glucocorticoid glucocorticoid glucocorticoids (or, less commonly, glucocorticosteroids) are a class of corticosteroids, which are a class of steroid hormones. glucocorticoids are corticosteroids that bind to the glucocorticoid receptor that is present in almost every vertebrate animal cell. the name "glucocorticoid" is a portmanteau (glucose + cortex + steroid) and is composed from its role in regulation of glucose metabolism, synthesis in the adrenal cortex, and its steroidal structure (see structure below). glucocorticoiddrug classchemical structure of cortisol (hydrocortisone), an endogenous glucocorticoid as well as medication.class identifierssynonymscorticosteroid; glucocorticosteroiduseadrenal insufficiency; allergic, inflammatory, and autoimmune disorders; asthma; organ transplantatc codeh02abbiological targetglucocorticoid receptorchemical classsteroidsin wikidata 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 diseases caused by an overactive immune system, such as allergies, asthma, autoimmune diseases, and sepsis. glucocorticoids have many diverse (pleiotropic) effects, including potentially harmful side effects. they also interfere with some of the abnormal mechanisms in cancer cells, so they are used in high doses to treat cancer. this includes inhibitory effects on lymphocyte proliferation, as in the treatment of lymphomas and leukemias, and the mitigation of side effects of anticancer drugs. glucocorticoids affect cells by binding to the glucocorticoid receptor. the activated glucocorticoid receptor-glucocorticoid complex up-regulates the expression of anti-inflammatory proteins in the nucleus (a process known as transactivation) and represses the expression of proinflammatory proteins in the cytosol by preventing the translocation of other transcription factors from the cytosol into the nucleus (transrepression). glucocorticoids are distinguished from mineralocorticoids and sex steroids by their specific receptors, target cells, and effects. in technical terms, "corticosteroid" refers to both glucocorticoids and mineralocorticoids (as both are mimics of hormones 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, metabolic, immunologic, and homeostatic functions. various synthetic glucocorticoids are available; these are widely utilized in general medical practice and numerous specialties, either as replacement therapy in glucocorticoid deficiency or to suppress the body's immune system. effects steroidogenesis showing glucocorticoids in green ellipse at right with the primary example being cortisol. 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: immunological and metabolic. in addition, glucocorticoids play important roles in fetal development and body fluid homeostasis. immune glucocorticoids function via interaction with the glucocorticoid receptor (see details below): 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. metabolic the name "glucocorticoid" derives from early observations that these hormones 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. 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 acids and glycerol from triglyceride breakdown, and is particularly important in carnivores and certain herbivores. enhancing the expression of enzymes involved in gluconeogenesis is probably the best-known metabolic function of glucocorticoids. mobilization of amino acids from extrahepatic tissues: these serve as substrates for gluconeogenesis. inhibition of glucose uptake in muscle and adipose tissue: a mechanism to conserve glucose 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 increase in hemoglobin concentration, likely due to hindrance of the ingestion of red blood cell by macrophage or other phagocyte. increased urinary uric acid increased urinary calcium and hypocalcemia alkalosis leukocytosis excessive glucocorticoid levels resulting from administration as a drug or 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. 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 and may also play a role in hippocampal development. glucocorticoids stimulate the maturation of the na+/k+/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. arousal and cognition 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. 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). 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. glucocorticoids have also been shown to have a significant impact on 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. 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. 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, a condition known as "steroid dementia". 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 induce water intake; peripherally, glucocorticoids could induce a potent diuresis. 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 translocates itself into the cell nucleus, where it binds to glucocorticoid response elements in the promoter region of the target genes resulting in the regulation of gene expression. this process is commonly referred to as transcriptional activation, or transactivation. the proteins encoded by these up-regulated genes have a wide range of effects, including, for example: anti-inflammatory – lipocortin i, 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 of genes that are transcribed via the activity of that factor. while this does occur, the results are not consistent for all cell types and conditions; there is no generally accepted, general mechanism for transrepression. 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. 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. 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. pharmacology 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+) and water; renal physiology). because they permeate the intestines easily, they are administered primarily per os (by mouth), but also by other methods, such as topically 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 albumin. in the liver, they quickly metabolize by conjugation with a sulfate or glucuronic acid, and are secreted in the urine. 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. 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. comparative oral corticosteroid potencies 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 mg prednisone once a day - - 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 allergic, inflammatory, and autoimmune disorders. inhaled glucocorticoids are the second-line treatment for asthma. they are also administered as post-transplantory immunosuppressants to prevent the acute transplant rejection and the graft-versus-host disease. nevertheless, they do not prevent an infection and also inhibit later 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 inflammatory conditions.