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Glucocorticoids (GC) are a class of steroid hormones characterised by an ability to bind with the glucocorticoid receptor (GR) and trigger similar effects. These may be either slow, mediated genomically through nuclear receptors, or fast, mediated nongenomically through membrane-associated receptors and signaling cascades. 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.
Cortisol (or hydrocortisone) is the most important human glucocorticoid. It is essential for life, and regulates or supports a variety of important cardiovascular, metabolic, immunologic, and homeostatic functions. Glucocorticoid receptors are found in the cells of almost all vertebrate tissues. Various synthetic glucocorticoids are available; these are used either as replacement therapy in glucocorticoid deficiency or to suppress the immune system.
Mode of actionEdit
Glucocorticoids bind to the cytosolic glucocorticoid receptor (GR). This type of receptor is activated by ligand binding. After a hormone binds to the corresponding receptor, the newly-formed receptor-ligand complex translocates itself into the cell nucleus, where it binds to glucocorticoid response elements (GRE) in the promoter region of the target genes resulting in the regulation of gene expression. This process is commonly referred to as transactivation.
The proteins encoded by these upregulated genes have a wide range of effects including for example:
- anti-inflammatory – lipocortin I and p11/calpactin binding protein
- increased gluconeogenesis – glucose-6-phosphatase and tyrosine aminotransferase
The opposite mechanism is called transrepression. The activated hormone receptor interacts with specific transcription factors (such as AP-1 and NF-κB) and prevents the transcription of targeted genes. Glucocorticoids are able to prevent the transcription of pro-inflammatory genes, including the IL-2 gene.
The ordinary glucocorticoids do not distinguish among transactivation and transrepression and influence both the "wanted" immune and "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 which express a modified GR which is incapable of DNA binding are still responsive to the antiinflammatory effects of glucocorticoids while the stimulation of gluconeogenesis by glucocorticoids is blocked. This result strongly suggests that most of the desirable antiinflammatory effects are due to transrepression while the undesirable metabolic effects arise from transactivation.
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 gluconeogenesis, particularly 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.
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.
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.
A variety of synthetic glucocorticoids, some far more potent than cortisol, have been created for therapeutic use. They differ in the pharmacokinetics (absorption factor, half-life, volume of distribution, clearance) and in pharmacodynamics (for example the capacity of mineralocorticoid activity: retention of sodium (Na+) and water; see also: renal physiology). Because they permeate the intestines easily, they are primarily administered per os (by mouth), but also by other methods, such as topically on skin. More than 90 percent of them bind different plasma proteins, however with a different binding specificity. Endogenous glucocorticoids and some synthetic corticoids have high affinity to the protein transcortin (also called CBG, corticosteroid-binding globulin), whereas all of them bind albumin. In the liver, they quickly metabolise 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, and aldosterone are not considered glucocorticoids, 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 acetate||0.8||0.8||oral 8, intramuscular 18+|
|Beclometasone|| 8 puffs 4 times a day|
equals 14 mg oral
prednisone once a day
|Deoxycorticosterone acetate (DOCA)||0||20||-|
Glucocorticoids may be used in low doses in adrenal insufficiency. In much higher doses, glucocorticoids are used to suppress various allergic, inflammatory, and autoimmune disorders. They are also administered as posttransplantory 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.
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 is 1.7 m²).
Glucocorticoids suppress the cell-mediated immunity. They act by inhibiting genes that code for the cytokines IL-1, IL-2, IL-3, IL-4, IL-5, IL-6, IL-8 and IFN-γ, the most important of which is IL-2. Smaller cytokine production reduces the T cell proliferation.
Glucocorticoids do however not only reduce T cell proliferation, another well known effect is glucocorticoid induced apoptosis. The effect is more prominent in immature T cells that still reside in the thymus, but also affect peripheral T cells. The exact mechanism underlying this glucocorticoid sensitivity still remains to be elucidated.[How to reference and link to summary or text]
Glucocorticoids also suppress the humoral immunity, causing B cells to express smaller amounts of IL-2 and of IL-2 receptors. This diminishes both B cell clone expansion and antibody synthesis. The diminished amounts of IL-2 also causes 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.[How to reference and link to summary or text]
Glucocorticoids influence all types of inflammatory events, no matter what their cause. They induce the lipocortin-1 (annexin-1) synthesis, which then binds to cell membranes, preventing the phospholipase A2 from coming into contact with its substrate arachidonic acid. This leads to diminished eicosanoid production. The cyclooxygenase (both COX-1 and COX-2) expression is also suppressed, potentiating the effect. In other words, the two main products in inflammation, Prostaglandins and Leukotrienes, are inhibited by the action of Glucocorticoids.
Glucocorticoids also stimulate the lipocortin-1 escaping to the extracellular space, where it binds to the leukocyte membrane receptors and inhibits various inflammatory events: epithelial adhesion, emigration, chemotaxis, phagocytosis, respiratory burst, and the release of various inflammatory mediators (lysosomal enzymes, cytokines, tissue plasminogen activator, chemokines, etc.) from neutrophils, macrophages, and mastocytes.
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 accellerated excretion or metabolism).
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. These are the side-effects that could be prevented:
- hyperglycemia due to increased gluconeogenesis, insulin resistance, and impaired glucose tolerance ("steroid diabetes"); caution in those with diabetes mellitus
- increased skin fragility, easy bruising
- reduced bone density (osteoporosis, osteonecrosis, higher fracture risk, slower fracture repair)
- weight gain due to increased visceral and truncal fat deposition (central obesity) and 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
- anovulation, irregularity of menstrual periods
- growth failure, pubertal delay
- increased plasma amino acids, increased 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 11β-hydroxysteroid dehydrogenase isoenzyme 2 (11β-HSD2) in mineralocorticoid target tissues. Mineralocorticoid effects can include salt and water retention, extracellular fluid volume expansion, hypertension, potassium depletion, and metabolic alkalosis.
The combination of clinical problems produced by prolonged, excess glucocorticoids, whether synthetic or endogenous, is termed Cushing's syndrome.
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 adrenal glands because the exogenous glucocorticoids suppress hypothalamic corticotropin-releasing hormone (CRH) and pituitary adrenocorticotropic hormone (ACTH). 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 there is wide individual variation in suppressive dose and time for adrenal recovery, 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.[How to reference and link to summary or text]
- If a patient has been receiving daily high doses for 5 days or less, they can be abruptly stopped (or reduced to physiologic replacement if patient is adrenal-deficient). Full adrenal recovery can be assumed to occur by a week afterward.
- If high doses were used for 6-10 days, reduce to replacement dose immediately and taper over 4 more days. Adrenal recovery can be assumed to occur within 2-4 weeks of completion of steroids.
- If high doses were used for 11-30 days, cut immediately to twice replacement, and then by 25% every 4 days. Stop entirely when dose is less than half of replacement. Full adrenal recovery should occur within 1-3 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 a.m. 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. It is difficult to predict the time to full adrenal recovery after prolonged suppressive exogenous steroids; 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.
- GITR (glucocorticoid-induced TNF receptor)
- Glucocorticoid receptor
- Immunosuppressive drug
- ↑ 1.0 1.1 1.2 Newton R (July 2000). Molecular mechanisms of glucocorticoid action: what is important?. Thorax 55 (7): 603–13.
- ↑ Schäcke H, Rehwinkel H, Asadullah K (May 2005). Dissociated glucocorticoid receptor ligands: compounds with an improved therapeutic index. Curr Opin Investig Drugs 6 (5): 503–7.
- ↑ Newton R, Holden NS (October 2007). Separating transrepression and transactivation: a distressing divorce for the glucocorticoid receptor?. Mol. Pharmacol. 72 (4): 799–809.
- ↑ Reichardt HM, Tronche F, Bauer A, Schütz G (2000). Molecular genetic analysis of glucocorticoid signaling using the Cre/loxP system. Biol. Chem. 381 (9-10): 961–4.
- ↑ From Liapi and Chrousos (ref. 2); Chapter 14. Glucocorticoid Therapy and Adrenal Suppression; http://www.endotext.org/adrenal/adrenal14/ch01s02.html
- ↑ Disease management of atopic dermatitis: a practice parameter; ANNALS OF ALLERGY, ASTHMA, & IMMUNOLOGY; VOLUME 79, SEPTEMBER, 1997; http://www.jcaai.readyportal.net/file_depot/0-10000000/20000-30000/27387/folder/63948/Atopic_Derm1997.pdf
- ↑ 7.0 7.1 Leung DY, Bloom JW (January 2003). Update on glucocorticoid action and resistance. J. Allergy Clin. Immunol. 111 (1): 3–22; quiz 23.
- MeSH Glucocorticoids
- R. Bowen. Glucocorticoids. Colorado State University. URL accessed on 2008-05-11.
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