View source for Glucocorticoid

{{Short description|Class of corticosteroids}}
{{cs1 config |name-list-style=vanc |display-authors=6}}
{{Infobox drug class
| Image = Cortisol2.svg
| ImageClass = skin-invert-image
| Alt =
| Caption = [[Chemical structure]] of [[cortisol]] ([[hydrocortisone]]), an [[endogenous]] glucocorticoid as well as a medication.
| Width = 250px
| Synonyms = Corticosteroid; Glucocorticosteroid
<!-- Class identifiers -->
| Use = [[Adrenal insufficiency]]; [[Allergy|allergic]], [[inflammation|inflammatory]], and [[autoimmune disorder]]s; [[asthma]]; [[organ transplant]]
| ATC_prefix = H02AB
| Biological_target = [[Glucocorticoid receptor]]
| Chemical_class = [[Steroid]]s
<!-- Clinical data -->
| Drugs.com =
| Consumer_Reports =
| medicinenet =
| rxlist =
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| MeshID =
}}
'''Glucocorticoids''' (or, less commonly, '''glucocorticosteroids''') are a class of [[corticosteroid]]s, which are a class of [[steroid hormone]]s. Glucocorticoids are corticosteroids that bind to the [[glucocorticoid receptor]]<ref name = "Pelt_2011">{{cite book | vauthors = Pelt AC | title = Glucocorticoids: effects, action mechanisms, and therapeutic uses | year = 2011 | publisher = Nova Science | location = Hauppauge, N.Y. | isbn = 978-1617287589 }}{{page?|date=November 2023}}</ref> that is present in almost every [[vertebrate]] animal cell. The name "glucocorticoid" is a [[portmanteau]] ('''gluco'''se + '''cort'''ex + ster'''oid''') and is composed from its role in regulation of [[glucose]] [[metabolism]], synthesis in the [[adrenal cortex]], and its [[steroid]]al structure (see structure below).

Glucocorticoids are part of the [[feedback]] mechanism in the [[immune system]], which reduces certain aspects of immune function, such as [[inflammation]]. They are therefore used in [[medicine]] to treat [[disease]]s caused by an [[Autoimmunity|overactive immune system]], such as [[Allergy|allergies]], [[asthma]], [[autoimmune diseases]], and [[sepsis]]. Glucocorticoids have many [[Side effect|diverse effects]] such as [[pleiotropy (drugs)|pleiotropy]], including [[Adverse drug reaction|potentially harmful side effects]].<ref name="RhenNEJM">{{cite journal | vauthors = Rhen T, Cidlowski JA | title = Antiinflammatory action of glucocorticoids–new mechanisms for old drugs | journal = The New England Journal of Medicine | volume = 353 | issue = 16 | pages = 1711–1723 | date = Oct 2005 | pmid = 16236742 | doi = 10.1056/NEJMra050541 | s2cid = 5744727 }}</ref> They also interfere with some of the abnormal mechanisms in [[cancer]] [[Cancer cell|cells]], so they are used in high doses to treat cancer. This includes inhibitory effects on [[lymphocyte]] proliferation, as in the treatment of [[lymphoma]]s and [[leukemia]]s, and the mitigation of side effects of [[Chemotherapy|anticancer drugs]].

Glucocorticoids affect cells by binding to the [[glucocorticoid receptor]]. The activated glucocorticoid receptor-glucocorticoid complex up-regulates the expression of [[anti-inflammatory]] [[protein]]s in the [[cell nucleus|nucleus]] (a process known as [[transactivation]]) and represses the expression of pro-inflammatory proteins in the [[cytosol]] by preventing the [[protein targeting|translocation]] of other [[transcription factor]]s from the cytosol into the nucleus ([[transrepression]]).<ref name="RhenNEJM"/>

Glucocorticoids are distinguished from [[mineralocorticoid]]s and [[sex steroid]]s by their specific [[Receptor (biochemistry)|receptors]], [[Codocyte|target cells]], and effects. In technical terms, "[[corticosteroid]]" refers to both glucocorticoids and [[mineralocorticoid]]s (as both are mimics of [[hormone]]s produced by the [[adrenal cortex]]), but is often used as a synonym for "glucocorticoid". Glucocorticoids are chiefly produced in the [[zona fasciculata]] of the [[adrenal cortex]], whereas mineralocorticoids are synthesized in the [[zona glomerulosa]].

[[Cortisol]] (or hydrocortisone) is the most important human glucocorticoid. It is essential for [[life]], and it regulates or supports a variety of important [[cardiovascular]], [[metabolism|metabolic]], [[immunology|immunologic]], and [[homeostasis|homeostatic]] functions. Increases in glucocorticoid concentrations are an integral part of [[Stress (biology)|stress]] response and are the most commonly used [[biomarker]]s to measure stress.<ref>{{cite journal | vauthors = Botía M, Escribano D, Martínez-Subiela S, Tvarijonaviciute A, Tecles F, López-Arjona M, Cerón JJ | title = Different Types of Glucocorticoids to Evaluate Stress and Welfare in Animals and Humans: General Concepts and Examples of Combined Use | journal = Metabolites | volume = 13 | issue = 1 | pages = 106 | date = January 2023 | pmid = 36677031 | pmc = 9865266 | doi = 10.3390/metabo13010106 | doi-access = free }}</ref> Glucocorticoids have numerous non-stress-related functions as well, and glucocorticoid concentrations can increase in response to pleasure or excitement.<ref>{{cite journal | vauthors = Ralph CR, Tilbrook AJ | title = INVITED REVIEW: The usefulness of measuring glucocorticoids for assessing animal welfare | journal = Journal of Animal Science | volume = 94 | issue = 2 | pages = 457–470 | date = February 2016 | pmid = 27065116 | doi = 10.2527/jas.2015-9645 }}</ref> Various [[Synthetic biology|synthetic]] glucocorticoids are available; these are widely utilized in [[Internal medicine|general medical practice]] and numerous [[Medical specialty|specialties]], either as replacement therapy in [[glucocorticoid deficiency]] or to suppress the body's immune system.

==Effects==
[[File:Steroidogenesis.svg|thumb|450px|class=skin-invert-image|[[Steroidogenesis]] showing glucocorticoids in green ellipse at right with the primary example being cortisol<ref name="HäggströmRichfield2014">{{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}}</ref> It is not a strictly bounded group, but a continuum of structures with increasing glucocorticoid effect.]]

Glucocorticoid effects may be broadly classified into two major categories: [[immunology|immunological]] and [[metabolism|metabolic]]. In addition, glucocorticoids play important roles in fetal [[developmental biology|development]] and [[body fluid]] homeostasis.{{cn|date=July 2024}}

===Immune===
Glucocorticoids function via interaction with the glucocorticoid receptor:{{cn|date=July 2024}}
* Upregulate the expression of anti-inflammatory proteins.
* Downregulate the expression of proinflammatory proteins.

Glucocorticoids are also shown to play a role in the development and homeostasis of [[T lymphocytes]]. This has been shown in transgenic mice with either increased or decreased sensitivity of T cell lineage to glucocorticoids.<ref name="Pazirandeh_2002">{{cite journal | vauthors = Pazirandeh A, Xue Y, Prestegaard T, Jondal M, Okret S | title = Effects of altered glucocorticoid sensitivity in the T cell lineage on thymocyte and T cell homeostasis | journal = FASEB Journal | volume = 16 | issue = 7 | pages = 727–729 | date = May 2002 | pmid = 11923224 | doi = 10.1096/fj.01-0891fje | doi-access = free | s2cid = 23891076 }}</ref>

===Metabolic===
The name "glucocorticoid" derives from early observations that these [[hormone]]s were involved in [[glucose metabolism]]. In the fasted state, [[cortisol]] stimulates several processes that collectively serve to increase and maintain normal concentrations of glucose in the blood.{{cn|date=July 2024}}

Metabolic effects:
* Stimulation of [[gluconeogenesis]], in particular, in the [[liver]]: This pathway results in the synthesis of glucose from non-[[hexose]] substrates, such as [[amino acid]]s and [[glycerol]] from triglyceride breakdown, and is particularly important in [[carnivore]]s and certain [[herbivore]]s. Enhancing the expression of [[enzyme]]s involved in gluconeogenesis is probably the best-known metabolic function of glucocorticoids.{{cn|date=July 2024}}
* Mobilization of [[amino acid]]s from [[wikt: extrahepatic|extrahepatic]] tissues: These serve as substrates for gluconeogenesis.{{cn|date=July 2024}}
* Inhibition of glucose uptake in muscle and [[adipose]] tissue: A mechanism to conserve glucose{{cn|date=July 2024}}
* Stimulation of [[fat breakdown]] in adipose tissue: The fatty acids released by [[lipolysis]] are used for production of energy in tissues like muscle, and the released [[glycerol]] provide another substrate for gluconeogenesis.
* Increase in sodium retention and potassium excretion leads to hypernatremia and hypokalemia<ref name=":0" />
* Increase in hemoglobin concentration, likely due to hindrance of the ingestion of red blood cell by macrophage or other phagocyte.<ref name="Pelt_2011" />
* Increased urinary uric acid<ref name="Sapolsky_1994" />
* Increased urinary calcium and hypocalcemia<ref name="pmid9723618" />
* Alkalosis<ref name="pmid19401723" />
* Leukocytosis<ref name="pmid9683321" />

Excessive glucocorticoid levels resulting from administration as a drug or [[Cushing's syndrome|hyperadrenocorticism]] have effects on many systems. Some examples include inhibition of bone formation, suppression of calcium absorption (both of which can lead to [[osteoporosis]]), delayed wound healing, muscle weakness, and increased risk of infection. These observations suggest a multitude of less-dramatic physiologic roles for glucocorticoids.<ref name="Pazirandeh_2002"/>

===Developmental===
Glucocorticoids have multiple effects on fetal development. An important example is their role in promoting maturation of the lung and production of the [[surfactant]] necessary for extrauterine lung function. Mice with [[homozygous]] disruptions in the [[corticotropin]]-releasing hormone gene (see below) die at birth due to pulmonary immaturity. In addition, glucocorticoids are necessary for normal brain development, by initiating terminal maturation, remodeling axons and dendrites, and affecting cell survival<ref name="pmid19401723">{{cite journal | vauthors = Lupien SJ, McEwen BS, Gunnar MR, Heim C | title = Effects of stress throughout the lifespan on the brain, behaviour and cognition | journal = Nature Reviews. Neuroscience | volume = 10 | issue = 6 | pages = 434–445 | date = Jun 2009 | pmid = 19401723 | doi = 10.1038/nrn2639 | s2cid = 205504945 }}</ref> and may also play a role in [[Glucocorticoids in Hippocampal Development|hippocampal development]]. Glucocorticoids stimulate the maturation of the Na<sup>+</sup>/K<sup>+</sup>/ATPase, nutrient transporters, and digestion enzymes, promoting the development of a functioning gastro-intestinal system. Glucocorticoids also support the development of the neonate's renal system by increasing glomerular filtration.{{cn|date=July 2024}}

===Arousal and cognition===
[[Image:YerkesDodsonLawGraph.png|thumb|class=skin-invert-image|alt=A graphical representation of the [[Yerkes-Dodson curve]] | A graphical representation of the [[Yerkes-Dodson curve]]]]

Glucocorticoids act on the [[hippocampus]], [[amygdala]], and [[frontal lobes]]. Along with [[adrenaline]], these enhance the formation of [[flashbulb memories]] of events associated with strong emotions, both positive and negative.<ref name="pmid9683321">{{cite journal | vauthors = Cahill L, McGaugh JL | title = Mechanisms of emotional arousal and lasting declarative memory | journal = Trends in Neurosciences | volume = 21 | issue = 7 | pages = 294–299 | date = Jul 1998 | pmid = 9683321 | doi = 10.1016/s0166-2236(97)01214-9 | s2cid = 29839557 }}</ref> This has been confirmed in studies, whereby blockade of either glucocorticoids or noradrenaline activity impaired the recall of emotionally relevant information. Additional sources have shown subjects whose fear learning was accompanied by high cortisol levels had better consolidation of this memory (this effect was more important in men).{{Better source needed|date=September 2021|reason=The cited source is a bit outdated: 1998}} The effect that glucocorticoids have on memory may be due to damage specifically to the CA1 area of the hippocampal formation.

In multiple animal studies, prolonged stress (causing prolonged increases in glucocorticoid levels) have shown destruction of the neurons in the hippocampus area of the brain, which has been connected to lower memory performance.<ref name=":0">{{cite book | vauthors = Carlson NR | title = Physiology of Behavior | edition = 11th | publisher = Allyn & Bacon | location = New York | year = 2010 | page = 605 | isbn = 978-0-205-23939-9 }}</ref><ref name="pmid11461709">{{cite journal | vauthors = Belanoff JK, Gross K, Yager A, Schatzberg AF | title = Corticosteroids and cognition | journal = Journal of Psychiatric Research | volume = 35 | issue = 3 | pages = 127–145 | year = 2001 | pmid = 11461709 | doi = 10.1016/S0022-3956(01)00018-8 }}</ref><ref name="Sapolsky_1994">{{cite journal | vauthors = Sapolsky RM | title = Glucocorticoids, stress and exacerbation of excitotoxic neuron death | journal = Seminars in Neuroscience |date=October 1994 | volume = 6 | issue = 5 | pages = 323–331 | doi = 10.1006/smns.1994.1041 | doi-access = free }}</ref>

Glucocorticoids have also been shown to have a significant impact on [[Alertness|vigilance]] ([[attention deficit disorder]]) and [[cognition]] (memory). This appears to follow the [[Yerkes-Dodson curve]], as studies have shown circulating levels of glucocorticoids vs. memory performance follow an upside-down U pattern, much like the Yerkes-Dodson curve. For example, [[long-term potentiation]] (LTP; the process of forming long-term memories) is optimal when glucocorticoid levels are mildly elevated, whereas significant decreases of LTP are observed after adrenalectomy (low-glucocorticoid state) or after exogenous glucocorticoid administration (high-glucocorticoid state). Elevated levels of glucocorticoids enhance memory for emotionally arousing events, but lead more often than not to poor memory for material unrelated to the source of stress/emotional arousal.<ref name="pmid17466428">{{cite journal | vauthors = Lupien SJ, Maheu F, Tu M, Fiocco A, Schramek TE | title = The effects of stress and stress hormones on human cognition: Implications for the field of brain and cognition | journal = Brain and Cognition | volume = 65 | issue = 3 | pages = 209–237 | date = Dec 2007 | pmid = 17466428 | doi = 10.1016/j.bandc.2007.02.007 | s2cid = 5778988 }}</ref> In contrast to the dose-dependent enhancing effects of glucocorticoids on memory consolidation, these stress hormones have been shown to inhibit the retrieval of already stored information.<ref name="pmid9723618">{{cite journal | vauthors = de Quervain DJ, Roozendaal B, McGaugh JL | title = Stress and glucocorticoids impair retrieval of long-term spatial memory | journal = Nature | volume = 394 | issue = 6695 | pages = 787–790 | date = Aug 1998 | pmid = 9723618 | doi = 10.1038/29542 | bibcode = 1998Natur.394..787D | s2cid = 4388676 }}</ref> Long-term exposure to glucocorticoid medications, such as asthma and anti-inflammatory medication, has been shown to create deficits in memory and attention both during and, to a lesser extent, after treatment,<ref name="Wolkowitz2001" >{{cite journal | vauthors = Wolkowitz OM, Lupien SJ, Bigler ED | title = The 'steroid dementia syndrome': a possible model of human glucocorticoid neurotoxicity | journal = Neurocase | volume = 13 | issue = 3 | pages = 189–200 | date = Jun 2007 | pmid = 17786779 | doi = 10.1080/13554790701475468 | s2cid = 39340010 }}</ref><ref name="sacks2005">{{cite journal | vauthors = Norra C, Arndt M, Kunert HJ | title = Steroid dementia: an overlooked diagnosis? | journal = Neurology | volume = 66 | issue = 1 | pages = 155; author reply 155 | date = Jan 2006 | pmid = 16401879 | doi = 10.1212/01.wnl.0000203713.04232.82 | s2cid = 11524545 }}</ref> a condition known as "[[Steroid dementia syndrome|steroid dementia]]".<ref name="varney1984">{{cite journal | vauthors = Varney NR, Alexander B, MacIndoe JH | title = Reversible steroid dementia in patients without steroid psychosis | journal = The American Journal of Psychiatry | volume = 141 | issue = 3 | pages = 369–372 | date = Mar 1984 | pmid = 6703100 | doi = 10.1176/ajp.141.3.369 | url = http://ajp.psychiatryonline.org/article.aspx?articleid=161461 }}</ref>

===Body fluid homeostasis===
Glucocorticoids could act centrally, as well as peripherally, to assist in the normalization of extracellular fluid volume by regulating body's action to [[atrial natriuretic peptide]] (ANP). Centrally, glucocorticoids could inhibit dehydration-induced water intake;<ref name="pmid21187974">{{cite journal | vauthors = Liu C, Guan J, Kang Y, Xiu H, Chen Y, Deng B, Liu K | title = Inhibition of dehydration-induced water intake by glucocorticoids is associated with activation of hypothalamic natriuretic peptide receptor-A in rat | journal = PLOS ONE | volume = 5 | issue = 12 | pages = e15607 | year = 2010 | pmid = 21187974 | pmc = 3004933 | doi = 10.1371/journal.pone.0015607 | bibcode = 2010PLoSO...515607L | doi-access = free }}</ref> peripherally, glucocorticoids could induce a potent diuresis.<ref name="pmid21737535">{{cite journal | vauthors = Liu C, Chen Y, Kang Y, Ni Z, Xiu H, Guan J, Liu K | s2cid = 1892149 | title = Glucocorticoids improve renal responsiveness to atrial natriuretic peptide by up-regulating natriuretic peptide receptor-A expression in the renal inner medullary collecting duct in decompensated heart failure | journal = The Journal of Pharmacology and Experimental Therapeutics | volume = 339 | issue = 1 | pages = 203–209 | date = Oct 2011 | pmid = 21737535 | doi = 10.1124/jpet.111.184796 }}</ref>

==Mechanism of action==
===Transactivation===
Glucocorticoids bind to the cytosolic [[glucocorticoid receptor]], a type of [[nuclear receptor]] that is activated by [[ligand]] binding. After a hormone binds to the corresponding receptor, the newly formed complex [[Protein translocation|translocates]] itself into the [[cell nucleus]], where it binds to [[glucocorticoid response elements]] in the [[promoter (biology)|promoter]] region of the target [[gene]]s resulting in the [[regulation of gene expression]]. This process is commonly referred to as transcriptional activation, or [[transactivation]].<ref name=Revollo2009/><ref name="Newton2007">{{cite journal | vauthors = Newton R, Holden NS | title = Separating transrepression and transactivation: a distressing divorce for the glucocorticoid receptor? | journal = Molecular Pharmacology | volume = 72 | issue = 4 | pages = 799–809 | date = Oct 2007 | pmid = 17622575 | doi = 10.1124/mol.107.038794 | s2cid = 52803631 }}</ref>

The proteins encoded by these up-regulated genes have a wide range of effects, including, for example:<ref name="Newton2007"/>
* [[Anti-inflammatory]] – [[annexin|lipocortin I]], [[S100A10|p11/calpactin binding protein]], secretory leukocyte protease inhibitor 1 ([[SLPI]]), and [[Mitogen-activated protein kinase]] [[phosphatase]] ([[MAPK phosphatase]])
* Increased [[gluconeogenesis]] – [[glucose 6-phosphatase]] and [[tyrosine aminotransferase]]

===Transrepression===
The opposite mechanism is called transcriptional repression, or [[transrepression]]. The classical understanding of this mechanism is that activated glucocorticoid receptor binds to DNA in the same site where another [[transcription factor]] would bind, which prevents the [[transcription (genetics)|transcription]] of genes that are transcribed via the activity of that factor.<ref name=Revollo2009/><ref name=Newton2007/> While this does occur, the results are not consistent for all cell types and conditions; there is no generally accepted, general mechanism for transrepression.<ref name=Newton2007/>

New mechanisms are being discovered where transcription is repressed, but the activated glucocorticoid receptor is not interacting with DNA, but rather with another transcription factor directly, thus interfering with it, or with other proteins that interfere with the function of other transcription factors. This latter mechanism appears to be the most likely way that activated glucocorticoid receptor interferes with [[NF-κB]] - namely by recruiting [[histone deacetylase]], which deacetylate the DNA in the promoter region leading to closing of the chromatin structure where NF-κB needs to bind.<ref name=Revollo2009/><ref name=Newton2007/>

===Nongenomic effects===
Activated glucocorticoid receptor has effects that have been experimentally shown to be independent of any effects on transcription and can only be due to direct binding of activated glucocorticoid receptor with other proteins or with mRNA.<ref name=Revollo2009>{{cite journal | vauthors = Revollo JR, Cidlowski JA | title = Mechanisms generating diversity in glucocorticoid receptor signaling | journal = Annals of the New York Academy of Sciences | volume = 1179 | issue =  1| pages = 167–178 | date = Oct 2009 | pmid = 19906239 | doi = 10.1111/j.1749-6632.2009.04986.x | bibcode = 2009NYASA1179..167R | s2cid = 28995545 | url = https://zenodo.org/record/1230766 }}</ref><ref name=Newton2007/>

For example, [[Src kinase]] which binds to inactive glucocorticoid receptor, is released when a glucocorticoid binds to glucocorticoid receptor, and phosphorylates a protein that in turn displaces an adaptor protein from a receptor important in inflammation, [[epidermal growth factor]], reducing its activity, which in turn results in reduced creation of [[arachidonic acid]] – a key proinflammatory molecule. This is one mechanism by which glucocorticoids have an anti-inflammatory effect.<ref name=Revollo2009/>

==Pharmacology==
[[Image:Dexamethasone structure.svg|thumb|right|250px|class=skin-invert-image|[[Dexamethasone]] – a synthetic glucocorticoid binds more powerfully to the [[glucocorticoid receptor]] than cortisol does. Dexamethasone is based on the cortisol structure but differs at three positions (extra double bond in the A-ring between carbons 1 and 2 and addition of a 9-α-fluoro group and a 16-α-methyl substituent).]]

A variety of synthetic glucocorticoids, some far more potent than cortisol, have been created for therapeutic use. They differ in both [[pharmacokinetics]] (absorption factor, half-life, volume of distribution, clearance) and [[pharmacodynamics]] (for example the capacity of [[mineralocorticoid]] activity: retention of [[sodium]] (Na{{sup|+}}) and [[Water (molecule)|water]]; [[Renal physiology#Maintaining body sodium and water balance|renal physiology]]). Because they permeate the [[intestine]]s easily, they are administered primarily ''per os'' ([[Oral administration|by mouth]]), but also by other methods, such as [[topical]]ly on [[skin]]. More than 90% of them bind different [[plasma proteins]], though with a different binding specificity. Endogenous glucocorticoids and some synthetic corticoids have high affinity to the protein [[transcortin]] (also called corticosteroid-binding globulin), whereas all of them bind [[serum albumin|albumin]]. In the liver, they quickly metabolize by conjugation with a [[sulfate]] or [[glucuronic acid]], and are secreted in the [[urine]].{{cn|date=July 2024}}

Glucocorticoid potency, duration of effect, and the overlapping mineralocorticoid potency vary. [[Cortisol]] is the standard of comparison for glucocorticoid potency. [[Hydrocortisone]] is the name used for pharmaceutical preparations of cortisol.{{cn|date=July 2024}}

The data below refer to oral administration. Oral potency may be less than [[parenteral]] potency because significant amounts (up to 50% in some cases) may not reach the circulation. [[Fludrocortisone acetate]] and [[deoxycorticosterone acetate]] are, by definition, mineralocorticoids rather than glucocorticoids, but they do have minor glucocorticoid potency and are included in this table to provide perspective on mineralocorticoid potency.{{cn|date=July 2024}}

{| class="wikitable"
|+ Comparative oral corticosteroid potencies<ref name="ChrousosPavlaki2000">{{cite book | vauthors = Nicolaides NC, Pavlaki AN, Maria Alexandra MA, Chrousos G| chapter = Glucocorticoid Therapy and Adrenal Suppression | date = 2018 | pmid = 25905379 | url = https://www.ncbi.nlm.nih.gov/books/NBK279156/|veditors=Feingold KR, Anawalt B, Boyce A, et al.|title = Endotext| publisher = MDText.com }}</ref><ref>{{cite book | vauthors = Liapi C, Chrousos GP | veditors = Yaffe SJ, Aranda JV |title=Pediatric Pharmacology: Therapeutic Principles in Practice |date=1992 |publisher=Saunders |location=Philadelphia |isbn=978-0721629711 |pages=466–475 |edition=2nd | chapter=Glucocorticoids}}</ref><ref>{{cite journal | vauthors = Leung DY, Hanifin JM, Charlesworth EN, Li JT, Bernstein IL, Berger WE, Blessing-Moore J, Fineman S, Lee FE, Nicklas RA, Spector SL | title = Disease management of atopic dermatitis: a practice parameter. Joint Task Force on Practice Parameters, representing the American Academy of Allergy, Asthma and Immunology, the American College of Allergy, Asthma and Immunology, and the Joint Council of Allergy, Asthma and Immunology. Work Group on Atopic Dermatitis | journal = Annals of Allergy, Asthma & Immunology | volume = 79 | issue = 3 | pages = 197–211 | date = September 1997 | pmid = 9305225 | doi = 10.1016/S1081-1206(10)63003-7 | url = http://www.jcaai.readyportal.net/file_depot/0-10000000/20000-30000/27387/folder/63948/Atopic_Derm1997.pdf | archive-url = https://web.archive.org/web/20160421125539/http://www.jcaai.readyportal.net/file_depot/0-10000000/20000-30000/27387/folder/63948/Atopic_Derm1997.pdf | archive-date = 2016-04-21 }}</ref><ref>{{cite journal | vauthors = Nayak S, Acharjya B | title = Deflazacort versus other glucocorticoids: a comparison | journal = Indian Journal of Dermatology | volume = 53 | issue = 4 | pages = 167–170 | date = 2021-08-09 | pmid = 19882026 | pmc = 2763756 | doi = 10.4103/0019-5154.44786 | doi-access = free }}</ref>
! Name
! Glucocorticoid potency
! [[Mineralocorticoid]] potency
! [[Terminal half-life]] (hours)
|-
| [[Cortisol]] ([[hydrocortisone]])
| 1
| 1
| 8
|-
| [[Cortisone]]
| 0.8
| 0.8
| 8
|-
| [[Prednisone]]
| 3.5–5
| 0.8
| 16–36
|-
| [[Prednisolone]]
| 4
| 0.8
| 16–36
|-
| [[Methylprednisolone]]
| 5–7.5
| 0.5
| 18–40
|-
| [[Dexamethasone]]
| 25–80
| 0
| 36–54
|-
| [[Betamethasone]]
| 25–30
| 0
| 36–54
|-
| [[Triamcinolone]]
| 5
| 0
| 12–36
|-
| [[Deflazacort]]
| 6.5
| –
| 1.3
|-
| [[Fludrocortisone acetate]]
| 15
| 200
| 24
|-
| [[Deoxycorticosterone acetate]]
| 0
| 20
| –
|-
| [[Aldosterone]]
| 0.3
| 200–1000
| –
|-
| [[Beclometasone]]
| 8 sprays 4 times every day equivalent to orally 14&nbsp;mg prednisone once a day
| –
| –
|}

{| class="wikitable"
|+Characteristics of Synthetic Glucocorticoids
!Synthetic Glucocorticoid
!Equivalent Dose (mg)
!Anti-inflammatory Activity<sup>1</sup>
!Mineralocorticoid Activity<sup>1</sup>
!Biological Half Life (hrs)
!References
|-
| colspan="6" |'''''Short-to medium-acting glucocorticoids'''''
|-
|Hydrocortisone
|20
|1
|1
|8–12
|<ref name="Katzung_2012">{{cite book|url=https://www.worldcat.org/oclc/761378641|title=Basic & clinical pharmacology|date=2012|publisher=McGraw-Hill Medical| vauthors = Katzung BG, Masters SB, Trevor AJ |isbn=978-0-07-176401-8|edition=12th|location=New York|oclc=761378641}}</ref><ref name="Paragliola_2017">{{cite journal | vauthors = Paragliola RM, Papi G, Pontecorvi A, Corsello SM | title = Treatment with Synthetic Glucocorticoids and the Hypothalamus-Pituitary-Adrenal Axis | journal = International Journal of Molecular Sciences | volume = 18 | issue = 10 | pages = 2201 | date = October 2017 | pmid = 29053578 | pmc = 5666882 | doi = 10.3390/ijms18102201 | doi-access = free }}</ref>
|-
|Cortisone
|25
|0.8
|0.8
|8–12
|<ref name="Katzung_2012"/><ref name="Paragliola_2017"/>
|-
|Prednisone
|5
|4
|0.3
|12–36
|<ref name="Katzung_2012"/><ref name="Paragliola_2017"/>
|-
|Prednisolone
|5
|4–5
|0.3
|12–36
|<ref name="Katzung_2012"/><ref name="Paragliola_2017"/>
|-
|Methylprednisolone
|4
|5
|0.25–0.5
|12–36
|<ref name="Katzung_2012"/><ref name="Paragliola_2017"/>
|-
|Meprednisone
|4
|5
|0
|
|<ref name="Katzung_2012"/>
|-
| colspan="6" |'''''Intermediate-acting glucocorticoids'''''
|-
|Triamcinolone
|4
|5
|0
|12–36
|<ref name="Katzung_2012"/><ref name="Paragliola_2017"/>
|-
|Paramethasone
|2
|10
|0
|N/A
|<ref name="Katzung_2012"/><ref name="Paragliola_2017"/>
|-
|Fluprednisolone
|1.5
|15
|0
|
|<ref name="Katzung_2012"/>
|-
| colspan="6" |'''''Long-acting glucocorticoids'''''
|-
|Betamethasone
|0.6
|25–40
|0
|36–72
|<ref name="Katzung_2012"/><ref name="Paragliola_2017"/><ref name="Fietta_2009">{{cite journal | vauthors = Fietta P, Fietta P, Delsante G | title = Central nervous system effects of natural and synthetic glucocorticoids | journal = Psychiatry and Clinical Neurosciences | volume = 63 | issue = 5 | pages = 613–22 | date = October 2009 | pmid = 19788629 | doi = 10.1111/j.1440-1819.2009.02005.x | s2cid = 28778979 | doi-access = free }}</ref>
|-
|Dexamethasone
|0.75
|30
|0
|36–72
|<ref name="Katzung_2012"/><ref name="Paragliola_2017"/>
|-
| colspan="6" |'''''Mineralocorticoids'''''
|-
|Fludrocortisone
|2
|10
|250
|18–36
|<ref name="Katzung_2012"/><ref name="Paragliola_2017"/>
|-
|Desoxycorticosterone acetate
|
|0
|20
|
|
|- class="sortbottom"
| colspan="6" style="width: 1px;" |<sup>1</sup>&nbsp;Activity is relative to hydrocortisone
|}

==Therapeutic use==
Glucocorticoids may be used in low doses in [[adrenal insufficiency]]. In much higher doses, oral or inhaled glucocorticoids are used to suppress various [[allergy|allergic]], [[inflammation|inflammatory]], and autoimmune disorders. Inhaled glucocorticoids are the second-line treatment for [[asthma]]. They are also administered as post-transplantory immunosuppressants to prevent the [[transplant rejection|acute transplant rejection]] and the [[graft-versus-host disease]]. Nevertheless, they do not prevent an infection and also inhibit later [[Regeneration (biology)|reparative processes]]. Newly emerging evidence showed that glucocorticoids could be used in the treatment of [[heart failure]] to increase the renal responsiveness to diuretics and natriuretic peptides. Glucocorticoids are historically used for pain relief in [[inflammation|inflammatory]] conditions.<ref name="pmid22942324">{{cite journal | vauthors = Tarner IH, Englbrecht M, Schneider M, van der Heijde DM, Müller-Ladner U | title = The role of corticosteroids for pain relief in persistent pain of inflammatory arthritis: a systematic literature review | journal = The Journal of Rheumatology. Supplement | volume = 90 | pages = 17–20 | year = 2012 | pmid = 22942324 | doi = 10.3899/jrheum.120337 | s2cid = 31663619 | doi-access = free }}</ref><ref name="pmid25908299">{{cite journal | vauthors = Haywood A, Good P, Khan S, Leupp A, Jenkins-Marsh S, Rickett K, Hardy JR | title = Corticosteroids for the management of cancer-related pain in adults | journal = The Cochrane Database of Systematic Reviews | issue = 4 | pages = CD010756 | year = 2015 | volume = 2021 | pmid = 25908299 | doi = 10.1002/14651858.CD010756.pub2 | pmc = 8127040 | url = https://espace.library.uq.edu.au/view/UQ:356978/UQ356978_OA.pdf | hdl = 10072/134448 | hdl-access = free }}</ref><ref name="pmid25187570">{{cite journal | vauthors = Chowdhury R, Naaseri S, Lee J, Rajeswaran G | title = Imaging and management of greater trochanteric pain syndrome | journal = Postgraduate Medical Journal | volume = 90 | issue = 1068 | pages = 576–581 | year = 2014 | pmid = 25187570 | doi = 10.1136/postgradmedj-2013-131828 | s2cid = 24344273 | doi-access = free }}</ref> However, corticosteroids show limited efficacy in pain relief and potential adverse events for their use in [[Tendinopathy|tendinopathies]].<ref name="Mohamadi 232–243">{{cite journal | vauthors = Mohamadi A, Chan JJ, Claessen FM, Ring D, Chen NC | title = Corticosteroid Injections Give Small and Transient Pain Relief in Rotator Cuff Tendinosis: A Meta-analysis | journal = Clinical Orthopaedics and Related Research | volume = 475 | issue = 1 | pages = 232–243 | date = January 2017 | pmid = 27469590 | pmc = 5174041 | doi = 10.1007/s11999-016-5002-1 }}</ref>

===Replacement===
Any glucocorticoid can be given in a dose that provides approximately the same glucocorticoid effects as normal [[cortisol]] production; this is referred to as physiologic, replacement, or maintenance dosing. This is approximately 6–12&nbsp;mg/m<sup>2</sup>/day of hydrocortisone (m<sup>2</sup> refers to [[body surface area]] (BSA), and is a measure of body size; an average man's BSA is 1.9 m<sup>2</sup>).{{cn|date=July 2024}}

===Therapeutic immunosuppression===
{{Hatnote|See section on "Immunodeficiency" below for adverse effects}}

Glucocorticoids cause [[immunosuppression]], and the therapeutic component of this effect is mainly the decreases in the function and numbers of [[lymphocyte]]s, including both [[B cell]]s and [[T cell]]s.

The major mechanism for this immunosuppression is through inhibition of nuclear factor kappa-light-chain-enhancer of activated B cells ([[NF-κB]]). NF-κB is a critical transcription factor involved in the synthesis of many mediators (i.e., cytokines) and proteins (i.e., adhesion proteins) that promote the immune response. Inhibition of this transcription factor, therefore, blunts the capacity of the immune system to mount a response.<ref name="RhenNEJM" />

Glucocorticoids suppress [[cell-mediated immunity]] by inhibiting genes that code for the cytokines [[Interleukin 1|IL-1]], [[Interleukin 2|IL-2]], [[Interleukin 3|IL-3]], [[Interleukin 4|IL-4]], [[Interleukin 5|IL-5]], [[Interleukin 6|IL-6]], [[Interleukin 8|IL-8]] and IFN-γ, the most important of which is IL-2. Smaller [[cytokine]] production reduces the [[T cell]] proliferation.<ref name=LeungBloom>{{cite journal | vauthors = Leung DY, Bloom JW | title = Update on glucocorticoid action and resistance | journal = The Journal of Allergy and Clinical Immunology | volume = 111 | issue = 1 | pages = 3–22; quiz 23 | date = Jan 2003 | pmid = 12532089 | doi = 10.1067/mai.2003.97 | doi-access = free }}</ref>

Glucocorticoids, however, not only reduce T cell proliferation, but also lead to another well known effect - glucocorticoid-induced apoptosis. The effect is more prominent in immature T cells still inside in the thymus, but peripheral T cells are also affected. The exact mechanism regulating this glucocorticoid sensitivity lies in the [[Bcl-2]] gene.<ref>{{cite journal | vauthors = Banuelos J, Shin S, Cao Y, Bochner BS, Morales-Nebreda L, Budinger GR, Zhou L, Li S, Xin J, Lingen MW, Dong C, Schleimer RP, Lu NZ | title = BCL-2 protects human and mouse Th17 cells from glucocorticoid-induced apoptosis | journal = Allergy | date = Jan 2016 | pmid = 26752231 | doi = 10.1111/all.12840 | volume=71 | issue = 5 | pages=640–650| pmc = 4844778 }}</ref>

Glucocorticoids also suppress the [[humoral immunity]], thereby causing a [[humoral immune deficiency]]. Glucocorticoids cause [[B cell]]s to express smaller amounts of IL-2 and of [[IL-2 receptor]]s. This diminishes both B cell clone expansion and [[antibody]] synthesis. The diminished amounts of IL-2 also cause fewer T lymphocyte cells to be activated.

The effect of glucocorticoids on [[Fc receptor]] expression in immune cells is complicated. Dexamethasone decreases [[IFN-gamma]] stimulated [[FCGR1A|Fc gamma RI]] expression in [[neutrophil]]s while conversely causing an increase in [[monocyte]]s.<ref name="pmid2141616">{{cite journal | vauthors = Pan LY, Mendel DB, Zurlo J, Guyre PM | title = Regulation of the steady state level of Fc gamma RI mRNA by IFN-gamma and dexamethasone in human monocytes, neutrophils, and U-937 cells | journal = Journal of Immunology | volume = 145 | issue = 1 | pages = 267–275 | year = 1990 | doi = 10.4049/jimmunol.145.1.267 | pmid = 2141616 | s2cid = 20754093 | doi-access = free }}</ref> Glucocorticoids may also decrease the expression of Fc receptors in macrophages,<ref name="pmid1829095">{{cite journal | vauthors = Ruiz P, Gomez F, King M, Lopez R, Darby C, Schreiber AD | title = In vivo glucocorticoid modulation of guinea pig splenic macrophage Fc gamma receptors | journal = The Journal of Clinical Investigation | volume = 88 | issue = 1 | pages = 149–157 | year = 1991 | pmid = 1829095 | pmc = 296015 | doi = 10.1172/JCI115271 }}</ref> but the evidence supporting this regulation in earlier studies has been questioned.<ref>{{cite book | veditors = van Furth R | title = Mononuclear phagocytes functional aspects | date = 1980 | publisher = M. Nijhoff | location = The Hague | isbn = 978-94-009-8793-7 | vauthors = Werb Z | chapter = Hormone receptors and normal regulation of macrophage physiological function | chapter-url = https://books.google.com/books?id=CHXvCAAAQBAJ&q=glucocorticoid+macrophage+phagocytosis+fc+receptors&pg=PA825 | page = 825 | quote = Glucocorticoids may also decrease the number of Fc receptors on macrophages, but this immunosuppressive function is controversial because of the lack of sensitivity in Fc receptor techniques and the high concentration of glucocorticoids used in previous experiments. }}</ref> The effect of [[Fc receptor]] expression in [[macrophage]]s is important since it is necessary for the [[phagocytosis]] of [[opsonin|opsonised]] cells. This is because Fc receptors bind [[antibodies]] attached to cells targeted for destruction by macrophages.

===Anti-inflammatory===
Glucocorticoids are potent anti-inflammatories, regardless of the inflammation's cause; their primary anti-inflammatory mechanism is [[lipocortin-1]] (annexin-1) synthesis. Lipocortin-1 both suppresses [[phospholipase A2]], thereby blocking [[eicosanoid]] production, and inhibits various [[leukocyte]] inflammatory events ([[epithelium|epithelial]] [[cell adhesion|adhesion]], [[emigration]], [[chemotaxis]], [[phagocytosis]], [[respiratory burst]], etc.). In other words, glucocorticoids not only suppress immune response, but also inhibit the two main products of inflammation, [[prostaglandins]] and [[leukotrienes]]. They inhibit prostaglandin synthesis at the level of [[phospholipase A2]] as well as at the level of [[cyclooxygenase]]/PGE isomerase (COX-1 and COX-2),<ref>{{cite journal | vauthors = Goppelt-Struebe M, Wolter D, Resch K | title = Glucocorticoids inhibit prostaglandin synthesis not only at the level of phospholipase A2 but also at the level of cyclo-oxygenase/PGE isomerase | journal = British Journal of Pharmacology | volume = 98 | issue = 4 | pages = 1287–1295 | date = Dec 1989 | pmid = 2514948 | pmc = 1854794 | doi = 10.1111/j.1476-5381.1989.tb12676.x }}</ref> the latter effect being much like that of [[Non-steroidal anti-inflammatory drug|NSAIDs]], thus potentiating the anti-inflammatory effect.

In addition, glucocorticoids also suppress [[cyclooxygenase]] expression.<ref>{{cite journal |vauthors=Jun SS, Chen Z, Pace MC, Shaul PW | title = Glucocorticoids downregulate cyclooxygenase-1 gene expression and prostacyclin synthesis in fetal pulmonary artery endothelium. | journal = Circulation Research | volume = 84 | issue = 2 | pages = 193–200 | date = Feb 1999 | pmid = 9933251 | doi = 10.1161/01.RES.84.2.193 | doi-access = free }}</ref>

Glucocorticoids marketed as anti-inflammatories are often topical formulations, such as nasal sprays for [[rhinitis]] or [[inhalers]] for [[asthma]]. These preparations have the advantage of only affecting the targeted area, thereby reducing side effects or potential interactions. In this case, the main compounds used are [[beclometasone]], [[budesonide]], [[fluticasone]], [[mometasone]] and [[ciclesonide]]. In rhinitis, sprays are used. For asthma, glucocorticoids are administered as [[inhalant]]s with a [[Metered-dose inhaler|metered-dose]] or [[dry powder inhaler]].<ref name=lange6th>{{cite book | vauthors = Flower R, Rang HP, Dale MM, Ritter JM | title = Rang & Dale's pharmacology | url = https://archive.org/details/rangdalespharmac0006dale | url-access = registration | publisher = Churchill Livingstone | location = Edinburgh | year = 2007 | isbn = 978-0-443-06911-6 }}</ref> In rare cases, symptoms of [[Radiation-induced thyroiditis|radiation induced thyroiditis]] has been treated with oral glucocorticoids.<ref>{{cite journal | vauthors = Mizokami T, Hamada K, Maruta T, Higashi K, Tajiri J | title = Painful Radiation Thyroiditis after <sup>131</sup>I Therapy for Graves' Hyperthyroidism: Clinical Features and Ultrasonographic Findings in Five Cases | journal = European Thyroid Journal | volume = 5 | issue = 3 | pages = 201–206 | date = September 2016 | pmid = 27843811 | pmc = 5091234 | doi = 10.1159/000448398 }}</ref>

===Hyperaldosteronism===
Glucocorticoids can be used in the management of [[familial hyperaldosteronism type 1]]. They are not effective, however, for use in the type 2 condition.{{cn|date=July 2024}}

===Heart failure===
Glucocorticoids could be used in the treatment of decompensated heart failure to potentiate renal responsiveness to diuretics, especially in heart failure patients with refractory diuretic resistance with large doses of loop diuretics.<ref name="pmid14435747">{{cite journal | vauthors = Rado JP, Blumenfeld G, Hammer S | title = The effect of prednisone and 6-methylprednisolone on mercurial diuresis in patients with refractory cardiac edema | journal = The American Journal of the Medical Sciences | volume = 238 | issue =  5| pages = 542–551 | date = Nov 1959 | pmid = 14435747 | doi =  10.1097/00000441-195911000-00003| s2cid = 38687480 }}</ref><ref name="pmid13520608">{{cite journal | vauthors = Riemer AD | title = Application of the newer corticosteroids to augment diuresis in congestive heart failure | journal = The American Journal of Cardiology | volume = 1 | issue = 4 | pages = 488–496 | date = Apr 1958 | pmid = 13520608 | doi = 10.1016/0002-9149(58)90120-6 }}</ref><ref name="pmid13632954">{{cite journal | vauthors = Newman DA | title = Reversal of intractable cardiac edema with prednisone | journal = New York State Journal of Medicine | volume = 59 | issue = 4 | pages = 625–633 | date = Feb 1959 | pmid = 13632954 }}</ref><ref name="pmid18971570">{{cite journal | vauthors = Zhang H, Liu C, Ji Z, Liu G, Zhao Q, Ao YG, Wang L, Deng B, Zhen Y, Tian L, Ji L, Liu K | title = Prednisone adding to usual care treatment for refractory decompensated congestive heart failure | journal = International Heart Journal | volume = 49 | issue = 5 | pages = 587–595 | date = Sep 2008 | pmid = 18971570 | doi = 10.1536/ihj.49.587 | doi-access = free }}</ref><ref name="pmid17876376">{{cite journal | vauthors = Liu C, Liu G, Zhou C, Ji Z, Zhen Y, Liu K | title = Potent diuretic effects of prednisone in heart failure patients with refractory diuretic resistance | journal = The Canadian Journal of Cardiology | volume = 23 | issue = 11 | pages = 865–868 | date = Sep 2007 | pmid = 17876376 | pmc = 2651362 | doi = 10.1016/s0828-282x(07)70840-1 }}</ref><ref name="pmid17086096">{{cite journal | vauthors = Liu C, Chen H, Zhou C, Ji Z, Liu G, Gao Y, Tian L, Yao L, Zheng Y, Zhao Q, Liu K | title = Potent potentiating diuretic effects of prednisone in congestive heart failure | journal = Journal of Cardiovascular Pharmacology | volume = 48 | issue = 4 | pages = 173–176 | date = Oct 2006 | pmid = 17086096 | doi = 10.1097/01.fjc.0000245242.57088.5b | s2cid = 45800521 | doi-access = free }}</ref><ref name="pmid21406321">{{cite journal | vauthors = Massari F, Mastropasqua F, Iacoviello M, Nuzzolese V, Torres D, Parrinello G | title = The glucocorticoid in acute decompensated heart failure: Dr Jekyll or Mr Hyde? | journal = The American Journal of Emergency Medicine | volume = 30 | issue = 3 | pages = 517.e5–10 | date = Mar 2012 | pmid = 21406321 | doi = 10.1016/j.ajem.2011.01.023 }}</ref>

== Resistance ==
[[File:Corticosteroid resistance mechanisms.svg|right|thumb|400px|class=skin-invert-image|Corticosteroid resistance mechanisms]]

Resistance to the therapeutic uses of glucocorticoids can present difficulty; for instance, 25% of cases of severe [[asthma]] may be unresponsive to steroids. This may be the result of genetic predisposition, ongoing exposure to the cause of the inflammation (such as [[allergen]]s), immunological phenomena that bypass glucocorticoids, pharmacokinetic disturbances (incomplete absorption or accelerated excretion or metabolism) and viral and/or bacterial respiratory infections.<ref name="LeungBloom" /><ref>{{cite journal | vauthors = Henderson I, Caiazzo E, McSharry C, Guzik TJ, Maffia P | title = Why do some asthma patients respond poorly to glucocorticoid therapy? | journal = Pharmacological Research | volume = 160 | pages = 105189 | date = October 2020 | pmid = 32911071 | pmc = 7672256 | doi = 10.1016/j.phrs.2020.105189 | doi-access = free }}</ref>

== Side effects ==
Glucocorticoid drugs currently being used act nonselectively, so in the long run they may impair many healthy anabolic processes. To prevent this, much research has been focused recently on the elaboration of selectively acting glucocorticoid drugs. Side effects include:
* Immunodeficiency (see section below)
* [[Hyperglycemia]] due to increased [[gluconeogenesis]], [[insulin resistance]], and impaired glucose tolerance ("[[steroid diabetes]]"); caution in those with [[diabetes mellitus]]
* Increased [[skin]] fragility, easy [[bruise|bruising]]
* Negative calcium balance due to reduced intestinal calcium absorption<ref name="pmid8495275">{{cite journal | vauthors = Gennari C | title = Differential effect of glucocorticoids on calcium absorption and bone mass | journal = British Journal of Rheumatology | volume = 32 | pages = 11–14 | date = May 1993 | issue = Suppl 2 | pmid = 8495275 | doi = 10.1093/rheumatology/32.suppl_2.11 }}</ref>
* [[Steroid-induced osteoporosis]]: reduced [[bone]] density ([[osteoporosis]], osteonecrosis, higher fracture risk, slower fracture repair)
* Weight gain due to increased visceral and truncal [[adipose tissue|fat]] deposition ([[central obesity]]) and [[appetite]] stimulation; see [[corticosteroid-induced lipodystrophy]]
* Hypercortisolemia with prolonged or excessive use (also known as, exogenous [[Cushing's syndrome]])
* Impaired memory and attention deficits<ref name="pmid8960717">{{cite journal | vauthors = Keenan PA, Jacobson MW, Soleymani RM, Mayes MD, Stress ME, Yaldoo DT | title = The effect on memory of chronic prednisone treatment in patients with systemic disease | journal = Neurology | volume = 47 | issue = 6 | pages = 1396–1402 | date = Dec 1996 | pmid = 8960717 | doi = 10.1212/WNL.47.6.1396 | s2cid = 20430943 }}</ref> See [[steroid dementia syndrome]].
* [[Adrenal insufficiency]] (if used for long time and stopped suddenly without a taper)
* [[Muscle]] and [[tendon]] breakdown (proteolysis), weakness, reduced muscle mass and repair<ref>{{cite journal | vauthors = Gelber JD | title = CORR Insights: Corticosteroid Injections Give Small and Transient Pain Relief in Rotator Cuff Tendinosis: A Meta-analysis | journal = Clinical Orthopaedics and Related Research | volume = 475 | issue = 1 | pages = 244–246 | date = January 2017 | pmid = 27572298 | pmc = 5174046 | doi = 10.1007/s11999-016-5044-4 }}</ref><ref name="Mohamadi 232–243"/>
* Expansion of malar fat pads and dilation of small [[blood vessel]]s in skin
* [[Lipomatosis]] within the [[epidural space]]<ref name="pmid10707048">{{cite journal | vauthors = Koch CA, Doppman JL, Patronas NJ, Nieman LK, Chrousos GP | title = Do glucocorticoids cause spinal epidural lipomatosis? When endocrinology and spinal surgery meet | journal = Trends in Endocrinology and Metabolism | volume = 11 | issue = 3 | pages = 86–90 | date = Apr 2000 | pmid = 10707048 | doi = 10.1016/S1043-2760(00)00236-8 | s2cid = 31233438 }}</ref>
* Excitatory effect on [[central nervous system]] (euphoria, psychosis)
* [[Anovulation]], irregularity of [[menstrual cycle|menstrual periods]]
* Growth failure, [[delayed puberty]]
* Increased plasma [[amino acid]]s, increased [[urea]] formation, negative nitrogen balance
* [[Glaucoma]] due to increased ocular pressure
* [[Cataracts]]
* [[Topical steroid withdrawal]]

In high doses, hydrocortisone (cortisol) and those glucocorticoids with appreciable mineralocorticoid potency can exert a mineralocorticoid effect as well, although in physiologic doses this is prevented by rapid degradation of cortisol by [[corticosteroid 11-beta-dehydrogenase isozyme 2|11β-hydroxysteroid dehydrogenase isoenzyme 2]] ([[Protein:HSD11B2|11β-HSD2]]) in mineralocorticoid target tissues. Mineralocorticoid effects can include salt and water retention, [[extracellular fluid]] volume expansion, [[hypertension]], [[potassium]] depletion, and [[metabolic alkalosis]].

===Immunodeficiency===
Glucocorticoids cause [[immunosuppression]], decreasing the function and/or numbers of [[neutrophil]]s, lymphocytes (including both [[B cell]]s and [[T cell]]s), [[monocyte]]s, [[macrophage]]s, and the [[Skin barrier|anatomical barrier]] function of the skin.<ref name="Klein2001">{{cite journal | vauthors = Klein NC, Go CH, Cunha BA | title = Infections associated with steroid use | journal = Infectious Disease Clinics of North America | volume = 15 | issue = 2 | pages = 423–432, viii | date = Jun 2001 | pmid = 11447704 | doi = 10.1016/s0891-5520(05)70154-9 }}</ref> This suppression, if large enough, can cause manifestations of [[immunodeficiency]], including [[T cell deficiency]], [[humoral immune deficiency]] and [[neutropenia]].{{cn|date=July 2024}}

{|class="wikitable"
|+ Main [[pathogen]]s of concern in glucocorticoid-induced immunodeficiency:<ref name="Klein2001" />
|-
! [[Pathogenic bacteria|Bacteria]]
|
* ''[[Enterobacteriaceae]] including [[Salmonella]] species''
* ''[[Legionella micdadei]]''
* ''[[Listeria monocytogenes]]''
* ''[[Mycobacterium tuberculosis]]''
* Nontuberculous ''[[mycobacteria]]''
* ''[[Nocardia asteroides]]''
* ''[[Rhodococcus equi]]''
* ''[[Staphylococcus aureus]]''
* ''[[Streptococci]]''
|-
! [[Fungi]]
|
* ''[[Aspergillus]]''
* ''[[Blastomyces]]''
* ''[[Candida (fungus)|Candida species]] including [[Candida albicans]]''
* ''[[Coccidioides immitis]]''
* ''[[Cryptococcus neoformans]]''
* ''[[Fusarium]]'' species
* ''[[Histoplasma capsulatum]]''
* ''[[Talaromyces marneffei]]''
* ''[[Pneumocystis jirovecii]]''
* ''[[Pseudallescheria boydii]]''
* [[Zygomycosis]]
|-
! [[Pathogenic virus|Viruses]]
|
* ''[[Adenovirus]]''
* ''[[Cytomegalovirus]]''
* ''[[Herpes simplex virus]]''
* ''[[Human papillomavirus]]''
* ''[[Influenza]]''/''[[parainfluenza]]''
* ''[[Respiratory syncytial virus]]''
* ''[[Varicella zoster]]''
|-
! Other
|
* [[Cryptosporidiosis]]/''[[Isospora belli]]''
* ''[[Strongyloides stercoralis]]''
* ''[[Toxoplasma gondii]]''
|}

===Withdrawal===
{{More medical citations needed|date=May 2018}}

In addition to the effects listed above, use of high-dose glucocorticoids for only a few days begins to produce suppression of the patient's [[adrenal glands]] suppressing hypothalamic [[corticotropin-releasing hormone]] (CRH) leading to suppressed production of [[adrenocorticotropic hormone]] (ACTH) by the anterior pituitary.<ref name="ChrousosPavlaki2000"/> With prolonged suppression, the adrenal glands atrophy (physically shrink), and can take months to recover full function after discontinuation of the exogenous glucocorticoid.

During this recovery time, the patient is vulnerable to [[adrenal insufficiency]] during times of stress, such as illness. While suppressive dose and time for adrenal recovery vary widely, clinical guidelines have been devised to estimate potential adrenal suppression and recovery, to reduce risk to the patient. The following is one example:
* If patients have been receiving daily high doses for five days or less, they can be abruptly stopped (or reduced to physiologic replacement if patients are adrenal-deficient). Full adrenal recovery can be assumed to occur by a week afterward.
* If high doses were used for six to 10 days, reduce to replacement dose immediately and taper over four more days. Adrenal recovery can be assumed to occur within two to four weeks of completion of steroids.
* If high doses were used for 11–30 days, cut immediately to twice replacement, and then by 25% every four days. Stop entirely when dose is less than half of replacement. Full adrenal recovery should occur within one to three months of completion of withdrawal.
* If high doses were used more than 30 days, cut dose immediately to twice replacement, and reduce by 25% each week until replacement is reached. Then change to oral hydrocortisone or cortisone as a single morning dose, and gradually decrease by 2.5&nbsp;mg each week. When the morning dose is less than replacement, the return of normal basal adrenal function may be documented by checking 0800 cortisol levels prior to the morning dose; stop drugs when 0800 cortisol is 10 μg/dl. Predicting the time to full adrenal recovery after prolonged suppressive exogenous steroids is difficult; some people may take nearly a year.
* Flare-up of the underlying condition for which steroids are given may require a more gradual taper than outlined above.

==See also==
{{col div|colwidth=30em}}
* [[List of corticosteroids]]
* [[List of corticosteroid cyclic ketals]]
* [[List of corticosteroid esters]]
* [[Aminoglutethimide]] blocks glucocorticoid secretion
* [[GITR]] (glucocorticoid-induced TNF receptor)
* [[Glucocorticoid receptor]]
* [[Immunosuppressive drug]]
* [[Membrane glucocorticoid receptor]]
* [[Metyrapone]] blocks glucocorticoid secretion
* [[Selective glucocorticoid receptor agonist]]
* [[Topical glucocorticoids]]
* [[Topical steroid]]
* [[Steroid atrophy]]
* [[Topical steroid addiction|Topical steroid withdrawal]]
* [[Non-steroidal anti-inflammatory drug]] (NSAID)
{{div col end}}

==References==
{{Reflist}}

==Further reading==
{{refbegin}}
* {{cite journal | vauthors = Wolkowitz OM, Burke H, Epel ES, Reus VI | title = Glucocorticoids. Mood, memory, and mechanisms | journal = Annals of the New York Academy of Sciences | volume = 1179 | pages = 19–40 | date = Oct 2009 | pmid = 19906230 | doi = 10.1111/j.1749-6632.2009.04980.x | s2cid = 222085554 }}
{{refend}}

==External links==
* {{MeshName|Glucocorticoids}}

{{Major drug groups}}
{{Endogenous steroids}}
{{Glucocorticoids and antiglucocorticoids}}
{{Glucocorticoid receptor modulators}}
{{Authority control}}

[[Category:Chemical substances for emergency medicine]]
[[Category:Corticosteroids]]
[[Category:Glucocorticoids]]
[[Category:Hepatotoxins]]