Cortisol#Memory

Cortisol plays a crucial role in regulating glucose metabolism and promotes gluconeogenesis (glucose synthesis) and glycogenolysis (breakdown of glycogen) in the liver, producing glucose to provide to other tissues.{{Citation |last=Thau |first=Lauren |title=Physiology, Cortisol |date=2025 |work=StatPearls |url=https://www.ncbi.nlm.nih.gov/books/NBK538239/#:~:text=In%20the%20liver,%20high%20cortisol,3-%20phosphate%20found%20in%20triglycerides. |access-date=2025-05-16 |place=Treasure Island (FL) |publisher=StatPearls Publishing |pmid=30855827 |last2=Gandhi |first2=Jayashree |last3=Sharma |first3=Sandeep}} It also increases blood glucose levels by reducing glucose uptake in muscle and adipose tissue, decreasing protein synthesis, and increasing the breakdown of fats into fatty acids (lipolysis). All of these metabolic steps have the net effect of increasing blood glucose levels, which fuel the brain and other tissues during the fight-or-flight response. Cortisol is also responsible for releasing amino acids from muscle, providing a substrate for gluconeogenesis. Its impact is complex and diverse.{{cite journal |vauthors=Khani S, Tayek JA |title=Cortisol increases gluconeogenesis in humans: its role in the metabolic syndrome |journal=Clin Sci (Lond) |volume=101 |issue=6 |pages=739–47 |date=December 2001 |pmid=11724664 |doi=10.1042/cs1010739 |url=http://portlandpress.com/clinsci/article-pdf/101/6/739/482314/cs1010739.pdf |access-date=2 February 2024 |archive-date=11 March 2024 |archive-url=https://web.archive.org/web/20240311202019/https://portlandpress.com/clinsci/article-abstract/101/6/739/67449/Cortisol-increases-gluconeogenesis-in-humans-its?redirectedFrom=PDF |url-status=live }}

In general, cortisol stimulates gluconeogenesis (the synthesis of 'new' glucose from non-carbohydrate sources, which occurs mainly in the liver, but also in the kidneys and small intestine under certain circumstances). The net effect is an increase in the concentration of glucose in the blood, further complemented by a decrease in the sensitivity of peripheral tissue to insulin, thus preventing this tissue from taking the glucose from the blood. Cortisol has a permissive effect on the actions of hormones that increase glucose production, such as glucagon and adrenaline.{{cite book|title=Integrated endocrinology| vauthors = Laycock JF |date=2013|publisher=Wiley-Blackwell|others=Meeran, Karim.|isbn=978-1-118-45064-2|location=Chichester, West Sussex, UK|oclc=794973804}}

Cortisol also plays an important, but indirect, role in liver and muscle glycogenolysis (the breaking down of glycogen to glucose-1-phosphate and glucose) which occurs as a result of the action of glucagon and adrenaline. Additionally, cortisol facilitates the activation of glycogen phosphorylase, which is necessary for adrenaline to have an effect on glycogenolysis.{{cite journal | vauthors = Coderre L, Srivastava AK, Chiasson JL | title = Role of glucocorticoid in the regulation of glycogen metabolism in skeletal muscle | journal = The American Journal of Physiology | volume = 260 | issue = 6 Pt 1 | pages = E927–32 | date = June 1991 | pmid = 1905485 | doi = 10.1152/ajpendo.1991.260.6.E927}}

It is paradoxical that cortisol promotes not only gluconeogenesis (biosynthesis of glucose molecules) in the liver, but also glycogenesis (polymerization of glucose molecules into glycogen): cortisol is thus better thought of as stimulating glucose/glycogen turnover in the liver.{{cite journal | vauthors = Macfarlane DP, Forbes S, Walker BR | title = Glucocorticoids and fatty acid metabolism in humans: fuelling fat redistribution in the metabolic syndrome |language=en-US| journal = The Journal of Endocrinology | volume = 197 | issue = 2 | pages = 189–204 | date = May 2008 | pmid = 18434349 | doi = 10.1677/JOE-08-0054 | doi-access = free }} This is in contrast to cortisol's effect in the skeletal muscle where glycogenolysis (breakdown of glycogen into glucose molecules) is promoted indirectly through catecholamines.{{cite book | vauthors = Kuo T, McQueen A, Chen TC, Wang JC | title = Glucocorticoid Signaling | chapter = Regulation of Glucose Homeostasis by Glucocorticoids | volume = 872 | pages = 99–126 | date = 2015 | pmid = 26215992 | pmc = 6185996 | doi = 10.1007/978-1-4939-2895-8_5 | isbn = 978-1-4939-2895-8 | series = Advances in Experimental Medicine and Biology | veditors = Wang JC, Harris C| publisher = Springer }} In this way, cortisol and catecholamines work synergistically to promote the breakdown of muscle glycogen into glucose for use in the muscle tissue.{{cite journal |vauthors=Sluiter JK, Frings-Dresen MH, Meijman TF, van der Beek AJ |title=Reactivity and recovery from different types of work measured by catecholamines and cortisol: a systematic literature overview |journal=Occup Environ Med |volume=57 |issue=5 |pages=298–315 |date=May 2000 |pmid=10769296 |pmc=1739955 |doi=10.1136/oem.57.5.298 |url=}}

Elevated levels of cortisol, if prolonged, can lead to proteolysis (breakdown of proteins) and muscle wasting.{{cite journal | vauthors = Simmons PS, Miles JM, Gerich JE, Haymond MW | title = Increased proteolysis. An effect of increases in plasma cortisol within the physiologic range | journal = The Journal of Clinical Investigation | volume = 73 | issue =2| pages = 412–20 | date = February 1984 | pmid= 6365973 | pmc= 425032 | doi = 10.1172/JCI111227 }} The reason for proteolysis is to provide the relevant tissue with a feedstock for gluconeogenesis; see glucogenic amino acids. The effects of cortisol on lipid metabolism are more complicated since lipogenesis is observed in patients with chronic, raised circulating glucocorticoid (i.e. cortisol) levels, although an acute increase in circulating cortisol promotes lipolysis.{{cite journal|vauthors=Djurhuus CB, Gravholt CH, Nielsen S, Mengel A, Christiansen JS, Schmitz OE, Møller N|s2cid=2609285|date=July 2002|title=Effects of cortisol on lipolysis and regional interstitial glycerol levels in humans|journal=American Journal of Physiology. Endocrinology and Metabolism|volume=283|issue=1|pages=E172–7|doi=10.1152/ajpendo.00544.2001|pmid=12067858}} The usual explanation to account for this apparent discrepancy is that the raised blood glucose concentration (through the action of cortisol) will stimulate insulin release. Insulin stimulates lipogenesis, so this is an indirect consequence of the raised cortisol concentration in the blood but it will only occur over a longer time scale.

Cortisol prevents the release of substances in the body that cause inflammation. It is used to treat conditions resulting from overactivity of the B-cell-mediated antibody response. Examples include inflammatory and rheumatoid diseases, as well as allergies. Low-dose topical hydrocortisone, available as a nonprescription medicine in some countries, is used to treat skin problems such as rashes and eczema.

Cortisol inhibits production of interleukin 12 (IL-12), interferon gamma (IFN-gamma), IFN-alpha, and tumor necrosis factor alpha (TNF-alpha) by antigen-presenting cells (APCs) and T helper cells (Th1 cells), but upregulates interleukin 4, interleukin 10, and interleukin 13 by Th2 cells. This results in a shift toward a Th2 immune response rather than general immunosuppression. The activation of the stress system (and resulting increase in cortisol and Th2 shift) seen during an infection is believed to be a protective mechanism which prevents an over-activation of the inflammatory response.{{cite journal | vauthors = Elenkov IJ | title = Glucocorticoids and the Th1/Th2 balance | journal = Annals of the New York Academy of Sciences | volume = 1024 | issue = 1 | pages = 138–46 | date = June 2004 | pmid = 15265778 | doi = 10.1196/annals.1321.010 | bibcode = 2004NYASA1024..138E | s2cid = 9575617 | url = https://zenodo.org/record/1235876 | access-date = 11 September 2018 | archive-date = 11 December 2022 | archive-url = https://web.archive.org/web/20221211215505/https://zenodo.org/record/1235876 | url-status = live }}

Cortisol can weaken the activity of the immune system. It prevents proliferation of T-cells by rendering the interleukin-2 producer T-cells unresponsive to interleukin-1, and unable to produce the T-cell growth factor IL-2. Cortisol downregulates the expression of the IL2 receptor IL-2R on the surface of the helper T-cell which is necessary to induce a Th1 'cellular' immune response, thus favoring a shift towards Th2 dominance and the release of the cytokines listed above which results in Th2 dominance and favors the 'humoral' B-cell mediated antibody immune response.{{cite journal | vauthors = 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 = Scandinavian Journal of Immunology | volume = 15 | issue = 1 | pages = 25–31 | date = January 1982 | pmid = 6461917 | doi = 10.1111/j.1365-3083.1982.tb00618.x | s2cid = 41292936 }}

Cortisol also has a negative-feedback effect on IL-1.{{cite book |vauthors=Besedovsky HO, Del Rey A, Sorkin E | chapter = Integration of Activated Immune Cell Products in Immune Endocrine Feedback Circuits |veditors=Oppenheim JJ, Jacobs DM | title = Leukocytes and Host Defense | series = Progress in Leukocyte Biology | volume = 5 | publisher = Alan R. Liss | location = New York | year = 1986 | page = 200 }}

The way this negative feedback works is that an immune stressor causes peripheral immune cells to release IL-1 and other cytokines such as IL-6 and TNF-alpha. These cytokines stimulate the hypothalamus, causing it to release corticotropin-releasing hormone (CRH). CRH in turn stimulates the production of adrenocorticotropic hormone (ACTH) among other things in the adrenal gland, which (among other things) increases production of cortisol. Cortisol then closes the loop as it inhibits TNF-alpha production in immune cells and makes them less responsive to IL-1.{{cite book |vauthors=Demers Lawrence M | chapter = Adrenal Cortical Disorders |veditors=Burtis Carl A, Ashwood Edward R, Bruns David E, Sawyer, Barbara G| title = Tietz Fundamentals of Clinical Chemistry | publisher = Saunders El Sevier | location = St. Louis, Missouri | year = 2008 | pages = 749–765 }}

Through this system, as long as an immune stressor is small, the response will be regulated to the correct level. Like a thermostat controlling a heater, the hypothalamus uses cortisol to turn off the heat once the production of cortisol matches the stress induced on the immune system. But in a severe infection or in a situation where the immune system is overly sensitized to an antigen (such as in allergic reactions) or there is a massive flood of antigens (as can happen with endotoxic bacteria) the correct set point might never be reached. Also because of downregulation of Th1 immunity by cortisol and other signaling molecules, certain types of infection, (notably Mycobacterium tuberculosis) can trick the body into getting locked in the wrong mode of attack, using an antibody-mediated humoral response when a cellular response is needed.

Lymphocytes include the B-cell lymphocytes that are the antibody-producing cells of the body, and are thus the main agents of humoral immunity. A larger number of lymphocytes in the lymph nodes, bone marrow, and skin means the body is increasing its humoral immune response. B-cell lymphocytes release antibodies into the bloodstream. These antibodies lower infection through three main pathways: neutralization, opsonization, and complement activation. Antibodies neutralize pathogens by binding to surface adhering proteins, keeping pathogens from binding to host cells. In opsonization, antibodies bind to the pathogen and create a target for phagocytic immune cells to find and latch onto, allowing them to destroy the pathogen more easily. Finally antibodies can also activate complement molecules which can combine in various ways to promote opsonization or even act directly to lyse a bacteria. There are many different kinds of antibody and their production is highly complex, involving several types of lymphocyte, but in general lymphocytes and other antibody regulating and producing cells will migrate to the lymph nodes to aid in the release of these antibodies into the bloodstream.{{cite book |vauthors=Murphy, Kenneth| chapter = The Humoral Immune Response | title = Janeway's Immunobiology, 8th ed.| publisher = Garland Science Taylor & Francis Group | location = New York, NY | year = 2012 | page = 387 }}

Rapid 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.

On the other side of things, there are natural killer cells; these cells have the ability to take down larger in size threats like bacteria, parasites, and tumor cells. A separate study{{cite journal | vauthors = Mavoungou E, Bouyou-Akotet MK, Kremsner PG | title = Effects of prolactin and cortisol on natural killer (NK) cell surface expression and function of human natural cytotoxicity receptors (NKp46, NKp44 and NKp30) | journal = Clinical and Experimental Immunology | volume = 139 | issue = 2 | pages = 287–96 | date = February 2005 | pmid = 15654827 | pmc = 1809301 | doi = 10.1111/j.1365-2249.2004.02686.x }} found that cortisol effectively disarmed natural killer cells, downregulating the expression of their natural cytotoxicity receptors. Prolactin has the opposite effect. It increases the expression of cytotoxicity receptors on natural killer cells, increasing their firepower.{{Citation needed|date=November 2023}}

Cortisol stimulates many copper enzymes (often to 50% of their total potential), including lysyl oxidase, an enzyme that cross-links collagen and elastin. Especially valuable for immune response is cortisol's stimulation of the superoxide dismutase,{{cite book |vauthors=Flohe L, Beckman R, Giertz H, Loschen G | chapter = Oxygen Centered Free Radicals as Mediators of Inflammation | editor = Sies H | title = Oxidative stress | publisher = Orlando | location = London | year = 1985 | page = 405 | isbn = 978-0-12-642760-8 }} since this copper enzyme is almost certainly used by the body to permit superoxides to poison bacteria.

Some viruses, such as influenza and SARS-CoV-1 and SARS-CoV-2, are known to suppress the secretion of stress hormones to avoid the organism's immune response, thus avoiding the immune protection of the organism. These viruses suppress cortisol by producing a protein that mimics the human ACTH hormone but is incomplete and does not have hormonal activity. ACTH is a hormone that stimulates the adrenal gland to produce cortisol and other steroid hormones. However, the organism makes antibodies against this viral protein, and those antibodies also kill the human ACTH hormone, which leads to the suppression of adrenal gland function. Such adrenal suppression is a way for a virus to evade immune detection and elimination.{{cite journal | doi=10.1002/cncr.31943 | title=The impact of psychosocial stress and stress management on immune responses in patients with cancer | date=2019 | last1=Antoni | first1=Michael H. | last2=Dhabhar | first2=Firdaus S. | journal=Cancer | volume=125 | issue=9 | pages=1417–1431 | pmid=30768779 | pmc=6467795 }}{{cite journal |vauthors=Wheatland R |title=Molecular mimicry of ACTH in SARS – implications for corticosteroid treatment and prophylaxis |journal=Med Hypotheses |volume=63 |issue=5 |pages=855–862 |date=May 2004 |pmid=15488660 |pmc=7126000 |doi=10.1016/j.mehy.2004.04.009 |url=}}{{cite journal |vauthors=Akbas EM, Akbas N |title=COVID-19, adrenal gland, glucocorticoids, and adrenal insufficiency |journal=Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub |volume=165 |issue=1 |pages=1–7 |date=March 2021 |pmid=33542545 |doi=10.5507/bp.2021.011 |url=|doi-access=free }} This viral strategy can have severe consequences for the host (human that is infected by the virus), as cortisol is essential for regulating various physiological processes, such as metabolism, blood pressure, inflammation, and immune response. A lack of cortisol can result in a condition called adrenal insufficiency, which can cause symptoms such as fatigue, weight loss, low blood pressure, nausea, vomiting, and abdominal pain. Adrenal insufficiency can also impair the ability of the host to cope with stress and infections, as cortisol helps to mobilize energy sources, increase heart rate, and downregulate non-essential metabolic processes during stress. Therefore, by suppressing cortisol production, some viruses can escape the immune system and weaken the host's overall health and resilience.{{cite journal |vauthors=Buford TW, Willoughby DS |title=Impact of DHEA(S) and cortisol on immune function in aging: a brief review |journal=Appl Physiol Nutr Metab |volume=33 |issue=3 |pages=429–33 |date=June 2008 |pmid=18461094 |doi=10.1139/H08-013 |url=}}

Cortisol counteracts insulin, contributes to hyperglycemia by stimulating gluconeogenesis and inhibits the peripheral use of glucose (insulin resistance){{cite journal |vauthors=Schernthaner-Reiter MH, Wolf P, Vila G, Luger A |title=The Interaction of Insulin and Pituitary Hormone Syndromes |journal=Front Endocrinol (Lausanne) |volume=12 |issue= |pages=626427 |date=2021 |pmid=33995272 |pmc=8113952 |doi=10.3389/fendo.2021.626427 |url= |doi-access=free }} by decreasing the translocation of glucose transporters (especially GLUT4) to the cell membrane.{{cite book | author = King MB | title = Lange Q & A | publisher = McGraw-Hill, Medical Pub. Division | location = New York | year = 2005 | isbn = 978-0-07-144578-8 | url-access = registration | url = https://archive.org/details/langeqausmlestep0005unse }} Cortisol also increases glycogen synthesis (glycogenesis) in the liver, storing glucose in easily accessible form.{{cite book |vauthors=Baynes J, Dominiczak M | title = Medical biochemistry | publisher = Mosby Elsevier | year = 2009 | isbn = 978-0-323-05371-6 }}

Cortisol reduces bone formation, favoring long-term development of osteoporosis (progressive bone disease). The mechanism behind this is two-fold: cortisol stimulates the production of RANKL by osteoblasts which stimulates, through binding to RANK receptors, the activity of osteoclasts – cells responsible for calcium resorption from bone – and also inhibits the production of osteoprotegerin (OPG) which acts as a decoy receptor and captures some RANKL before it can activate the osteoclasts through RANK. In other words, when RANKL binds to OPG, no response occurs as opposed to the binding to RANK which leads to the activation of osteoclasts.

It transports potassium out of cells in exchange for an equal number of sodium ions (see above). This can trigger the hyperkalemia of metabolic shock from surgery. Cortisol also reduces calcium absorption in the intestine.{{cite journal | vauthors = Deutsch E | title = [Pathogenesis of thrombocytopenia. 2. Distribution disorders, pseudo-thrombocytopenias] |language=de| journal = Fortschritte der Medizin | volume = 96 | issue = 14 | pages = 761–2 | date = April 1978 | pmid = 346457 }} Cortisol down-regulates the synthesis of collagen.{{cite journal | vauthors = Kucharz EJ | title = Hormonal control of collagen metabolism. Part II | journal = Endocrinologie | volume = 26 | issue = 4 | pages = 229–37 | year = 1988 | pmid = 3062759 }}

Cortisol raises the free amino acids in the serum by inhibiting collagen formation, decreasing amino acid uptake by muscle, and inhibiting protein synthesis.{{cite encyclopedia |author=Manchester, KL |editor=Allison, NH |editor2=Munro JB|year=1964 |title =Sites of Hormonal Regulation of Protein Metabolism |encyclopedia=Mammalian Protein Metabolism |publisher=Academic Press |location=New York |page=229? 273?}} Cortisol (as opticortinol) may inversely inhibit IgA precursor cells in the intestines of calves.{{cite journal | vauthors = Husband AJ, Brandon MR, Lascelles AK | title = The effect of corticosteroid on absorption and endogenous production of immunoglobulins in calves | journal = The Australian Journal of Experimental Biology and Medical Science | volume = 51 | issue = 5 | pages = 707–10 | date = October 1973 | pmid = 4207041 | doi = 10.1038/icb.1973.67 }} Cortisol also inhibits IgA in serum, as it does IgM; however, it is not shown to inhibit IgE.{{cite journal | vauthors = Posey WC, Nelson HS, Branch B, Pearlman DS | title = The effects of acute corticosteroid therapy for asthma on serum immunoglobulin levels | journal = The Journal of Allergy and Clinical Immunology | volume = 62 | issue = 6 | pages = 340–8 | date = December 1978 | pmid = 712020 | doi = 10.1016/0091-6749(78)90134-3 }}

Cortisol increases glomerular filtration rate,{{cite journal |vauthors=Li X, Xiang X, Hu J, Goswami R, Yang S, Zhang A, Wang Y, Li Q, Bi X |title=Association Between Serum Cortisol and Chronic Kidney Disease in Patients with Essential Hypertension |journal=Kidney Blood Press Res |volume=41 |issue=4 |pages=384–91 |date=2016 |pmid=27344357 |doi=10.1159/000443435 |s2cid=8633049 |url=|doi-access=free }} and renal plasma flow from the kidneys thus increasing phosphate excretion,{{cite journal |vauthors=Hill KJ, Lumbers ER, Elbourne I |title=The actions of cortisol on fetal renal function |journal=J Dev Physiol |volume=10 |issue=1 |pages=85–96 |date=February 1988 |pmid=3351211 |doi= |url=}}{{cite journal |vauthors=Biber J, Murer H, Mohebbi N, Wagner CA |title=Renal Handling of Phosphate and Sulfate |journal=Compr Physiol |volume=4 |issue=2 |pages=771–92 |date=April 2014 |pmid=24715567 |doi=10.1002/cphy.c120031 |isbn=9780470650714 |url=https://www.zora.uzh.ch/id/eprint/95625/1/Renal_handling_of_phosphate_and.pdf |access-date=16 September 2023 |archive-date=1 November 2023 |archive-url=https://web.archive.org/web/20231101095038/https://www.zora.uzh.ch/id/eprint/95625/1/Renal_handling_of_phosphate_and.pdf |url-status=live }} as well as increasing sodium and water retention and potassium excretion by acting on mineralocorticoid receptors. It also increases sodium and water absorption and potassium excretion in the intestines.{{cite book | veditors = Kure DW, Pollock RE, Weichselbaum RR, Bast RC, Ganglier TS, Holland JF, Frei E | title = Holland-Frei Cancer Medicine | date = 2003 | publisher = Decker | location = Hamilton, Ontario | isbn = 978-1-55009-213-4 | edition = 6th | vauthors = McKay LI, Cidlowski JA | chapter = Physiologic and Pharmacologic Effects of Corticosteroids | chapter-url = https://www.ncbi.nlm.nih.gov/books/NBK13780/ | url-access = registration | url = https://archive.org/details/cancermedicine60002unse }}

Cortisol promotes sodium absorption through the small intestine of mammals.{{cite journal | vauthors = 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 = Scandinavian Journal of Gastroenterology | volume = 16 | issue = 5 | pages = 667–71 | year = 1981 | pmid = 7323700 | doi = 10.3109/00365528109182028 }} Sodium depletion, however, does not affect cortisol levels{{cite journal | vauthors = 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 = Journal of Steroid Biochemistry | volume = 8 | issue = 8 | pages = 799–804 | date = August 1977 | pmid = 592808 | doi = 10.1016/0022-4731(77)90086-3 }} so cortisol cannot be used to regulate serum sodium. Cortisol's original purpose may have been sodium transport. This hypothesis is supported by the fact that freshwater fish use cortisol to stimulate sodium inward, while saltwater fish have a cortisol-based system for expelling excess sodium.{{cite book |vauthors=Gorbman A, Dickhoff WW, Vigna SR, Clark NB, Muller AF | title = Comparative endocrinology | publisher = Wiley | location = New York | year = 1983 | isbn = 978-0-471-06266-0 }}

A sodium load augments the intense potassium excretion by cortisol. Corticosterone is comparable to cortisol in this case.{{cite book |vauthors=Muller AF, Oconnor CM | title = An International Symposium on Aldosterone | publisher = Little Brown & Co | year = 1958 | page = 58 }} For potassium to move out of the cell, cortisol moves an equal number of sodium ions into the cell.{{cite journal | vauthors = Knight RP, Kornfeld DS, Glaser GH, Bondy PK | title = Effects of intravenous hydrocortisone on electrolytes of serum and urine in man | journal = The Journal of Clinical Endocrinology and Metabolism | volume = 15 | issue = 2 | pages = 176–81 | date = February 1955 | pmid = 13233328 | doi = 10.1210/jcem-15-2-176 }} This should make pH regulation much easier (unlike the normal potassium-deficiency situation, in which two sodium ions move in for each three potassium ions that move out—closer to the deoxycorticosterone effect).

Cortisol stimulates gastric-acid secretion.{{cite book | title=The Human Adrenal Gland | url=https://archive.org/details/humanadrenalglan00soff | url-access=registration | publisher=Lea & Febiger |vauthors=Soffer LJ, Dorfman RI, Gabrilove JL | year=1961 | location=Philadelphia}} Cortisol's only direct effect on the hydrogen-ion excretion of the kidneys is to stimulate the excretion of ammonium ions by deactivating the renal glutaminase enzyme.{{cite journal | vauthors = Kokoshchuk GI, Pakhmurnyĭ BA |title =Role of glucocorticoids in regulating the acid-excreting function of the kidneys | journal = Fiziologicheskii Zhurnal SSSR imeni I. M. Sechenova | volume = 65 | issue = 5 | pages = 751–4 | date = May 1979 | pmid = 110627 }}

Cortisol works with adrenaline (epinephrine) 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.{{cite web | vauthors = Kennedy R |url=http://www.medical-library.net/content/view/1401/41/ |publisher=The Doctors' Medical Library |title=Cortisol (Hydrocortisone) |access-date=14 June 2013 |archive-url=https://web.archive.org/web/20130703071625/http://www.medical-library.net/content/view/1401/41 |archive-date=3 July 2013 |url-status=dead }} However, long-term exposure to cortisol damages cells in the hippocampus;{{cite journal |vauthors = McAuley MT, Kenny RA, Kirkwood TB, Wilkinson DJ, Jones JJ, Miller VM |title = A mathematical model of aging-related and cortisol induced hippocampal dysfunction |journal = BMC Neuroscience |volume = 10 |page = 26 |date = March 2009 |pmid = 19320982 |pmc = 2680862 |doi = 10.1186/1471-2202-10-26 |doi-access = free }} this damage results in impaired learning.

File:Change in plasma cortisol cycle over 24 hours.jpg

Diurnal cycles of cortisol levels are found in humans.{{cite book |vauthors=Martin PA, Crump MH | chapter = The adrenal gland |veditors=Dooley MP, Pineda MH | title = McDonald's veterinary endocrinology and reproduction | edition = 5th | publisher = Iowa State Press | location = Ames, Iowa | year = 2003 | isbn = 978-0-8138-1106-2 }}

Sustained stress can lead to high levels of circulating cortisol (regarded as one of the more important of the several "stress hormones").{{cite book | vauthors = Lundberg U | chapter = Neuroendocrine Measures | veditors = Contrada R, Baum A | title = The Handbook of Stress Science: Biology, Psychology, and Health | url = https://books.google.com/books?id=EXVlk8pnEKIC | location = New York | publisher = Springer Publishing Company | date = 2010 | page = 351 | isbn = 978-0-8261-1771-7 | access-date = 12 March 2020 | quote = [...] epinephrine, norepinephrine, and cortisol are considered the most important 'stress hormones,' although a number of other hormones are also influenced by stress [...]. | archive-date = 11 March 2024 | archive-url = https://web.archive.org/web/20240311202051/https://books.google.com/books?id=EXVlk8pnEKIC | url-status = live }}

During human pregnancy, increased fetal production of cortisol between weeks 30 and 32 initiates production of fetal lung pulmonary surfactant to promote maturation of the lungs. In fetal lambs, glucocorticoids (principally cortisol) increase after about day 130, with lung surfactant increasing greatly, in response, by about day 135,{{cite journal |vauthors = Mescher EJ, Platzker AC, Ballard PL, Kitterman JA, Clements JA, Tooley WH |title = Ontogeny of tracheal fluid, pulmonary surfactant, and plasma corticoids in the fetal lamb |journal = Journal of Applied Physiology |volume = 39 |issue = 6 |pages = 1017–21 |date = December 1975 |pmid = 2573 |doi = 10.1152/jappl.1975.39.6.1017}} and although lamb fetal cortisol is mostly of maternal origin during the first 122 days, 88% or more is of fetal origin by day 136 of gestation.{{cite journal |vauthors = Hennessy DP, Coghlan JP, Hardy KJ, Scoggins BA, Wintour EM |title = The origin of cortisol in the blood of fetal sheep |journal = The Journal of Endocrinology |volume = 95 |issue = 1 |pages = 71–9 |date = October 1982 |pmid = 7130892 |doi = 10.1677/joe.0.0950071 }} Although the timing of fetal cortisol concentration elevation in sheep may vary somewhat, it averages about 11.8 days before the onset of labor.{{cite journal |vauthors = Magyar DM, Fridshal D, Elsner CW, Glatz T, Eliot J, Klein AH, Lowe KC, Buster JE, Nathanielsz PW |title = Time-trend analysis of plasma cortisol concentrations in the fetal sheep in relation to parturition |journal = Endocrinology |volume = 107 |issue = 1 |pages = 155–9 |date = July 1980 |pmid = 7379742 |doi = 10.1210/endo-107-1-155 }} In several livestock species (e.g. cattle, sheep, goats, and pigs), the surge of fetal cortisol late in gestation triggers the onset of parturition by removing the progesterone block of cervical dilation and myometrial contraction. The mechanisms yielding this effect on progesterone differ among species. In the sheep, where progesterone sufficient for maintaining pregnancy is produced by the placenta after about day 70 of gestation,{{cite journal |vauthors = Ricketts AP, Flint AP |title = Onset of synthesis of progesterone by ovine placenta |journal = The Journal of Endocrinology |volume = 86 |issue = 2 |pages = 337–47 |date = August 1980 |pmid = 6933207 |doi = 10.1677/joe.0.0860337 }}{{cite journal |vauthors = Al-Gubory KH, Solari A, Mirman B |title = Effects of luteectomy on the maintenance of pregnancy, circulating progesterone concentrations and lambing performance in sheep |journal = Reproduction, Fertility, and Development |volume = 11 |issue = 6 |pages = 317–22 |year = 1999 |pmid = 10972299 |doi = 10.1071/RD99079 }} the prepartum fetal cortisol surge induces placental enzymatic conversion of progesterone to estrogen. (The elevated level of estrogen stimulates prostaglandin secretion and oxytocin receptor development.)

Exposure of fetuses to cortisol during gestation can have a variety of developmental outcomes, including alterations in prenatal and postnatal growth patterns. In marmosets, a species of New World primates, pregnant females have varying levels of cortisol during gestation, both within and between females. Infants born to mothers with high gestational cortisol during the first trimester of pregnancy had lower rates of growth in body mass indices than infants born to mothers with low gestational cortisol (about 20% lower). However, postnatal growth rates in these high-cortisol infants were more rapid than low-cortisol infants later in postnatal periods, and complete catch-up in growth had occurred by 540 days of age. These results suggest that gestational exposure to cortisol in fetuses has important potential fetal programming effects on both pre and postnatal growth in primates.{{cite journal |vauthors = Mustoe AC, Birnie AK, Korgan AC, Santo JB, French JA |title = Natural variation in gestational cortisol is associated with patterns of growth in marmoset monkeys (Callithrix geoffroyi) |journal = General and Comparative Endocrinology |volume = 175 |issue = 3 |pages = 519–26 |date = February 2012 |pmid = 22212825 |pmc = 3268124 |doi = 10.1016/j.ygcen.2011.12.020 }}

{{See also|Moon face}}

Increased cortisol levels may lead to facial swelling and bloating, creating a round and puffy appearance, referred to as "cortisol face." This is not due to everyday stress, but due to rare hormonal disorders.{{cite news |title=What is cortisol? How to lower levels amid concerns over "cortisol face" - CBS News |url=https://www.cbsnews.com/news/how-to-lower-cortisol-levels-cortisol-face-concerns/ |access-date=11 August 2024 |work=www.cbsnews.com |date=8 August 2024 |archive-date=11 August 2024 |archive-url=https://web.archive.org/web/20240811182830/https://www.cbsnews.com/news/how-to-lower-cortisol-levels-cortisol-face-concerns/ |url-status=live }}{{cite news |title=What Is Cortisol Face? — and Can Stress Really Change Your Appearance? |url=https://people.com/what-is-cortisol-face-8693467 |access-date=11 August 2024 |work=Peoplemag |language=en |archive-date=11 August 2024 |archive-url=https://web.archive.org/web/20240811182830/https://people.com/what-is-cortisol-face-8693467 |url-status=live }}{{cite news |last1=Marshall |first1=Mallika |title=What is the trending TikTok topic "cortisol face" and what causes it? - CBS Boston |url=https://www.cbsnews.com/boston/news/cortisol-face-tiktok-trending-topic/ |access-date=11 August 2024 |work=www.cbsnews.com |date=31 July 2024 |archive-date=11 August 2024 |archive-url=https://web.archive.org/web/20240811182830/https://www.cbsnews.com/boston/news/cortisol-face-tiktok-trending-topic/ |url-status=live }}

Cortisol is produced in the human body by the adrenal gland's zona fasciculata, the second of three layers comprising the adrenal cortex. This cortex forms the outer "bark" of each adrenal gland, situated atop the kidneys. The release of cortisol is controlled by the hypothalamus of a brain. Secretion of corticotropin-releasing hormone by the hypothalamus triggers cells in its neighboring anterior pituitary to secrete adrenocorticotropic hormone (ACTH) into the vascular system, through which blood carries it to the adrenal cortex. ACTH stimulates the synthesis of cortisol and other glucocorticoids, mineralocorticoid aldosterone, and dehydroepiandrosterone.

Normal values indicated in the following tables pertain to humans (normal levels vary among species). Measured cortisol levels, and therefore reference ranges, depend on the sample type, analytical method used, and factors such as age and sex. Test results should, therefore, always be interpreted using the reference range from the laboratory that produced the result.{{cite journal |vauthors=Bianchi L, Campi B, Sessa MR, De Marco G, Ferrarini E, Zucchi R, Marcocci C, Vitti P, Manetti L, Saba A, Agretti P |title=Measurement of urinary free cortisol by LC-MS-MS: adoption of a literature reference range and comparison with our current immunometric method |journal=J Endocrinol Invest |volume=42 |issue=11 |pages=1299–1305 |date=November 2019 |pmid=31012054 |doi=10.1007/s40618-019-01050-5 |s2cid=128361547 |url=}}{{cite journal |vauthors=Panton KK, Mikkelsen G, Irgens WØ, Hovde AK, Killingmo MW, Øien MA, Thorsby PM, Åsberg A |title=New reference intervals for cortisol, cortisol binding globulin and free cortisol index in women using ethinyl estradiol |journal=Scand J Clin Lab Invest |volume=79 |issue=5 |pages=314–319 |date=September 2019 |pmid=31161807 |doi=10.1080/00365513.2019.1622031 |s2cid=174806302 |url=|doi-access=free |hdl=11250/2739760 |hdl-access=free }}{{cite journal |vauthors=Pai J, Joshi RK, Bhaskar S, Patil S, Bv S, R S, Iyengar AR, Agarwal N, Shorie M |title=Revisiting the cortisol reference ranges in humans: the role of demographics |journal=Endocrine |volume=82 |issue=2 |pages=414–418 |date=November 2023 |pmid=37501014 |doi=10.1007/s12020-023-03456-x |s2cid=260246830 |url=https://www.researchsquare.com/article/rs-2840050/latest.pdf |access-date=2 February 2024 |archive-date=3 December 2023 |archive-url=https://web.archive.org/web/20231203012804/https://www.researchsquare.com/article/rs-2840050/latest.pdf |url-status=live }} An individual's cortisol levels can be detected in blood, serum, urine, saliva, and sweat.{{cite journal |last1=Yeasmin |first1=Sanjida |last2=Ullah |first2=Ahasan |last3=Wu |first3=Bo |last4=Zhang |first4=Xueqiao |last5=Cheng |first5=Li-Jing |title=Enzyme-Mimics for Sensitive and Selective Steroid Metabolite Detection |journal=ACS Applied Materials & Interfaces |date=2023 |volume=15 |issue=11 |doi=10.1021/acsami.2c21980 |pmid=36908226 |s2cid=257494057 |url=https://pubs.acs.org/doi/10.1021/acsami.2c21980 |access-date=8 April 2023 |url-access=subscription |archive-date=8 April 2023 |archive-url=https://web.archive.org/web/20230408234418/https://pubs.acs.org/doi/10.1021/acsami.2c21980 |url-status=live }}

Using the molecular weight of 362.460 g/mole, the conversion factor from μg/dL to nmol/L is approximately 27.6;{{cite journal |vauthors=Di Dalmazi G, Fanelli F, Zavatta G, Ricci Bitti S, Mezzullo M, Repaci A, Pelusi C, Gambineri A, Altieri P, Mosconi C, Balacchi C, Golfieri R, Cosentino ER, Borghi C, Vicennati V, Pasquali R, Pagotto U |title=The Steroid Profile of Adrenal Incidentalomas: Subtyping Subjects With High Cardiovascular Risk |journal=J Clin Endocrinol Metab |volume=104 |issue=11 |pages=5519–5528 |date=November 2019 |pmid=31381072 |doi=10.1210/jc.2019-00365 |s2cid=199437371 |url=|doi-access=free }}{{cite journal |vauthors=Scott SM, Watterberg KL |title=Effect of gestational age, postnatal age, and illness on plasma cortisol concentrations in premature infants |journal=Pediatr Res |volume=37 |issue=1 |pages=112–6 |date=January 1995 |pmid=7700725 |doi=10.1203/00006450-199501000-00021 |s2cid=21870513 |url=|doi-access=free }} thus, 10 μg/dL is about 276 nmol/L.

Cortisol follows a circadian rhythm, and to accurately measure cortisol levels is best to test four times per day through saliva. An individual may have normal total cortisol but have a lower than normal level during a certain period of the day and a higher than normal level during a different period. Therefore, some scholars question the clinical utility of cortisol measurement.{{cite journal | vauthors = Izawa S, Sugaya N, Ogawa N, Shirotsuki K, Nomura S | title = A validation study on fingernail cortisol: correlations with one-month cortisol levels estimated by hair and saliva samples | journal = Stress | volume = 24| issue = 6| pages = 734–741 | date = April 2021 | pmid = 33792492 | doi = 10.1080/10253890.2021.1895113 | s2cid = 232481968 | url = | doi-access = free }}{{cite journal | vauthors = Turpeinen U, Hämäläinen E | title = Determination of cortisol in serum, saliva and urine | journal = Best Practice & Research. Clinical Endocrinology & Metabolism | volume = 27 | issue = 6 | pages = 795–801 | date = December 2013 | pmid = 24275191 | doi = 10.1016/j.beem.2013.10.008 | url = }}{{cite journal | vauthors = Dolomie-Fagour L, Corcuff JB | title = [Is free plasmatic cortisol measurement useful in intensive care unit?] |language =fr| journal = Annales de Biologie Clinique | volume = 66 | issue = 1 | pages = 31–41 | date = 2008 | pmid = 18227002 | doi = 10.1684/abc.2008.0189 | doi-broken-date = 1 November 2024 | url = }}{{cite journal | vauthors = Maidana P, Bruno OD, Mesch V | title = [A critical analysis of cortisol measurements: an update] |language=es| journal = Medicina | volume = 73 | issue = 6 | pages = 579–84 | date = 2013 | pmid = 24356273 | doi = | url = }}

Cortisol is lipophilic, and is transported bound to transcortin (also known as corticosteroid-binding globulin (CBG)) and albumin, while only a small part of the total serum cortisol is unbound and has biological activity.{{cite journal | vauthors = Verbeeten KC, Ahmet AH | title = The role of corticosteroid-binding globulin in the evaluation of adrenal insufficiency | journal = Journal of Pediatric Endocrinology & Metabolism | volume = 31 | issue = 2 | pages = 107–115 | date = January 2018 | pmid = 29194043 | doi = 10.1515/jpem-2017-0270 | s2cid = 28588420 | doi-access = free }} This binding of cortisol to transcortin is accomplished through hydrophobic interactions in which cortisol binds in a 1:1 ratio.{{cite journal | vauthors = Henley D, Lightman S, Carrell R | title = Cortisol and CBG - Getting cortisol to the right place at the right time | journal = Pharmacology & Therapeutics | volume = 166 | pages = 128–135 | date = October 2016 | pmid = 27411675 | doi = 10.1016/j.pharmthera.2016.06.020 | hdl = 1983/d7ed507d-52d5-496b-ae1f-de220ae1b190 | url = https://research-information.bris.ac.uk/ws/files/183969438/CBG_Final_Henley_revised_submitted2.pdf | access-date = 8 March 2023 | archive-date = 20 August 2023 | archive-url = https://web.archive.org/web/20230820212304/https://research-information.bris.ac.uk/ws/files/183969438/CBG_Final_Henley_revised_submitted2.pdf | url-status = live }} Serum cortisol assays measures total cortisol, and its results may be misleading for patients with altered serum protein concentrations. The salivary cortisol test avoids this problem because only free cortisol can pass through the blood-saliva barrier.{{cite journal |vauthors=de Medeiros GF, Lafenêtre P, Janthakhin Y, Cerpa JC, Zhang CL, Mehta MM, Mortessagne P, Helbling JC, Ferreira G, Moisan MP |title=Corticosteroid-Binding Globulin Deficiency Specifically Impairs Contextual and Recognition Memory Consolidation in Male Mice |journal=Neuroendocrinology |volume=109 |issue=4 |pages=322–332 |date=2019 |pmid=30904918 |doi=10.1159/000499827 |s2cid=85498121 |url=}}{{cite journal |vauthors=Henley DE, Lightman SL |title=New insights into corticosteroid-binding globulin and glucocorticoid delivery |journal=Neuroscience |volume=180 |issue= |pages=1–8 |date=April 2011 |pmid=21371536 |doi=10.1016/j.neuroscience.2011.02.053 |s2cid=26843500 |url=}}{{cite journal |vauthors=Salzano C, Saracino G, Cardillo G |title=Possible Adrenal Involvement in Long COVID Syndrome |journal=Medicina (Kaunas) |volume=57 |issue=10 |date=October 2021 |page=1087 |pmid=34684123 |pmc=8537520 |doi=10.3390/medicina57101087 |url= |doi-access=free }}{{cite journal |vauthors=Granger DA, Hibel LC, Fortunato CK, Kapelewski CH |title=Medication effects on salivary cortisol: tactics and strategy to minimize impact in behavioral and developmental science |journal=Psychoneuroendocrinology |volume=34 |issue=10 |pages=1437–48 |date=November 2009 |pmid=19632788 |doi=10.1016/j.psyneuen.2009.06.017 |s2cid=3100315 |url=}} Transcortin particles are too large to pass through this barrier,{{cite journal|doi=10.1017/S0962728600030657 |title=Can non-invasive glucocorticoid measures be used as reliable indicators of stress in animals? |date=2006 |last1=Lane |first1=J. |journal=Animal Welfare |volume=15 |issue=4 |pages=331–342 |s2cid=80026053 }} that consists of epithelial cell layers of the oral mucosa and salivary glands.{{cite journal |vauthors=Lin GC, Smajlhodzic M, Bandian AM, Friedl HP, Leitgeb T, Oerter S, Stadler K, Giese U, Peham JR, Bingle L, Neuhaus W |title=An In Vitro Barrier Model of the Human Submandibular Salivary Gland Epithelium Based on a Single Cell Clone of Cell Line HTB-41: Establishment and Application for Biomarker Transport Studies |journal=Biomedicines |volume=8 |issue=9 |date=August 2020 |page=302 |pmid=32842479 |pmc=7555419 |doi=10.3390/biomedicines8090302 |url= |doi-access=free }}

Cortisol may be incorporated into hair from blood, sweat, and sebum. A 3 centimeter segment of scalp hair can represent 3 months of hair growth, although growth rates can vary in different regions of the scalp. Cortisol in hair is a reliable indicator of chronic cortisol exposure.{{cite journal | vauthors = Lee DY, Kim E, Choi MH | title=Technical and clinical aspects of cortisol as a biochemical marker of chronic stress | journal= BMB Reports | volume=48 | issue=4 | pages=209–216 | year=2015 | doi= 10.5483/bmbrep.2015.48.4.275 | pmc=4436856 | pmid=25560699}}

Automated immunoassays lack specificity and show significant cross-reactivity due to interactions with structural analogs of cortisol, and show differences between assays. Liquid chromatography-tandem mass spectrometry (LC-MS/MS) can improve specificity and sensitivity.{{cite journal | vauthors = El-Farhan N, Rees DA, Evans C | title = Measuring cortisol in serum, urine and saliva - are our assays good enough? | journal = Annals of Clinical Biochemistry | volume = 54 | issue = 3 | pages = 308–322 | date = May 2017 | pmid = 28068807 | doi = 10.1177/0004563216687335 | s2cid = 206397561 | doi-access = free }}

Some medical disorders are related to abnormal cortisol production, such as:

• Primary hypercortisolism (Cushing's syndrome): excessive levels of cortisol{{cite web|url=https://www.lecturio.com/concepts/cushings-syndrome/|title=Cushing's Syndrome|website=The Lecturio Medical Concept Library|access-date=11 July 2021|archive-date=22 September 2021|archive-url=https://web.archive.org/web/20210922231327/https://www.lecturio.com/concepts/cushings-syndrome/|url-status=live}}
• Secondary hypercortisolism (pituitary tumor resulting in Cushing's disease,{{cite web|title=Cushing's Syndrome|url=http://endocrine.niddk.nih.gov/pubs/cushings/cushings.aspx#1|publisher=National Endocrine and Metabolic Diseases Information Service (NEMDIS)|access-date=16 March 2015|date=July 2008|quote=These benign, or noncancerous, tumors of the pituitary gland secrete extra ACTH. Most people with the disorder have a single adenoma. This form of the syndrome, known as Cushing's disease|archive-url=https://web.archive.org/web/20150210104139/http://endocrine.niddk.nih.gov/pubs/cushings/cushings.aspx#1|archive-date=10 February 2015|url-status=dead}}{{cite book | vauthors = Forbis P | title = Stedman's medical eponyms | date = 2005 | publisher = Lippincott Williams & Wilkins | location = Baltimore, Md. | isbn = 978-0-7817-5443-9 | page = 167 | edition = 2nd | url = https://books.google.com/books?id=isqcnR6ryz0C&pg=PA167 | access-date = 30 August 2017 | archive-date = 24 February 2024 | archive-url = https://web.archive.org/web/20240224160912/https://books.google.com/books?id=isqcnR6ryz0C&pg=PA167#v=onepage&q&f=false | url-status = live }} pseudo-Cushing's syndrome)
• Primary hypocortisolism (Addison's disease, Nelson's syndrome): insufficient levels of cortisol
• Secondary hypocortisolism (pituitary tumor, Sheehan's syndrome)

The primary control of cortisol is the pituitary gland peptide, ACTH, which probably controls cortisol by controlling the movement of calcium into the cortisol-secreting target cells.{{cite journal | vauthors = Davies E, Kenyon CJ, Fraser R | title = The role of calcium ions in the mechanism of ACTH stimulation of cortisol synthesis | journal = Steroids | volume = 45 | issue = 6 | pages = 551–60 | date = June 1985 | pmid = 3012830 | doi = 10.1016/0039-128X(85)90019-4 | s2cid = 24454836 }} 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.{{cite journal | vauthors = 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 | date = September 1986 | pmid = 3015567 | doi = 10.1210/endo-119-3-1126 }} (In swine, which do not produce arginine vasopressin, lysine vasopressin acts synergistically with CRH.{{cite journal | vauthors = Minton JE, Parsons KM | title = Adrenocorticotropic hormone and cortisol response to corticotropin-releasing factor and lysine vasopressin in pigs | journal = Journal of Animal Science | volume = 71 | issue = 3 | pages = 724–9 | date = March 1993 | pmid = 8385088 | doi = 10.2527/1993.713724x}})

When activated macrophages start to secrete IL-1, which synergistically with CRH increases ACTH, T-cells also secrete glucosteroid response modifying factor (GRMF), as well as IL-1; both increase the amount of cortisol required to inhibit almost all the immune cells.{{cite journal | vauthors = 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 = Journal of Immunology | volume = 132 | issue = 2 | pages = 821–7 | date = February 1984 | doi = 10.4049/jimmunol.132.2.821 | pmid = 6228602 | s2cid = 27300153 | doi-access = free }} Immune cells then assume their own regulation, but at a higher cortisol setpoint. The increase in cortisol in diarrheic calves is minimal over healthy calves, however, and falls over time.{{cite journal | vauthors = Dvorak M | year = 1971 | title = Plasma 17-Hydroxycorticosteroid Levels in Healthy and Diarrheic Calves | journal = British Veterinarian Journal | volume = 127 | page = 372 }} The cells do not lose all their fight-or-flight override because of interleukin-1's synergism with CRH. Cortisol even has a negative feedback effect on interleukin-1—especially useful to treat diseases that force the hypothalamus to secrete too much CRH, such as those caused by endotoxic bacteria. The suppressor immune cells are not affected by GRMF, so the immune cells' effective setpoint may be even higher than the setpoint for physiological processes. GRMF affects primarily the liver (rather than the kidneys) for some physiological processes.{{cite journal | vauthors = Stith RD, McCallum RE | title = General effect of endotoxin on glucocorticoid receptors in mammalian tissues | journal = Circulatory Shock | volume = 18 | issue = 4 | pages = 301–9 | year = 1986 | pmid = 3084123 }}

High-potassium media (which stimulates aldosterone secretion in vitro) also stimulate cortisol secretion from the fasciculata zone of canine adrenals{{cite journal | vauthors = Mikosha AS, Pushkarov IS, Chelnakova IS, Remennikov GY | year = 1991 | title = 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 | journal = Fiziol. [Kiev] | volume = 37 | page = 60 }}{{cite web|title=Ameer Saadallah Al – Zacko|url=http://medicinemosul.uomosul.edu.iq/files/pages/page_9904388.pdf|access-date=11 July 2013|archive-url=https://web.archive.org/web/20131111193718/http://medicinemosul.uomosul.edu.iq/files/pages/page_9904388.pdf|archive-date=11 November 2013|url-status=dead}} — unlike corticosterone, upon which potassium has no effect.{{cite journal | vauthors = Mendelsohn FA, Mackie C | s2cid = 24873537 | title = Relation of intracellular K+ and steroidogenesis in isolated adrenal zona glomerulosa and fasciculata cells | journal = Clinical Science and Molecular Medicine | volume = 49 | issue = 1 | pages = 13–26 | date = July 1975 | pmid = 168026 | doi = 10.1042/cs0490013}}

Potassium loading also increases ACTH and cortisol in humans.{{cite journal | vauthors = Ueda Y, Honda M, Tsuchiya M, Watanabe H, Izumi Y, Shiratsuchi T, Inoue T, Hatano M | title = Response of plasma ACTH and adrenocortical hormones to potassium loading in essential hypertension | journal = Japanese Circulation Journal | volume = 46 | issue = 4 | pages = 317–22 | date = April 1982 | pmid = 6283190 | doi = 10.1253/jcj.46.317 | doi-access = free }} This is probably the reason why potassium deficiency causes cortisol to decline (as mentioned) and causes a decrease in conversion of 11-deoxycortisol to cortisol.{{cite journal | vauthors = Bauman K, Muller J | year = 1972 | title = Effect of potassium on the final status of aldosterone biosynthesis in the rat. I 18-hydroxylation and 18hydroxy dehydrogenation. II beta-hydroxylation | journal = Acta Endocrinol. | volume = 69 | issue = 4 | pages= I 701–717, II 718–730 |doi=10.1530/acta.0.0690701| pmid = 5067076 }} This may also have a role in rheumatoid-arthritis pain; cell potassium is always low in RA.{{cite journal | vauthors = LaCelle PL, Morgan ES, Atwater EC | year = 1964 | title = An investigation of total body potassium in patients with rheumatoid arthritis | journal = Proceedings of the Annual Meeting of the American Rheumatism Association, Arthritis and Rheumatism | volume = 7 | issue = 3 | page = 321 }}

Ascorbic acid presence, particularly in high doses has also been shown to mediate response to psychological stress and speed the decrease of the levels of circulating cortisol in the body post-stress. This can be evidenced through a decrease in systolic and diastolic blood pressures and decreased salivary cortisol levels after treatment with ascorbic acid.{{cite journal | vauthors = Brody S, Preut R, Schommer K, Schürmeyer TH | title = A randomized controlled trial of high dose ascorbic acid for reduction of blood pressure, cortisol, and subjective responses to psychological stress | journal = Psychopharmacology | volume = 159 | issue = 3 | pages = 319–24 | date = January 2002 | pmid = 11862365 | doi = 10.1007/s00213-001-0929-6 | s2cid = 2778669 }}

• Viral infections increase cortisol levels through activation of the HPA axis by cytokines.{{cite journal | vauthors = Silverman MN, Pearce BD, Biron CA, Miller AH | title = Immune modulation of the hypothalamic-pituitary-adrenal (HPA) axis during viral infection | journal = Viral Immunology | volume = 18 | issue = 1 | pages = 41–78 | year = 2005 | pmid = 15802953 | pmc = 1224723 | doi = 10.1089/vim.2005.18.41 }}
• Intense (high VO₂ max) or prolonged aerobic exercise transiently increases cortisol levels to increase gluconeogenesis and maintain blood glucose;{{cite journal | vauthors = 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 = International Journal of Sports Medicine | volume = 20 | issue = 2 | pages = 128–35 | date = February 1999 | pmid = 10190775 | doi = 10.1055/s-2007-971106 | s2cid = 2572545 }} however, cortisol declines to normal levels after eating (i.e., restoring a neutral energy balance).{{cite journal | vauthors = Fuqua JS, Rogol AD | title = Neuroendocrine alterations in the exercising human: implications for energy homeostasis | journal = Metabolism | volume = 62 | issue = 7 | pages = 911–21 | date = July 2013 | pmid = 23415825 | doi = 10.1016/j.metabol.2013.01.016}}
• Severe trauma or stressful events can elevate cortisol levels in the blood for prolonged periods.{{cite book |vauthors=Smith JL, Gropper SA, Groff JL | title = Advanced nutrition and humanmetabolism | publisher = Wadsworth Cengage Learning | location = Belmont, CA | year = 2009 | page = 247 | isbn = 978-0-495-11657-8 }}
• Low-carbohydrate diets cause a short-term increase in resting cortisol (≈3 weeks), and increase the cortisol response to aerobic exercise in the short- and long-term.{{cite journal | vauthors = Whittaker J, Harris M | title = Low-carbohydrate diets and men's cortisol and testosterone: Systematic review and meta-analysis | journal = Nutrition and Health | pages = 543–554 | date = March 2022 | volume = 28 | issue = 4 | pmid = 35254136 | doi = 10.1177/02601060221083079 | pmc = 9716400 | s2cid = 247251547 }}
• Increase in the concentration of ghrelin, the hunger stimulating hormone, increases levels of cortisol.{{cite journal | vauthors = Stachowicz M, Lebiedzińska A |date= December 2016 |title=The effect of diet components on the level of cortisol |journal=European Food Research and Technology |volume=242 |issue=12 |pages=2001–2009 |doi=10.1007/s00217-016-2772-3 |s2cid= 88721472 |issn=1438-2385|doi-access=free }}

File:Steroidogenesis.svg, showing cortisol at right{{cite journal | vauthors = Häggström M, Richfield D |year=2014|title=Diagram of the pathways of human steroidogenesis |journal=WikiJournal of Medicine |volume=1 |issue=1 |doi=10.15347/wjm/2014.005 |issn=2002-4436 |doi-access=free}}]]

Cortisol is synthesized from cholesterol. Synthesis takes place in the zona fasciculata of an adrenal cortex.{{cite book|doi=10.1007/978-1-4419-1005-9_171|isbn=978-1-4419-1005-9|chapter=Cortisol |title=Encyclopedia of Behavioral Medicine |date=2013 |pages=507–512 | vauthors = Stalder T, Kirschbaum C }}{{cite journal|date=20 November 2021|doi=10.1186/s12917-021-03069-4|title=Changes in metabolic and hormonal profiles during transition period in dairy cattle – the role of spexin|doi-access=free |journal=BMC Veterinary Research |volume=17 |issue=1 |page=359 |pmid=34798894 |pmc=8605515 | vauthors = Mikuła R, Pruszyńska-Oszmałek E, Pszczola M, Rząsińska J, Sassek M, Nowak KW, Nogowski L, Kołodziejski PA }}{{cite journal |vauthors=Payne AH, Hales DB |title=Overview of steroidogenic enzymes in the pathway from cholesterol to active steroid hormones |journal=Endocr Rev |volume=25 |issue=6 |pages=947–70 |date=December 2004 |pmid=15583024 |doi=10.1210/er.2003-0030}}

The name "cortisol" is derived from the word 'cortex'. Cortex means "the outer layer"—a reference to the adrenal cortex, the part of the adrenal gland where cortisol is produced.{{cite web | url=https://www.etymonline.com/word/cortisol | title=Cortisol {{pipe}} Etymology of cortisol by etymonline | access-date=23 April 2024 | archive-date=22 December 2022 | archive-url=https://web.archive.org/web/20221222174911/https://www.etymonline.com/word/cortisol | url-status=live }}

While the adrenal cortex in humans also produces aldosterone in the zona glomerulosa and some sex hormones in the zona reticularis, cortisol is its main secretion in humans and several other species. In cattle, corticosterone levels may approach{{cite journal | vauthors = Willett LB, Erb RE | title = Short term changes in plasma corticoids in dairy cattle | journal = Journal of Animal Science | volume = 34 | issue = 1 | pages = 103–11 | date = January 1972 | pmid = 5062063 | doi = 10.2527/jas1972.341103x}} or exceed cortisol levels.{{cite web | url=https://www.merckvetmanual.com/metabolic-disorders/disorders-of-potassium-metabolism/hypokalemia-in-adult-cattle | title=Hypokalemia in Adult Cattle - Metabolic Disorders | access-date=23 April 2024 | archive-date=9 December 2023 | archive-url=https://web.archive.org/web/20231209143012/https://www.merckvetmanual.com/metabolic-disorders/disorders-of-potassium-metabolism/hypokalemia-in-adult-cattle | url-status=live }}{{cite web | url=https://www.merckvetmanual.com/pharmacology/inflammation/corticosteroids-in-animals | title=Corticosteroids in Animals - Pharmacology | access-date=23 April 2024 | archive-date=20 April 2024 | archive-url=https://web.archive.org/web/20240420163445/https://www.merckvetmanual.com/pharmacology/inflammation/corticosteroids-in-animals | url-status=live }} In humans, the medulla of the adrenal gland lies under its cortex, mainly secreting the catecholamines adrenaline (epinephrine) and noradrenaline (norepinephrine) under sympathetic stimulation.{{cite book|date=19 January 2022|isbn=978-3-030-84737-1 |title=Endocrine Surgery Comprehensive Board Exam Guide |publisher=Springer | vauthors = Shifrin AL, Raffaelli M, Randolph GW, Gimm O }}

Synthesis of cortisol in the adrenal gland is stimulated by the anterior lobe of the pituitary gland with ACTH; ACTH production is, in turn, stimulated by CRH, which is released by the hypothalamus. ACTH increases the concentration of cholesterol in the inner mitochondrial membrane, via regulation of the steroidogenic acute regulatory protein. It also stimulates the main rate-limiting step in cortisol synthesis, in which cholesterol is converted to pregnenolone and catalyzed by Cytochrome P450SCC (side-chain cleavage enzyme).{{cite book | vauthors = Margioris AN, Tsatsanis C | veditors = Chrousos G | title = Adrenal physiology and diseases | year = 2011 | chapter = ACTH Action on the Adrenal | chapter-url = http://www.endotext.org/adrenal/adrenal5/adrenalframe5.htm | publisher = Endotext.org | access-date = 5 June 2012 | archive-date = 29 November 2011 | archive-url = https://web.archive.org/web/20111129102929/http://www.endotext.org/adrenal/adrenal5/adrenalframe5.htm | url-status = dead }}

Cortisol is metabolized reversibly to cortisone{{cite journal | vauthors = Finken MJ, Andrews RC, Andrew R, Walker BR | title = Cortisol metabolism in healthy young adults: sexual dimorphism in activities of A-ring reductases, but not 11beta-hydroxysteroid dehydrogenases | journal = The Journal of Clinical Endocrinology and Metabolism | volume = 84 | issue = 9 | pages = 3316–3321 | date = September 1999 | pmid = 10487705 | doi = 10.1210/jcem.84.9.6009 | doi-access = free }} by the 11-beta hydroxysteroid dehydrogenase system (11-beta HSD), which consists of two enzymes: 11-beta HSD1 and 11-beta HSD2. The metabolism of cortisol to cortisone involves oxidation of the hydroxyl group at the 11-beta position.{{cite journal | vauthors = Dammann C, Stapelfeld C, Maser E | title = Expression and activity of the cortisol-activating enzyme 11β-hydroxysteroid dehydrogenase type 1 is tissue and species-specific | journal = Chemico-Biological Interactions | volume = 303 | pages = 57–61 | date = April 2019 | pmid = 30796905 | doi = 10.1016/j.cbi.2019.02.018 | bibcode = 2019CBI...303...57D | s2cid = 73467693 }}

Cortisol is also metabolized irreversibly 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-limiting factors, respectively. 5-Beta reductase is also the rate-limiting factor in the conversion of cortisone to tetrahydrocortisone.{{medical citation needed|date=April 2024}}

Cortisol is also metabolized irreversibly into 6β-hydroxycortisol by cytochrome p450-3A monooxygenases, mainly, CYP3A4.{{cite web |url=https://pubchem.ncbi.nlm.nih.gov/compound/6beta-Hydroxycortisol |title=6beta-Hydroxycortisol |access-date=20 November 2021 |archive-date=20 November 2021 |archive-url=https://web.archive.org/web/20211120230517/https://pubchem.ncbi.nlm.nih.gov/compound/6beta-Hydroxycortisol |url-status=live }}{{cite journal |vauthors=Luceri F, Fattori S, Luceri C, Zorn M, Mannaioni P, Messeri G |title=Gas chromatography-mass spectrometry measurement of 6beta-OH-cortisol/cortisol ratio in human urine: a specific marker of enzymatic induction |journal=Clin Chem Lab Med |volume=39 |issue=12 |pages=1234–9 |date=December 2001 |pmid=11798083 |doi=10.1515/CCLM.2001.198|s2cid=12216877 }}{{cite journal |vauthors=Huang FR, Zhou C, Zhang XY, Shen Y, Zhang HW, Wang YQ, Sun LN |title=Impact of CYP2C19 genotype on voriconazole exposure and effect of voriconazole on the activity of CYP3A in patients with haematological malignancies |journal=Xenobiotica |volume=51 |issue=10 |pages=1199–1206 |date=October 2021 |pmid=34402388 |doi=10.1080/00498254.2021.1969481|s2cid=237150260 }} Drugs that induce CYP3A4 may accelerate cortisol clearance.{{cite journal |vauthors=Aquinos BM, García Arabehety J, Canteros TM, de Miguel V, Scibona P, Fainstein-Day P |title=[Adrenal crisis associated with modafinil use] |language=es |journal=Medicina (B Aires) |volume=81 |issue=5 |pages=846–849 |date=2021 |pmid=34633961}}

Cortisol is a naturally occurring pregnane corticosteroid and is also known as 11β,17α,21-trihydroxypregn-4-ene-3,20-dione.

In animals, cortisol is often used as an indicator of stress and can be measured in blood,{{cite journal | vauthors = van Staaveren N, Teixeira DL, Hanlon A, Boyle LA | title = The effect of mixing entire male pigs prior to transport to slaughter on behaviour, welfare and carcass lesions | journal = PLOS ONE | volume = 10 | issue = 4 | pages = e0122841 | year = 2015 | pmid = 25830336 | pmc = 4382277 | doi = 10.1371/journal.pone.0122841 | bibcode = 2015PLoSO..1022841V | doi-access = free }} saliva, urine,{{cite journal | vauthors = Schalke E, Stichnoth J, Ott S, Jones-Baade R | title = Clinical signs caused by the use of electric training collars on dogs in everyday life situations | journal = Applied Animal Behaviour Science | volume =105 | issue =4 | pages = 369–380 | year =2007 | doi = 10.1016/j.applanim.2006.11.002| s2cid = 31552322 }} hair,{{cite journal | vauthors = Accorsi PA, Carloni E, Valsecchi P, Viggiani R, Gamberoni M, Tamanini C, Seren E | title = Cortisol determination in hair and faeces from domestic cats and dogs | journal = General and Comparative Endocrinology | volume = 155 | issue = 2 | pages = 398–402 | date = January 2008 | pmid = 17727851 | doi = 10.1016/j.ygcen.2007.07.002 }} and faeces.{{cite journal | vauthors = Möstl E, Messmann S, Bagu E, Robia C, Palme R | title = Measurement of glucocorticoid metabolite concentrations in feces of domestic livestock | journal = Zentralblatt für Veterinarmedizin. Reihe A | volume = 46 | issue = 10 | pages = 621–631 | date = December 1999 | pmid = 10638300 | doi = 10.1046/j.1439-0442.1999.00256.x }}

• Cortisone, a hormone
• Cortisol awakening response
• List of corticosteroids
• Membrane glucocorticoid receptor

{{Reflist|30em}}

{{Commons category}}

• [http://gmd.mpimp-golm.mpg.de/Spectrums/925c5612-4ecd-461b-bb52-173189b86299.aspx Cortisol MS Spectrum]
• [https://web.archive.org/web/20121113144240/http://www.acb.org.uk/docs/NHLM/Cortisol.pdf Cortisol: analyte monograph] – The Association for Clinical Biochemistry and Laboratory Medicine

{{Hormones}}

{{Endogenous steroids}}

{{Glucocorticoid receptor modulators}}

{{Mineralocorticoid receptor modulators}}

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