Glucocorticoid

Glucocorticoids (or, less commonly, glucocorticosteroids) are a class of corticosteroids, which are in turn 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 of "glucose", "cortex", and "steroid", referring to its role in regulating the metabolism of glucose, its synthesis in the adrenal cortex, and its steroidal structure.

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 side effects, including adverse drug reactions. They also interfere with some of the abnormal mechanisms in cancer cells, so they are used in high doses to treat cancer. In particular, they inhibit lymphocyte proliferation, which is significant for lymphomas and leukemias. They can also lessen some 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 proteins in the nucleus (a process known as transactivation) and represses the expression of pro-inflammatory proteins in the cytosol by preventing the translocation of other transcription factors from the cytosol into the nucleus (transrepression). Glucocorticoids have numerous non-stress-related functions as well, and glucocorticoid concentrations can increase in response to pleasure or excitement. 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

thumb|450px|class=skin-invert-image|[[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:

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, 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 provides another substrate for gluconeogenesis.
• Increase in sodium retention and potassium excretion leading to hypernatremia and hypokalemia 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

thumb|class=skin-invert-image|alt=A graphical representation of the Yerkes–Dodson curve | A graphical representation of the [[Yerkes–Dodson law|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, cognition and memory. This appears to follow the curve described by Yerkes–Dodson law, as studies have shown circulating levels of glucocorticoids vs. memory performance follow an upside-down U pattern. 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-induced 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:

! 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

| –

| –

|}

{| class="wikitable"

|+Characteristics of Synthetic Glucocorticoids

!Synthetic Glucocorticoid

!Equivalent Dose (mg)

!Anti-inflammatory Activity¹

!Mineralocorticoid Activity¹

!Biological Half Life (hrs)

!References

|-

| colspan="6" |Short-to medium-acting glucocorticoids

|-

|Hydrocortisone

|20

|1

|1

|8–12

|

|-

|Cortisone

|25

|0.8

|0.8

|8–12

|

|-

|Dexamethasone

|0.75

|30

|0

|36–72

| However, corticosteroids show limited efficacy in pain relief and potential adverse events for their use in tendinopathies.

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 mg/m²/day of hydrocortisone (m² refers to body surface area (BSA), and is a measure of body size; an average man's BSA is 1.9 m²).

Therapeutic immunosuppression

Glucocorticoids cause immunosuppression, and the therapeutic component of this effect is mainly the decreases in the function and numbers of lymphocytes, including both B cells and T cells.

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.

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.

Glucocorticoids also suppress the humoral (antibody-mediated) immunity, thereby causing a humoral immune deficiency. Glucocorticoids cause 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 cause fewer T lymphocyte cells to be activated.

The effect of glucocorticoids on Fc receptor expression in immune cells is complicated. Dexamethasone decreases IFN-γ stimulated Fc gamma RI expression in neutrophils while conversely causing an increase in monocytes. Glucocorticoids may also decrease the expression of Fc receptors in macrophages, but the evidence supporting this regulation in earlier studies has been questioned. The effect of Fc receptor expression in macrophages is important since it is necessary for the phagocytosis of 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 (epithelial adhesion, 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, thus 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. In rare cases, symptoms of Radiation-induced thyroiditis has been treated with oral glucocorticoids.

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.

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.

Resistance

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 allergens), immunological phenomena that bypass glucocorticoids, pharmacokinetic disturbances (incomplete absorption or accelerated excretion or metabolism) and viral and/or bacterial respiratory infections.

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 bruising
• Negative calcium balance due to reduced intestinal calcium absorption
• Steroid-induced osteoporosis: 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; see corticosteroid-induced lipodystrophy
• Hypercortisolemia with prolonged or excessive use (also known as, exogenous Cushing's syndrome)
• Impaired memory and attention deficits 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
• Excitatory effect on central nervous system (euphoria, psychosis)
• Anovulation, irregularity of menstrual periods
• Growth failure, delayed puberty
• Increased plasma amino acids, 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 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.

Immunodeficiency

Glucocorticoids cause immunosuppression, decreasing the function and/or numbers of neutrophils, lymphocytes (including both B cells and T cells), monocytes, macrophages, and the anatomical barrier function of the skin. This suppression, if large enough, can cause manifestations of immunodeficiency, including T cell deficiency, humoral immune deficiency and neutropenia.

{|class="wikitable"

|+ Main pathogens of concern in glucocorticoid-induced immunodeficiency: