] (THE).

An alteration in 11-beta HSD1 has been suggested to play a role in the [[pathogenesis]] of [[obesity]], [[hypertension]], and [[insulin resistance]], sometimes referred to  as the [[metabolic syndrome]].<ref>[http://www.ncbi.nlm.nih.gov/pubmed/15466942] Tomlinson JW, Walker EA, Bujalska IJ, Draper N, Lavery GG, Cooper MS, Hewison M, Stewart PM. 11beta-hydroxysteroid dehydrogenase type 1: a tissue-specific regulator of glucocorticoid response. Endocr Rev. 2004 Oct;25(5):831-66.</ref>

An alteration in 11-beta HSD2 has been implicated in [[essential hypertension]] and is known to lead to the [[syndrome of apparent mineralocorticoid excess]] (SAME).{{Citation needed|date=November 2007}}

== Media ==

<gallery>
file:11-Deoxycortisol.png|[[11-Deoxycortisol]]
</gallery>

== See also ==

* [[Adrenaline]]
* [[ACTH stimulation test]]
* [[Dexamethasone suppression test]]
* [[Corticotropin-releasing hormone]]
* [[Cushing's syndrome]]
* [[HPA axis]]
* [[Hypopituitarism]]
* [[Posttraumatic stress disorder]]
* [[Central serous retinopathy]]

== References ==

{{Reflist|colwidth=30em}}

{{Hormones}}
{{Corticosteroids}}
{{Cholesterol and steroid intermediates}}
{{Antidiarrheals, intestinal anti-inflammatory/anti-infective agents}}
{{Otologicals}}

[[Category:Glucocorticoids]]
[[Category:Stress]]
[[Category:Anxiety]]
[[Category:World Health Organization essential medicines]]
[[Category:Otologicals]]

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