Glucocorticoids (GC) are a class of steroidal structure (see structure to the right).
GCs are part of the feedback mechanism in the immune system that turns immune activity (inflammation) down. They are therefore used in medicine to treat diseases caused by an overactive immune system, such as allergies, asthma, autoimmune diseases and sepsis. GCs have many diverse (pleiotropic) effects, including potentially harmful side effects, and as a result are rarely sold over the counter. They also interfere with some of the abnormal mechanisms in cancer cells, so they are used in high doses to treat cancer. This includes mainly inhibitory effects on lymphocyte proliferation (treatment of lymphomas and leukaemias) and mitigation of side effects of anticancer drugs.
GCs cause their effects by binding to the glucocorticoid receptor (GR). The activated GR complex, in turn, 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 adrenal cortex), but is often used as a synonym for “glucocorticoid”.
homeostatic functions. Various synthetic glucocorticoids are available; these are used either as replacement therapy in glucocorticoid deficiency or to suppress the immune system.
Glucocorticoid effects may be broadly classified into two major categories: development.
As discussed in more detail below, glucocorticoids function through interaction with the glucocorticoid receptor:
- up-regulate the expression of anti-inflammatory proteins.
- down-regulate 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.
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 blood.
- Stimulation of enzymes involved in gluconeogenesis is probably the best-known metabolic function of glucocorticoids.
- Mobilization of extrahepatic tissues: These serve as substrates for gluconeogenesis.
- Inhibition of glucose uptake in muscle and adipose tissue: A mechanism to conserve glucose
- Stimulation of glycerol provide another substrate for gluconeogenesis.
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.
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.
Arousal and cognition
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). Glucocorticoids have also been shown to have a significant impact on vigilance and cognitive performance. 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 (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-GC state) or after exogenous glucocorticoid administration (high-GC 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.
Mechanism of action
Glucocorticoids bind to the cytosolic 
The proteins encoded by these up-regulated genes have a wide range of effects, including, for example:
The opposite mechanism is called transrepression. The activated hormone receptor interacts with specific transcription factors (such as AP-1 and NF-?B) and prevents the transcription of targeted genes. Glucocorticoids are able to prevent the transcription of proinflammatory genes, including interleukins IL-1B, IL-4, IL-5, and IL-8, chemokines, cytokines, GM-CSF, and TNFA genes.
The ordinary glucocorticoids do not distinguish among transactivation and transrepression and influence both the “wanted” immune and the “unwanted” genes regulating the metabolic and cardiovascular functions. Intensive research is aimed at discovering selectively acting glucocorticoids that will be able to repress only the immune system.
Genetically modified mice that express a modified GR incapable of DNA binding are still responsive to the anti-inflammatory effects of glucocorticoids, while the stimulation of gluconeogenesis by glucocorticoids is blocked. This result strongly suggests most of the desirable anti-inflammatory effects are due to transrepression, while the undesirable metabolic effects arise from transactivation, a hypothesis also underlying the development of selective glucocorticoid receptor agonists.
Glucocorticoids have been shown to exert a number of rapid actions that are independent of the regulations of gene transcription. Binding of corticosteroids to the glucocorticoid receptor (GR) stimulates 
Acute or chronic administration of corticosteroids causes 
Some of the immunosuppressive effects of glucocorticoids are mediated by nongenomic signalling involving the glucocortiocid receptor (GR). A multiprotein complex composed of the unliganded glucocorticoid receptor, Hsp90, and the tyrosine kinases LCK and FYN is recruited to the antigen-activated T cell receptor (TCR) in T cells. This GR complex is necessary for TCR signalling. On binding of glucocorticoids to GR, this complex dissociates, thus blocking TCR signalling.
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 overlapping mineralocorticoid potency varies. Cortisol (hydrocortisone) is the standard of comparison for glucocorticoid potency. Hydrocortisone is the name used for pharmaceutical preparations of cortisol. Data refer to oral dosing, except when mentioned. Oral potency may be less than parenteral potency because significant amounts (up to 50% in some cases) may not be absorbed from the intestine. Fludrocortisone, DOCA (Deoxycorticosterone acetate), and aldosterone are, by definition, not considered glucocorticoids, although they may have minor glucocorticoid potency, and are included in this table to provide perspective on mineralocorticoid potency.
|Name||Glucocorticoid potency||Mineralocorticoid potency||Duration of action (t1/2 in hours)|
|Cortisone||0.8||0.8||oral 8, intramuscular 18+|
|Beclometasone||8 puffs 4 times a day|
equals 14 mg oral
prednisone once a day[clarification needed]
|Deoxycorticosterone acetate (DOCA)||0||20||–|
Glucocorticoids may be used in low doses in reparative processes.
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 mg/m²/day (m² refers to body surface area (BSA), and is a measure of body size; an average man’s BSA is 1.7 m²).
Glucocorticoids cause T cells.
The major mechanism for this immunosuppression through inhibition of nuclear factor kappa-light-chain-enhancer of activated B cells(NF-?B). NF-?B 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. 
Glucocorticoids suppress cell-mediated immunity by inhibiting genes that code for the cytokines IL-1, IL-2, IL-3, IL-4, IL-5, IL-6, IL-8 and IFN-?, the most important of which is IL-2. Smaller cytokine production reduces the T cell proliferation.
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 underlying this glucocorticoid sensitivity still remains to be elucidated.
Glucocorticoids also suppress the antibody synthesis. The diminished amounts of IL-2 also cause fewer T lymphocyte cells to be activated.
Since glucocorticoid is a steroid, it regulates transcription factors; another factor it down-regulates is the expression of Fc receptors on macrophages, so there is a decreased phagocytosis of opsonised cells.
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 (epithelial 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), the latter effect being much like that of NSAIDs, potentiating the anti-inflammatory effect.
In addition, glucocorticoids also suppress cyclooxygenase expression.
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 inhalants with a metered-dose or dry powder inhaler.
Glucocorticoids can be used in the management of familial hyperaldosteronism type 1. They are not effective, however, for use in the type 2 condition.
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 allergens), immunological phenomena that bypass glucocorticoids, and pharmacokinetic disturbances (incomplete absorption or accelerated excretion or metabolism).
 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 separate section below)
- diabetes mellitus
- increased bruising
- negative calcium balance due to reduced intestinal calcium absorption
- osteoporosis, osteonecrosis, higher fracture risk, slower fracture repair)
- weight gain due to increased visceral and truncal appetite stimulation
- adrenal insufficiency (if used for long time and stopped suddenly without a taper)
- muscle breakdown (proteolysis), weakness, reduced muscle mass and repair
- expansion of malar fat pads and dilation of small blood vessels in skin
- menstrual periods
- growth failure, delayed puberty
- increased plasma urea formation, negative nitrogen balance
- excitatory effect on central nervous system (euphoria, psychosis)
- glaucoma due to increased cranial pressure
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 metabolic alkalosis.
The combination of clinical problems produced by prolonged, excess glucocorticoids, whether synthetic or endogenous, is termed Cushing’s syndrome.
Glucocorticoids cause neutropenia.
In addition to the effects listed above, use of high-dose steroids for more than a week begins to produce suppression of the patient’s adrenocorticotropic hormone. 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, but many variations exist or may be appropriate in individual circumstances.
- 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 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 ?g/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.
Hogg, J. A.; Beal, P. F.; Nathan, A. H.; Lincoln, F. H.; Schneider, W. P.; Magerlein, B. J.; Hanze, A. R.; Jackson, R. W. (1955). Journal of the American Chemical Society 77 (16): 4436. 10.1021/ja01621a092.
- GITR (glucocorticoid-induced TNF receptor)
- Glucocorticoid receptor
- Immunosuppressive drug
- Selective glucocorticoid receptor agonist (SEGRA)
- Topical steroid
- de Quervain, D et al., Stress and glucocorticoids impair retrieval of long-term spatial memory. Nature, 394, 787-790 (1998)
- de Quervain, D et al., Acute cortisone administration impairs retrieval of long-term declarative memory in humans. Nature Neuroscience, 3, 313-314 (2000)
- Williams Hematology, 8ed, Ch.65, Neutropenia and Neutrophylia
- From Liapi and Chrousos (ref. 2); Chapter 14. Glucocorticoid Therapy and Adrenal Suppression; http://www.endotext.org/adrenal/adrenal14/adrenalframe14.htm
- . Retrieved 2009-07-09.
- Glucocorticoids at the US National Library of Medicine Medical Subject Headings (MeSH)
- R. Bowen (2006-05-26). “Glucocorticoids”. Colorado State University. http://www.vivo.colostate.edu/hbooks/pathphys/endocrine/adrenal/gluco.html. Retrieved 2008-05-11.