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Corticosteroid
Drug class
Cortisol (hydrocortisone), a corticosteroid with both glucocorticoid and mineralocorticoid activity and effects.
Class identifiers
SynonymsCorticoid
UseVarious
ATC codeH02
Biological targetGlucocorticoid receptor, Mineralocorticoid receptor
Chemical classSteroids
Legal status
In Wikidata

Corticosteroids are a class of steroid hormones that are produced in the adrenal cortex of vertebrates, as well as the synthetic analogues of these hormones. Two main classes of corticosteroids, glucocorticoids and mineralocorticoids, are involved in a wide range of physiological processes, including stress response, immune response, and regulation of inflammation, carbohydrate metabolism, protein catabolism, blood electrolyte levels, and behavior.[1]

Some common naturally occurring steroid hormones are cortisol (C
21H
30O
5), corticosterone (C
21H
30O
4), cortisone (C
21H
28O
5) and aldosterone (C
21H
28O
5) (cortisone and aldosterone are isomers). The main corticosteroids produced by the adrenal cortex are cortisol and aldosterone.[1]

The etymology of the cortico- part of the name refers to the adrenal cortex, which makes these steroid hormones. Thus a corticosteroid is a "cortex steroid".

Classes

[edit]
Cortisol
Cortisone
Corticosterone
Aldosterone

Medical uses

[edit]

Synthetic pharmaceutical drugs with corticosteroid-like effects are used in a variety of conditions, ranging from hematological neoplasms[3] to brain tumors or skin diseases. Dexamethasone and its derivatives are almost pure glucocorticoids, while prednisone and its derivatives have some mineralocorticoid action in addition to the glucocorticoid effect. Fludrocortisone (Florinef) is a synthetic mineralocorticoid. Hydrocortisone (cortisol) is typically used for replacement therapy, e.g. for adrenal insufficiency and congenital adrenal hyperplasia.[citation needed]

Medical conditions treated with systemic corticosteroids:[2][4]

Topical formulations are also available for the skin, eyes (uveitis), lungs (asthma), nose (rhinitis), and bowels. Corticosteroids are also used supportively to prevent nausea, often in combination with 5-HT3 antagonists (e.g., ondansetron).[citation needed]

Typical undesired effects of glucocorticoids present quite uniformly as drug-induced Cushing's syndrome. Typical mineralocorticoid side-effects are hypertension (abnormally high blood pressure), steroid induced diabetes mellitus, psychosis, poor sleep, hypokalemia (low potassium levels in the blood), hypernatremia (high sodium levels in the blood) without causing peripheral edema, metabolic alkalosis and connective tissue weakness.[5] Wound healing or ulcer formation may be inhibited by the immunosuppressive effects.[citation needed]

A variety of steroid medications, from anti-allergy nasal sprays (Nasonex, Flonase) to topical skin creams, to eye drops (Tobradex), to prednisone have been implicated in the development of central serous retinopathy (CSR).[6][7]

Corticosteroids have been widely used in treating people with traumatic brain injury.[8] A systematic review identified 20 randomised controlled trials and included 12,303 participants, then compared patients who received corticosteroids with patients who received no treatment. The authors recommended people with traumatic head injury should not be routinely treated with corticosteroids.[9]

Pharmacology

[edit]

Corticosteroids act as agonists of the glucocorticoid receptor and/or the mineralocorticoid receptor.[citation needed]

In addition to their corticosteroid activity, some corticosteroids may have some progestogenic activity and may produce sex-related side effects.[10][11][12][13]

Pharmacogenetics

[edit]

Asthma

[edit]

Patients' response to inhaled corticosteroids has some basis in genetic variations. Two genes of interest are CHRH1 (corticotropin-releasing hormone receptor 1) and TBX21 (transcription factor T-bet). Both genes display some degree of polymorphic variation in humans, which may explain how some patients respond better to inhaled corticosteroid therapy than others.[14][15] However, not all asthma patients respond to corticosteroids and large sub groups of asthma patients are corticosteroid resistant.[16]

A study funded by the Patient-Centered Outcomes Research Institute of children and teens with mild persistent asthma found that using the control inhaler as needed worked the same as daily use in improving asthma control, number of asthma flares, how well the lungs work, and quality of life. Children and teens using the inhaler as needed used about one-fourth the amount of corticosteroid medicine as children and teens using it daily.[17][18]

Adverse effects

[edit]
Lower arm of a 47-year-old female showing skin damage caused by topical corticosteroid use.

Use of corticosteroids has numerous side-effects, some of which may be severe:

  • Severe amoebic colitis: Fulminant amoebic colitis is associated with high case fatality and can occur in patients infected with the parasite Entamoeba histolytica after exposure to corticosteroid medications.[19]
  • Neuropsychiatric: steroid psychosis,[20] and anxiety,[21] depression. Therapeutic doses may cause a feeling of artificial well-being ("steroid euphoria").[22] The neuropsychiatric effects are partly mediated by sensitization of the body to the actions of adrenaline. Therapeutically, the bulk of corticosteroid dose is given in the morning to mimic the body's diurnal rhythm; if given at night, the feeling of being energized will interfere with sleep. An extensive review is provided by Flores and Gumina.[23]
  • Cardiovascular: Corticosteroids can cause sodium retention through a direct action on the kidney, in a manner analogous to the mineralocorticoid aldosterone. This can result in fluid retention and hypertension.
  • Metabolic: Corticosteroids cause a movement of body fat to the face and torso, resulting in "moon face", "buffalo hump", and "pot belly" or "beer belly", and cause movement of body fat away from the limbs. This has been termed corticosteroid-induced lipodystrophy. Due to the diversion of amino-acids to glucose, they are considered anti-anabolic, and long term therapy can cause muscle wasting (muscle atrophy).[24] Besides muscle atrophy, steroid myopathy includes muscle pains (myalgias), muscle weakness (typically of the proximal muscles), serum creatine kinase normal, EMG myopathic, and some have type II (fast-twitch/glycolytic) fibre atrophy.[25]
  • Endocrine: By increasing the production of glucose from amino-acid breakdown and opposing the action of insulin, corticosteroids can cause hyperglycemia,[26] insulin resistance and diabetes mellitus.[27]
  • Skeletal: Steroid-induced osteoporosis may be a side-effect of long-term corticosteroid use.[28][29][30] Use of inhaled corticosteroids among children with asthma may result in decreased height.[31]
  • Gastro-intestinal: While cases of colitis have been reported, corticosteroids are often prescribed when the colitis, although due to suppression of the immune response to pathogens, should be considered only after ruling out infection or microbe/fungal overgrowth in the gastrointestinal tract. While the evidence for corticosteroids causing peptic ulceration is relatively poor except for high doses taken for over a month,[32] the majority of doctors as of 2010 still believe this is the case, and would consider protective prophylactic measures.[33]
  • Eyes: chronic use may predispose to cataract and glaucoma. Clinical and experimental evidence indicates that corticosteroids can cause permanent eye damage by inducing central serous retinopathy (CSR, also known as central serous chorioretinopathy, CSC).[34] This should be borne in mind when treating patients with optic neuritis. There is experimental and clinical evidence that, at least in optic neuritis speed of treatment initiation is important.[35]
  • Vulnerability to infection: By suppressing immune reactions (which is one of the main reasons for their use in allergies), steroids may cause infections to flare up, notably candidiasis.[36]
  • Pregnancy: Corticosteroids have a low but significant teratogenic effect, causing a few birth defects per 1,000 pregnant women treated. Corticosteroids are therefore contraindicated in pregnancy.[37]
  • Habituation: Topical steroid addiction (TSA) or red burning skin has been reported in long-term users of topical steroids (users who applied topical steroids to their skin over a period of weeks, months, or years).[38][39] TSA is characterised by uncontrollable, spreading dermatitis and worsening skin inflammation which requires a stronger topical steroid to get the same result as the first prescription. When topical steroid medication is lost, the skin experiences redness, burning, itching, hot skin, swelling, and/or oozing for a length of time. This is also called 'red skin syndrome' or 'topical steroid withdrawal' (TSW). After the withdrawal period is over the atopic dermatitis can cease or is less severe than it was before.[40]
  • In children the short term use of steroids by mouth increases the risk of vomiting, behavioral changes, and sleeping problems.[41]
  • Dysphonia: Inhaled corticosteroids are used for treatment of asthma as a standard treatment. This can cause local adverse effects like vocal cord dysfunction.[42]

Biosynthesis

[edit]
Steroidogenesis, including corticosteroid biosynthesis.

The corticosteroids are synthesized from cholesterol within the adrenal cortex.[1] Most steroidogenic reactions are catalysed by enzymes of the cytochrome P450 family. They are located within the mitochondria and require adrenodoxin as a cofactor (except 21-hydroxylase and 17α-hydroxylase).[citation needed]

Aldosterone and corticosterone share the first part of their biosynthetic pathway. The last part is mediated either by the aldosterone synthase (for aldosterone) or by the 11β-hydroxylase (for corticosterone). These enzymes are nearly identical (they share 11β-hydroxylation and 18-hydroxylation functions), but aldosterone synthase is also able to perform an 18-oxidation. Moreover, aldosterone synthase is found within the zona glomerulosa at the outer edge of the adrenal cortex; 11β-hydroxylase is found in the zona fasciculata and zona glomerulosa.[citation needed]

Classification

[edit]

By chemical structure

[edit]

In general, corticosteroids are grouped into four classes, based on chemical structure. Allergic reactions to one member of a class typically indicate an intolerance of all members of the class. This is known as the "Coopman classification".[43][44]

The highlighted steroids are often used in the screening of allergies to topical steroids.[45]

Group A – Hydrocortisone type

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Hydrocortisone, hydrocortisone acetate, cortisone acetate, tixocortol pivalate, prednisolone, methylprednisolone, and prednisone.

[edit]

Amcinonide, budesonide, desonide, fluocinolone acetonide, fluocinonide, halcinonide, triamcinolone acetonide, and Deflazacort (O-isopropylidene derivative)

Group C – Betamethasone type

[edit]

Beclometasone, betamethasone, dexamethasone, fluocortolone, halometasone, and mometasone.

Group D – Esters

[edit]
Group D1 – Halogenated (less labile)
[edit]

Alclometasone dipropionate, betamethasone dipropionate, betamethasone valerate, clobetasol propionate, clobetasone butyrate, fluprednidene acetate, and mometasone furoate.

Group D2 – Labile prodrug esters
[edit]

Ciclesonide, cortisone acetate, hydrocortisone aceponate, hydrocortisone acetate, hydrocortisone buteprate, hydrocortisone butyrate, hydrocortisone valerate, prednicarbate, and tixocortol pivalate.

By route of administration

[edit]

Topical steroids

[edit]
Main article: Topical steroid

For use topically on the skin, eye, and mucous membranes.

Topical corticosteroids are divided in potency classes I to IV in most countries (A to D in Japan). Seven categories are used in the United States to determine the level of potency of any given topical corticosteroid.

Inhaled steroids

[edit]

For nasal mucosa, sinuses, bronchi, and lungs.[46]

This group includes:

There also exist certain combination preparations such as Advair Diskus in the United States, containing fluticasone propionate and salmeterol (a long-acting bronchodilator), and Symbicort, containing budesonide and formoterol fumarate dihydrate (another long-acting bronchodilator).[47] They are both approved for use in children over 12 years old.

Oral forms

[edit]

Such as prednisone, prednisolone, methylprednisolone, or dexamethasone.[48]

Systemic forms

[edit]

Available in injectables for intravenous and parenteral routes.[48]

History

[edit]
Introduction of early corticosteroids[49][50][51]
Corticosteroid Introduced
Cortisone 1948
Hydrocortisone 1951
Fludrocortisone acetate 1954[52]
Prednisolone 1955
Prednisone 1955[53]
Methylprednisolone 1956
Triamcinolone 1956
Dexamethasone 1958
Betamethasone 1958
Triamcinolone acetonide 1958
Fluorometholone 1959
Deflazacort 1969[54]

Tadeusz Reichstein, Edward Calvin Kendall, and Philip Showalter Hench were awarded the Nobel Prize for Physiology and Medicine in 1950 for their work on hormones of the adrenal cortex, which culminated in the isolation of cortisone.[55]

Initially hailed as a miracle cure and liberally prescribed during the 1950s, steroid treatment brought about adverse events of such a magnitude that the next major category of anti-inflammatory drugs, the nonsteroidal anti-inflammatory drugs (NSAIDs), was so named in order to demarcate from the opprobrium.[56]

Lewis Sarett of Merck & Co. was the first to synthesize cortisone, using a 36-step process that started with deoxycholic acid, which was extracted from ox bile.[57] The low efficiency of converting deoxycholic acid into cortisone led to a cost of US$200 per gram in 1947. Russell Marker, at Syntex, discovered a much cheaper and more convenient starting material, diosgenin from wild Mexican yams. His conversion of diosgenin into progesterone by a four-step process now known as Marker degradation was an important step in mass production of all steroidal hormones, including cortisone and chemicals used in hormonal contraception.[58]

In 1952, D.H. Peterson and H.C. Murray of Upjohn developed a process that used Rhizopus mold to oxidize progesterone into a compound that was readily converted to cortisone.[59] The ability to cheaply synthesize large quantities of cortisone from the diosgenin in yams resulted in a rapid drop in price to US$6 per gram[when?], falling to $0.46 per gram by 1980. Percy Julian's research also aided progress in the field.[60] The exact nature of cortisone's anti-inflammatory action remained a mystery for years after, however, until the leukocyte adhesion cascade and the role of phospholipase A2 in the production of prostaglandins and leukotrienes was fully understood in the early 1980s.[citation needed]

Corticosteroids were voted Allergen of the Year in 2005 by the American Contact Dermatitis Society.[61]

See also

[edit]

References

[edit]
Revisions and contributorsEdit on WikipediaRead on Wikipedia

Corticosteroid

View on Grokipedia
from Grokipedia
Corticosteroids are a class of hormones produced by the , primarily consisting of glucocorticoids (such as in humans) and mineralocorticoids (such as aldosterone), which play essential roles in regulating , immune function, balance, and stress responses in vertebrates. In , synthetic corticosteroids mimic these natural hormones and are among the most widely prescribed medications, valued for their potent , immunosuppressive, and anti-allergic properties, with a global market of approximately $5.9 billion as of 2025. Physiologically, glucocorticoids influence carbohydrate, protein, and fat metabolism, promote , and suppress by modulating immune cell activity and production, while mineralocorticoids maintain sodium and through renal transport, ensuring and regulation. These hormones are secreted in response to (ACTH) from the , exhibiting diurnal rhythms that peak in the morning to support daily and stress . Disruptions in corticosteroid production, such as in , can lead to life-threatening imbalances, underscoring their critical role in whole-body . In clinical practice, corticosteroids are administered via multiple routes—including oral, intravenous, inhaled, topical, and intra-articular—to treat a broad spectrum of conditions, from acute allergic reactions and exacerbations to chronic autoimmune disorders like and . Synthetic glucocorticoids, which dominate therapeutic use, are classified by their relative potency and duration of action (short-, intermediate-, or long-acting), with examples including (low potency, short-acting) and dexamethasone (high potency, long-acting); activity is less emphasized in most formulations but present in agents like for . Their versatility extends to to prevent graft rejection, management of , and dermatologic conditions via topical applications, though long-term use requires careful monitoring due to potential systemic effects. The mechanisms of action involve both genomic and nongenomic pathways: genomically, corticosteroids bind intracellular receptors, translocate to the nucleus, and alter gene transcription to inhibit proinflammatory mediators like and promote anti-inflammatory proteins; nongenomically, they exert rapid effects by interacting with cell membranes to suppress and pathways. This dual action enables precise modulation of immune and inflammatory responses, making corticosteroids foundational in modern despite ongoing into minimizing side effects through targeted delivery systems.

Biological Role

Natural Corticosteroids

Corticosteroids are a class of steroid hormones produced endogenously in the adrenal cortex of vertebrates. Glucocorticoids are synthesized primarily in the zona fasciculata layer, while mineralocorticoids originate from the zona glomerulosa layer. The principal natural glucocorticoid in humans is cortisol, also known as hydrocortisone, which serves as a derivative of pregn-4-ene-3,20-dione with hydroxyl groups at positions 11β, 17α, and 21. Basal secretion of cortisol typically ranges from 5 to 25 mg per day in adults, exhibiting a diurnal rhythm with peak levels in the early morning and lower levels at night; under stress conditions, production can increase substantially to meet physiological demands. The primary natural mineralocorticoid is aldosterone, characterized by the structure 11β,21-dihydroxy-3,20-dioxopregn-4-en-18-al, which plays a crucial role in regulating electrolyte balance through promoting renal sodium retention and potassium excretion. Secretion of these natural corticosteroids is tightly regulated by the hypothalamic-pituitary-adrenal (HPA) axis, where corticotropin-releasing hormone (CRH) from the hypothalamus stimulates the anterior pituitary to release adrenocorticotropic hormone (ACTH), which in turn prompts the adrenal cortex to produce and secrete glucocorticoids and mineralocorticoids. This regulatory mechanism exhibits evolutionary conservation across vertebrates, from ancient fishes to mammals, underscoring its fundamental role in stress responses and homeostasis.

Biosynthesis and Regulation

Corticosteroids are synthesized in the through a series of enzymatic reactions starting from , a process known as steroidogenesis. The initial and rate-limiting step involves the conversion of to by the mitochondrial enzyme (CYP11A1), which requires cholesterol transport into mitochondria facilitated by (StAR). then serves as the precursor for both glucocorticoids and mineralocorticoids, with the pathway diverging based on specific hydroxylations. In the mineralocorticoid pathway, is isomerized to progesterone by (3β-HSD), followed by 21-hydroxylation to via (CYP21A2). Subsequent 11β-hydroxylation by aldosterone synthase (CYP11B2) yields , and further oxidation of the aldehyde group at C-18 produces aldosterone, primarily in the . For glucocorticoids, the pathway branches after : 17α-hydroxylation by 17α-hydroxylase () leads to 17α-hydroxypregnenolone, which is converted to via 3β-HSD. This undergoes 21-hydroxylation to (CYP21A2), and final 11β-hydroxylation by 11β-hydroxylase (CYP11B1) in the forms . The production of corticosteroids is tightly regulated by the hypothalamic-pituitary-adrenal (HPA) axis to maintain . (CRH) from the stimulates (ACTH) release from the , which in turn promotes adrenal steroidogenesis by upregulating and key enzymes like CYP11A1 and CYP11B1. A loop operates whereby binds to receptors in the and pituitary, inhibiting CRH and ACTH secretion to prevent overproduction. This feedback is modulated by ultradian and circadian rhythms, with levels exhibiting a daily driven by the ; peak concentrations occur in the early morning (around 6-8 a.m.), declining to a at , ensuring rhythmic to daily cycles. During stress, such as or trauma, the HPA axis activates rapidly via neural inputs and CRH surges, elevating ACTH and thus to mobilize energy reserves and suppress . Defects in the biosynthetic pathway can lead to disorders like (CAH), most commonly due to (CYP21A2) deficiency, which impairs and aldosterone synthesis, causing precursor accumulation and androgen excess. This autosomal recessive condition has a global incidence of approximately 1 in 15,000 births for the classical form, resulting in salt-wasting crises in severe cases or in milder ones. Other enzyme deficiencies, such as in CYP11B1, similarly disrupt production and highlight the pathway's vulnerability to genetic mutations.

Classification

By Molecular Structure

Synthetic corticosteroids are derived from the skeleton, a C21 structure comprising four fused rings—three six-membered (A, B, C) and one five-membered (D)—with key functional groups including a Δ⁴-3-keto moiety in ring A and 17α,21-dihydroxy substitutions in ring D, which underpin their and activities. These modifications to the core backbone allow for tailored pharmacological properties, such as potency and stability, and form the basis for structural into groups A through D, originally proposed to predict in but also highlighting structure-activity relationships. Group A corticosteroids, exemplified by and , feature minimal alterations to the basic framework, lacking significant substitutions at positions 16 or 17 beyond short-chain esters at C21, which results in relatively low potency and limited topical efficacy compared to more modified analogs. These compounds closely mimic natural and are often used in mild formulations due to their reduced receptor affinity. In contrast, Group B includes acetonide derivatives, characterized by a cyclic 16,17-ketal () formation that protects the dihydroxy groups and enhances for improved penetration and stability in topical applications; representative examples are and , which exhibit moderate potency suitable for dermatological use. This structural feature minimizes and extends duration of action on the skin surface. Group C corticosteroids, such as betamethasone and dexamethasone, incorporate a 16α-methyl group often combined with 9α-fluorination, dramatically increasing selectivity and potency while preserving the core Δ⁴-3-keto and 17α,21-dihydroxy elements; these modifications enable high receptor binding affinity, making them effective for systemic and potent topical therapies. Group D comprises esterified prodrugs designed to improve and in formulations, subdivided into D1 (e.g., betamethasone dipropionate and , with 16-methyl, 9α-fluoro, and C17/C21 long-chain esters for superpotent activity) and D2 (e.g., and , lacking 16-methylation but featuring C17 esters for moderate potency). These esters are hydrolyzed to active forms, optimizing delivery without altering the intrinsic activity. Key structure-activity trends across these groups reveal that 9α-fluorination enhances potency by stabilizing the molecule and improving binding to the , as seen in dexamethasone's up to 30-fold greater activity relative to . Likewise, 16α-methylation reduces effects by sterically hindering activation of the while maintaining or augmenting efficacy, a modification pivotal in shifting therapeutic profiles toward pure .

By Physiological Function

Corticosteroids are classified by physiological function into two primary categories: glucocorticoids and mineralocorticoids, based on their distinct effects on , , and . This functional division reflects their binding to specific receptors and the resulting downstream physiological impacts, with synthetic analogs often engineered for selectivity. Glucocorticoids primarily exert anti-inflammatory and immunosuppressive effects by modulating gene transcription through the (GR). They bind to GR in the , forming a complex that translocates to the nucleus, where it promotes of anti-inflammatory genes (e.g., annexin-1) and transrepression of pro-inflammatory transcription factors like . Natural examples include (), while synthetic ones such as and dexamethasone are commonly used; relative glucocorticoid potency is indexed to (assigned 1), with at 4 times and dexamethasone at 25-30 times higher. These agents also influence carbohydrate, protein, and fat metabolism, promoting and to maintain blood glucose during stress. Mineralocorticoids regulate and by promoting sodium retention and primarily in the renal distal tubules via the (MR). They activate MR to increase expression of epithelial sodium channels (ENaC) and Na+/K+-ATPase, enhancing sodium reabsorption and water retention while facilitating secretion. The principal natural mineralocorticoid is aldosterone, with synthetic used therapeutically; aldosterone exhibits negligible activity but approximately 400 times the potency of , while demonstrates only about one-thousandth of aldosterone's effective activity due to enzymatic inactivation by 11β-hydroxysteroid dehydrogenase type 2 (11β-HSD2) in target tissues. There is notable overlap in receptor binding, as both glucocorticoids and mineralocorticoids can interact with and GR, but has equal affinity for aldosterone and ex vivo. Most synthetic corticosteroids are designed with structural modifications (e.g., 9α-fluorination in dexamethasone) to enhance GR selectivity and minimize activation, thereby reducing unwanted mineralocorticoid side effects like and . In clinical practice, glucocorticoids dominate therapeutic applications due to their broad anti-inflammatory and immunosuppressive roles, whereas mineralocorticoids are primarily reserved for replacement therapy in conditions like to restore . This functional classification guides drug selection to optimize efficacy while limiting off-target effects.

By Potency and Duration of Action

Corticosteroids are classified by potency relative to in assays, such as the cotton pellet model, which evaluates inhibition of formation in animal models. Low-potency agents, like , have a relative potency of 1x and are suitable for mild conditions requiring minimal suppression. Medium-potency corticosteroids, such as (4x potency), provide balanced efficacy for moderate inflammation. High-potency options, including dexamethasone (25x potency), offer stronger effects for severe cases but increase side effect risks. For topical use, super-high potency agents like (600x relative to 1% in vasoconstrictor assays) are reserved for resistant dermatological conditions. Duration of action is categorized by biological half-life, reflecting hypothalamic-pituitary-adrenal axis suppression rather than plasma clearance. Short-acting corticosteroids, such as (half-life 8-12 hours), require more frequent dosing for sustained effects. Intermediate-acting agents, like prednisolone (half-life 18-36 hours), support once- or twice-daily regimens in chronic therapy. Long-acting formulations, exemplified by dexamethasone (half-life 36-54 hours), allow for less frequent administration but prolong recovery of endogenous production. Potency and duration are influenced by pharmacokinetic factors, including protein binding to corticosteroid-binding globulin (CBG), where approximately 90% of is bound, extending circulation time for highly bound analogs. Metabolism by (11β-HSD) enzymes, particularly type 1 and 2, interconverts active to inactive , modulating local and systemic availability and thus effective duration. Route of administration alters effective potency due to differences in absorption and ; for instance, 1 mg of betamethasone administered topically may provide effects equivalent to 5 mg of oral in targeted .
CorticosteroidRelative Potency (vs. )Duration of ActionBiological Half-Life (hours)
1Short-acting8-12
4Intermediate-acting12-36
5Intermediate-acting12-36
Dexamethasone25Long-acting36-54
Betamethasone25Long-acting36-54
(topical)600Variable (topical)N/A

Pharmacology

Mechanism of Action

Corticosteroids exert their physiological and therapeutic effects primarily through binding to two main types of intracellular receptors: the (GR, encoded by NR3C1) and the (MR, encoded by NR3C2). The GR mediates anti-inflammatory and immunosuppressive actions, while the MR primarily regulates and , such as sodium retention and excretion. Both receptors belong to the superfamily of ligand-activated transcription factors, which upon activation modulate in target cells. The classical mechanism of action involves the genomic pathway, where corticosteroids diffuse across the cell membrane and bind to the GR in the cytoplasm, inducing a conformational change that releases chaperone proteins like heat shock protein 90 (HSP90). The ligand-bound GR then homodimerizes and translocates to the nucleus, where it binds to specific DNA sequences known as glucocorticoid response elements (GREs), typically palindromic motifs like GGAACAnnnTGTTCT. This binding facilitates transactivation by recruiting co-activators to promote transcription of target genes, such as ANXA1 encoding lipocortin-1 (annexin A1), which inhibits phospholipase A2 (PLA2) and thereby reduces arachidonic acid release and subsequent prostaglandin synthesis. Alternatively, GR can mediate transrepression by interacting with pro-inflammatory transcription factors without direct DNA binding, suppressing genes involved in inflammation. In addition to these delayed genomic effects, corticosteroids produce rapid non-genomic actions, occurring within seconds to minutes, that do not require gene transcription or protein synthesis. These effects are mediated through membrane-associated GR (mGR) or interactions with cytosolic signaling pathways, such as of mitogen-activated protein kinases (MAPK), including ERK1/2, p38, and JNK. For instance, in vascular cells, dexamethasone rapidly enhances norepinephrine-induced within 10 minutes via Rho-kinase and increased myosin light chain , independent of classical GR nuclear translocation. A key aspect of corticosteroid anti-inflammatory activity involves the inhibition of transcription factors and activator protein-1 (AP-1). The GR tethers to or directly interacts with and AP-1 subunits (e.g., p65 and c-Jun), preventing their binding to DNA and thereby repressing transcription of pro-inflammatory genes, including those encoding interleukin-1 (IL-1) and tumor necrosis factor-alpha (TNF-α). This mechanism significantly reduces production and immune cell activation. Additionally, GR can induce the expression of , an inhibitor of , further amplifying this suppressive effect. Synthetic corticosteroids, such as dexamethasone, differ from natural ones like in their receptor interactions; they exhibit higher affinity for the GR due to structural modifications, leading to enhanced transrepression of inflammatory genes with potentially fewer mineralocorticoid-like side effects. Newer synthetic glucocorticoids, such as vamorolone (approved in 2023), are designed as dissociated steroids that preferentially induce transrepression while minimizing , potentially reducing metabolic side effects. Unlike natural glucocorticoids, which bind to corticosteroid-binding globulin (CBG) and are inactivated by type 2 (11β-HSD2) in tissues like the , synthetic analogs resist these processes, resulting in prolonged and more potent effects.

Pharmacokinetics

Corticosteroids exhibit varied absorption profiles depending on the and formulation. Orally administered corticosteroids, such as , demonstrate ranging from 70% to 80%, with rapid absorption peaking at approximately 2 hours for immediate-release forms; administration with food or milk is recommended to mitigate gastrointestinal upset, though it may slightly delay absorption. Topical corticosteroids' percutaneous is influenced by the , with ointments promoting greater penetration due to their occlusive properties compared to creams, which are less absorbent and suited for non-occlusive applications; factors like and occlusion further enhance systemic uptake. Inhaled corticosteroids achieve rapid onset through direct absorption via the , minimizing systemic exposure while targeting respiratory tissues. Following absorption, corticosteroids are widely distributed throughout the body. They exhibit high , typically 90% to 95%, primarily to and corticosteroid-binding (CBG), though binding affinity varies by agent—hydrocortisone and prednisolone show saturable binding to CBG, while dexamethasone binds mainly to . The volume of distribution ranges from 0.5 to 1 L/kg for and up to 1 to 2 L/kg for synthetic analogs like , reflecting their and tissue penetration; unbound fractions, such as for prednisolone, can reach 4 to 5 L/kg in certain conditions. Due to their non-ionized, lipophilic nature, corticosteroids readily cross the blood-brain barrier, enabling effects. Metabolism of corticosteroids occurs predominantly in the liver via cytochrome P450 3A4 (CYP3A4) enzymes, leading to inactivation and increased water solubility for excretion. Prodrugs like prednisone are rapidly converted to their active forms, such as prednisolone, within 30 minutes of intravenous administration or via hepatic reduction. Additionally, 11β-hydroxysteroid dehydrogenase enzymes (11β-HSD1 and 11β-HSD2) facilitate interconversion between inactive cortisone and active cortisol, regulating local glucocorticoid activity in tissues like the kidney and liver. Excretion primarily occurs renally, with inactive metabolites conjugated as glucuronides or sulfates and eliminated in urine, alongside minor biliary clearance. Half-lives vary significantly: endogenous has a plasma half-life of 2 to 3 hours, while synthetic corticosteroids exhibit longer durations, such as 3 to 4 hours for and prednisolone in adults, extending to 4 hours for dexamethasone; biological half-lives are notably prolonged, ranging from 12 hours for to 18 to 54 hours for longer-acting agents. Formulation plays a key role in modulating , particularly for sustained-release options. Depot injections, such as acetate, provide prolonged release over days to weeks by forming insoluble suspensions at the injection site, thereby extending duration and reducing dosing frequency compared to immediate-release forms.

Medical Uses

Anti-inflammatory and Immunosuppressive Applications

Corticosteroids exert potent and immunosuppressive effects, making them a cornerstone in managing acute and chronic immune-mediated disorders. By binding to receptors, they translocate to the nucleus and inhibit pro-inflammatory pathways, including , leading to reduced production and immune cell activation. This mechanism underpins their role in suppressing excessive immune responses in autoimmune diseases and preventing graft rejection in transplantation. Clinical applications emphasize high efficacy in rapidly controlling flares while balancing risks through tailored dosing. In autoimmune diseases, high-dose intravenous is a standard intervention for acute exacerbations of systemic lupus erythematosus (SLE). For lupus flares, regimens typically involve 500–1000 mg/day for 3–5 days, inducing rapid remission and allowing subsequent oral tapering to 5–20 mg/day. This approach has demonstrated effectiveness in controlling moderate to severe flares, with lower cumulative doses preferred to minimize toxicity. Similarly, in , high-dose intravenous at 1 g/day for 3–5 days accelerates recovery from relapses by hastening resolution of neurological symptoms, outperforming in randomized trials. Organ transplantation relies on corticosteroids for perioperative to prevent acute rejection. is commonly initiated at 1 mg/kg/day intravenously or orally immediately post-transplant, followed by a taper to maintenance doses of 5–10 mg/day within weeks. This strategy, often combined with inhibitors and antimetabolites, achieves graft survival rates exceeding 90% at one year in recipients, with tapering protocols reducing long-term steroid exposure. For , oral is preferred for mild active due to its high topical activity and low systemic . The standard dose is 9 mg/day for up to 8 weeks, targeting ileocolonic involvement with remission induction rates comparable to systemic prednisolone (around 50–60%) but with significantly fewer glucocorticoid-related adverse effects. Targeted-release formulations enhance delivery to inflamed mucosa, making it suitable for maintenance in select cases. In , low-dose (5–10 mg/day) functions as bridge therapy to provide rapid symptom relief while disease-modifying antirheumatic drugs like take effect. This short-term use improves pain and function in early disease, with meta-analyses showing superior outcomes over in reducing disease activity scores. Long-term low-dose regimens are avoided when possible to limit complications. Dosing strategies for severe cases incorporate pulse therapy, where intravenous boluses (e.g., 500–1000 mg/day for 3 days) are used to achieve swift in refractory autoimmune conditions. This intermittent high-dose approach minimizes cumulative exposure compared to continuous therapy. Steroid-sparing agents, such as (7.5–25 mg/week), are routinely added to enable dose reduction or discontinuation of corticosteroids, preserving efficacy while mitigating risks like ; clinical trials confirm 's role in halving requirements in various autoimmune settings. Efficacy in acute gout is supported by meta-analyses of randomized trials, where oral prednisolone (30–35 mg/day for 5–10 days) yields pain reduction comparable to NSAIDs, with over 70% of patients achieving at least 50% improvement in pain scores by day 4 and similar joint tenderness resolution rates. This positions prednisolone as a viable alternative, particularly in patients with contraindications to other therapies.

Endocrine and Metabolic Disorders

Corticosteroids play a critical role in replacement therapy for primary adrenal insufficiency, also known as , where the adrenal glands fail to produce adequate glucocorticoids and mineralocorticoids. Treatment typically involves at a total daily dose of 15-25 mg, administered in divided doses to mimic the body's natural , such as 10 mg upon waking, 5 mg at midday, and 5 mg in the evening. In addition, is prescribed at 0.05-0.2 mg daily to replace aldosterone and manage sodium retention, , and balance, with doses adjusted based on clinical response including . In secondary adrenal insufficiency, resulting from pituitary or hypothalamic dysfunction, replacement is required without supplementation, as the remains intact and aldosterone production is preserved. or alternatives like are used, often starting with a taper regimen such as dexamethasone post-pituitary to assess recovery of the hypothalamic-pituitary-adrenal axis. For example, a common approach involves initial high-dose dexamethasone followed by gradual reduction to physiologic levels, monitoring for signs of under- or over-replacement. Congenital adrenal hyperplasia (CAH), particularly due to deficiency, necessitates lifelong therapy to suppress excessive adrenal production driven by elevated (ACTH). is the preferred agent, dosed at 10-15 mg/m² per day in children, divided into three doses, with adjustments guided by monitoring 17-hydroxyprogesterone levels to achieve suppression without inducing iatrogenic . In adults, doses are typically 15-25 mg daily, tailored to minimize androgen excess while preserving growth and . Management of primarily involves surgical resection of the cortisol-secreting tumor, but postoperative is common due to chronic suppression of the adrenal glands, requiring temporary replacement. A tapering regimen, such as starting at 20-30 mg daily and reducing over weeks to months, is used until recovery, confirmed by low-dose ACTH stimulation testing. Adjunctive therapies like or may be employed preoperatively to block excess production and normalize levels prior to . Monitoring the adequacy of corticosteroid replacement involves periodic ACTH stimulation tests, where a standard dose of cosyntropin is administered, and response is measured; a peak below 18-20 mcg/dL indicates insufficient replacement. During acute illness or stress, doses should be tripled from the basal amount— for instance, increasing to 75-100 mg daily in divided doses—to prevent .

Respiratory and Allergic Conditions

Corticosteroids play a central role in managing respiratory and allergic conditions by reducing airway inflammation and modulating immune responses. Inhaled corticosteroids (ICS) are particularly effective for chronic airway diseases like and (COPD), delivering targeted therapy to minimize systemic exposure. Systemic and topical formulations address acute allergic reactions and skin manifestations, respectively, with dosing tailored to severity and patient age to optimize efficacy while limiting risks. In , ICS such as fluticasone serve as first-line controller for persistent cases, suppressing airway and improving symptom control. Recommended daily doses range from 100-250 μg for low-intensity needs to 250-500 μg for medium-intensity maintenance in adults and adolescents, often administered via or . According to GINA guidelines, regular ICS use reduces exacerbation rates by up to 50-60% compared to short-acting beta-agonist monotherapy alone, with evidence from randomized trials showing reductions of 0.46 (95% CI, 0.34-0.62). Low-dose ICS-formoterol as maintenance and reliever further decreases severe exacerbations by 64% versus as-needed , making it the preferred regimen for adults and adolescents. For COPD, ICS are reserved for patients with frequent s (≥2 per year or ≥1 leading to hospitalization), typically in combination with long-acting beta-agonists (LABA) like /formoterol for those in Group E. This dual therapy improves lung function and reduces exacerbation frequency by 25% compared to LABA monotherapy, with greatest benefits in patients with blood counts ≥300 cells/μL. Acute flares are managed with oral bursts at 40 mg daily for 5 days, which shortens recovery time and lowers relapse risk without requiring tapering for such short durations, as supported by the REDUCE . Nebulized may serve as an alternative in select cases, though oral routes are equally effective. Allergic conditions benefit from corticosteroids as adjuncts to primary interventions. In anaphylaxis, intramuscular epinephrine (0.01 mg/kg, maximum 0.3-0.5 mg) is administered first, followed by oral at 0.5-1 mg/kg daily for 2-5 days to prevent biphasic reactions, though routine use is not always recommended due to limited evidence for shortening recovery. For cases persisting after multiple epinephrine doses, intravenous dexamethasone at 0.3 mg/kg may be considered to further suppress . In allergic skin conditions like eczema, low-potency topical 1% cream is applied once or twice daily to affected areas, covering mild and pruritus in non-facial regions for up to 2-4 weeks, with fingertip units guiding application to avoid overuse. Pediatric applications emphasize minimizing long-term risks, with lower ICS doses recommended for to limit growth suppression, which studies show as a small, dose-dependent effect (e.g., 0.58 cm reduction in the first year with 400 μg/day). For children aged 6-11 years, low doses start at 50-100 μg/day fluticasone, escalating only if needed, while those ≤5 years begin at 50 μg/day via pressurized . Spacer devices enhance delivery efficiency and reduce oropharyngeal deposition, thereby lowering systemic absorption and potential growth impacts when used with ICS.

Adverse Effects

Short-term Side Effects

Short-term use of corticosteroids, commonly prescribed orally for durations of 7-10 days, can lead to a range of transient adverse effects that are generally mild, reversible, and less severe than those associated with prolonged therapy. These effects arise from the drugs' potent influence on metabolic, gastrointestinal, neurological, and , often manifesting within days of initiation. While typically reversible, they necessitate careful monitoring to mitigate discomfort and complications during therapy. Common manifestations include increased appetite and moderate weight gain, insomnia, mood alterations (such as euphoria, irritability, or aggressiveness), fluid retention with possible , and gastrointestinal disturbances (e.g., stomach pain). Severe long-term complications, such as osteoporosis, steroid-induced diabetes, or muscle wasting, are rare following such brief courses. However, even short-term use has been associated with increased risks of serious adverse events, including sepsis, venous thromboembolism, and fractures. Population-based studies have reported incidence rate ratios of approximately 5.3 for sepsis, 3.3 for venous thromboembolism, and 1.9 for fractures within 30 days of initiation, with elevated risks observed even at lower doses (<20 mg prednisone equivalent per day), though absolute risks remain relatively small. These risks may be higher at elevated doses or in patients with predisposing factors. These effects are often more pronounced with high doses, such as equivalent to more than 40 mg of per day, and may manifest within days to weeks of initiation. Metabolic effects primarily involve , resulting from and induction of , as detailed in the section, with attendant risk of precipitating or exacerbating . Increased appetite and resultant weight gain also contribute to metabolic perturbations. This occurs in approximately 20-30% of patients receiving short courses exceeding 40 mg of daily, with higher rates (up to 32%) reported in meta-analyses of hospitalized individuals without prior . Patients with preexisting or glucose intolerance are at elevated risk, potentially requiring insulin adjustments. Gastrointestinal disturbances include nausea, heartburn, dyspepsia, and an increased of peptic ulcers, with corticosteroids alone conferring about a twofold compared to nonusers. The hazard escalates significantly when combined with nonsteroidal drugs (NSAIDs), raising the 4.4-fold overall and up to 15-fold in concurrent users. Prophylaxis with inhibitors (PPIs) is recommended, especially alongside NSAIDs or anticoagulants, to reduce ulceration and . Neuropsychiatric reactions encompass mood swings including irritability and , insomnia, and, rarely, acute . Anxiety and sleep disturbances affect up to 28% of users, while severe manifestations like occur in less than 5% at high doses (e.g., >80 mg/day equivalent), typically resolving after dose reduction. Children and those with underlying psychiatric vulnerabilities may experience heightened susceptibility. Fluid and electrolyte imbalances manifest as sodium retention, leading to fluid retention, , and , particularly with agents possessing activity like or . These effects emerge at higher doses and contribute to transient elevations within days, more pronounced in short-term high-dose regimens. Potassium excretion may also increase, though is less common acutely. Musculoskeletal complications such as proximal can develop after prolonged bursts of high-dose therapy (e.g., 40-60 mg/day for 2-3 weeks), causing symmetric weakness in the hip and shoulder girdles. This reversible condition spares respiratory muscles in non-ICU settings and improves with steroid withdrawal and . Effective management of these short-term side effects includes gradual dose tapering for courses longer than 2-3 weeks to prevent adrenal suppression and inflammation, allowing the hypothalamic-pituitary-adrenal axis to recover over weeks to months. For treatments lasting less than 10 days, gradual tapering is generally not required. In diabetics, glucose monitoring is essential—four times daily for inpatients and at least twice weekly for outpatients—targeting levels of 6-10 mmol/L to preempt hyperglycemia-related issues.

Long-term Complications

Prolonged corticosteroid therapy, particularly at doses exceeding 7.5 mg/day of equivalent for more than three months, is associated with a range of cumulative systemic complications that can lead to irreversible organ damage and increased morbidity. These effects arise from the drugs' interference with normal physiological processes, including bone metabolism, endocrine regulation, vascular function, ocular structures, pediatric development, and immune surveillance, necessitating careful monitoring and preventive strategies during treatment. One of the most significant long-term complications is , characterized by accelerated loss due to corticosteroids' inhibition of function and promotion of activity. Patients on doses greater than 7.5 mg/day of experience an annual density reduction of 2-5% in trabecular sites like the spine, with up to 50% developing overall and a 75% increased risk within the first three months of . Risk factors include advanced age, female sex, low , , alcohol use, , and underlying conditions such as . Prevention involves calcium and supplementation, weight-bearing exercise, and bisphosphonates (e.g., alendronate or ) for those at moderate to high risk on prolonged ; the FRAX tool integrates these factors to assess 10-year probability in patients over 40 years, guiding intervention thresholds. Annual scans are recommended for monitoring . Avascular necrosis, particularly of the , is another serious musculoskeletal complication, with an incidence of 3-20% in patients receiving high cumulative doses (e.g., >2 g equivalent). It results from disrupted blood supply to due to fat emboli and vascular changes, often presenting with ; early detection via MRI and surgical interventions like core decompression may be required. Cushingoid features, including moon facies, , central , and striae, develop commonly with prolonged high-dose therapy due to excess effects mimicking endogenous overproduction. These cosmetic and metabolic changes affect and are managed primarily through dose reduction, alternate-day dosing, or switching to agents with lower activity. Adrenal suppression represents another critical endocrine complication, where exogenous corticosteroids inhibit the hypothalamic-pituitary-adrenal (HPA) axis through negative feedback, leading to atrophy of the adrenal cortex and potential adrenal crisis upon abrupt withdrawal. This risk is prominent with daily doses of 20 mg/day or higher for three weeks or more, manifesting as fatigue, hypotension, and hyponatremia during stress. Recovery of the HPA axis typically requires 6-12 months after gradual tapering, though it can extend longer in some cases; assessment via morning cortisol levels or ACTH stimulation tests is essential during discontinuation. Cardiovascular complications from long-term use include accelerated and , driven by corticosteroid-induced , , and sodium retention. risk doubles with doses exceeding 10 mg/day of , with an incidence of up to 37% in patients over 65 years on high doses for more than three months; overall risk can increase 2- to 6-fold depending on cumulative exposure. Management focuses on control, monitoring, and lifestyle modifications, with therapy considered for . Ocular effects are dose- and duration-dependent, with posterior subcapsular cataracts developing in 15-20% of patients after five or more years of , particularly at doses over 10 mg/day, due to lens epithelial cell and . arises from corticosteroid-mediated changes in the , increasing and damage risk by 18-36%; annual slit-lamp examinations are advised for early detection. In children, prolonged corticosteroid exposure suppresses linear growth by inhibiting secretion and proliferation, with growth halt occurring at doses above 0.5 mg/kg/day of equivalent. This effect is more pronounced with daily rather than alternate-day regimens, though catch-up growth often resumes after discontinuation, potentially restoring potential if is limited. Regular monitoring every six months is recommended, with consideration of in severe cases. Finally, long-term therapy elevates infection risk through , with a 2- to 4-fold increase in opportunistic infections such as (PCP) at doses over 20 mg/day for four weeks or more, especially in combination with other agents. Prophylaxis with trimethoprim-sulfamethoxazole is indicated for high-risk patients, and vaccination guidelines emphasize updating inactivated vaccines (e.g., , pneumococcal) 2-4 weeks prior to starting therapy while avoiding live vaccines during high-dose periods.

Pharmacogenetics

Genetic Influences on Response

Genetic polymorphisms in the NR3C1 gene, which encodes the (GR), significantly influence inter-individual variability in corticosteroid response by altering receptor sensitivity and activity. The BclI polymorphism (rs41423247, C>G) in NR3C1 is one of the most studied variants; the G is associated with increased sensitivity due to enhanced receptor function, leading to greater effects at lower doses in conditions like , where carriers exhibit improved clinical outcomes compared to non-carriers. Similarly, haplotypes involving multiple NR3C1 single nucleotide polymorphisms (SNPs) can affect pharmacodynamic responses; for instance, certain combinations reduce efficiency, contributing to variable efficacy across patients. The A3669G variant (rs6198) in NR3C1, present in 3-5% of Caucasian populations, increases mRNA stability of the inactive GRβ isoform, resulting in relative resistance and potential for adverse effects during long-term corticosteroid therapy. Pharmacokinetic variability is further modulated by polymorphisms in enzymes, particularly and , which metabolize corticosteroids like prednisolone and may require dose adjustments. Efflux transporter genes like ABCB1 (encoding ) also impact oral bioavailability of corticosteroids through SNPs such as rs1045642 (C>T), where the T is associated with altered absorption in the intestine, leading to variable systemic exposure and . This effect is particularly relevant for oral formulations. Population differences exacerbate these variabilities; African Americans exhibit higher rates of resistance in treatment, attributed to elevated frequencies of NR3C1 variants that impair receptor signaling, contributing to poorer responses compared to European ancestries. Genome-wide association studies (GWAS) have identified additional loci influencing corticosteroid response, such as the T gene (official symbol TBXT) associated with lung function improvements in asthma patients on inhaled corticosteroids, explaining a portion of the heritability in treatment outcomes. These findings underscore the polygenic nature of response variability. Pharmacogenomic testing, including panels targeting NR3C1, /5, and ABCB1, is emerging for personalized dosing optimization, with preliminary evidence from GWAS supporting genotype-guided adjustments to enhance efficacy and minimize toxicity in clinical settings. As of 2025, advances in approaches, such as polygenic risk scores, are integrating with pharmacogenetics to predict differential corticosteroid responses in chronic diseases like and COPD.

Applications in Specific Diseases

In asthma, pharmacogenetic variants in the (CRHR1) gene, such as the rs242941 polymorphism, have been associated with reduced responsiveness to inhaled (ICS), with the T allele linked to poorer function improvements and higher exacerbation risks. Similarly, variants in the FCER1 gene, which encodes the high-affinity IgE receptor, influence ICS efficacy by modulating allergic inflammation pathways, contributing to variable treatment outcomes. Approximately 15-20% of patients exhibit non-response to ICS, often attributable to these genetic factors, highlighting the need for to identify potential poor responders. Pharmacogenetic algorithms incorporating CRHR1 and related variants are being developed to guide ICS dosing, enabling personalized adjustments to optimize therapeutic response while minimizing unnecessary exposure. In (), isoforms of the alpha (GRα) play a key role in modulating efficacy, with the N363S polymorphism (rs6195) conferring increased sensitivity and approximately doubling the odds of clinical response in carriers. This variant enhances anti-inflammatory effects, leading to better symptom control when integrated with standard assessments like the Disease Activity Score 28 (DAS28), which combines tender/swollen joint counts, patient global assessment, and to tailor dosing. for GRα polymorphisms allows for stratified therapy, reducing the trial-and-error approach in management and improving remission rates in genetically susceptible patients. For (IBD), the ABCB1 C3435T polymorphism (rs1045642) affects absorption by altering efflux activity, with the TT genotype associated with higher drug bioavailability and increased likelihood of achieving remission in and patients. Carriers of the T experience enhanced mucosal anti-inflammatory effects from , a topically corticosteroid, resulting in superior endoscopic and clinical outcomes compared to C homozygotes. This pharmacogenetic insight supports genotype-directed therapy, particularly in maintenance phases, to avoid suboptimal dosing in variant carriers. Clinical trials have demonstrated the practical benefits of pharmacogenetic-guided corticosteroid , underscoring the value of pre-treatment screening in enhancing across corticosteroid-responsive conditions. Such trials emphasize integrating genetic with clinical metrics. Looking ahead, pharmacogenetic testing for corticosteroid therapy is advancing toward broader clinical adoption, with FDA-approved assays for (TPMT) variants already guiding dosing in steroid-thiopurine combinations for IBD and to prevent toxicity. Cost-effectiveness analyses indicate that pharmacogenomic testing for ICS response in can save healthcare costs by avoiding ineffective and reducing hospitalizations.

History

Discovery and Early Research

In 1855, British physician first described the clinical syndrome of , characterized by symptoms such as profound weakness, gastrointestinal disturbances, pigmentation of the skin, and emaciation, based on observations of 11 patients whose post-mortem examinations revealed destruction of the adrenal glands. This landmark publication, titled "On the Constitutional and Local Effects of Disease of the Supra-Renal Capsules," established the vital role of the adrenal glands and laid the foundation for understanding their hormonal functions, though the underlying mechanisms remained unknown at the time. During the 1930s, biochemist Edward C. Kendall at the advanced adrenal research by isolating several compounds from beef adrenal glands, including Compound E (later identified as ) in crystalline form in 1936, marking the first purification of a key adrenal hormone. Concurrently, Swiss chemist Tadeus Reichstein, working independently, synthesized intermediates and isolated multiple adrenal substances, including in 1936, through systematic chemical degradation and reconstruction of adrenal extracts. These efforts elucidated the chemical structures of corticosteroids and demonstrated their potential physiological importance, though their specific biological activities were not yet fully characterized. In the , animal studies confirmed the life-sustaining properties of adrenal extracts; for instance, extracts administered to adrenalectomized dogs and rats prevented fatal collapse mimicking , highlighting the essential role of cortical hormones in maintaining electrolyte balance and survival. This preclinical evidence paved the way for human applications. In 1948, rheumatologist Philip S. Hench conducted the first of at the , administering it to 14 patients with severe , resulting in dramatic remissions characterized by reduced joint swelling, pain relief, and restored mobility within days. The groundbreaking contributions of Kendall, Reichstein, and Hench were recognized with the 1950 in Physiology or Medicine for "discoveries relating to the hormones of the , their structure and biological effects," particularly their application in treating . However, early production posed significant challenges, as extracting 1 gram of required processing the adrenal glands from approximately 2,500 cattle due to the hormone's low concentration in glandular tissue, limiting availability to mere milligrams for initial trials.

Development of Synthetic Analogs

The development of synthetic corticosteroids began in the , building on the isolation of natural adrenal hormones to create analogs with enhanced potency and reduced side effects. One of the earliest innovations was 9α-fluorohydrocortisone, introduced in 1954, which represented the first potent synthetic corticosteroid featuring substitution to boost activity while maintaining effects. This compound, developed through chemical modifications at Merck, marked a shift toward targeted molecular engineering for therapeutic efficacy. Shortly thereafter, was introduced in 1955 as a synthetic analog of , offering reduced activity compared to earlier compounds, which minimized fluid retention and risks during systemic use. The U.S. (FDA) approved on February 21, 1955, facilitating its widespread adoption for anti-inflammatory therapy. Dexamethasone followed in 1958, another fluorinated analog with high potency and low effects, receiving FDA approval on October 30, 1958, which expanded options for long-term management of inflammatory conditions. The 1960s saw innovations focused on topical and inhaled formulations to localize effects and reduce systemic exposure. Betamethasone valerate, a potent topical corticosteroid, was introduced in 1967, revolutionizing treatment for by providing superior skin penetration and anti-inflammatory action with fewer atrophic side effects than prior topicals. This esterified form enhanced for dermatologic applications, setting a standard for potency classification in topical steroids. Inhaled beclomethasone dipropionate emerged in 1972, offering a breakthrough for management by delivering effects directly to the airways, thereby minimizing systemic absorption and associated complications like adrenal suppression. During the and 1980s, efforts emphasized long-acting and organ-specific formulations. , first developed in 1959 as an injectable depot form, underwent refinements in the for sustained release, providing prolonged effects over weeks via intramuscular administration, which improved compliance in chronic conditions. , introduced in 1981 by Astra, featured a non-halogenated structure with high topical potency and rapid first-pass metabolism, making it ideal for and with reduced systemic impact. Regulatory milestones supported these advances; glucocorticoids such as prednisolone (with as a therapeutic alternative) were included in the World Health Organization's first Model List of in 1977, affirming their global importance for accessible care. Key chemical innovations drove potency enhancements, particularly halogenation with fluorine or chlorine at the 9α position, which increased receptor affinity and anti-inflammatory strength by up to 10-fold compared to non-halogenated precursors, as seen in analogs like dexamethasone and betamethasone. Targeted delivery systems also advanced; liposomal formulations of corticosteroids, developed in the 1990s, encapsulated drugs in phospholipid vesicles to improve skin retention and reduce systemic dissemination, exemplified by liposomal for enhanced topical efficacy in inflammatory dermatoses. In the post-2000 era, synthetic corticosteroids have assumed biologics-sparing roles in combination therapies, allowing lower doses to bridge or augment biologic agents in autoimmune diseases like , with population studies showing a 3.8% annual reduction in corticosteroid use since the mid-2000s due to these integrations. A notable recent milestone came in 2020 with the RECOVERY trial, which demonstrated that dexamethasone reduced 28-day mortality by up to 30% in hospitalized patients requiring oxygen or ventilation, prompting updated guidelines for its use in severe respiratory infections.

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