Corticosteroids — Systemic Uses and Side Effects

• Glucocorticoid Receptor (GR) Mechanism — Genomic and Non-Genomic Effects: Corticosteroids diffuse across cell membranes and bind to the glucocorticoid receptor, a ligand-activated transcription factor present in virtually all cells. Once ligand-bound, the GR translocates to the nucleus where it binds to glucocorticoid response elements (GREs) in DNA regulatory regions. This transactivation directly increases expression of anti-inflammatory genes (e.g., IL-10, TGF-β, lipocortin-1) while transrepression inhibits pro-inflammatory transcription factors (NF-κB, AP-1), suppressing IL-2, TNF-α, IL-6, and GM-CSF production. Additionally, non-genomic mechanisms occur within minutes via rapid GR signaling at the cell membrane, modulating ion channels, phospholipase C, and MAPK pathways. The therapeutic window between glucocorticoid and mineralocorticoid receptor activation varies by agent—synthetic corticosteroids like dexamethasone and prednisone have favorable selectivity for GR over mineralocorticoid receptor (MR), whereas hydrocortisone exhibits significant MR activity, explaining sodium retention and hypokalemia with high-dose hydrocortisone.

• Immunosuppression and Anti-inflammatory Effects: At the cellular level, corticosteroids reduce lymphocyte proliferation by decreasing IL-2 production and IL-2 receptor expression, resulting in dramatic declines in circulating lymphocytes (particularly T cells) within hours. They induce apoptosis in thymic lymphocytes and inhibit dendritic cell maturation and antigen presentation. Macrophage activation is suppressed through downregulation of adhesion molecules (ICAM-1, ELAM-1) and chemokine receptors, reducing leukocyte recruitment to inflammatory sites. Neutrophils are paradoxically increased in blood (due to demargination and decreased apoptosis) while their antimicrobial function is impaired. Production of complement components and immunoglobulins decreases. These effects combine to suppress both Th1 (cell-mediated) and Th2 (humoral) immunity, explaining increased susceptibility to infections. The anti-inflammatory effects also involve stabilization of lysosomal membranes, preventing release of degradative enzymes and reducing vasodilatation, edema, and fibrin deposition.

• Metabolic and Endocrine Effects: Corticosteroids promote gluconeogenesis in the liver via upregulation of PEPCK and G6Pase, simultaneously antagonizing insulin action in peripheral tissues—these dual effects explain hyperglycemia and glucose intolerance. Protein catabolism is accelerated in muscle and skin through increased expression of proteolytic enzymes and decreased amino acid uptake, resulting in myopathy and impaired wound healing. Lipolysis is enhanced in extremities while fat redistribution promotes central/visceral obesity due to preferential MR activation in adipose tissue. Bone metabolism is disrupted through multiple mechanisms: decreased intestinal calcium absorption, increased urinary calcium excretion, suppression of bone formation via reduced osteoblast differentiation (decreased Wnt/β-catenin signaling) and increased osteoblast apoptosis, and enhanced osteoclast activity through RANKL upregulation. These changes result in net bone loss of 5-15% annually with high-dose therapy. Corticosteroids suppress the hypothalamic-pituitary-adrenal (HPA) axis by inhibiting CRH and ACTH release, causing secondary adrenal insufficiency—suppression occurs dose-dependently, typically affecting HPA function at doses ≥20 mg prednisone daily for >2 weeks.

• Vascular and Hemodynamic Effects: Corticosteroids increase peripheral vascular resistance and enhance catecholamine sensitivity through upregulation of α-adrenergic receptors and restoration of vascular tone, effects mediated by both GR and MR activation. Increased glomerular filtration rate and renal sodium reabsorption promote volume expansion and hypertension. Endothelial dysfunction develops chronically through impaired nitric oxide synthase activity and increased endothelin-1, predisposing to atherosclerotic disease. Sterile inflammation is suppressed through reduced expression of adhesion molecules and chemokines, explaining anti-inflammatory efficacy.

• Ocular and Intraocular Pressure Effects: Corticosteroids impair aqueous humor drainage through effects on trabecular meshwork cells, increasing intraocular pressure particularly in genetically predisposed individuals (estimated 5-15% of the general population has steroid-responsive elevation, while 1-5% develops clinically significant glaucoma). Posterior subcapsular cataracts develop through osmotic stress on lens epithelial cells and direct effects on lens protein synthesis. Central serous chorioretinopathy can occur through alteration of retinal pigment epithelium permeability and choroidal vasodilation.

• Autoimmune and Rheumatologic Diseases: These represent the largest category of chronic corticosteroid use. Systemic lupus erythematosus (SLE), vasculitis (ANCA-associated, polyarteritis nodosa), polymyalgia rheumatica, temporal arteritis, myasthenia gravis, and autoimmune hemolytic anemia frequently require corticosteroids as first-line agents or as adjuncts to steroid-sparing immunosuppressive drugs. Patients with these conditions typically require sustained treatment (months to years), leading to cumulative exposure and increased adverse effect risk.

• Allergic and Inflammatory Conditions: Severe asthma exacerbations, anaphylaxis, angioedema, severe allergic rhinitis, and eosinophilic granulomatosis with polyangiitis (Churg-Strauss syndrome) necessitate corticosteroid therapy. Acute exacerbations may require short-term high-dose therapy with rapid taper, whereas chronic severe asthma may require maintenance therapy.

• Pulmonary Diseases: Interstitial lung disease, chronic obstructive pulmonary disease (COPD) with acute exacerbations, acute respiratory distress syndrome (ARDS), and sarcoidosis frequently require systemic corticosteroids, often in combination with other agents. Duration varies from days (acute exacerbations) to months (progressive fibrosis).

• Oncologic Conditions: Corticosteroids serve dual roles—as adjuvant therapy in lymphomas and leukemias (where they directly induce lymphocyte apoptosis) and as supportive care to manage cancer-related symptoms (nausea, fatigue, anorexia) and complications (cerebral edema from CNS metastases, spinal cord compression, tumor-related hypercalcemia). Both short-term high-dose and chronic low-dose regimens are employed depending on the malignancy.

• Infectious Diseases: Despite immunosuppressive effects, corticosteroids are indicated adjunctively in specific infections: tuberculous meningitis (reduces mortality and neurologic sequelae), bacterial meningitis (improves outcomes when given with antibiotics), Pneumocystis jirovecii pneumonia (PCP) in advanced HIV (CD4 <100) with hypoxemia, and COVID-19 with severe hypoxemia. The anti-inflammatory benefits in these settings outweigh infection risks when appropriately timed.

• Endocrine Emergencies: Acute adrenal insufficiency (Addisonian crisis) is a life-threatening indication requiring immediate high-dose IV hydrocortisone (100 mg every 6-8 hours). Thyroid storm and hypercalcemia of malignancy also warrant corticosteroid therapy.

• Neurologic Conditions: Multiple sclerosis relapses, spinal cord injury (high-dose methylprednisolone within 8 hours of injury), brain tumors causing cerebral edema, and increased intracranial pressure are treated with corticosteroids. Acute demyelinating disorders benefit from IV methylprednisolone.

• Gastrointestinal Diseases: Inflammatory bowel disease (Crohn's disease, ulcerative colitis), autoimmune hepatitis, and primary biliary cirrhosis frequently require corticosteroids, though steroid-sparing agents are preferred for maintenance therapy due to adverse effect burden.

• Renal Diseases: Nephrotic syndrome (minimal change disease, IgA nephropathy), rapidly progressive glomerulonephritis, and lupus nephritis commonly require corticosteroids as first-line or adjunctive therapy.

• Risk Factors Predicting Adverse Effects:
• Dose and Duration: High cumulative doses (typically defined as ≥40 g prednisone equivalent over lifetime) and prolonged therapy (>3 months) substantially increase adverse effect risk; every 10 mg/day increase in dose approximately doubles infection risk
• Age: Elderly patients experience more severe bone loss, hypertension, metabolic derangements, and infectious complications; pediatric patients have growth suppression concerns
• Comorbidities: Pre-existing diabetes, hypertension, osteoporosis, cardiovascular disease, glaucoma, and history of tuberculosis or other infections dramatically increase risk
• Individual Genetic Factors: Glucocorticoid receptor polymorphisms influence metabolic and immune responses; variations in 11β-hydroxysteroid dehydrogenase activity affect local corticosteroid metabolism
• Concurrent Medications: NSAIDs, diuretics, anticoagulants, and certain immunosuppressants interact with corticosteroids, amplifying adverse effects

• Metabolic and Endocrine Effects (onset: days to weeks):
• Hyperglycemia and Diabetes Mellitus: New-onset or worsened glycemic control occurs in 20-50% of patients receiving systemic corticosteroids; this manifests as elevated fasting glucose, elevated random glucose, increased HbA1c, or new polyuria/polydipsia. The mechanism combines impaired insulin secretion with insulin resistance in muscle and adipose tissue. Steroid-induced diabetes is typically reversible upon corticosteroid withdrawal but may persist in some cases.
• Truncal/Central Obesity with Fat Redistribution: This pathognomonic finding results from preferential visceral fat deposition combined with fat loss from face and extremities; develops within weeks to months and may persist after steroid discontinuation due to altered set-point of energy metabolism
• Dyslipidemia: Elevated total cholesterol, LDL-cholesterol, and triglycerides occur in 50-70% of patients due to increased hepatic synthesis and decreased clearance; HDL-cholesterol decreases, worsening the atherogenic lipid profile

• Cushingoid Habitus (onset: weeks to months; chronic use):
• Moon facies (rounded, plethoric face due to fat redistribution and fluid retention)
• Buffalo hump (dorsocervical fat pad from altered lipolysis)
• Supraclavicular fullness and generalized facial puffiness
• Skin Changes: Purple striae (stretch marks from collagen breakdown), easy bruising (capillary fragility from collagen loss), facial erythema, skin atrophy, and poor wound healing

• Psychiatric and Neuropsychological Manifestations (onset: days to weeks; higher with doses >40 mg prednisone daily):
• Hypomania and Mania: Euphoria, decreased need for sleep, racing thoughts, increased goal-directed activity; occur in 5-10% of patients
• Depression: Mood lability, tearfulness, anhedonia, fatigue; can progress to suicidal ideation (risk highest during taper when mood crashes)
• Anxiety: Nervousness, tremor, palpitations
• Cognitive Dysfunction: Memory impairment, confusion, difficulty concentrating; particularly concerning in elderly patients
• Psychosis: Hallucinations, delusions, disorganized behavior; rare but serious, more common at high doses (>60 mg prednisone daily)

• Musculoskeletal Manifestations:
• Steroid-Induced Osteoporosis: Develops rapidly with 5-15% bone loss annually; presents with vertebral compression fractures, hip fractures (highest fracture risk is in first 3 months of therapy), and kyphosis. Risk is highest in postmenopausal women and elderly men. Vertebral fractures may occur with minimal trauma and may be clinically silent until acute collapse causes severe back pain.
• Steroid Myopathy: Proximal muscle weakness (hip, shoulder girdle weakness causing difficulty rising from chair or climbing stairs) occurs in 50-80% of patients on chronic high-dose therapy; results from muscle atrophy and impaired contractility. Severity correlates with cumulative dose. CPK levels are typically normal, distinguishing from polymyositis. Pain is usually absent, and reflexes remain intact.
• Avascular Necrosis (Osteonecrosis): Typically affects femoral head, femoral condyle, or humeral head; presents with sudden onset pain with weight-bearing or movement. Risk is dose-dependent and cumulative; occurs in 5-15% of patients receiving high-dose prolonged therapy.

• Infectious Complications (onset: variable, can occur acutely or develop insidiously):
• Bacterial Infections: Increased frequency and severity of pneumonia, urinary tract infections, skin infections, and sepsis due to impaired neutrophil function and decreased cell-mediated immunity. Presentation may be atypical or fulminant.
• Opportunistic Infections: Pneumocystis jirovecii pneumonia (PCP) risk increases at doses ≥20 mg prednisone daily for >1 month; presents with subacute dyspnea, nonproductive cough, chest discomfort, and hypoxemia. Tuberculosis reactivation occurs in 1-2% of patients on moderate-dose corticosteroids, particularly those with positive tuberculin skin test or chest X-ray findings. Fungal infections (candidiasis, aspergillosis, cryptococcal meningitis, coccidioidomycosis) risk increases, particularly with higher doses and in immunocompromised hosts. Cytomegalovirus (CMV) reactivation can occur. Herpes zoster reactivation occurs more frequently, sometimes disseminated.
• Atypical Presentations: Infection severity may be underestimated due to suppressed inflammatory response; fever may be blunted, and classic signs of infection (elevated WBC, infiltrates on imaging) may be absent.

• Cardiovascular and Hypertensive Manifestations (onset: days to weeks):
• Hypertension: Occurs in 20-40% of patients on chronic therapy; results from sodium retention (MR activation), enhanced catecholamine sensitivity, and endothelial dysfunction. May be severe requiring multiple antihypertensive agents.
• Arrhythmias: Hypokalemia from mineralocorticoid effects predisposes to atrial fibrillation and other supraventricular arrhythmias
• Thrombotic Events: Increased risk of deep venous thrombosis and pulmonary embolism due to hypercoagulability and vascular endothelial dysfunction, particularly in immobilized patients

• Gastrointestinal Manifestations (onset: variable):
• Peptic Ulcer Disease and Gastritis: Increased risk especially when combined with NSAIDs; may present with abdominal pain, hematemesis, or melena. Increased gastric acid secretion contributes.
• Pancreatitis: Rare but serious; presents with severe abdominal pain, elevated lipase and amylase
• **Increased Appetite and Weight

Toxicities and their mechanisms

• HPA axis suppression and adrenal crisis: exogenous glucocorticoid feedback silences CRH/ACTH, causing adrenal cortical atrophy. Abrupt discontinuation, intercurrent illness, or surgery precipitates hypotension refractory to fluids, hypoglycemia, hyponatremia, and eosinophilia. There is no antidote to steroid excess — the "reversal agent" for the crisis of withdrawal is stress-dose IV hydrocortisone plus isotonic saline and dextrose, as outlined by the Endocrine Society's adrenal insufficiency guideline.
• Glucocorticoid-induced osteoporosis (GIOP): suppressed osteoblastogenesis plus RANKL-driven osteoclast activation. The ACR Guideline for Prevention and Treatment of GIOP recommends calcium and vitamin D for all patients anticipated to receive ≥3 months of therapy, FRAX assessment with glucocorticoid adjustment, and an oral bisphosphonate (alendronate) as first-line pharmacologic therapy in moderate- to high-risk patients.
• Hyperglycemia: hepatic gluconeogenesis plus peripheral insulin resistance produce a predominantly postprandial/afternoon hyperglycemia with once-daily morning prednisone, so fasting glucose alone under-detects it. The ADA Standards of Care support glucose monitoring and insulin (often intermediate-acting or prandial-weighted) rather than fixed basal-only regimens.
• Infection: impaired cell-mediated immunity. Latent TB screening before prolonged therapy is standard (CDC), and Pneumocystis prophylaxis with TMP-SMX is customary at roughly ≥20 mg prednisone daily for a month or more, especially with a second immunosuppressant. Consider strongyloides screening in patients with endemic exposure given hyperinfection risk.
• Other: peptic ulceration (risk chiefly when combined with NSAIDs — add a PPI), posterior subcapsular cataract and ocular hypertension, neuropsychiatric effects, hypokalemic metabolic alkalosis with mineralocorticoid-active agents, and linear growth suppression in children.

• **Iatrogenic Cushing syndrome has a suppressed ACTH and suppressed serum cortisol**, low DHEA-S, and bilaterally small adrenals — the opposite of an ACTH-secreting adenoma. Absence of hyperpigmentation and virilization is the giveaway; the common distractor is ordering a dexamethasone suppression test in a patient already on prednisone.
• Steroid myopathy has a normal CK and normal inflammatory markers; painless proximal weakness with intact reflexes. Elevated CK with proximal weakness points to inflammatory myopathy or statin toxicity instead — the single best next step is dose reduction/taper, not adding immunosuppression.
• Neutrophilic leukocytosis without a left shift reflects demargination and delayed neutrophil apoptosis, not infection. Corticosteroids simultaneously cause lymphopenia and eosinopenia — a rising neutrophil count with a falling eosinophil count is drug effect.
• Sudden groin/hip pain in a steroid-treated patient with normal radiographs: think avascular necrosis of the femoral head, and the best next step is MRI, which detects marrow edema long before plain films show subchondral collapse (the crescent sign).
• Any patient on >3 weeks of supraphysiologic steroid must be tapered, and needs perioperative/illness stress dosing — the classic vignette is intraoperative hypotension unresponsive to fluids and pressors in a patient whose chronic prednisone was held.
• Dexamethasone is the most potent, longest-acting agent with essentially no mineralocorticoid activity; hydrocortisone has the most. This is why dexamethasone is chosen when cortisol assays or cosyntropin testing must remain interpretable, and why hydrocortisone is chosen for adrenal crisis.
• In pregnancy, the placenta matters: 11β-HSD2 inactivates prednisone, making it preferred for maternal disease, whereas betamethasone or dexamethasone cross the placenta and are used by ACOG for antenatal fetal lung maturity in anticipated preterm birth.
• CYP3A4 inhibitors (ritonavir, cobicistat, itraconazole) plus even inhaled fluticasone can cause florid iatrogenic Cushing syndrome with adrenal suppression — a favorite "unexpected source of steroid" stem.