CORTICOSTEROIDS

• ACRONYMS AND DEFINITIONS

• ACR - American College of Rheumatology
• ACTH - Adrenocorticotropic hormone
• HPA - Hypothalamic-pituitary-adrenal
• IBD - Inflammatory bowel disease
• NHLBI - National Heart, Lung, and Blood Institute
• RAAS - Renin-angiotensin-aldosterone system
• RCT - Randomized controlled trial

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• DEFINITIONS

• Adrenocorticotropic hormone (ACTH) - adrenocorticotropic hormone, also called corticotropin, is a hormone released by the anterior pituitary that stimulates the release of cortisol from the adrenal gland. ACTH release is controlled by the hypothalamus, and it follows a diurnal pattern with peak levels occurring around 8AM and nadir levels occurring around midnight. See hypothalamic-pituitary-adrenal axis for information on disorders that affect ACTH secretion. [8,9]

• Aldosterone - aldosterone is the main mineralocorticoid secreted by the adrenal glands. Its release is stimulated by rising serum potassium levels and angiotensin II (see potassium regulation for more). Aldosterone acts primarily in the renal collecting ducts where it stimulates the uptake of sodium and water in exchange for potassium. [8,9]

• Corticosteroids - corticosteroid is a term used to encompass steroids that are synthesized and secreted by the adrenal cortex. The main corticosteroids in humans are cortisol and aldosterone.

• Cortisol - cortisol is the main corticosteroid produced by the adrenal gland. Its release is regulated by ACTH, and under normal conditions, 10 - 20 mg of cortisol are produced each day. Most cortisol (95%) circulates bound to cortisol-binding globulin and albumin, and only 5% is in the free form which is the active form. Cortisol has equal affinity for glucocorticoid and mineralocorticoid receptors, but its primary action is as a glucocorticoid. This occurs because the renal enzyme 11βHSD2 metabolizes cortisol to its inactive form, cortisone, thus preventing it from interacting with mineralocorticoid receptors. Excessive amounts of cortisol can overwhelm the enzyme causing cortisol to have mineralocorticoid activity. Hydrocortisone is the synthetic version of cortisol. See hypothalamic-pituitary-adrenal axis for information on disorders that affect cortisol secretion. [7,9]

• Cortisone - cortisone is the inactive form of cortisol. Cortisol is converted to cortisone by the enzyme 11βHSD2 which is found primarily in the kidneys. Cortisone can be converted back to cortisol by the enzyme 11βHSD1 which is found primarily in liver and fat tissue. A synthetic version of cortisone is also available (see cortisone acetate below) [8,9]

• Dehydroepiandrosterone (DHEA) - DHEA is a mild androgen produced by the adrenal cortex. See female hormone physiology for more.

• Glucocorticoids - glucocorticoids are a class of steroids that have a broad range of effects on inflammation and metabolism. Their name is derived from the fact that they are involved in regulating glucose metabolism. Cortisol is the main endogenous glucocorticoid, and exogenous glucocorticoids (e.g. prednisone) are frequently prescribed to treat an array of conditions.

• Mineralocorticoids - mineralocorticoids are hormones that are involved in the regulation of water and sodium balance. Aldosterone is the primary endogenous mineralocorticoid, and its main action is in the kidneys where it stimulates the reabsorption of sodium and water in exchange for potassium.

• 11β-hydroxysteroid dehydrogenase (11βHSD) - 11βHSD is an enzyme that converts cortisol to cortisone and vice versa. 11βHSD type 1 (11βHSD1) is found primarily in liver and fat tissue, and 11βHSD type 2 (11βHSD2) is found in the kidneys. Under physiologic conditions, the main action of 11βHSD1 is to convert cortisone to cortisol, and the main action of 11βHSD2 is to convert cortisol to cortisone. Deficiencies of the 11βHSD enzyme can be inherited through genetic disorders or they can be acquired (e.g. licorice inhibits 11βHSD). Testing for a deficiency can be done by measuring the amount of cortisol and cortisone in a 24-hour urine. A cortisone to cortisol ratio of < 1 suggests 11βHSD deficiency where a ratio of 2:1 or 3:1 suggests normal function. [4,8,9,11]

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• CORTICOSTEROID HOMEOSTASIS

• Overview
• The two main corticosteroids in humans are cortisol and aldosterone. Under normal conditions, cortisol acts primarily as a glucocorticoid and aldosterone acts as a mineralocorticoid. As a glucocorticoid, cortisol has a wide range of metabolic and inflammatory effects that are reviewed below. The main action of aldosterone takes place in the kidneys where it stimulates the reabsorption of water and sodium in exchange for potassium. Under normal conditions, the adrenal glands secrete 10 - 20 mg of cortisol a day, but production can increase as much as sixfold in response to stress (e.g. fear, infection, trauma, surgery). Cortisol release from the adrenal glands is regulated by ACTH, and it follows a diurnal pattern with levels peaking in the morning around 8AM and bottoming out around midnight.
• Cortisol has equal affinity for glucocorticoid and mineralocorticoid receptors, but it is rapidly metabolized to its inactive form (cortisone) in the kidneys by 11βHSD2 and this prevents it from stimulating mineralocorticoid receptors under normal conditions. Most synthetic steroids have been designed to have a greater affinity for glucocorticoid receptors (see properties of different steroids) because this takes advantage of their anti-inflammatory properties while minimizing their mineralocorticoid effects (e.g. fluid retention). However, at high doses and/or prolonged dosing, mineralocorticoid effects can still occur. Fludrocortisone is one exception. It has a high affinity for mineralocorticoid receptors and is used to replace aldosterone in patients with adrenal insufficiency. See hypothalamic-pituitary-adrenal axis for information on disorders that affect cortisol secretion. [4,6,7,8,9]

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• CORTICOSTEROID EFFECTS

• Metabolic effects
• Glucocorticoids have a wide range of metabolic effects. Some effects are seen acutely (e.g. gluconeogenesis), and others only occur with prolonged use (e.g. fat redistribution)
• Glucose and protein metabolism
• Glucocorticoids stimulate the conversion of amino acids into glucose (gluconeogenesis). With long-term use, this can lead to muscle wasting and thinning of the skin.
• Glucocorticoids inhibit the effects of insulin thereby preventing the uptake of glucose by cells
• Gluconeogenesis and insulin inhibition cause the hyperglycemia that is often seen with glucocorticoids
• Lipid metabolism
• Glucocorticoids promote the release of fatty acids from adipose tissue. Fatty acids are then converted into glucose.
• Long-term glucocorticoid exposure causes a redistribution of fat through an unknown mechanism. This redistribution leads to increased fat in the neck region (buffalo hump) and face (moon face). [4,6,8]

• Immune system
• Glucocorticoids have a number of effects on the immune system, most of which lead to suppression of the immune response. It's because of their immunosuppressive properties that they are some of the most prescribed medications in the world.
• General immune system effects
• Inhibition of the release of inflammatory mediators by stabilizing lysosomal membranes
• Decreased capillary permeability which reduces swelling and inhibits the migration of inflammatory cells
• Suppression of phospholipase A₂ and decreased expression of COX-2 (see NSAID mechanism of action)
• Inhibition of the genes that produce inflammatory mediators (e.g. interleukin, interferon, tumor necrosis factor)
• White blood cell (WBC) effects
• Inhibition of the migration of white blood cells into inflamed areas
• Atrophy of lymphoid tissue which leads to decreased output of T-cells and antibodies
• Reduction in the number of circulating eosinophils, monocytes, and lymphocytes. This effect occurs almost immediately.
• Increase in the number of circulating neutrophils. Cortisol increases circulating neutrophils through the following mechanisms: (1) stimulation of neutrophil maturation in the bone marrow, (2) promotion of neutrophil release into the circulation, (3) inhibition of neutrophil migration into inflamed tissues, (4) prevention of neutrophil apoptosis.
• The increase in neutrophils is greater than the reduction in eosinophils and lymphocytes so the net effect is an increase in the WBC count [4,7,8,12]

• Other effects
• Psychiatric - glucocorticoids can have a wide range of psychiatric effects that include agitation, insomnia, irritability, moodiness, euphoria, memory impairment, and psychosis. The mechanism by which these effects occur is not completely understood.
• Bone effects - glucocorticoids have been shown to stimulate osteoclast activity while suppressing osteoblast activity. Long-term use can lead to osteoporosis and increased fracture risk.
• Mineralocorticoid effects - with high doses and/or long-term use, many glucocorticoids will have some mineralocorticoid activity. For example, a 50 mg prednisone dose has the mineralocorticoid activity of a 0.1 mg fludrocortisone dose (see corticosteroid properties below). Mineralocorticoid effects can cause fluid retention and its sequelae (e.g. hypertension, edema) [5,7]

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• DOSAGE FORMS

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• PROPERTIES OF CORTICOSTEROIDS

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• FDA-APPROVED INDICATIONS

• Inflammatory conditions
• Steroids are FDA-approved for the treatment of a large number of inflammatory conditions
• Some common examples include:
• Asthma and allergies
• Rheumatoid arthritis
• Lupus
• Gout
• Dermatitis and eczema
• Crohn's disease and ulcerative colitis
• Kidney diseases (ex. Nephrotic syndrome)
• Multiple sclerosis
• Organ transplants
• Idiopathic thrombocytopenia


• Adrenal insufficiency
• Steroids are also used as replacement therapy in conditions where the body does not make sufficient amounts of cortisol (e.g. Addison's disease).

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• SIDE EFFECTS

• Overview
• Side effects of corticosteroids depend on the length of use
• Short-term use does not typically have lasting effects
• Chronic steroid therapy can have a number of adverse effects

• Short-term use (incidence not well-defined)
• Increased appetite
• Elevated blood sugar - in one study, prednisone 25 - 60 mg a day increased the 2hr GTT by ∼ 100 mg/dl in nondiabetics [2]
• Increased blood pressure
• Gastric irritation
• Behavior and mood changes

• Long-term use (incidence not well-defined)
• Fluid retention
• Weight gain
• Potassium loss
• Calcium loss
• Cushing's syndrome
• Menstrual changes
• Diabetes
• Skin atrophy and bruising
• Poor wound healing
• See precautions for more

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• CONTRAINDICATIONS

• Vaccines - complete all appropriate immunizations before initiating therapy if possible. Live attenuated vaccines should not be given, and the response to inactivated vaccines may be reduced (list of U.S. vaccines including type). See ACR vaccination guidelines for specific recommendations on administering vaccines to patients receiving corticosteroids.

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• PRECAUTIONS

• HPA axis suppression
• Long-term steroid use can cause suppression of the HPA axis. HPA axis suppression leads to cortisol deficiency when exogenous steroids are withdrawn.
• Tapering steroids may help prevent suppression. See tapering steroids below for more.

• Gastritis and peptic ulcers
• Steroids can attenuate the stomach's ability to protect itself against digestive acids. This can worsen or lead to gastritis and/or peptic ulcers.
• Concomitant NSAIDs may increase the risk and should be avoided when possible

• Diabetes
• Corticosteroids raise blood sugar levels and may worsen diabetes
• In one study, a single dose of prednisone 60 mg increased the plasma glucose level 50 - 100 mg/dl for up to 8 hours after a 75 gram oral glucose challenge in nondiabetics [2]
• Use steroids with caution in diabetics, particularly those who are uncontrolled

• Osteonecrosis of the femoral or humeral head
• Long-term steroid use may increase the risk of osteonecrosis of the femoral or humeral head

• Osteoporosis
• Long-term steroid use is a risk factor for osteoporosis
• The mechanism appears to occur through calcium loss and direct effects on bone formation
• See osteoporosis for more

• Infection
• Long-term steroid use suppresses immunity and may increase the risk of serious infection

• Heart attack
• Steroids may increase the risk of ventricular free wall rupture in patients who have suffered a recent heart attack

• Stunted growth
• Long-term steroid use may suppress bone growth and stunt adult heights in children
• This is true even for inhaled corticosteroids used in asthma. See inhaled corticosteroids for more.

• Cataracts
• Long-term steroid use may increase the risk of cataracts

• Glaucoma
• Long-term steroid use may increase the risk of glaucoma

• Myasthenia gravis
• An acute myopathy has been observed with the use of high doses of corticosteroids in patients with myasthenia gravis

• Kaposi's sarcoma
• Kaposi's sarcoma has been reported in patients receiving corticosteroid therapy, most often for chronic conditions
• Discontinuing steroids may lead to remission

• Skin testing
• Steroids may suppress reactions to skin testing (e.g. PPD, allergy) and lead to false-negative interpretation

• Pregnancy
• Observational studies have shown a small but inconsistent increased risk of orofacial clefts with the use of corticosteroids during the first trimester of pregnancy. Intrauterine growth restriction and decreased birth weight have also been reported, however, the underlying maternal condition may also contribute to these risks.
• Patients and providers should weigh the potential risks and benefits when prescribing corticosteroids during pregnancy

• Kidney disease
• Clearance is decreased. Use caution.

• Liver disease
• Steroids have not been studied extensively in liver disease. Use caution.

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• DRUG INTERACTIONS

• NOTE: Drug interactions presented here are NOT all-inclusive. Other interactions may exist. The interactions presented here are meant to encompass commonly prescribed medications and/or interactions that are well-documented. Always consult your physician or pharmacist before taking medications concurrently. CLICK HERE for more information on drug interactions.


• Corticosteroids
• Anticholinesterase agents - Concomitant use of anticholinesterase agents and corticosteroids may produce severe weakness in patients with myasthenia gravis
• Amphotericin B - corticosteroids may worsen the potassium loss caused by amphotericin B
• Cholestyramine - cholestyramine may increase the clearance of corticosteroids
• Cyclosporine - increased activity of both cyclosporine and corticosteroids may occur when the two are used concurrently
• CYP3A4 inhibitors and inducers - corticosteroids are CYP3A4 substrates. CYP3A4 inhibitors may increase steroid levels and CYP3A4 inducers may decrease steroid levels.
• Digoxin - corticosteroids may increase the risk of arrhythmias due to hypokalemia
• Estrogens and oral contraceptives - estrogens may decrease the hepatic metabolism of certain corticosteroids, thereby increasing their effect
• Isoniazid - corticosteroids may decrease isoniazid levels
• Loop diuretics - corticosteroids may worsen potassium loss from loop diuretics
• NSAIDs (ibuprofen, naprosyn, aspirin, etc.) - NSAIDs may increase the risk of gastrointestinal side effects seen with steroids
• Testosterone replacement therapies - testosterone may increase the fluid retention seen with corticosteroids. Use caution.
• Thiazide diuretics - corticosteroids may worsen potassium loss from thiazide diuretics
• Warfarin - corticosteroids may inhibit the effects of warfarin.

• Metabolism and clearance
• CYP3A4 - substrate

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• DOSING

• Primary adrenal insufficiency (adults)
• Glucocorticoid replacement
• First-line: hydrocortisone 15 - 25 mg/day given in 2 - 3 divided doses OR cortisone acetate 20 - 35 mg/day given in 2 - 3 divided doses
• Second-line: prednisolone 3 - 5 mg/day given once daily or in 2 divided doses
• Monitor therapy by assessing body weight, postural blood pressure, energy levels, and signs of frank glucocorticoid excess
• Mineralocorticoid replacement
• For patients with confirmed aldosterone deficiency, fludrocortisone is recommended
• Starting: 0.050 - 0.100 mg once daily
• Maintenance: doses ranging from 0.1 mg three times a week to 0.2 mg daily have been employed
• Adjust dose up or down based on salt craving, postural hypotension, edema, electrolytes, and hypertension [10]

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• CORTICOSTEROID TAPERING

• Overview
• One of the biggest issues with corticosteroids is knowing when and how to taper steroids in order to prevent, or facilitate the correction of hypothalamic-pituitary-adrenal (HPA) axis suppression
• There is surprisingly little information in the medical literature to help guide these decisions, and there is no consensus among experts on how it should be done
• A study in the NEJM that was performed in 1992 found no significant correlation between the length or dose of steroid therapy and HPA axis suppression. The study included patients who had been taking steroids for a period of 1 week to 15 years. [PMID 1309389]
• Given the dearth of information, tapering decisions have to be made on an individual patient basis


• General principles of corticosteroid tapering:
• Individuals can vary greatly in their susceptibility to HPA axis suppression
• Length and dose of steroid therapy are imperfect predictors of HPA axis suppression
• In general, most patients who have been on steroids for less than 4 weeks will have minimal or no HPA axis suppression, although suppression can still be seen in a small number of patients [3]
• A simple tapering regimen for patients who have been on extended therapy is to reduce the dose of steroids by 10 - 20% every 1 - 2 weeks
• HPA axis testing may be informative in some patients, but in practice, it is rarely performed
• Symptoms of adrenal insufficiency include: hypotension, weakness, fatigue, hypoglycemia, decreased appetite, nausea and vomiting, low sodium, and mental changes

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• PRICE ($) INFO

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• BIBLIOGRAPHY

• 1 - Manufacturer's package insert
• 2 - PMID 22180452 Prednisone affects inflammation, glucose tolerance, and bone turnover within hours of treatment in healthy individuals, Eur J Endocrinol (2012)
• 3 - PMID 1309389 The effect of long-term glucocorticoid therapy on pituitary-adrenal responses to exogenous corticotropin-releasing hormone, NEJM (1992)
• 4 - Nicolaides NC, Pavlaki AN, Maria Alexandra MA, et al. Glucocorticoid Therapy and Adrenal Suppression. [Updated 2018 Oct 19]. In: Feingold KR, Anawalt B, Boyce A, et al., editors. Endotext [Internet]. South Dartmouth (MA): MDText.com, Inc.; 2000-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK279156/
• 5 - PMID 23947590 A practical guide to the monitoring and management of the complications of systemic corticosteroid therapy, Allergy Asthma Clin Immunol (2013)
• 6 - Pharmacologic Characteristics of Corticosteroids, J Neurocrit Care 2017;10(2):53-59
• 7 - PMID 23506281 Basic and clinical pharmacology of glucocorticosteroids, Anesth Prog (2013)
• 8 - Guyton, Arthur C. Guyton And Hall Textbook Of Medical Physiology. Philadelphia, PA : Saunders/Elsevier, 13 ed. (2016)
• 9 - Rhoades, David R. Bell. Medical Physiology : Principles for Clinical Medicine. Philadelphia:Wolters Kluwer Health/Lippincott Williams & Wilkins, 5th ed. (2018)
• 10 - PMID 26760044 Diagnosis and Treatment of Primary Adrenal Insufficiency: An Endocrine Society Clinical Practice Guideline
• 11 - Mayo Clinic labortatories
• 12 - PMID 30563002 - How Glucocorticoids Affect the Neutrophil Life, Int J Mol Sci (2018)