Hydrocortisone

Hydrocortisone
Clinical data
Trade namesCortef, others
Other namesCortisol; 11β,17α,21-Trihydroxypregn-4-ene-3,20-dione; 11β,17α,21-Trihydroxyprogesterone
AHFS/Drugs.comMonograph
MedlinePlusa682206
License data
Pregnancy
category
  • AU: A
Routes of
administration		By mouth, intravenous, topical, rectal
Drug classGlucocorticoid; Mineralocorticoid
ATC code
Legal status
Legal status
  • AU: S4 (Prescription only) / S3 / S2
  • NZ: Pharmacist only
  • UK: POM (Prescription only) / P / GSL
  • US: OTC / Rx-only
  • EU: OTC / Rx-only
Pharmacokinetic data
BioavailabilityOral: 96 ± 20%
Protein binding92 ± 2% (92–93%)
Metabolism11β-HSDsTooltip 11β-Hydroxysteroid dehydrogenases, others
MetabolitesCortisone, others
Onset of actionOral: 1.2 ± 0.4 hours (Tmax)
Elimination half-life1.2–2.0 hours
Duration of action8–12 hours
ExcretionUrine: >90% (<1% unchanged)
Identifiers
  • (8S,9S,10R,11S,13S,14S,17R)-11,17-Dihydroxy-17-(2-hydroxyacetyl)-10,13-dimethyl-2,6,7,8,9,11,12,14,15,16-decahydro-1H-cyclopenta[a]phenanthren-3-one
CAS Number
PubChem CID
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
Chemical and physical data
FormulaC21H30O5
Molar mass362.466 g·mol−1
3D model (JSmol)
  • O=C4\C=C2/[C@]([C@H]1[C@@H](O)C[C@@]3([C@@](O)(C(=O)CO)CC[C@H]3[C@@H]1CC2)C)(C)CC4
  • InChI=1S/C21H30O5/c1-19-7-5-13(23)9-12(19)3-4-14-15-6-8-21(26,17(25)11-22)20(15,2)10-16(24)18(14)19/h9,14-16,18,22,24,26H,3-8,10-11H2,1-2H3/t14-,15-,16-,18+,19-,20-,21-/m0/s1 checkY
  • Key:JYGXADMDTFJGBT-VWUMJDOOSA-N checkY
 X markNcheckY (what is this?)  (verify)

Hydrocortisone is the name for the hormone cortisol when supplied as a medication. It is a corticosteroid and works as an anti-inflammatory and by immune suppression. Uses include conditions such as adrenocortical insufficiency, adrenogenital syndrome, high blood calcium, thyroiditis, rheumatoid arthritis, dermatitis, asthma, and COPD. It is the treatment of choice for adrenocortical insufficiency. It can be given by mouth, topically, rectally or by injection. Stopping treatment after long-term use should be done slowly.

Common side effects may include mood changes, increased appetite, hyperglycemia, hypertension, and edema (swelling). With long-term use, common side effects include osteoporosis, adrenal insufficiency, upset stomach, physical weakness, easy bruising, and candidiasis (yeast infections). It is unclear if it is safe for use during pregnancy.

Hydrocortisone was patented in 1936 and approved for medical use in 1941. It is on the World Health Organization's List of Essential Medicines. It is available as a generic medication. In 2023, it was the 182nd most commonly prescribed medication in the United States, with more than 2 million prescriptions.

Medical uses

Hydrocortisone is the pharmaceutical term for cortisol used in oral administration, intravenous injection, or topical application. It is used as an immunosuppressive drug, given by injection in the treatment of severe allergic reactions such as anaphylaxis and angioedema, in place of prednisolone in patients needing steroid treatment but unable to take oral medication, and perioperatively in patients on long-term steroid treatment to prevent an adrenal crisis. It may also be injected into inflamed joints resulting from diseases such as gout.[citation needed]

It may be used topically for allergic rashes, eczema, psoriasis, itching, and other inflammatory skin conditions. Topical hydrocortisone creams and ointments are available in most countries without prescription in strengths ranging from 0.05% to 2.5% (depending on local regulations) with stronger forms available by prescription only.[citation needed]

It may also be used rectally in suppositories to relieve the swelling, itch, and irritation in hemorrhoids.

It may be used as an acetate form (hydrocortisone acetate), which has slightly different pharmacokinetics and pharmacodynamics.

Side effects

Side effects of hydrocortisone include hypertension, salt and water retention, hypokalemia, adrenal suppression, immunosuppression, increased risk of infections and infectious reactivation, Cushingoid symptoms, and neuropsychiatric symptoms such as depression, among many others. The side effects of hydrocortisone are dose-dependent, with many of them occurring only at higher doses.

Hydrocortisone has been found to suppress rapid eye movement sleep (REM sleep) and to enhance slow wave sleep (SWS). In addition, it has been found to increase nighttime awakenings and time spent awake. The effects of hydrocortisone on sleep may be dose-dependent and different or even opposite at low versus high doses. It is thought that the glucocorticoid activity of hydrocortisone is responsible for REM sleep suppression, while its mineralocorticoid activity mediates its SWS enhancement.

Pharmacology

Pharmacodynamics

Hydrocortisone is a corticosteroid, acting specifically as both a glucocorticoid and as a mineralocorticoid. That is, it is an agonist of the glucocorticoid and mineralocorticoid receptors.[citation needed]

Hydrocortisone has low potency relative to synthetic corticosteroids. Compared to hydrocortisone, prednisolone is about 4 times as potent and dexamethasone about 40 times as potent in terms of anti-inflammatory effect. Prednisolone can also be used as cortisol replacement, and at replacement dose levels (rather than anti-inflammatory levels), prednisolone is about 8 times more potent than cortisol. The equivalent doses and relative potencies of hydrocortisone compared to various other synthetic corticosteroids have also been reviewed and summarized.

The endogenous production rate of cortisol is approximately 5.7 to 9.9 mg/m2 per day, which corresponds to an oral hydrocortisone dose of approximately 15 to 20 mg/day (for a 70-kg person). One review described daily cortisol production of 10 mg in healthy volunteers and reported that daily cortisol production could increase up to 400 mg in conditions of severe stress (e.g., surgery).

The total and/or free concentrations of cortisol/hydrocortisone required for various glucocorticoid effects have been determined.

In addition to its corticosteroid receptor agonism, hydrocortisone has been reported to be a highly potent biphasic regulator of the GABAA receptor, acting as a positive allosteric modulator at low concentrations (1–10 pM) and as a negative allosteric modulator at high concentrations (10–1,000 nM).

Pharmacokinetics

Absorption

The bioavailability of oral hydrocortisone is about 96% ± 20% (SD). The pharmacokinetics of hydrocortisone are non-linear. The peak level of oral hydrocortisone is 15.3 ± 2.9 (SD) μg/L per 1 mg dose. The time to peak concentrations of oral hydrocortisone is 1.2 ± 0.4 (SD) hours.

The topical percutaneous absorption of hydrocortisone varies widely depending on experimental circumstances and has been reported to range from 0.5 to 14.9% in different studies. Some skin application sites, like the scrotum and vulva, absorb hydrocortisone much more efficiently than other application sites, like the forearm. In one study, the amount of hydrocortisone absorbed ranged from 0.2% to 36.2% depending on the application site, with the ball of the foot having the lowest absorption and the scrotum having the highest absorption. The absorption of hydrocortisone by the vulva has ranged from 4.4 to 8.1%, relative to 1.3 to 2.8% for the arm, in different studies and subjects.

Distribution

Most cortisol in the blood (all but about 4%) is bound to proteins, including corticosteroid binding globulin (CBG) and serum albumin. A pharmacokinetic review stated that 92% ± 2% (SD) (92–93%) of hydrocortisone is plasma protein-bound. Free cortisol passes easily through cellular membranes. Inside cells it interacts with corticosteroid receptors.

Metabolism

Hydrocortisone is metabolized by 11β-hydroxysteroid dehydrogenases (11β-HSDs) into cortisone, an inactive metabolite. It is additionally 5α-, 5β-, and 3α-reduced into dihydrocortisols, dihydrocortisones, tetrahydrocortisols, and tetrahydrocortisones.

Elimination

Hydrocortisone and its metabolites are more than 90% conjugated in the liver and excreted in urine. Only a very small proportion of hydrocortisone is excreted unchanged (<1%).

The elimination half-life of hydrocortisone ranges from about 1.2 to 2.0 hours, with an average of around 1.5 hours, regardless of oral versus parenteral administration. The duration of action of systemic hydrocortisone has been listed as 8 to 12 hours.

Chemistry

Hydrocortisone, also known as 11β,17α,21-trihydroxypregn-4-ene-3,20-dione, is a naturally occurring pregnane steroid. A variety of hydrocortisone esters exist and have been marketed for medical use.

History

Hydrocortisone was discovered in the 1930s. It was introduced as a prescription medication in the United States in 1952. In 1979, topical hydrocortisone became available as a non-prescription over-the-counter drug in the United States.

Society and culture

In March 2021, the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) adopted a positive opinion, recommending the granting of a marketing authorization for the medicinal product Efmody, intended for the treatment of congenital adrenal hyperplasia (CAH) in people aged twelve years and older. The applicant for this medicinal product is Diurnal Europe BV. Hydrocortisone (Efmody) was approved for medical use in the European Union, in May 2021, for the treatment of congenital adrenal hyperplasia (CAH) in people aged twelve years and older.

Anti-competitive practices

In the UK, the Competition and Markets Authority (CMA) concluded an investigation into the supply of hydrocortisone tablets, finding that from October 2008 onwards, drug suppliers Auden McKenzie and Actavis plc had charged "excessive and unfair prices" for 10mg and 20mg tablets and entered into agreements with potential competitors, paying companies who agreed not to enter the hydrocortisone market and enabling Auden McKenzie and Actavis to supply the drugs as "generic" rather than branded products and thereby escape price controls until eventually other companies entered the market. Auden and Actavis overcharged the UK's National Health Service for over ten years. Fines totalling over £255m were levied against the companies involved in this breach of competition law.

Research

Depression

Cortisol is released in response to stress and both cortisol and stress have been extensively implicated in depression. People with depression show hypothalamic–pituitary–adrenal axis (HPA axis) hyperactivity, elevated cortisol levels, flattened diurnal cortisol rhythms, and reduced glucocorticoid sensitivity. Findings on the cortisol awakening response (CAR) in people with depression have been mixed, with some studies finding a greater CAR and others finding a blunted CAR, possibly related to different types of depression. Most research has focused on lowering cortisol levels or reducing cortisol signaling to treat depression, as the predominant paradigm has been that excess glucocorticoid signaling may contribute to depression. Relatedly, chronic administration of high doses of corticosteroids have been found to produce depression and other adverse effects. Antiglucocorticoids like corticotropin-releasing hormone antagonists, mifepristone, and metyrapone were extensively studied for treatment of depression, but were found to be ineffective and were abandoned, though some study on these agents persists.

Cortisol has an inverted U-shaped association with mood and other functions, with both hypercortisolemia (e.g., Cushing's syndrome) and hypocortisolemia (e.g., Addison's disease) associated with depression compared to more moderate levels. Relatedly, depression is thought to be a heterogeneous condition, and different subtypes of depression may have different levels of HPA axis and cortisol signaling. Although hypercortisolemia is most often implicated in depression, a subset of people with depression instead show hypocortisolemia. Atypical depression has been associated with lower cortisol levels, while melancholic and psychotic depression have been linked to higher cortisol levels.

Cortisol release in response to stress is most commonly perceived or assumed as mediating negative affect. However, in contrast to the case of chronic stress and cortisol elevation, numerous studies have shown that cortisol is instead related to mood-protective and anxiolytic effects during acute stress and actually functions as an adaptive and resilience-promoting hormone in this context. Along similar lines, short-term administration of high doses of corticosteroids is well-known to produce euphoria and mania. There are even rare case reports of corticosteroid misuse, addiction, and dependence. In relation to the preceding, acute or transient administration of hydrocortisone has been found to enhance mood and resilience and may provide beneficial effects in people with depression per various clinical studies. Similarly, restitution of daily cortisol rhythms with administration of low-dose hydrocortisone early in the day theoretically might also be helpful for some types of depression.

Post-traumatic stress disorder

Hydrocortisone has been assessed in the treatment of post-traumatic stress disorder (PTSD) in a variety of clinical studies. It is proposed to work by reducing retrieval of aversive memories and facilitating extinction of aversive memories. In addition to treatment of PTSD, hydrocortisone has been studied and found effective in reducing risk of developing PTSD when given in the aftermath of a traumatic event. It has been found to be the most effective intervention for prevention of PTSD, whereas a variety of other modalities were ineffective.

Phobias

Hydrocortisone has been studied in the treatment of phobias such as social phobia and specific phobias. It has been found to diminish fear in response to phobia-specific stimuli by reducing retrieval of aversive memories. In addition, the drug has been found to enhance extinction of phobias with exposure therapy.

Chronic fatigue syndrome

Cortisol levels have been found to be altered in people with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). Hypocortisolism may be involved in this condition and in related conditions like fibromyalgia. Hydrocortisone has been clinically studied in the treatment of ME/CFS. A 2016 systematic review found that it had been assessed for this purpose in six clinical studies. Its clinical effectiveness was conflicting in the studies, ranging from not effective, to slightly or mildly effective, to moderately effective. Four of the studies came from one research group. The systematic review called for higher-quality trials. A 2015 systematic review found that the clinical data on hydrocortisone for ME/CFS was inconclusive. A 2010 narrative review reported that hydrocortisone provided short-term reductions in fatigue and symptoms, but had limitations like temporary benefits, rapid loss of effectiveness upon discontinuation, only a minority of individuals benefiting, and there being no known treatment response predictors, concluding that hydrocortisone could not be recommended for treatment of ME/CFS.

COVID-19

Hydrocortisone was found to be effective in reducing mortality rate of critically ill COVID-19 patients when compared to other usual care or a placebo.

References

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  58. 1 2 3 George MY, Abdel Mageed SS, Mansour DE, Fawzi SF (December 2025). "The cortisol axis and psychiatric disorders: an updated review". Pharmacological Reports. 77 (6): 1573–1599. doi:10.1007/s43440-025-00782-x. PMC 12647353. PMID 40956392.
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  60. 1 2 3 Gaffey AE, Walsh EC, Ladd CO, Hoks RM, Abercrombie HC (March 2019). "Alterations in Systemic and Cognitive Glucocorticoid Sensitivity in Depression". Biological Psychiatry. Cognitive Neuroscience and Neuroimaging. 4 (3): 310–320. doi:10.1016/j.bpsc.2018.11.007. PMC 6399042. PMID 30686583. Relatedly, the evidence reported herein supports research suggesting that therapeutics targeting cortisol signaling hold promise as antidepressant treatments (48,90,91,93,94). Unfortunately, it is ineffective to boost the cortisol signal chronically by administering the steroid cortisol itself, for a variety of reasons, including deleterious effects of chronically high levels of circulating cortisol (11). However, brief treatment with cortisol and corticosteroid agonists has shown beneficial effects in depression and PTSD (39,48,50,93).
  61. 1 2 Pariante CM (July 2006). "The glucocorticoid receptor: part of the solution or part of the problem?". Journal of Psychopharmacology. 20 (4 Suppl): 79–84. doi:10.1177/1359786806066063. PMID 16785275. [...] treatment with GR and MR agonists, like dexamethasone, prednisolone and cortisol, has shown antidepressant action (Dinan et al., 1997; Bouwer et al., 2000; DeBattista et al., 2000) and ameliorating effects on declarative memory (Bremner et al., 2004) in depressed patients. While some studies described only an acute, transient improvement in depressive symptoms (Goodwin et al., 1992; DeBattista et al., 2000), other studies have shown that a short-term treatment with a GR agonist has persistent antidepressant effects (Dinan et al., 1997).
  62. 1 2 3 Herbert J (March 2013). "Cortisol and depression: three questions for psychiatry". Psychological Medicine. 43 (3): 449–469. doi:10.1017/S0033291712000955. PMID 22564216. Clearly much more information on the contribution of GR antagonists to the treatment of MDD is required; a simple overall blockade might not be the optimal approach in some cases of established MDD (e.g. those with disordered rhythms). There are reports of improved mood in MDD subjects after either a cortisol infusion (Goodwin et al. 1992) or dexamethasone in a dose that would suppress elevated cortisol (Dinan et al. 1997). Can these results be reinterpreted in the light of the more complex ideas about variations in cortisol in MDD set out above? [...] We do not know whether non-response is related to distorted daily cortisol rhythms, or whether restitution of these rhythms (for example by administration in the morning of a low dose of cortisol) might assist pharmacological responsiveness. Such investigations might be highly informative. [...] Patients with disturbed cortisol rhythms might benefit from restitution of those rhythms; they may be distinct from those with more generally elevated levels, who might benefit from cortisol blockade. Selective manipulations of cortisol, based on adequate assessment of individual cortisol rhythms, should play a role in treatment (in combination with antidepressants or behavioural therapy).
  63. 1 2 3 4 Dwyer JB, Aftab A, Radhakrishnan R, Widge A, Rodriguez CI, Carpenter LL, et al. (August 2020). "Hormonal Treatments for Major Depressive Disorder: State of the Art". The American Journal of Psychiatry. 177 (8): 686–705. doi:10.1176/appi.ajp.2020.19080848. PMC 7841732. PMID 32456504. In general, patients with major depression are reported to exhibit hyperactivity of the HPA axis, with impaired sensitivity to negative feedback; however, subsets of patients with hypocortisolemia have been reported (25).
  64. ↑ Dedovic K, Ngiam J (2015). "The cortisol awakening response and major depression: examining the evidence". Neuropsychiatric Disease and Treatment. 11: 1181–1189. doi:10.2147/NDT.S62289. PMC 4437603. PMID 25999722.
  65. ↑ Chida Y, Steptoe A (March 2009). "Cortisol awakening response and psychosocial factors: a systematic review and meta-analysis". Biological Psychology. 80 (3): 265–278. doi:10.1016/j.biopsycho.2008.10.004. PMID 19022335. The lack of overall associations between depression and the CAR was not because of an absence of effects, but rather because depression has been related both to increased (Bhagwagar et al., 2003; Pruessner et al., 2003) and reduced (Stetler and Miller, 2005; Ellenbogen et al., 2006) CARs. These discrepancies may relate to the intensity of depression, with some studies investigating major depressive disorder while others concerned elevated depressed mood in the normal range. Additionally, some studies managed less than complete control for factors associated with depression.
  66. 1 2 3 Warrington TP, Bostwick JM (October 2006). "Psychiatric adverse effects of corticosteroids". Mayo Clinic Proceedings. 81 (10): 1361–1367. doi:10.4065/81.10.1361. PMID 17036562. Although disturbances of mood, cognition, sleep, and behavior as well as frank delirium or even psychosis are possible, the most common adverse effects of short-term corticosteroid therapy are euphoria and hypomania. Conversely, long-term therapy tends to induce depressive symptoms. Dosage is directly related to the incidence of adverse effects but is not related to the timing, severity, or duration of these effects. [...] CORTICOSTEROID ABUSE: Several case reports describe corticosteroid abuse or dependence driven by the euphoria these medications can induce. These cases typically involve high-dose oral or intravenous formulations, but at least 1 case of dexamethasone nasal spray abuse has been reported.33 Most cases of corticosteroid abuse have been described in patients with a premorbid history of either psychiatric illness or drug or alcohol dependence.34
  67. 1 2 3 Kenna HA, Poon AW, de los Angeles CP, Koran LM (October 2011). "Psychiatric complications of treatment with corticosteroids: review with case report". Psychiatry and Clinical Neurosciences. 65 (6): 549–560. doi:10.1111/j.1440-1819.2011.02260.x. PMID 22003987. A number of more recent publications support the conclusion that symptoms of hypomania or mania are the most common psychiatric adverse effect of corticosteroid treatment.12,13,18,20,47,49 Some recent studies have suggested, however, that the risk of depression increases with prolonged or chronic exposure.48,50–52 [...] Rarely, corticosteroids have been abused for their euphoria-producing effects, producing drug dependency.31–33
  68. 1 2 Fietta P, Fietta P, Delsante G (October 2009). "Central nervous system effects of natural and synthetic glucocorticoids". Psychiatry and Clinical Neurosciences. 63 (5): 613–622. doi:10.1111/j.1440-1819.2009.02005.x. PMID 19788629. These AE are generally dose and time dependent (infrequent at prednisone-equivalent doses <20 mg/day) and usually reversible. [...] Manic symptoms have been mostly associated with short SGC courses, and depressive disorder with long-term treatments. [...] The effects of cortisol on mood and affect appear to be dose dependent. A transient moderate elevation in cortisolemia due to acute stress has a protective effect on mood in critical situations.15 Otherwise, in permanently hypercortisolemic patients suffering from Cushing's syndrome (CS) and Cushing's disease (CD), psychiatric disturbances were reported in a high percentage of cases (57–83%).16–19 [...] Notably, the duration of treatment may influence the PAE qualitative aspects. Brief SGC bursts at moderate/high dose have been mostly associated with symptoms of mania [...] Otherwise, unlike short-term treatments, long-term therapies appeared to be more associated with depressive disorder,42,45 [...]
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  73. 1 2 3 Wolkowitz OM, Burke H, Epel ES, Reus VI (October 2009). "Glucocorticoids. Mood, memory, and mechanisms". Annals of the New York Academy of Sciences. 1179: 19–40. doi:10.1111/j.1749-6632.2009.04980.x. PMID 19906230. Glucocorticoid Treatment of Depression: In what seems a diametrically opposite approach to altering GC activity in depressed patients, several small-scale studies reported that administration of GCs, such as dexamethasone, prednisone, or hydrocortisone, is associated with antidepressant effects in some depressed patients.141–150 These findings could support the GC insufficiency hypothesis of depression by showing that increasing GC levels (and presumably signaling) lessens depressive symptoms, [...]
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  79. 1 2 3 Abercrombie HC, Barnes AL, Nord EC, Finley AJ, Higgins ET, Grupe DW, et al. (January 2023). "Inverse association between stress induced cortisol elevations and negative emotional reactivity to stress in humans". Stress. 26 (1) 2174780. doi:10.1080/10253890.2023.2174780. PMC 9930177. PMID 36772851. Greater cortisol reactivity to stress is often assumed to lead to heightened negative affective reactivity to stress. Conversely, a growing body of evidence demonstrates mood-protective effects of cortisol elevations in the context of acute stress. [...] multiple studies investigating acute stressors demonstrate mood-protective effects of cortisol (Het et al., 2012; Nakataki et al., 2017; Soravia et al., 2006). For instance, pharmacological administration of cortisol prior to a stressor has anxiolytic or mood buffering effects in multiple placebo-controlled studies (Het & Wolf, 2007; Nakataki et al., 2017; Soravia et al., 2006). Thus, evidence is accruing to support mood-protective effects of both exogenous and endogenous cortisol elevation in relation to acute stress. Mood-protective effects of transient cortisol elevations contrast with pervasive notions of cortisol's detrimental effects. Modern conceptualizations are dominated by knowledge of the deleterious effects of chronic cortisol elevations (McEwen, 2019). The psychologically adaptive effects of transient cortisol elevations in response to acute stress are less well-known (McEwen, 2019). [...] Intervention focused on transiently enhancing the cortisol signal is an important area for future clinical investigation (Gaffey et al., 2019). [...]
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