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A. Metabolic and Endocrine Functions

  1. Normally produced by the adrenal glands, mainly in the fasciculata
  2. Baseline secretion of glucocorticoids required for normal functioning
    1. Major glucocorticoid is cortisol
    2. Cortisol is secreted with diurnal variation
    3. Highest levels occur in morning hours
    4. Lowest levels occur in very early AM (around 2-3:00 AM)
  3. Cortisol production increases in stress
    1. Major controlling hormone is ACTH (adrenocorticotropic hormone)
    2. ACTH is made in the anterior pituitary
    3. ACTH is processed from the prohormone pro-opiomelanocortin (POMC)
    4. ACTH production is stimulated by hypothalamic corticotropin releasing hormone (CRH)
    5. Cortisol levels normally rise by >3 fold during severe stress
  4. Major Effects of Glucocorticoids
    1. Stress hormone responses with counterregulatory activity against insulin
    2. Catabolic effects - nitrogen wasting, muscle wasting
    3. Maintenance of normal vascular tone (as glucocorticoids and mineralocorticoids)
    4. Increase hepatic glucose production
    5. Stimulate hyperglycemia (may produce frank diabetes)
    6. Stimulate triglyceride synthesis (may lead to hypertriglyceridemia)
    7. Stimulate fluid retention
    8. Stimulate production of adipose tissue (for example, fat pad)
  5. Cortisol also has some mineralocorticoid activity
    1. Sodium retention and fluid retention (due to sodium)
    2. Potassium excretion
    3. Note: cortisol can bind to the steroid receptor in the kidney which controls Na/K ATPase
    4. The kidney has an enzyme which metabolizes cortisol but not aldosterone
  6. Most endocrine effects of glucocorticoids are due to activation of gene transcription [1]
    1. Glucocorticoid receptor (GR) exists in inactive state in cytoplasm bound to chaperone
    2. Glucocorticoids bind to GR causing chaperone dissociation and nuclear translocation
    3. Glucocorticoid-GR dimerizes and binds to glucocorticoid response element (GRE) on DNA
    4. Binding of dimerized glucocorticoid-GR to GRE stimulates gene transcription
    5. Some transcription stimulation is due to induction of histone acetyltransferase (HAT)
    6. HAT acetylates mainly H4 histones and opens chromatin to allow transcription
    7. Most endocrine transcription activation required dimerized glucocorticoid GR

B. Anti-Inflammatory Activities [1,3,6]

  1. Extremely effective, subacutely (6-24 hours) acting anti-inflammatory agents
    1. Block late (but not early) inflammatory responses
    2. Especially potent at suppressing Eosinophil and Lymphocyte function
  2. Inhibit Cytokine Production by Lymphocytes
    1. Blocks cytokine production by both T helper 1 and 2 cells
    2. Blocks cytokine production by B cells (and probably also monocytes/macrophages)
    3. Reduces major inflammatory cytokines, IL-1, IL-2, IL-6, IL-12, IL-18, TNFa, IFNg
    4. Reduces IL-4 and IL-5 production, leading to reduced IgE and eosinophil production
    5. Reduces chemokines IL-8, RANTES, MIP-1a, MCP-1, MCP-3, MCP-4, eotaxin
    6. Reduces expression of adhesion molecules ICAM-1, VCAM-1, E-Selectin
    7. Increases anti-inflammatory cytokines annexin-1, IL-10, IL-1 receptor antagonist, others
    8. Inhibits nuclear factor kappa B (NF-kB) function, a transciption factor involved in many inflammatory pathways
  3. Blocks Production of Arachidonic Acid Metabolites
    1. Blocks prostaglandins through 3 independent mechanisms:
    2. Induction and activation of annexin I
      1. Induction of MAPK phosphatase I,
      2. Blocks COX2 transcription (by NF-kB inhibition)
    3. Increases synthesis of annexin-1 (lipocortin; 37K protein)
    4. This enzyme blocks production of PLA2 (phospholipase A2)
      1. Thus preventing synthesis of arachidonic acid
      2. This leads to decreased synthesis of prostaglandins, leukotrienes, thromboxanes
    5. Reduces leukotriene (LT) and tromboxane synthesis
    6. Decreased peripheral blood eosinophilia (reduce IL-4, IL-5, eotaxin production)
  4. Modestly Reduces Neutrophil (and other Leukocyte) Migration
    1. Inhibit integrin and other adhesion molecule expression on endothelium, other cells
    2. Prevents neutrophil migration through blood vessels
    3. Leads to neutrophil "demargination" off of blood vessel walls
    4. This causes an apparent neutrophilia, also called "stress response"
    5. In general, white cell counts (WBC) should be <15K/µL when due to steroid effects
    6. Glucocorticoids do not induce immature WBC
    7. Presence of immature forms on WBC differential generally indicates infection
  5. Most anti-inflammatory activities are due to repression of transcription [1,3]
    1. Inhibition of NF-kB function as described above
    2. Blockade of p38 mitogen activated kinase (MAPK)
    3. Stimulation of histone deacetylase (HDAC) which deacetylase histones (mainly H4)
    4. Dimerization of glucocorticoid-GR likely not required for anti-inflammatory activity
    5. Theophylline may enhance the HDAC activity of glucocorticoids
  6. Glucocorticoid Resistance [1]
    1. High levels of inflammatory cytokines (such as IL-2 + IL-4) reduce glucocorticoid responses
    2. Inflammatory cytokines stimulating p38 MAPK induce glucocorticoid resistance
    3. p38 MAPK phosphorylates GR and reduces their response to glucocorticoids
    4. Inhibition of HDAC activity of glucocorticoid also found in steroid-resistant asthma

C. Relative Activities Of Commonly Used Glucocorticoids

DrugAnti-InflammatoryMineralocorticoid
Dexamethasone250
Prednisone40
Methyl Prednisolone50
Cortisol1+
Fludrocortisone4+++

D. Utility of Glucocorticoids
  1. These agents are some of the most commonly used drugs in medicine
  2. Used in the short term (<1 month), they have excellent therapeutic ratios
  3. Long term use of glucocorticoids (except as replacement therapy) should always be avoided
  4. Anti-Inflammatory Effects [1]
    1. Majority of rheumatologic syndromes respond to glucocorticoids
    2. Asthma
    3. Acute Bronchitis and COPD exacerbations
    4. Allergies
    5. Inflammatory Bowel Disease (IBD) - systemic release, local release, enemas [2]
    6. Inflammatory skin diseases: psoriasis, allergic dermatitis, bullous diseases
  5. Adjunctive therapy for various hematologic cancers (mainly lymphomas)
  6. Reduction of Edema - particularly in the central nervous system
  7. Replacement therapy for Adrenal Insufficiency
  8. Use in Severe Illness
    1. Recommendations for use based relative hypoadrenalism in critically ill patients
    2. Normal persons increase hypothalamic-pituitary-adrenal action in response to stress
    3. Patients with occult adrenal insufficiency may decompensate in stressful situations
    4. All patients with history of steroid use need high dose replacement therapy
    5. All patients with history of adrenal insufficiency will need replacement therapy also
    6. Prolonged methylprednisolone, 2mg/kg/day IV, begun after day 7, greatly improved extubation rate [4,5] and mortality [4] in patients with resistant ARDS
    7. Methylprednislone begun after at least 7 days of ARDS had no overall mortality benefit at 2 and 6 months [5]
    8. Methylprednisolone begun after 14 days of ARDS increased 2- and 6-month mortality [5]
    9. Methylprednisolone after 7 days increase number of ventilator-free and shock-free days within the first 28 days (improved oxygenation but not mortality) [5]
    10. Methylprednisolone blunts fever response but has not affected infection rates [4,5]
    11. Most trials have been negative for overall benefit in ARDS, so routine use of glucocorticoids in ARDS is not supported by evidence
    12. No clear benefit or harm in patients with sepsis syndrome
  9. Preterm Infants [7]
    1. Should be given to all infants <34 weeks and most 34-38 weeks each week
    2. Should be used for PROM (though less effective in this situation)
    3. Decreases risk of death, RDS, and IVH in preterm infants
  10. Local Injections of Glucocorticoids [14]
    1. For a variety of joint and tendon associated pain syndromes
    2. Consider as adjunct to acetaminophen and NSAIDs and/or after fluid drainage
    3. Often for knee osteoarthritis, shoulder pain, carpal tunnel, other tendonitis, gout
    4. Usually given with lidocaine or other local anesthetic
    5. Injection of "long acting, depo" formulation ("Depo-Medrol")
    6. Usually effective for 1 month or longer; may be "curative"
    7. Injection of glucocorticoids into knees every 3 months did not accelerate cartilage loss [9]

E. Overview of Glucocorticoid Side Effects [3]

  1. Acute and Subacute Complications
    1. Gastrointestinal Problems (see below)
    2. Hyperglycemia - Glucose Intolerance ± Diabetes (treatment may be indicated)
    3. Osteonecrosis (Aseptic Necrosis) - usually femoral head
    4. Fluid retention, with facial puffiness
    5. Hirsutism, especially facial
    6. Pituitary and Adrenal Insufficiency (see below)
    7. Infection - risk strongly related to dose and duration; consider atypical bacteria, fungi [6]
    8. Psychosis - often anxiety, panic, mania, depression, particularly at high doses
  2. Chronic Complications
    1. Osteoporosis (even on low doses)
    2. Cardiovascular - dyslipidemia, hyptriglyceridemia, hypertension
    3. Skin - atrophy, easy bruising
    4. Muscle - atrophy, glucocorticoid myopathy
    5. Buffalo hump (fat deposition) and truncal obesity
    6. Adrenal atrophy
    7. Eyes - cataracts, glaucoma
    8. Peripheral Neuropathy - nerve atrophy
    9. Cataract Formation - both systemic and inhaled glucocorticoids (dose-dependent)
    10. Osteonecrosis (may have some cumulative component)
    11. Inhibition of growth in children (mainly with systemic glucocorticoids)
    12. In children, chronic inhaled budesonide had only transient effects on growth [8,9]
  3. Gastrointestinal
    1. Steroids often lead to worsening of gastritis and gastric ulcers
    2. Prevent duodenal ulcer healing
    3. Glucocorticoids do not appear to cause peptic ulcers of any type
  4. Cardiovascular
    1. Hypertension
    2. Accelerated atheroscerlosis due to dyslipidemia
    3. Dilative cardiomyopathy (related to skeletal muscle atrophy)
    4. Increased risk (2.5X) for cardiovascular events with high-dose systemic glucocorticoids [13]
  5. Ocular
    1. Cataracts - even with inhaled glucocorticoids
    2. Open angle glaucoma (particularly in older persons)
  6. High dose intravenous methylprednisolone potentiates warfarin [12]
  7. Even low dose prednisone is associated with increased adverse effects
  8. 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

  1. Major long term problem (30-50%), even with low doses of glucocorticoids
  2. Chronic inhaled glucocorticoids for asthma associated with mild reduced BMD [15,16]
  3. Calcium and Vitamin D
    1. Calcium (1gm/day) + Calcitriol (0.5-1µg po qd) effective in decreased LS bone loss
    2. Calcium (1gm/d) + 500 IU/d Vitamin D3 prevented steroid induced osteoporosis [18]
    3. Patients should receive Vitamin D (400IU/d) along with calcium (1000-1500mg po qd) [18]
    4. Ongoing debate on the value of calcium and vitamiin D in osteoporosis prevention
  4. Bisphosphonates ± Anabolic Agents [11,29]
    1. Bisphonates are clearly more effective than vitamin D alone in reducing bone loss [17]
    2. Alendronate 70mg/week or risedronate 35mg/wk are very effective
  5. Alendronate (Fosamax®) [19]
    1. 70mg po weekly or 10mg po qd [17] is well tolerated and very effective
    2. Alendronate greatly reduced N-telopeptide levels elevations induced by glucocorticoids
    3. Alendronate is strongly recommended for prevention of glucocorticoid induced bone loss
    4. Must be taken with great deal of fluids to reduce esophagitis
  6. Risedronate (Actonel®) [20]
    1. About 3-5X more potent than alendronate
    2. FDA approved for osteoporosis, 2.5-5.0mg/day
    3. Once weekly dosing (35mg) tablets now available and recommended
    4. Side effects comparable to placebo (including esophagitis) [21]
  7. Testosterone (monthly injections) prevent steroid induced osteopenia in men [22]
  8. Teriparatide (Forteo®) [10]
    1. Recombinant human PTH amino acids 1-34
    2. This represents active domain of the normal human 84 amino acid PTH polypeptide
    3. Teriparatide 20µg qd improves BMD and reduces vertebral fractures more than alendronate over 12-18 months in patients on chronic glucocorticoids [10]
    4. For patients with fractures, teriparatide is strongly recommended

F. Pituitary and Adrenal Insufficiency [23,24]

  1. Exogenous glucocorticoids inhibit hypothalamic-pituitary-adrenal axis in a feedback loop
  2. This inhibition can be temporary or prolonged [23,25]
    1. Degree and duration of inhibition are variable between individuals
    2. Glucocorticoids given for 7-10 days only can usually be tapered off quickly
    3. High peak and total steroid doses do not always lead to adrenal insufficiency
    4. Recommend rapid corticotropin (ACTH) stimulation test to predict insufficiency
  3. Patients on <6mg/d prednisone for >1 month are unlikely to have adrenal suppression
    1. However, these patients may not respond properly to physiological stress
    2. Most patients on ANY glucocorticoids will need replacement in stressful situations
  4. Various syndromes can occur after tapering / withdrawal of exogenous glucocorticoids
    1. Adrenal insufficiency - defined by biochemical measurements
    2. Flare of disease being treated - defined by clinical and laboratory assessment
    3. Steroid withdrawal syndrome - symptoms of adrenal insufficiency with normal cortisol
  5. Predicting Adrenal Insufficiency [24]
    1. Corticotropin stimulation test predicts insufficiency
    2. Short 250µg ACTH stimulating test: cortisol measured before, 30 and 60 minutes after
    3. Use of 1µg ACTH (1-24 corticotropin) is likely superior to 250µg stimulation test [25]
    4. Baseline normal cortisol is >8µg/dL
    5. Normal ACTH or CRH stimulated cortisol >19µg/dL
    6. Baseline plasma cortisol level is a poor marker for adrenal function
  6. Tapering Regimens are Non-Standard (see below)

G. Infections and Glucocorticoids [26]

  1. Major increase in infections likely due to suppression of T cell function
    1. Both T helper and T killer (CTL) cell functions are suppressed
    2. Glucocorticoids induce apoptosis in both T and B cells
    3. Also inhibit antigen presenting functions of many cell types
  2. Therefore, many infections handled by granuloma formation are increased
    1. Mycobacterium tuberculosis (TB) and other mycobacteria
    2. Fungal infections (deep)
    3. Superficial fungal infections: candidial infections (intetrigo, thrush, others)
  3. Reactivation of Viral Infections can occur
    1. Varicella Zoster (Shingles)
    2. Herpes Simplex
  4. Increased incidence of Pneumocystis carinii infection [27]
    1. Likely due to inhibition of T cell-macrophage interactions
    2. Macrophage production of TNFa and intact neutrophil function required for clearance
    3. Addition of moderate dose steroids to anti-pneumocystis therapy improves symptoms
    4. Consider pneumocystis prophylaxis in persons taking high dose glucocorticoids

H. Reducing Glucocorticoid Side Effects and Risks

  1. Single morning dose is strongly recommended for chronic use
  2. For patients likely to be on chronic (>2-3 weeks of) therapy, consider baseline:
    1. Bone densitometry (see above)
    2. Tuberculosis Test - PPD (positive PPD requires further evaluation, isoniazid at least)
    3. Tests for hepatitis B and C viruses
    4. HIV Test
    5. Ova and Parasite Exam (Stool Sample) for persons from endemic areas
    6. Blood pressure, electrolytes and glucose
  3. After patient responds to initial therapy, taper dose
    1. Rapidity of taper depends on disease, starting dose, and duration of therapy
    2. Great deal of inter-patient variability in tolerance to taper
    3. Dose and duration should be considered in designing tapering
    4. Fairly rapid tapering (5-10mg decreases per week) to 20mg per day usually okay
    5. Some diseases permit alternate day dosing with good control and reduced side effects
    6. Reductions of ~2.5mg per week for doses below 20mg usually recommended
    7. For treatment >1-2 months, tapering when dose is <12mg/day should be slow
    8. Slow taper is ~1-2mg/week, and alternate day tapering may be considered
    9. If possible, taper doses to every other day therapy (thus, dosing every 48 hours)
    10. Chronic alternate day therapy is much safer than daily treatment

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