https://www.wikidoc.org/index.php?title=Glucocorticoids&feed=atom&action=historyGlucocorticoids - Revision history2024-03-29T05:54:40ZRevision history for this page on the wikiMediaWiki 1.40.0https://www.wikidoc.org/index.php?title=Glucocorticoids&diff=675416&oldid=prevWikiBot: Robot: Automated text replacement (-{{SIB}} + & -{{EH}} + & -{{EJ}} + & -{{Editor Help}} + & -{{Editor Join}} +)2012-08-09T15:34:37Z<p>Robot: Automated text replacement (-{{SIB}} + & -{{EH}} + & -{{EJ}} + & -{{Editor Help}} + & -{{Editor Join}} +)</p>
<p><b>New page</b></p><div>{{SI}}<br />
{{CMG}}<br />
<br />
<br />
<br />
== Overview ==<br />
'''Glucocorticoids''' are a class of [[steroid hormone]]s characterised by an ability to bind with the [[cortisol]] [[receptor (biochemistry)|receptor]] and trigger similar effects. Glucocorticoids are distinguished from [[mineralocorticoid]]s and [[sex steroid]]s by the specific receptors, target cells, and effects. Technically, the term ''[[corticosteroid]]'' refers to both glucocorticoids and mineralocorticoids, but is often used as a synonym for ''glucocorticoid''. <br />
<br />
[[Cortisol]] (or hydrocortisone) is the most important human glucocorticoid. It is essential for life and regulates or supports a variety of important [[cardiovascular]], [[metabolism|metabolic]], [[immunology|immunologic]], and [[homeostasis|homeostatic]] functions. [[Glucocorticoid receptor]]s are found in the cells of almost all [[vertebrate]] tissues.<br />
<br />
==Effects==<br />
<br />
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 blood. These effects include: <br />
<br />
*Stimulation of [[gluconeogenesis]], particularly in the [[liver]]: This pathway results in the synthesis of glucose from non-[[hexose]] substrates such as [[amino acid]]s and [[lipid]]s and is particularly important in carnivores and certain herbivores. Enhancing the expression of [[enzyme]]s involved in [[gluconeogenesis]] is probably the best known metabolic function of glucocorticoids. <br />
*Mobilization of amino acids from [[Wiktionary:extrahepatic|extrahepatic]] tissues: These serve as substrates for [[gluconeogenesis]]. <br />
*Inhibition of glucose uptake in muscle and [[adipose]] tissue: A mechanism to conserve glucose. <br />
*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.<br />
<br />
Glucocorticoids have potent [[anti-inflammatory]] and [[immunosuppressive]] properties. This is particularly evident when they are administered at pharmacological doses, but also is important in normal immune responses. As a consequence, glucocorticoids are widely used as drugs to treat inflammatory conditions such as [[arthritis]] or [[dermatitis]], and as adjunction therapy for conditions such as [[autoimmune disease]]s. <br />
<br />
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. <br />
<br />
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.<br />
<br />
==Mode of action==<br />
<br />
<br />
Glucocorticoids bind to the cytosolic [[glucocorticoid receptor]]. This type of [[receptor (biochemistry)|receptor]] is activated by [[ligand]] binding. After a hormone binds to the corresponding receptor, the newly formed [[Complex (chemistry)#Receptor-ligand complexes|receptor-ligand complex]] translocates itself into the [[cell nucleus]], where it binds to many [[glucocorticoid response elements]] (GRE) in the [[promoter]] region of the target [[gene]]s.<br />
The opposite mechanism is called '''[[transrepression]]'''.The activated [[hormone receptor]] interacts with specific transcription factors and prevents the [[transcription (genetics)|transcription]] of targeted genes. Glucocorticoids are able to prevent the transcription of any of immune genes, including the [[Interleukin_2|IL-2]] gene.<br />
<br />
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. Currently, intensive research is aimed at discovering selectively acting glucocorticoids that will be able to repress only the immune system.<br />
<br />
==Pharmacologic properties==<br />
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 (molecule)|water]]; see also: [[Renal physiology#Maintaining body sodium and water balance|renal physiology]]). Because they absorb well through the [[intestine]]s, they are primarily administered ''per os'' (by [[mouth]]), but also by other methods, such as [[topical]]ly on [[skin]]. More than 90 per cent 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 protein), while all of them bind [[serum albumin|albumin]]. In the liver, they quickly metabolise by conjugation with a [[sulfate]] or [[glucuronic acid]] and are secreted in the [[urine]].<br />
<br />
Glucocorticoid potency, duration of effect, and overlapping mineralocorticoid potency varies (Table).<br />
<br />
{| cellpadding=3 cellspacing=3 border=1 style="border-collapse:collapse"<br />
|+ Comparative steroid potencies<br />
|bgcolor="#dddddd"| '''Name'''<br />
|bgcolor="#dddddd"| '''Glucocorticoid potency'''<br />
|bgcolor="#dddddd"| '''Mineralocorticoid potency'''<br />
|bgcolor="#dddddd"| '''Duration of action''' (t<sub>1/2</sub> in hours)<br />
|-<br />
| [[Hydrocortisone]] (Cortisol)<br />
| 1<br />
| 1<br />
| 8<br />
|-<br />
| Cortisone acetate<br />
| 0.8<br />
| 0.8<br />
| oral 8, intramuscular 18+<br />
|-<br />
| [[Prednisone]]<br />
| 3.5-5<br />
| 0.8<br />
| 16-36<br />
|-<br />
| [[Prednisolone]]<br />
| 4<br />
| 0.8<br />
| 16-36<br />
|-<br />
| [[Methylprednisolone]]<br />
| 5-7.5<br />
| 0.5<br />
| 18-40<br />
|-<br />
| [[Dexamethasone]]<br />
| 25-80<br />
| 0<br />
| 36-54<br />
|-<br />
| [[Betamethasone]]<br />
| 25-30<br />
| 0<br />
| 36-54<br />
|-<br />
| [[Triamcinolone acetonide|Triamcinolone]]<br />
| 5<br />
| 0<br />
| 12-36<br />
|-<br />
| [[Beclometasone]]<br />
| 8 puffs 4 times a day<br/>equals 14 mg oral<br/>prednisone once a day<br />
| -<br />
| -<br />
|-<br />
| [[Fludrocortisone]] acetate<br />
| 15<br />
| 200<br />
| -<br />
|-<br />
| Deoxycorticosterone acetate (DOCA)<br />
| 0<br />
| 20<br />
| -<br />
|-<br />
| [[Aldosterone]]<br />
| 0.3<br />
| 200-1000<br />
| -<br />
|}<br />
<br />
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. Note that oral potency may be less than parenteral potency because significant amounts (up to 50% in some cases) may not be absorbed from the intestine. Note that fludrocortisone, DOCA, and aldosterone are not considered glucocorticoids and are included in this table to provide perspective on mineralocorticoid potency.<br />
<br />
Hydrocortisone cream or ointment is available nonprescription up to 1% strength. Stronger forms generally require prescription.[http://www.drnase.com/Prescipt_ions_non.htm]<br />
<br />
==Physiologic replacement of glucocorticoid==<br />
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/m<sup>2</sup>/day (m<sup>2</sup> refers to [[body surface area]] (BSA) and is a measure of body size; an average man is 1.7 m<sup>2</sup>).<br />
<br />
==Medical uses and effects of high dose glucocorticoids==<br />
In much higher doses (termed ''pharmacologic doses''), glucocorticoids are used to suppress various [[allergy|allergic]], [[inflammation|inflammatory]], and autoimmune disorders. They are also administered as posttransplantory 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 reparative processes.<br />
<br />
Some drugs used are cortisol (hydrocortisone), prednisone and dexamethasone.<br />
<br />
===Immunosuppressive mechanism===<br />
Glucocorticoids suppress the [[cell-mediated immunity]]. They act 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-&gamma;, the most important of which is the IL-2. Smaller [[cytokine]] production reduces the [[T cell]] proliferation.<br />
<br />
Glucocorticoids also suppress the [[humoral immunity]], causing [[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 causes fewer T lymphocyte cells to be activated.<br />
<br />
Since glucocorticoid is a [[steroid]], it regulates [[transcription factors]]; another factor it down regulates is the expression of [[Fc receptor]]s on [[macrophage]]s, so there is a decreased [[phagocytosis]] of [[opsonin|opsonised]] cells.<br />
<br />
===Antiinflammatory effects===<br />
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 membrane]]s preventing the [[phospholipase A2]] from coming into contact with its [[substrate (biochemistry)|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.<br />
<br />
Glucocorticoids also stimulate the lipocortin-1 escaping to the extracellular space, where it binds to the [[leukocyte]] membrane receptors and inhibits various inflammatory events: [[epithelium|epithelial]] [[cell adhesion|adhesion]], [[emigration]], [[chemotaxis]], [[phagocytosis]], [[respiratory burst]] and the release of various inflammatory mediators (lysosomal enzymes, cytokines, [[tissue plasminogen activator]], [[chemokine]]s etc.) from [[neutrophil]]s, [[macrophage]]s and [[mastocyte]]s.<br />
<br />
===Side effects===<br />
<br />
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:<br />
*immunosuppression<br />
*[[hyperglycemia]] due to increased [[gluconeogenesis]], [[insulin resistance]] and impaired glucose tolerance ("[[steroid diabetes]]"); caution in those with [[diabetes mellitus]]<br />
*increased [[skin]] fragility, easy [[bruise|bruising]]<br />
*reduced [[bone]] density ([[osteoporosis]], higher fracture risk, slower fracture repair)<br />
*weight gain due to increased visceral and truncal [[adipose tissue|fat]] deposition ([[central obesity]]) and [[appetite]] stimulation<br />
*[[adrenal insufficiency]] (if used for long time and stopped suddenly without a taper)<br />
*[[muscle]] breakdown (proteolysis), weakness; reduced muscle mass and repair<br />
*expansion of malar fat pads and dilation of small [[blood vessel]]s in skin<br />
*[[anovulation]], irregularity of [[menstrual cycle|menstrual periods]]<br />
*growth failure, [[delayed puberty|pubertal delay]]<br />
*increased plasma [[amino acid]]s, increased [[urea]] formation; negative nitrogen balance<br />
*excitatory effect on [[central nervous system]]<br />
<br />
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 ([[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]].<br />
<br />
The combination of clinical problems produced by prolonged, excess glucocorticoids, whether synthetic or endogenous, is termed [[Cushing's syndrome]].<br />
<br />
==Adrenal suppression and withdrawal==<br />
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.<br />
<br />
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.<br />
*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.<br />
*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.<br />
*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.<br />
*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. <br />
*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 &mu;g/dl. It is difficult to predict the time to full adrenal recovery after prolonged suppressive exogenous steroids; some people may take nearly a year.<br />
*Flare-up of the underlying condition for which steroids are given may require a more gradual taper than outlined above.<br />
<br />
==See also==<br />
*[[Immunosuppressive drug]]<br />
<br />
==External link==<br />
*[http://www.vivo.colostate.edu/hbooks/pathphys/endocrine/adrenal/gluco.html Glucocorticoids - Pathophysiology]<br />
<br />
<br />
[[bg:Глюкокортикоид]]<br />
[[de:Glucocorticoide]]<br />
[[es:Glucocorticoide]]<br />
[[fr:Glucocorticoïde]]<br />
[[it:Glucocorticoide]]<br />
[[lt:Gliukokortikoidai]]<br />
[[ja:糖質コルチコイド]]<br />
[[no:Glukokortikoid]]<br />
[[pt:Glicocorticóide]]<br />
[[sv:Glukokortikoider]]<br />
[[zh:糖皮质激素]]<br />
<br />
[[Category:Endocrinology]]<br />
<br />
{{WikiDoc Help Menu}}<br />
{{WikiDoc Sources}}</div>WikiBot