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]
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).
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.
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]Asystematic 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]
In addition to their corticosteroid activity, some corticosteroids may have some progestogenic activity and may produce sex-related side effects.[10][11][12][13]
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]
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]
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[update] 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]
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".[42][43]
The highlighted steroids are often used in the screening of allergies to topical steroids.[44]
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.
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.[55] Corticosteroids were voted Allergen of the Year in 2005 by the American Contact Dermatitis Society.[56]
Lewis SarettofMerck & Co. was the first to synthesize cortisone, using a 36-step process that started with deoxycholic acid, which was extracted from oxbile.[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.
^Faggiano A, Mazzilli R, Natalicchio A, Adinolfi V, Argentiero A, Danesi R, et al. (December 2022). "Corticosteroids in oncology: Use, overuse, indications, contraindications. An Italian Association of Medical Oncology (AIOM)/ Italian Association of Medical Diabetologists (AMD)/ Italian Society of Endocrinology (SIE)/ Italian Society of Pharmacology (SIF) multidisciplinary consensus position paper". Critical Reviews in Oncology/Hematology. 180: 103826. doi:10.1016/j.critrevonc.2022.103826. hdl:10447/582211. PMID36191821. S2CID252663155.
^Lumry WR (October 1999). "A review of the preclinical and clinical data of newer intranasal steroids used in the treatment of allergic rhinitis". The Journal of Allergy and Clinical Immunology. 104 (4 Pt 1): S150–S158. doi:10.1016/s0091-6749(99)70311-8. PMID10518812.
^Brook EM, Hu CH, Kingston KA, Matzkin EG (March 2017). "Corticosteroid Injections: A Review of Sex-Related Side Effects". Orthopedics. 40 (2): e211–e215. doi:10.3928/01477447-20161116-07. PMID27874912.
^Luzzani F, Gallico L, Glässer A (1982). "In vitro and ex vivo binding to uterine progestin receptors of the rat as a tool to assay progestational activity of glucocorticoids". Methods and Findings in Experimental and Clinical Pharmacology. 4 (4): 237–242. PMID7121132.
^Cunningham GR, Goldzieher JW, de la Pena A, Oliver M (January 1978). "The mechanism of ovulation inhibition by triamcinolone acetonide". The Journal of Clinical Endocrinology and Metabolism. 46 (1): 8–14. doi:10.1210/jcem-46-1-8. PMID376542.
^Sumino K, Bacharier LB, Taylor J, Chadwick-Mansker K, Curtis V, Nash A, et al. (January 2020). "A Pragmatic Trial of Symptom-Based Inhaled Corticosteroid Use in African-American Children with Mild Asthma". The Journal of Allergy and Clinical Immunology. In Practice. 8 (1): 176–185.e2. doi:10.1016/j.jaip.2019.06.030. PMID31371165. S2CID199380330.
^Martínek J, Hlavova K, Zavada F, Seifert B, Rejchrt S, Urban O, Zavoral M (October 2010). ""A surviving myth"--corticosteroids are still considered ulcerogenic by a majority of physicians". Scandinavian Journal of Gastroenterology. 45 (10): 1156–1161. doi:10.3109/00365521.2010.497935. PMID20569095. S2CID5140517.
^Fukushima C, Matsuse H, Tomari S, Obase Y, Miyazaki Y, Shimoda T, Kohno S (June 2003). "Oral candidiasis associated with inhaled corticosteroid use: comparison of fluticasone and beclomethasone". Annals of Allergy, Asthma & Immunology. 90 (6): 646–651. doi:10.1016/S1081-1206(10)61870-4. PMID12839324.
^Shepard TH, Brent RL, Friedman JM, Jones KL, Miller RK, Moore CA, Polifka JE (April 2002). "Update on new developments in the study of human teratogens". Teratology. 65 (4): 153–161. doi:10.1002/tera.10032. PMID11948561.
^Rietschel RL (2007). Fisher's Contact Dermatitis, 6/e. Hamilton, Ont: BC Decker Inc. p. 256. ISBN978-1-55009-378-0.
^Coopman S, Degreef H, Dooms-Goossens A (July 1989). "Identification of cross-reaction patterns in allergic contact dermatitis from topical corticosteroids". The British Journal of Dermatology. 121 (1): 27–34. doi:10.1111/j.1365-2133.1989.tb01396.x. PMID2757954. S2CID40425526.
^Wolverton SE (2001). Comprehensive Dermatologic Drug Therapy. WB Saunders. p. 562.
^Khan MO, Park KK, Lee HJ (2005). "Antedrugs: an approach to safer drugs". Current Medicinal Chemistry. 12 (19): 2227–2239. doi:10.2174/0929867054864840. PMID16178782.
^Marker RE, Wagner RB (September 1947). "Steroidal sapogenins". Journal of the American Chemical Society. 69 (9): 2167–2230. doi:10.1021/ja01201a032. PMID20262743.
^Peterson DH, Murray HC (1952). "Microbiological Oxygenation of Steroids at Carbon 11". J. Am. Chem. Soc. 74 (7): 1871–2. doi:10.1021/ja01127a531.
