A. Metabolic and Endocrine Functions
- Normally produced by the adrenal glands, mainly in the fasciculata
- Baseline secretion of glucocorticoids required for normal functioning
- Major glucocorticoid is cortisol
- Cortisol is secreted with diurnal variation
- Highest levels occur in morning hours
- Lowest levels occur in very early AM (around 2-3:00 AM)
- Cortisol production increases in stress
- Major controlling hormone is ACTH (adrenocorticotropic hormone)
- ACTH is made in the anterior pituitary
- ACTH is processed from the prohormone pro-opiomelanocortin (POMC)
- ACTH production is stimulated by hypothalamic corticotropin releasing hormone (CRH)
- Cortisol levels normally rise by >3 fold during severe stress
- Major Effects of Glucocorticoids
- Stress hormone responses with counterregulatory activity against insulin
- Catabolic effects - nitrogen wasting, muscle wasting
- Maintenance of normal vascular tone (as glucocorticoids and mineralocorticoids)
- Increase hepatic glucose production
- Stimulate hyperglycemia (may produce frank diabetes)
- Stimulate triglyceride synthesis (may lead to hypertriglyceridemia)
- Stimulate fluid retention
- Stimulate production of adipose tissue (for example, fat pad)
- Cortisol also has some mineralocorticoid activity
- Sodium retention and fluid retention (due to sodium)
- Potassium excretion
- Note: cortisol can bind to the steroid receptor in the kidney which controls Na/K ATPase
- The kidney has an enzyme which metabolizes cortisol but not aldosterone
- Most endocrine effects of glucocorticoids are due to activation of gene transcription [1]
- Glucocorticoid receptor (GR) exists in inactive state in cytoplasm bound to chaperone
- Glucocorticoids bind to GR causing chaperone dissociation and nuclear translocation
- Glucocorticoid-GR dimerizes and binds to glucocorticoid response element (GRE) on DNA
- Binding of dimerized glucocorticoid-GR to GRE stimulates gene transcription
- Some transcription stimulation is due to induction of histone acetyltransferase (HAT)
- HAT acetylates mainly H4 histones and opens chromatin to allow transcription
- Most endocrine transcription activation required dimerized glucocorticoid GR
B. Anti-Inflammatory Activities [1,3,6]
- Extremely effective, subacutely (6-24 hours) acting anti-inflammatory agents
- Block late (but not early) inflammatory responses
- Especially potent at suppressing Eosinophil and Lymphocyte function
- Inhibit Cytokine Production by Lymphocytes
- Blocks cytokine production by both T helper 1 and 2 cells
- Blocks cytokine production by B cells (and probably also monocytes/macrophages)
- Reduces major inflammatory cytokines, IL-1, IL-2, IL-6, IL-12, IL-18, TNFa, IFNg
- Reduces IL-4 and IL-5 production, leading to reduced IgE and eosinophil production
- Reduces chemokines IL-8, RANTES, MIP-1a, MCP-1, MCP-3, MCP-4, eotaxin
- Reduces expression of adhesion molecules ICAM-1, VCAM-1, E-Selectin
- Increases anti-inflammatory cytokines annexin-1, IL-10, IL-1 receptor antagonist, others
- Inhibits nuclear factor kappa B (NF-kB) function, a transciption factor involved in many inflammatory pathways
- Blocks Production of Arachidonic Acid Metabolites
- Blocks prostaglandins through 3 independent mechanisms:
- Induction and activation of annexin I
- Induction of MAPK phosphatase I,
- Blocks COX2 transcription (by NF-kB inhibition)
- Increases synthesis of annexin-1 (lipocortin; 37K protein)
- This enzyme blocks production of PLA2 (phospholipase A2)
- Thus preventing synthesis of arachidonic acid
- This leads to decreased synthesis of prostaglandins, leukotrienes, thromboxanes
- Reduces leukotriene (LT) and tromboxane synthesis
- Decreased peripheral blood eosinophilia (reduce IL-4, IL-5, eotaxin production)
- Modestly Reduces Neutrophil (and other Leukocyte) Migration
- Inhibit integrin and other adhesion molecule expression on endothelium, other cells
- Prevents neutrophil migration through blood vessels
- Leads to neutrophil "demargination" off of blood vessel walls
- This causes an apparent neutrophilia, also called "stress response"
- In general, white cell counts (WBC) should be <15K/µL when due to steroid effects
- Glucocorticoids do not induce immature WBC
- Presence of immature forms on WBC differential generally indicates infection
- Most anti-inflammatory activities are due to repression of transcription [1,3]
- Inhibition of NF-kB function as described above
- Blockade of p38 mitogen activated kinase (MAPK)
- Stimulation of histone deacetylase (HDAC) which deacetylase histones (mainly H4)
- Dimerization of glucocorticoid-GR likely not required for anti-inflammatory activity
- Theophylline may enhance the HDAC activity of glucocorticoids
- Glucocorticoid Resistance [1]
- High levels of inflammatory cytokines (such as IL-2 + IL-4) reduce glucocorticoid responses
- Inflammatory cytokines stimulating p38 MAPK induce glucocorticoid resistance
- p38 MAPK phosphorylates GR and reduces their response to glucocorticoids
- Inhibition of HDAC activity of glucocorticoid also found in steroid-resistant asthma
C. Relative Activities Of Commonly Used Glucocorticoids
D. Utility of Glucocorticoids - These agents are some of the most commonly used drugs in medicine
- Used in the short term (<1 month), they have excellent therapeutic ratios
- Long term use of glucocorticoids (except as replacement therapy) should always be avoided
- Anti-Inflammatory Effects [1]
- Majority of rheumatologic syndromes respond to glucocorticoids
- Asthma
- Acute Bronchitis and COPD exacerbations
- Allergies
- Inflammatory Bowel Disease (IBD) - systemic release, local release, enemas [2]
- Inflammatory skin diseases: psoriasis, allergic dermatitis, bullous diseases
- Adjunctive therapy for various hematologic cancers (mainly lymphomas)
- Reduction of Edema - particularly in the central nervous system
- Replacement therapy for Adrenal Insufficiency
- Use in Severe Illness
- Recommendations for use based relative hypoadrenalism in critically ill patients
- Normal persons increase hypothalamic-pituitary-adrenal action in response to stress
- Patients with occult adrenal insufficiency may decompensate in stressful situations
- All patients with history of steroid use need high dose replacement therapy
- All patients with history of adrenal insufficiency will need replacement therapy also
- Prolonged methylprednisolone, 2mg/kg/day IV, begun after day 7, greatly improved extubation rate [4,5] and mortality [4] in patients with resistant ARDS
- Methylprednislone begun after at least 7 days of ARDS had no overall mortality benefit at 2 and 6 months [5]
- Methylprednisolone begun after 14 days of ARDS increased 2- and 6-month mortality [5]
- Methylprednisolone after 7 days increase number of ventilator-free and shock-free days within the first 28 days (improved oxygenation but not mortality) [5]
- Methylprednisolone blunts fever response but has not affected infection rates [4,5]
- Most trials have been negative for overall benefit in ARDS, so routine use of glucocorticoids in ARDS is not supported by evidence
- No clear benefit or harm in patients with sepsis syndrome
- Preterm Infants [7]
- Should be given to all infants <34 weeks and most 34-38 weeks each week
- Should be used for PROM (though less effective in this situation)
- Decreases risk of death, RDS, and IVH in preterm infants
- Local Injections of Glucocorticoids [14]
- For a variety of joint and tendon associated pain syndromes
- Consider as adjunct to acetaminophen and NSAIDs and/or after fluid drainage
- Often for knee osteoarthritis, shoulder pain, carpal tunnel, other tendonitis, gout
- Usually given with lidocaine or other local anesthetic
- Injection of "long acting, depo" formulation ("Depo-Medrol")
- Usually effective for 1 month or longer; may be "curative"
- Injection of glucocorticoids into knees every 3 months did not accelerate cartilage loss [9]
E. Overview of Glucocorticoid Side Effects [3]
- Acute and Subacute Complications
- Gastrointestinal Problems (see below)
- Hyperglycemia - Glucose Intolerance ± Diabetes (treatment may be indicated)
- Osteonecrosis (Aseptic Necrosis) - usually femoral head
- Fluid retention, with facial puffiness
- Hirsutism, especially facial
- Pituitary and Adrenal Insufficiency (see below)
- Infection - risk strongly related to dose and duration; consider atypical bacteria, fungi [6]
- Psychosis - often anxiety, panic, mania, depression, particularly at high doses
- Chronic Complications
- Osteoporosis (even on low doses)
- Cardiovascular - dyslipidemia, hyptriglyceridemia, hypertension
- Skin - atrophy, easy bruising
- Muscle - atrophy, glucocorticoid myopathy
- Buffalo hump (fat deposition) and truncal obesity
- Adrenal atrophy
- Eyes - cataracts, glaucoma
- Peripheral Neuropathy - nerve atrophy
- Cataract Formation - both systemic and inhaled glucocorticoids (dose-dependent)
- Osteonecrosis (may have some cumulative component)
- Inhibition of growth in children (mainly with systemic glucocorticoids)
- In children, chronic inhaled budesonide had only transient effects on growth [8,9]
- Gastrointestinal
- Steroids often lead to worsening of gastritis and gastric ulcers
- Prevent duodenal ulcer healing
- Glucocorticoids do not appear to cause peptic ulcers of any type
- Cardiovascular
- Hypertension
- Accelerated atheroscerlosis due to dyslipidemia
- Dilative cardiomyopathy (related to skeletal muscle atrophy)
- Increased risk (2.5X) for cardiovascular events with high-dose systemic glucocorticoids [13]
- Ocular
- Cataracts - even with inhaled glucocorticoids
- Open angle glaucoma (particularly in older persons)
- High dose intravenous methylprednisolone potentiates warfarin [12]
- Even low dose prednisone is associated with increased adverse effects
- Early postnatal prophylactic dexamethasone is no longer recommended as it causes long term redcution in IQ, motor skills and coordination, and overall disabilities [28]
F. Glucocorticoid Induced Osteoporosis
- Major long term problem (30-50%), even with low doses of glucocorticoids
- Chronic inhaled glucocorticoids for asthma associated with mild reduced BMD [15,16]
- Calcium and Vitamin D
- Calcium (1gm/day) + Calcitriol (0.5-1µg po qd) effective in decreased LS bone loss
- Calcium (1gm/d) + 500 IU/d Vitamin D3 prevented steroid induced osteoporosis [18]
- Patients should receive Vitamin D (400IU/d) along with calcium (1000-1500mg po qd) [18]
- Ongoing debate on the value of calcium and vitamiin D in osteoporosis prevention
- Bisphosphonates ± Anabolic Agents [11,29]
- Bisphonates are clearly more effective than vitamin D alone in reducing bone loss [17]
- Alendronate 70mg/week or risedronate 35mg/wk are very effective
- Alendronate (Fosamax®) [19]
- 70mg po weekly or 10mg po qd [17] is well tolerated and very effective
- Alendronate greatly reduced N-telopeptide levels elevations induced by glucocorticoids
- Alendronate is strongly recommended for prevention of glucocorticoid induced bone loss
- Must be taken with great deal of fluids to reduce esophagitis
- Risedronate (Actonel®) [20]
- About 3-5X more potent than alendronate
- FDA approved for osteoporosis, 2.5-5.0mg/day
- Once weekly dosing (35mg) tablets now available and recommended
- Side effects comparable to placebo (including esophagitis) [21]
- Testosterone (monthly injections) prevent steroid induced osteopenia in men [22]
- Teriparatide (Forteo®) [10]
- Recombinant human PTH amino acids 1-34
- This represents active domain of the normal human 84 amino acid PTH polypeptide
- Teriparatide 20µg qd improves BMD and reduces vertebral fractures more than alendronate over 12-18 months in patients on chronic glucocorticoids [10]
- For patients with fractures, teriparatide is strongly recommended
F. Pituitary and Adrenal Insufficiency [23,24]
- Exogenous glucocorticoids inhibit hypothalamic-pituitary-adrenal axis in a feedback loop
- This inhibition can be temporary or prolonged [23,25]
- Degree and duration of inhibition are variable between individuals
- Glucocorticoids given for 7-10 days only can usually be tapered off quickly
- High peak and total steroid doses do not always lead to adrenal insufficiency
- Recommend rapid corticotropin (ACTH) stimulation test to predict insufficiency
- Patients on <6mg/d prednisone for >1 month are unlikely to have adrenal suppression
- However, these patients may not respond properly to physiological stress
- Most patients on ANY glucocorticoids will need replacement in stressful situations
- Various syndromes can occur after tapering / withdrawal of exogenous glucocorticoids
- Adrenal insufficiency - defined by biochemical measurements
- Flare of disease being treated - defined by clinical and laboratory assessment
- Steroid withdrawal syndrome - symptoms of adrenal insufficiency with normal cortisol
- Predicting Adrenal Insufficiency [24]
- Corticotropin stimulation test predicts insufficiency
- Short 250µg ACTH stimulating test: cortisol measured before, 30 and 60 minutes after
- Use of 1µg ACTH (1-24 corticotropin) is likely superior to 250µg stimulation test [25]
- Baseline normal cortisol is >8µg/dL
- Normal ACTH or CRH stimulated cortisol >19µg/dL
- Baseline plasma cortisol level is a poor marker for adrenal function
- Tapering Regimens are Non-Standard (see below)
G. Infections and Glucocorticoids [26]
- Major increase in infections likely due to suppression of T cell function
- Both T helper and T killer (CTL) cell functions are suppressed
- Glucocorticoids induce apoptosis in both T and B cells
- Also inhibit antigen presenting functions of many cell types
- Therefore, many infections handled by granuloma formation are increased
- Mycobacterium tuberculosis (TB) and other mycobacteria
- Fungal infections (deep)
- Superficial fungal infections: candidial infections (intetrigo, thrush, others)
- Reactivation of Viral Infections can occur
- Varicella Zoster (Shingles)
- Herpes Simplex
- Increased incidence of Pneumocystis carinii infection [27]
- Likely due to inhibition of T cell-macrophage interactions
- Macrophage production of TNFa and intact neutrophil function required for clearance
- Addition of moderate dose steroids to anti-pneumocystis therapy improves symptoms
- Consider pneumocystis prophylaxis in persons taking high dose glucocorticoids
H. Reducing Glucocorticoid Side Effects and Risks
- Single morning dose is strongly recommended for chronic use
- For patients likely to be on chronic (>2-3 weeks of) therapy, consider baseline:
- Bone densitometry (see above)
- Tuberculosis Test - PPD (positive PPD requires further evaluation, isoniazid at least)
- Tests for hepatitis B and C viruses
- HIV Test
- Ova and Parasite Exam (Stool Sample) for persons from endemic areas
- Blood pressure, electrolytes and glucose
- After patient responds to initial therapy, taper dose
- Rapidity of taper depends on disease, starting dose, and duration of therapy
- Great deal of inter-patient variability in tolerance to taper
- Dose and duration should be considered in designing tapering
- Fairly rapid tapering (5-10mg decreases per week) to 20mg per day usually okay
- Some diseases permit alternate day dosing with good control and reduced side effects
- Reductions of ~2.5mg per week for doses below 20mg usually recommended
- For treatment >1-2 months, tapering when dose is <12mg/day should be slow
- Slow taper is ~1-2mg/week, and alternate day tapering may be considered
- If possible, taper doses to every other day therapy (thus, dosing every 48 hours)
- Chronic alternate day therapy is much safer than daily treatment
References
- Barnes PJ and Adcock IM. 2003. Ann Intern Med. 139(5):359

- Budesonide for Crohn's Disease. 2002. Med Let. 44(1122):6

- Rhen T and Cidlowski JA. 2005. NEJM. 353(16):1711

- Meduri GU, Headley AS, Golden E, et al. 1998. JAMA. 280(2):159

- National Heart Lung and Blood Institute ARDS Trials Network. 2006. NEJM. 354(16):1671

- Lionakis MS and Kontoyiannis DP. 2003. Lancet. 362(9398):1828

- Leviton LC, Goldenberg RL, Baker CS, et al. 1999. JAMA. 281(1):46

- Childhood Asthma Management Program Research Group. 2000. NEJM. 343(15):1054

- Agertoft L and Pedersen S. 2000. NEJM. 343(15):1064

- Saag KG, Shane E, Boonen S, et al. 2007. NEJM. 357(20):2028

- 30. Heffernan MP, Saag KG, Rovinson JK, Callen JP. 2006. 295(11):1300

- Costedoat-Chalumeau N, Amoura Z, Aymard G, et al. 2000. Ann Intern Med. 132(8):631

- Wei L, MacDonald TM, Walker BR. 2004. Ann Intern Med. 141(10):764

- Raynauld JP, Buckland-Wright C, Ward R, et al. 2003. Arthritis Rheum. 48(2):370

- Wong CA, Walsh LJ, Smith CJP, et al. 2000. Lancet. 355(9213):1399

- Israel E, Banerjee TR, Fitzmaurice GM, et al. 2001. NEJM. 345(13):941

- De Nijs RN, Jacobs JW, Lerns WF, et al. 2006. NEJM. 355(7):675

- Amin S, LaValley MP, Simms RW, Felson DT. 1999. Arthritis Rheum. 42:1740

- Saag KG, Emkey R, Schnitzer TJ, et al. 1998. NEJM. 339(5):292

- Harris ST, Watts NB, Genant HK, et al. 1999. JAMA. 282(14):1344

- McClung MR, Geusens P, Miller PD, et al. 2001. NEJM. 344(5):333

- Reid IR, Wattie DJ, Evans MC, Stapleton JP. 1996. Arch Intern Med. 156(11):1173

- LaRochelle GE Jr, et al. 1993. Am J Med. 95(9):258
- Krasner AS. 1999. JAMA. 282(7):671

- Henzen C, Suter A, Lerch E, et al. 2000. Lancet. 355(9203):542

- Boumpas DT, Austin HA III, Fessler BJ, et al. 1995. Ann Intern Med. 122(12):940

- Thomas CF Jr and Limper AH. 2004. NEJM. 350(24):2487

- Yeh TF, Lin YJ, Lin HC, et al. 2004. NEJM. 350913):1304

- Summey MT and Yosipovitch G. 2006. Arch Dermatol. 142(1):82
