Chemistry:Hydrocortisone

From HandWiki

Hydrocortisone is the name for the hormone cortisol when supplied as a medication.[1] It is a corticosteroid and works as an anti-inflammatory and by immune suppression.[2] Uses include conditions such as adrenocortical insufficiency, adrenogenital syndrome, high blood calcium, thyroiditis, rheumatoid arthritis, dermatitis, asthma, and COPD.[2] It is the treatment of choice for adrenocortical insufficiency.[3] It can be given by mouth, topically, rectally or by injection.[2] Stopping treatment after long-term use should be done slowly.[2]

Common side effects may include mood changes, increased appetite, hyperglycemia, hypertension, and edema (swelling).[4] With long-term use, common side effects include osteoporosis, adrenal insufficiency, upset stomach, physical weakness, easy bruising, and candidiasis (yeast infections).[2][4] It is unclear if it is safe for use during pregnancy.[5]

Hydrocortisone was patented in 1936 and approved for medical use in 1941.[6][7] It is on the World Health Organization's List of Essential Medicines.[8] It is available as a generic medication.[2] In 2023, it was the 182nd most commonly prescribed medication in the United States, with more than 2 million prescriptions.[9][10]

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 also be used rectally in suppositories to relieve the swelling, itch, and irritation in hemorrhoids.[11]

It may be used as an acetate form (hydrocortisone acetate), which has slightly different pharmacokinetics and pharmacodynamics.[11][12]

  • Cortisol for injection
    Cortisol for injection
  • A tube of hydrocortisone cream, purchased over-the-counter
    A tube of hydrocortisone cream, purchased over-the-counter
  • Hydrocortisone 10 mg oral tablets (depicted a package for Russian market)
    Hydrocortisone 10 mg oral tablets (depicted a package for Russian market)

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.[13] The side effects of hydrocortisone are dose-dependent, with many of them occurring only at higher doses.[13]

Hydrocortisone has been found to suppress rapid eye movement sleep (REM sleep) and to enhance slow wave sleep (SWS).[14][15][16][17][18][19] In addition, it has been found to increase nighttime awakenings and time spent awake.[16][18] The effects of hydrocortisone on sleep may be dose-dependent and different or even opposite at low versus high doses.[20][21] It is thought that the glucocorticoid activity of hydrocortisone is responsible for REM sleep suppression, while its mineralocorticoid activity mediates its SWS enhancement.[21][22][19]

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.[23] Compared to hydrocortisone, prednisolone is about 4 times as potent and dexamethasone about 40 times as potent in terms of anti-inflammatory effect.[24] 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.[25] The equivalent doses and relative potencies of hydrocortisone compared to various other synthetic corticosteroids have also been reviewed and summarized.[23]

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).[26][27] 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).[28]

The total and/or free concentrations of cortisol/hydrocortisone required for various glucocorticoid effects have been determined.[28]

Pharmacokinetics

Absorption

The bioavailability of oral hydrocortisone is about 96% ± 20% (SD).[28][29] The pharmacokinetics of hydrocortisone are non-linear.[28] The peak level of oral hydrocortisone is 15.3 ± 2.9 (SD) μg/L per 1 mg dose.[28] The time to peak concentrations of oral hydrocortisone is 1.2 ± 0.4 (SD) hours.[28]

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.[30] Some skin application sites, like the scrotum and vulva, absorb hydrocortisone much more efficiently than other application sites, like the forearm.[30][31][32] 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.[32] 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.[32][33][34]

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.[28] Free cortisol passes easily through cellular membranes.[35] Inside cells it interacts with corticosteroid receptors.[36]

Metabolism

Hydrocortisone is metabolized by 11β-hydroxysteroid dehydrogenases (11β-HSDs) into cortisone, an inactive metabolite.[29][28] It is additionally 5α-, 5β-, and 3α-reduced into dihydrocortisols, dihydrocortisones, tetrahydrocortisols, and tetrahydrocortisones.[37][28][29]

Elimination

Hydrocortisone and its metabolites are more than 90% conjugated in the liver and excreted in urine.[38] Only a very small proportion of hydrocortisone is excreted unchanged (<1%).[38]

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.[28][29] The duration of action of systemic hydrocortisone has been listed as 8 to 12 hours.[23]

Chemistry

See also: Chemistry:List of corticosteroids and List of corticosteroid esters § Hydrocortisone esters

Hydrocortisone, also known as 11β,17α,21-trihydroxypregn-4-ene-3,20-dione, is a naturally occurring pregnane steroid.[39][40] A variety of hydrocortisone esters exist and have been marketed for medical use.[39][40]

History

Hydrocortisone was discovered in the 1930s.[41] It was introduced as a prescription medication in the United States in 1952.[42] In 1979, topical hydrocortisone became available as a non-prescription over-the-counter drug in the United States.[42]

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.[43] The applicant for this medicinal product is Diurnal Europe BV.[43] 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.[44]

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.[45]

Research

Depression

Cortisol is released in response to stress and both cortisol and stress have been extensively implicated in depression.[46][47] People with depression show hypothalamic–pituitary–adrenal axis (HPA axis) hyperactivity, elevated cortisol levels, flattened diurnal cortisol rhythms, and reduced glucocorticoid sensitivity.[46][48][49][50][51] 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.[52][53][50] 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.[46] Relatedly, chronic administration of high doses of corticosteroids have been found to produce depression and other adverse effects.[48][54][55][56] 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.[57][51][58][59][60]

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.[61][62][63][64] Relatedly, depression is thought to be a heterogeneous condition, and different subtypes of depression may have different levels of HPA axis and cortisol signaling.[61][65][51][66][63][64] Although hypercortisolemia is most often implicated in depression, a subset of people with depression instead show hypocortisolemia.[51][63][64] Atypical depression has been associated with lower cortisol levels, while melancholic and psychotic depression have been linked to higher cortisol levels.[66]

Cortisol release in response to stress is most commonly perceived or assumed as mediating negative affect.[67][68] 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.[67][68] Along similar lines, short-term administration of high doses of corticosteroids is well-known to produce euphoria and mania.[54][55][56][69] There are even rare case reports of corticosteroid misuse, addiction, and dependence.[55][54][70] 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.[70][49][61][48][67] 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.[50]

Post-traumatic stress disorder

Hydrocortisone has been assessed in the treatment of post-traumatic stress disorder (PTSD) in a variety of clinical studies.[71] It is proposed to work by reducing retrieval of aversive memories and facilitating extinction of aversive memories.[71] 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.[71][72][73] It has been found to be the most effective intervention for prevention of PTSD, whereas a variety of other modalities were ineffective.[71][72][73]

Phobias

Hydrocortisone has been studied in the treatment of phobias such as social phobia and specific phobias.[71] It has been found to diminish fear in response to phobia-specific stimuli by reducing retrieval of aversive memories.[71] In addition, the drug has been found to enhance extinction of phobias with exposure therapy.[71]

Chronic fatigue syndrome

Cortisol levels have been found to be altered in people with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS).[74][75][76] Hydrocortisone has been clinically studied in the treatment of ME/CFS.[77][78][79] A 2016 systematic review found that it had been assessed for this purpose in six clinical studies.[77] Its clinical effectiveness was conflicting in the studies, ranging from not effective, to slightly or mildly effective, to moderately effective.[77] Four of the studies came from one research group.[77] The systematic review called for higher-quality trials.[77] A 2015 systematic review found that the clinical data on hydrocortisone for ME/CFS was inconclusive.[80]

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.[81]

References

  1. ↑ (in en) Principles and Practice of Endocrinology and Metabolism. Lippincott Williams & Wilkins. 2001. p. 762. ISBN 978-0-7817-1750-2. https://books.google.com/books?id=FVfzRvaucq8C&pg=PA762. 
  2. ↑ 2.0 2.1 2.2 2.3 2.4 2.5 "Hydrocortisone". American Society of Health-System Pharmacists. 9 February 2015. https://www.drugs.com/monograph/hydrocortisone.html. 
  3. ↑ Tarascon Pocket Pharmacopoeia 2015 Deluxe Lab-Coat Edition. Jones & Bartlett Learning. 2015. p. 202. ISBN 978-1-284-05756-0. 
  4. ↑ 4.0 4.1 "Hydrocortisone: Uses, Side Effects, Interactions, Pictures, Warnings & Dosing - WebMD" (in en). https://www.webmd.com/drugs/2/drug-6731-581/hydrocortisone-oral/hydrocortisone-oral/details. 
  5. ↑ "Hydrocortisone Pregnancy and Breastfeeding Warnings". https://www.drugs.com/pregnancy/hydrocortisone.html. 
  6. ↑ U.S. Patent 2,183,589
  7. ↑ (in en) Analogue-based Drug Discovery. John Wiley & Sons. 2006. p. 484. ISBN 978-3-527-60749-5. https://books.google.com/books?id=FjKfqkaKkAAC&pg=PA484. Retrieved 7 September 2020. 
  8. ↑ World Health Organization model list of essential medicines: 21st list 2019. Geneva: World Health Organization. 2019. WHO/MVP/EMP/IAU/2019.06. 
  9. ↑ "Top 300 of 2023". https://clincalc.com/DrugStats/Top300Drugs.aspx. 
  10. ↑ "Hydrocortisone Drug Usage Statistics, United States, 2013 - 2023". https://clincalc.com/DrugStats/Drugs/Hydrocortisone. 
  11. ↑ 11.0 11.1 Cite error: Invalid <ref> tag; no text was provided for refs named anusol-acetate
  12. ↑ "[Comparative study of prednisolone versus hydrocortisone acetate for treatment of patients with the classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency]" (in Portuguese). Arq Bras Endocrinol Metabol 52 (1): 101–8. February 2008. doi:10.1590/s0004-27302008000100014. PMID 18345402. 
  13. ↑ 13.0 13.1 https://www.accessdata.fda.gov/drugsatfda_docs/label/2024/008697s040lbl.pdf
  14. ↑ "Effects of hormones on sleep". Horm Res 49 (3-4): 125–130. 1998. doi:10.1159/000023158. PMID 9550112. "Since the pioneering work by Gillin et al. [49], a host of studies have investigated the effects of steroids on the sleep EEG. Suppression of REM sleep is a robust finding after the administration of glucocorticoids. Furthermore, most studies agree that the amount of SWS is enhanced after acute glucocorticoid administration [for review, see 50]. After continuous as well as after pulsatile iv infusion of cortisol, SWS was elevated [38, 39, 51]. Furthermore, EEG spectral analysis revealed that the pulsatile cortisol injections enhanced the slow wave activity in young normal men [52]. In addition, nocturnal GH release was elevated after pulsatile cortisol boluses [39, 52]. Similarly, SWS, slow wave activity and GH release were increased and REM sleep was decreased under pulsatile iv cortisol also in elderly normal men and women [40].". 
  15. ↑ "Memory consolidation during sleep: interactive effects of sleep stages and HPA regulation". Stress 11 (1): 28–41. January 2008. doi:10.1080/10253890701408822. PMID 17853075. "Whereas higher doses of cortisol can change the distribution of sleep stages towards increased SWS and reduced REM sleep (Born et al. 1987, 1989; Friess et al. 1994), the relatively low dose given here did not significantly change time spent in the different sleep stages in comparison with placebo.". 
  16. ↑ 16.0 16.1 "Headache, drugs and sleep". Cephalalgia 34 (10): 756–766. September 2014. doi:10.1177/0333102414542662. PMID 25053748. "In terms of the physiological effects on sleep, it seems corticosteroids reduce REM sleep and increase nocturnal awakenings and increase wake after sleep onset times (90,91). [...] 90. Fehm HL, Benkowitsch R, Kern W, et al. Influences of corticosteroids, dexamethasone and hydrocortisone on sleep in humans. Neuropsychobiology 1986; 16: 198–204. 91. Born J, Zwick A, Roth G, et al. Differential effects of hydrocortisone, fluocortolone, and aldosterone on nocturnal sleep in humans. Acta Endocrinol (Copenh) 1987; 116: 129–137.". 
  17. ↑ Reddy, Raghu M.; Subramanian, Shyamsunder (2009). "Sleep Disturbances Due to Pulmonary Medications". Current Respiratory Medicine Reviews 5 (4): 225–229. doi:10.2174/157339809790112393. https://www.eurekaselect.com/article/30428. Retrieved 27 March 2026. "Corticosteroids can also affect sleep stages and awakenings during sleep. The most consistent effect demonstrated on polysomnogram is decreased REM sleep. Fehm et al. [5] conducted a double blind cross over trail to study the effects of dexamethasone and hydrocortisone on sleep stages. 1 mg of dexamethasone given prior to sleep led to a decrease in both REM sleep and slow wave sleep duration. 100 mgs of hydrocortisone infusion led to decreased REM sleep but increase in slow wave sleep. [...] Born et al. [7] also studied the effects of hydrocortisone 80 mgs or placebo infused throughout the night for 2 consecutive nights in 10 healthy male adults and showed substantial reduction in REM sleep and increase in slow wave sleep.". 
  18. ↑ 18.0 18.1 "Influences of corticosteroids, dexamethasone and hydrocortisone on sleep in humans". Neuropsychobiology 16 (4): 198–204. 1986. doi:10.1159/000118326. PMID 3614616. 
  19. ↑ 19.0 19.1 "Differential effects of hydrocortisone, fluocortolone, and aldosterone on nocturnal sleep in humans". Acta Endocrinol (Copenh) 116 (1): 129–137. September 1987. doi:10.1530/acta.0.1160129. PMID 3661052. 
  20. ↑ "On the interactions of the hypothalamic-pituitary-adrenal (HPA) axis and sleep: normal HPA axis activity and circadian rhythm, exemplary sleep disorders". J Clin Endocrinol Metab 90 (5): 3106–3114. May 2005. doi:10.1210/jc.2004-1056. PMID 15728214. "Additional studies also suggest that relative MR vs. GR activation influences sleep EEG differently and suggest that glucocorticoids inhibit or enhance SWS depending on the dose of exogenous corticosterone used (23, 25, 26). Although high-affinity mineralocorticoid receptors are predominately occupied at lower doses of the steroid, greater occupancy of the low affinity GR is seen at higher doses of corticosterone (14). Consistent with this dose-related effect, the administration of hydrocortisone to healthy males can at times increase SWS and at other times increase wakefulness and stage 1 sleep, the latter occurring at higher doses (23). [...] Low doses of hydrocortisone decrease wakefulness and increase SWS, and high doses increase wakefulness and decrease SWS (25, 26).". 
  21. ↑ 21.0 21.1 "Hormones, hormonal agents, and neuropeptides involved in the neuroendocrine regulation of sleep in humans". Hormones (Athens) 8 (4): 232–248. 2009. doi:10.14310/horm.2002.1239. PMID 20045796. 
  22. ↑ "Gluco- and antimineralocorticoid effects on human sleep: a role of central corticosteroid receptors". Am J Physiol 260 (2 Pt 1): E183–E188. February 1991. doi:10.1152/ajpendo.1991.260.2.E183. PMID 1996621. 
  23. ↑ 23.0 23.1 23.2 "A practical guide to the monitoring and management of the complications of systemic corticosteroid therapy". Allergy Asthma Clin Immunol 9 (1). August 2013. doi:10.1186/1710-1492-9-30. PMID 23947590. 
  24. ↑ "Dexamethasone". drugs.com. https://www.drugs.com/pro/dexamethasone.html. 
  25. ↑ "One-year clinical evaluation of single morning dose prednisolone therapy for 21-hydroxylase deficiency". Arquivos Brasileiros de Endocrinologia e Metabologia 48 (5): 705–712. October 2004. doi:10.1590/S0004-27302004000500017. PMID 15761542. 
  26. ↑ Cortisol Excess and Insufficiency. Frontiers of Hormone Research. S. Karger AG. 2016. p. 1-PA61. ISBN 978-3-318-05840-6. https://books.google.com/books?id=jew6DAAAQBAJ&pg=RA1-PA61. Retrieved 10 April 2023. 
  27. ↑ Pediatric Adrenal Diseases: Workshop, May 16-18, 2010, Turin (Italy). Karger Medical and Scientific Publishers. 2011. pp. 174–. ISBN 978-3-8055-9643-5. OCLC 1020003143. https://books.google.com/books?id=gde44-zDr_oC&pg=PA174. Retrieved 10 April 2023. 
  28. ↑ 28.00 28.01 28.02 28.03 28.04 28.05 28.06 28.07 28.08 28.09 Cite error: Invalid <ref> tag; no text was provided for refs named pmid15634032
  29. ↑ 29.0 29.1 29.2 29.3 Cite error: Invalid <ref> tag; no text was provided for refs named pmid18611115
  30. ↑ 30.0 30.1 "Percutaneous absorption of topical corticosteroids". Current Problems in Dermatology 21: 45–60. 1993. doi:10.1159/000422362. ISBN 978-3-8055-5712-2. PMID 8299376. 
  31. ↑ "Effects of anatomical location on in vivo percutaneous penetration in man". Cutaneous and Ocular Toxicology 39 (3): 213–222. September 2020. doi:10.1080/15569527.2020.1787434. PMID 32643443. 
  32. ↑ 32.0 32.1 32.2 "Regional Variation in Percutaneous Absorption". Percutaneous Absorption. CRC Press. 8 June 2021. pp. 165–174. doi:10.1201/9780429202971-11. ISBN 978-0-429-20297-1. 
  33. ↑ "Human percutaneous penetration of hydrocortisone: the vulva". Archives of Dermatological Research 267 (3): 313–316. 1980. doi:10.1007/BF00403852. PMID 7406539. 
  34. ↑ "Percutaneous absorption of hydrocortisone and testosterone on the vulva and forearm: effect of the menopause and site". The British Journal of Dermatology 134 (2): 229–233. February 1996. doi:10.1111/j.1365-2133.1996.tb07606.x. PMID 8746334. 
  35. ↑ "Bioavailability of oral hydrocortisone in patients with congenital adrenal hyperplasia due to 21-hydroxylase deficiency". The Journal of Endocrinology 169 (1): 65–70. April 2001. doi:10.1677/joe.0.1690065. PMID 11250647. 
  36. ↑ Medical Physiology (2nd ed.). Philadelphia: Saunders. 2011. ISBN 978-1-4377-1753-2. 
  37. ↑ "The role of 5-reduction in physiology and metabolic disease: evidence from cellular, pre-clinical and human studies". The Journal of Steroid Biochemistry and Molecular Biology 207. March 2021. doi:10.1016/j.jsbmb.2021.105808. PMID 33418075. 
  38. ↑ 38.0 38.1 https://www.accessdata.fda.gov/drugsatfda_docs/nda/2021/213876Orig1s000PharmR.pdf
  39. ↑ 39.0 39.1 The Dictionary of Drugs: Chemical Data: Chemical Data, Structures and Bibliographies. Springer. 14 November 2014. p. 316. ISBN 978-1-4757-2085-3. https://books.google.com/books?id=0vXTBwAAQBAJ&pg=PA316. 
  40. ↑ 40.0 40.1 Index Nominum 2000: International Drug Directory. Taylor & Francis. 2000. pp. 524–. ISBN 978-3-88763-075-1. https://books.google.com/books?id=5GpcTQD_L2oC&pg=PA524. Retrieved 19 June 2020. 
  41. ↑ "Hydrocortisone: Uses, Interactions, Mechanism of Action". 5 August 1952. https://go.drugbank.com/drugs/DB00741. 
  42. ↑ 42.0 42.1 Pray, W. Steven (20 April 2009). "Appropriate Use of Nonprescription Hydrocortisone". https://www.uspharmacist.com/article/appropriate-use-of-nonprescription-hydrocortisone. 
  43. ↑ 43.0 43.1 "Efmody: Pending EC decision". 25 March 2021. https://www.ema.europa.eu/en/medicines/human/summaries-opinion/efmody.  Text was copied from this source which is copyright European Medicines Agency. Reproduction is authorized provided the source is acknowledged.
  44. ↑ "Efmody EPAR". 24 March 2021. https://www.ema.europa.eu/en/medicines/human/EPAR/efmody.  Text was copied from this source which is copyright European Medicines Agency. Reproduction is authorized provided the source is acknowledged.
  45. ↑ This article contains OGL licensed text This article incorporates text published under the British Open Government Licence: Competition and Markets Authority, Decision: Hydrocortisone tablets. Excessive and unfair pricing and Anti-competitive agreements, published 31 March 2022, accessed 1 June 2023
  46. ↑ 46.0 46.1 46.2 "The cortisol axis and psychiatric disorders: an updated review". Pharmacol Rep 77 (6): 1573–1599. December 2025. doi:10.1007/s43440-025-00782-x. PMID 40956392. 
  47. ↑ Sickmann, Helle M.; Li, Yan; Mørk, Arne; Sanchez, Connie; Gulinello, Maria (2014). "Does Stress Elicit Depression? Evidence From Clinical and Preclinical Studies". Behavioral Neurobiology of Stress-related Disorders. 18. Berlin, Heidelberg: Springer Berlin Heidelberg. p. 123–159. doi:10.1007/7854_2014_292. ISBN 978-3-662-45125-0. https://link.springer.com/10.1007/7854_2014_292. Retrieved 23 March 2026. 
  48. ↑ 48.0 48.1 48.2 "Alterations in Systemic and Cognitive Glucocorticoid Sensitivity in Depression". Biol Psychiatry Cogn Neurosci Neuroimaging 4 (3): 310–320. March 2019. doi:10.1016/j.bpsc.2018.11.007. 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).". 
  49. ↑ 49.0 49.1 "The glucocorticoid receptor: part of the solution or part of the problem?". J Psychopharmacol 20 (4 Suppl): 79–84. July 2006. 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).". 
  50. ↑ 50.0 50.1 50.2 "Cortisol and depression: three questions for psychiatry". Psychol Med 43 (3): 449–469. March 2013. 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).". 
  51. ↑ 51.0 51.1 51.2 51.3 "Hormonal Treatments for Major Depressive Disorder: State of the Art". Am J Psychiatry 177 (8): 686–705. August 2020. doi:10.1176/appi.ajp.2020.19080848. 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).". 
  52. ↑ "The cortisol awakening response and major depression: examining the evidence". Neuropsychiatr Dis Treat 11: 1181–1189. 2015. doi:10.2147/NDT.S62289. PMID 25999722. 
  53. ↑ "Cortisol awakening response and psychosocial factors: a systematic review and meta-analysis". Biol Psychol 80 (3): 265–278. March 2009. 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.". 
  54. ↑ 54.0 54.1 54.2 "Psychiatric adverse effects of corticosteroids". Mayo Clin Proc 81 (10): 1361–1367. October 2006. 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". 
  55. ↑ 55.0 55.1 55.2 "Psychiatric complications of treatment with corticosteroids: review with case report". Psychiatry Clin Neurosci 65 (6): 549–560. October 2011. 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". 
  56. ↑ 56.0 56.1 "Central nervous system effects of natural and synthetic glucocorticoids". Psychiatry Clin Neurosci 63 (5): 613–622. October 2009. 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 [...]". 
  57. ↑ Yoon, Seoyoung; Kim, Yong-Ku (2024). "Endocrinological Treatment Targets for Depressive Disorder". Recent Advances and Challenges in the Treatment of Major Depressive Disorder. 1456. Singapore: Springer Nature Singapore. p. 3–25. doi:10.1007/978-981-97-4402-2_1. ISBN 978-981--974401-5. https://link.springer.com/10.1007/978-981-97-4402-2_1. Retrieved 23 March 2026. 
  58. ↑ [One of the most studied and confirmed biological features of MDD is abnormal activity of the HPA axis. [...] Despite these findings, whether direct targeting of the HPA axis leads to improvement of MDD is unclear. [...] several (mostly small-scaled) RCTs have evaluated glucocorticoid-lowering compounds in MDD, including metyrapone, the mineralocorticoid receptor agonist fludrocortisone or the glucocorticoid receptor antagonist mifepristone 99,100. However, results from these trials were inconsistent 99,100. Further studies are required to identify subgroups of patients who are more likely to respond to treatments targeting the HPA axis. "Major depressive disorder"]. Nat Rev Dis Primers 9 (1): 44. August 2023. doi:10.1038/s41572-023-00454-1. PMID 37620370. One of the most studied and confirmed biological features of MDD is abnormal activity of the HPA axis. [...] Despite these findings, whether direct targeting of the HPA axis leads to improvement of MDD is unclear. [...] several (mostly small-scaled) RCTs have evaluated glucocorticoid-lowering compounds in MDD, including metyrapone, the mineralocorticoid receptor agonist fludrocortisone or the glucocorticoid receptor antagonist mifepristone 99,100. However, results from these trials were inconsistent 99,100. Further studies are required to identify subgroups of patients who are more likely to respond to treatments targeting the HPA axis.. 
  59. ↑ "Cortisol and Major Depressive Disorder-Translating Findings From Humans to Animal Models and Back". Front Psychiatry 10: 974. 2019. doi:10.3389/fpsyt.2019.00974. PMID 32038323. 
  60. ↑ "Depression clinical trials worldwide: a systematic analysis of the ICTRP and comparison with ClinicalTrials.gov". Transl Psychiatry 14 (1): 315. July 2024. doi:10.1038/s41398-024-03031-6. PMID 39085220. 
  61. ↑ 61.0 61.1 61.2 "Glucocorticoids. Mood, memory, and mechanisms". Ann N Y Acad Sci 1179: 19–40. October 2009. 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, [...]". 
  62. ↑ "Corticosteroid effects in the brain: U-shape it". Trends Pharmacol Sci 27 (5): 244–250. May 2006. doi:10.1016/j.tips.2006.03.007. PMID 16584791. 
  63. ↑ 63.0 63.1 63.2 "Major depression in late life is associated with both hypo- and hypercortisolemia". Biol Psychiatry 62 (5): 479–486. September 2007. doi:10.1016/j.biopsych.2006.11.033. PMID 17481591. "[...] In contrast, in a sample of frail nursing-home patients, depression was associated with decreased serum cortisol levels (Morrison et al. 2000). Furthermore, in an older outpatient population, decreased 24-hour urinary cortisol levels were found especially in patients with longstanding and recurrent depressive episodes (Oldehinkel et al. 2001). [...] A number of studies indeed show hypoactivity of the HPA axis in chronic-stress-related states that are more prevalent in women and are often associated with depression such as fibromyalgia (Griep et al. 1998), burnout (Pruessner et al. 1999), and chronic fatigue syndrome (Cleare 2004).". 
  64. ↑ 64.0 64.1 64.2 "Relative hypo- and hypercortisolism are both associated with depression and lower quality of life in bipolar disorder: a cross-sectional study". PLoS One 9 (6). 2014. doi:10.1371/journal.pone.0098682. PMID 24932586. 
  65. ↑ "Baseline cortisol and the efficacy of antiglucocorticoid treatment in mood disorders: A meta-analysis". Psychoneuroendocrinology 110. December 2019. doi:10.1016/j.psyneuen.2019.104420. PMID 31499391. 
  66. ↑ 66.0 66.1 "Depression and hypothalamic-pituitary-adrenal activation: a quantitative summary of four decades of research". Psychosom Med 73 (2): 114–126. 2011. doi:10.1097/PSY.0b013e31820ad12b. PMID 21257974. 
  67. ↑ 67.0 67.1 67.2 "Inverse association between stress induced cortisol elevations and negative emotional reactivity to stress in humans". Stress 26 (1). January 2023. doi:10.1080/10253890.2023.2174780. 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). [...]". 
  68. ↑ 68.0 68.1 "Glucocorticoids and resilience". Horm Behav 111: 131–134. May 2019. doi:10.1016/j.yhbeh.2018.11.005. PMID 30448249. "All organisms endure frequent challenges to homeostasis, or stressors, that require adaptation. Depending on the individual, the context, and the magnitude of stress, this active adaptation can lead to behavioral susceptibility or resilience. The latter is an under-appreciated consequence of stress, as the damaging effects of chronic stress and chronically elevated glucocorticoids have received much more attention. We suggest here that neural pathways promoting resilience are initiated at the time of stress, and that they involve glucocorticoid signaling.". 
  69. ↑ "Corticosteroids and mania: A systematic review". World J Biol Psychiatry 25 (3): 161–174. March 2024. doi:10.1080/15622975.2024.2312572. PMID 38363330. 
  70. ↑ 70.0 70.1 "Hypothalamic-pituitary-adrenocortical axis: neuropsychiatric aspects". Compr Physiol 4 (2): 715–738. April 2014. doi:10.1002/cphy.c130036. PMID 24715565. "Glucocorticoids can also have mood-elevating effects, whose loss might fit better into a model of GR-impaired depression (392). Such effects are manifested in psychiatrically normal subjects as euphoria after exogenous administration, as depression after steroid withdrawal, and in a few cases, as steroid abuse (50, 210, 394). Mood improvements after glucocorticoid treatment occur before significant amelioration of the diseases for which the steroids were prescribed (373, 394), making it unlikely that euphoric effects were due to relief of disease symptoms. Recent findings that glucocorticoids inhibit activity induced by sad images in the subgenual anterior cingulate and ventromedial prefrontal cortex suggest some neuroanatomical substrates for these positive mood effects (392). Consistent with the possibility that inadequate glucocorticoid levels can also predispose to depression, depression rates in Addison's Disease have been estimated to be approximately twice as high as in the general population (404). Limited but intriguing data indicate that glucocorticoids can improve mood in depression either when given alone (17, 87, 137, 226), or as adjuncts to conventional antidepressants (37, 102).". 
  71. ↑ 71.0 71.1 71.2 71.3 71.4 71.5 71.6 "Glucocorticoid-induced enhancement of extinction-from animal models to clinical trials". Psychopharmacology (Berl) 236 (1): 183–199. January 2019. doi:10.1007/s00213-018-5116-0. PMID 30610352. 
  72. ↑ 72.0 72.1 "Pharmacological interventions for preventing post-traumatic stress disorder (PTSD)". Cochrane Database Syst Rev 2014 (7). July 2014. doi:10.1002/14651858.CD006239.pub2. PMID 25001071. 
  73. ↑ 73.0 73.1 "Pharmacological prevention of post-traumatic stress disorder and acute stress disorder: a systematic review and meta-analysis". Lancet Psychiatry 2 (5): 413–421. May 2015. doi:10.1016/S2215-0366(14)00121-7. PMID 26360285. 
  74. ↑ "A systematic review and meta-analysis of urinary biomarkers in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS)". J Transl Med 21 (1). July 2023. doi:10.1186/s12967-023-04295-0. PMID 37408028. 
  75. ↑ "Meta-analysis and meta-regression of hypothalamic-pituitary-adrenal axis activity in functional somatic disorders". Biol Psychol 87 (2): 183–194. May 2011. doi:10.1016/j.biopsycho.2011.02.002. PMID 21315796. 
  76. ↑ "Unstimulated cortisol secretory activity in everyday life and its relationship with fatigue and chronic fatigue syndrome: a systematic review and subset meta-analysis". Psychoneuroendocrinology 38 (11): 2405–2422. November 2013. doi:10.1016/j.psyneuen.2013.07.004. PMID 23916911. 
  77. ↑ 77.0 77.1 77.2 77.3 77.4 "A Systematic Review of Drug Therapies for Chronic Fatigue Syndrome/Myalgic Encephalomyelitis". Clin Ther 38 (6): 1263–1271.e9. June 2016. doi:10.1016/j.clinthera.2016.04.038. PMID 27229907. 
  78. ↑ "Low-dose hydrocortisone in chronic fatigue syndrome: a randomised crossover trial". Lancet 353 (9151): 455–458. February 1999. doi:10.1016/S0140-6736(98)04074-4. PMID 9989716. 
  79. ↑ "Low-dose hydrocortisone for treatment of chronic fatigue syndrome: a randomized controlled trial". JAMA 280 (12): 1061–1066. 1998. doi:10.1001/jama.280.12.1061. PMID 9757853. 
  80. ↑ "Treatment of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: A Systematic Review for a National Institutes of Health Pathways to Prevention Workshop". Ann Intern Med 162 (12): 841–850. June 2015. doi:10.7326/M15-0114. PMID 26075755. 
  81. ↑ "Association Between Administration of Systemic Corticosteroids and Mortality Among Critically Ill Patients With COVID-19: A Meta-analysis". JAMA 324 (13): 1330–1341. October 2020. doi:10.1001/jama.2020.17023. PMID 32876694. 

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