Mechanism of action
Cortisol (hydrocortisone) binds to intracellular glucocorticoid receptors (GR) in target tissues. The hormone-receptor complex translocates to the nucleus, where it regulates gene transcription by binding to glucocorticoid response elements (GREs) on DNA. This genomic action requires 30 minutes to hours for full effect.
Anti-inflammatory and immunosuppressive effects are mediated through multiple pathways:
- Inhibition of phospholipase A2 via induction of lipocortin-1 (annexin-1), reducing arachidonic acid release and subsequent prostaglandin and leukotriene synthesis
- Suppression of NF-κB and AP-1 transcription factors, decreasing cytokine production (IL-1, IL-2, IL-6, TNF-α, IFN-γ)
- Inhibition of leukocyte migration and function
- Stabilization of lysosomal membranes
- Reduction of capillary permeability
Metabolic effects include stimulation of gluconeogenesis in the liver, antagonism of insulin action in peripheral tissues (increasing blood glucose), promotion of lipolysis, and protein catabolism in muscle. Cortisol also has weak mineralocorticoid activity at higher doses, causing sodium retention and potassium excretion.
In adrenal insufficiency, replacement hydrocortisone restores physiologic glucocorticoid activity essential for vascular tone, stress response, and metabolic homeostasis.
- Never abruptly stop glucocorticoids after prolonged use—HPA suppression can cause life-threatening adrenal crisis.
- Cortisol inhibits phospholipase A2 via lipocortin-1, blocking arachidonic acid release and prostaglandin synthesis.
- Adrenal crisis presents with hypotension, hypoglycemia, hyperkalemia, and hyponatremia; treat immediately with IV hydrocortisone.
- Chronic glucocorticoid use causes osteoporosis by inhibiting osteoblasts and increasing osteoclast activity.
- CYP3A4 inducers (rifampin, phenytoin) increase cortisol metabolism and can precipitate adrenal insufficiency.
- Stress-dose steroids (2–3× maintenance) are required during surgery, severe illness, or trauma in patients on chronic therapy.
- Topical hydrocortisone is low-potency; safe for face and infants but can cause skin atrophy with prolonged use.
- Cortisol crosses the placenta; chronic high-dose use may increase cleft palate risk, but physiologic replacement is safe.
Indications
Endocrine replacement:
- Primary adrenal insufficiency (Addison disease)
- Secondary adrenal insufficiency (pituitary or hypothalamic dysfunction)
- Acute adrenal crisis (life-threatening emergency)
- Congenital adrenal hyperplasia (CAH)
Acute critical care:
- Septic shock (adjunctive therapy in refractory cases)
- Anaphylaxis (adjunct to epinephrine)
- Severe acute asthma exacerbation
Inflammatory and autoimmune conditions:
- Severe allergic reactions
- Inflammatory bowel disease (acute flares)
- Rheumatologic emergencies
Topical formulations (hydrocortisone creams, ointments):
- Atopic dermatitis
- Contact dermatitis
- Eczema
- Mild to moderate inflammatory skin conditions
Other routes:
- Ophthalmic: uveitis, allergic conjunctivitis
- Otic: external otitis with inflammation
- Rectal: ulcerative colitis, proctitis
- Intra-articular: inflammatory arthritis
Dosing follows the product label and clinical indication. Physiologic replacement mimics the circadian rhythm with higher morning doses.
Pharmacokinetics
Absorption: Hydrocortisone is well absorbed orally (bioavailability ~96%). Topical absorption varies with vehicle, skin integrity, and occlusion. IV and IM formulations provide immediate systemic availability.
Distribution: Cortisol is ~90% protein-bound, primarily to corticosteroid-binding globulin (CBG, transcortin) and albumin. Free (unbound) cortisol is the biologically active fraction. Volume of distribution is moderate. Cortisol crosses the placenta and enters breast milk.
Metabolism: Hepatic metabolism via 11β-hydroxysteroid dehydrogenase (11β-HSD) converts cortisol to inactive cortisone. Further metabolism occurs through reduction and conjugation pathways. Renal and hepatic impairment may reduce clearance.
Elimination: Metabolites are excreted in urine. Plasma half-life of hydrocortisone is approximately 80–120 minutes, but biologic half-life (duration of HPA suppression) is 8–12 hours.
Special considerations: In states of low CBG (nephrotic syndrome, liver disease), free cortisol fraction increases, enhancing effects. Enzyme inducers (phenytoin, rifampin, barbiturates) increase cortisol metabolism and may necessitate dose adjustment in replacement therapy.
Adverse effects
Adverse effects are dose- and duration-dependent. Short courses are generally well tolerated; chronic use carries significant risk.
Endocrine and metabolic:
- HPA axis suppression (most critical): prolonged use suppresses endogenous ACTH and cortisol secretion; abrupt withdrawal can precipitate adrenal crisis
- Hyperglycemia, new-onset diabetes, or worsening glycemic control
- Cushing syndrome (moon facies, buffalo hump, central obesity, purple striae)
- Growth suppression in children
- Dyslipidemia
Musculoskeletal:
- Osteoporosis and increased fracture risk (inhibits osteoblasts, increases osteoclast activity)
- Proximal myopathy
- Avascular necrosis (femoral head)
Cardiovascular:
- Hypertension (mineralocorticoid effects: sodium retention)
- Fluid retention and edema
- Increased cardiovascular risk with chronic use
Gastrointestinal:
- Peptic ulcer disease (risk debated; increased when combined with NSAIDs)
- Gastritis
- Pancreatitis (rare)
Immunologic and infectious:
- Increased infection susceptibility (bacterial, viral, fungal, opportunistic)
- Impaired wound healing
- Reactivation of latent tuberculosis
Psychiatric:
- Mood changes: euphoria, depression, anxiety
- Psychosis, mania (especially at high doses)
- Insomnia
Ophthalmic (with prolonged use):
- Posterior subcapsular cataracts
- Glaucoma
Dermatologic (topical):
- Skin atrophy
- Striae
- Telangiectasias
- Perioral dermatitis
- Systemic absorption with prolonged use on large areas or under occlusion
Contraindications and warnings
Contraindications:
- Systemic fungal infections (absolute for systemic use)
- Hypersensitivity to hydrocortisone or formulation components
- Live or live-attenuated vaccines (relative; immunosuppression risk)
Warnings and precautions:
HPA axis suppression: The cardinal rule is never abruptly discontinue glucocorticoids after more than 2–3 weeks of use. Taper slowly to allow HPA axis recovery. Patients may require stress-dose steroids during illness, surgery, or trauma for up to 12 months after stopping chronic therapy.
Infections: Screen for latent tuberculosis before initiating chronic therapy. Monitor for signs of infection; symptoms may be masked. Avoid live vaccines.
Cardiovascular: Monitor blood pressure and fluid status. Use caution in heart failure.
Gastrointestinal: Risk of perforation in inflammatory bowel disease or diverticulitis. Use caution in peptic ulcer disease.
Psychiatric effects: Screen for psychiatric history. Monitor mood and behavior, especially at initiation or dose changes.
Bone health: Consider bone density monitoring and calcium/vitamin D supplementation in chronic use. Bisphosphonates may be indicated for osteoporosis prevention.
Diabetes: Monitor blood glucose closely; may require adjustment of antidiabetic therapy.
Pregnancy: Cortisol crosses the placenta. Chronic high-dose use is associated with cleft palate risk in animal models, though physiologic replacement doses are considered safe. Maternal adrenal insufficiency must be treated. Pregnancy category C (historical classification).
Pediatrics: Growth monitoring is essential during chronic therapy. Use the lowest effective dose.
Ophthalmic risks: Regular eye exams in chronic users (cataract, glaucoma screening).
Drug interactions
CYP3A4 inducers (rifampin, phenytoin, carbamazepine, barbiturates, St. John's wort) increase cortisol metabolism, potentially reducing efficacy and precipitating adrenal insufficiency in replacement therapy. Dose increase may be needed.
CYP3A4 inhibitors (ketoconazole, itraconazole, ritonavir, clarithromycin, grapefruit juice) decrease cortisol metabolism, increasing systemic exposure and risk of Cushing syndrome. Dose reduction may be required. Ketoconazole is sometimes used intentionally to suppress cortisol in Cushing syndrome.
NSAIDs and aspirin: Concurrent use may increase gastrointestinal bleeding and ulceration risk. Cortisol may reduce salicylate levels; monitor for salicylate toxicity upon steroid withdrawal.
Warfarin: Glucocorticoids may alter anticoagulant effect (usually enhance), requiring INR monitoring and dose adjustment.
Oral contraceptives and estrogen: Increase CBG levels, raising total cortisol but not necessarily free cortisol; clinical significance is limited in replacement therapy.
Diuretics (loop, thiazide): Additive potassium loss; monitor electrolytes, especially in patients on chronic therapy.
Antidiabetic agents: Cortisol antagonizes insulin; may require increased doses of insulin or oral hypoglycemics.
Live vaccines: Immunosuppression from cortisol increases risk of vaccine-strain infection. Avoid live vaccines during high-dose or chronic therapy.
Anticholinesterases (myasthenia gravis treatment): Glucocorticoids may antagonize effects; monitor for worsening weakness.
Clinical pearls
Stress dosing is critical. Patients on chronic glucocorticoid therapy or with adrenal insufficiency require 2–3 times their maintenance dose during physiologic stress (surgery, severe infection, trauma). Failure to provide stress-dose steroids can lead to adrenal crisis.
Adrenal crisis is a medical emergency. Suspect in any patient with unexplained hypotension, hypoglycemia, hyperkalemia, and hyponatremia. Treat immediately with IV hydrocortisone, fluids, and dextrose. Do not wait for confirmatory ACTH stimulation test results.
Circadian dosing improves outcomes. Physiologic cortisol secretion peaks in the early morning. Mimic this pattern by giving two-thirds of the daily dose in the morning and one-third in the early afternoon to reduce HPA suppression and improve quality of life.
Check for etiology in new adrenal insufficiency. Primary (Addison disease) presents with hyperpigmentation due to elevated ACTH. Secondary (pituitary) lacks hyperpigmentation. Autoimmune adrenalitis is the most common cause in developed countries; tuberculosis is common globally.
Topical potency matters. Hydrocortisone is a low-potency topical steroid, appropriate for face, intertriginous areas, and infants. Higher-potency steroids should not be used on thin skin or under occlusion without supervision.
Beware of exogenous Cushing syndrome. Patients on chronic high-dose therapy develop iatrogenic Cushing syndrome. Consider risk vs. benefit and taper to the lowest effective dose.
Always taper. Even 2–3 weeks of pharmacologic doses may suppress the HPA axis. Taper gradually over weeks to months depending on duration of therapy. Abrupt cessation can be fatal.
Monitor bone density. Glucocorticoid-induced osteoporosis is common with chronic use. Initiate calcium, vitamin D, and consider bisphosphonates in high-risk patients.
Screen for latent TB. Reactivation risk is real. Obtain PPD or IGRA before starting long-term therapy, especially in endemic areas or high-risk populations.
Drug-drug interactions are clinically significant. Rifampin and anticonvulsants can precipitate adrenal crisis in patients on replacement therapy by accelerating cortisol metabolism.
CUSHINGOID features: Cataracts, Ulcers (peptic), Skin thinning/Striae, Hypertension/Hyperglycemia, Infections, Necrosis (avascular, femoral head), Glycosuria/Growth suppression, Osteoporosis, Immunosuppression, Diabetes
Practice questions
1. A 32-year-old woman with Addison disease on hydrocortisone replacement therapy is scheduled for an elective cholecystectomy. She takes hydrocortisone twice daily for maintenance. On the day of surgery, what is the most appropriate perioperative glucocorticoid management?
2. A 45-year-old man has been taking prednisone daily for 6 weeks to treat a severe exacerbation of ulcerative colitis. His symptoms have improved, and his gastroenterologist plans to discontinue the prednisone. What is the most appropriate approach to stopping the medication?
3. A 28-year-old woman presents to the emergency department with hypotension (BP 80/50 mmHg), nausea, vomiting, and confusion. Laboratory studies show sodium 128 mEq/L, potassium 5.9 mEq/L, and glucose 55 mg/dL. She has a history of autoimmune hypothyroidism. What is the most appropriate immediate treatment?
Frequently asked questions
How does cortisol work?
Cortisol binds intracellular glucocorticoid receptors, which translocate to the nucleus and regulate gene transcription. It inhibits phospholipase A2 (reducing prostaglandins and leukotrienes), suppresses NF-κB (decreasing cytokine production), and stabilizes cell membranes. Metabolically, it increases gluconeogenesis, antagonizes insulin, and promotes protein catabolism. This produces potent anti-inflammatory, immunosuppressive, and metabolic effects.
What are the side effects of cortisol?
The most critical side effect is HPA axis suppression with chronic use, risking adrenal crisis if abruptly stopped. Other effects include hyperglycemia, osteoporosis, infections, hypertension, fluid retention, mood changes, cataracts, glaucoma, skin atrophy, weight gain, and Cushing syndrome (moon facies, central obesity, striae). Risks are dose- and duration-dependent. Short courses are generally well tolerated.
What is cortisol used for?
Cortisol (hydrocortisone) is used for adrenal insufficiency (Addison disease, secondary adrenal insufficiency), acute adrenal crisis, septic shock, anaphylaxis, severe asthma, and inflammatory conditions. Topical hydrocortisone treats dermatitis, eczema, and mild inflammatory skin conditions. It is essential replacement therapy in primary and secondary adrenal insufficiency and congenital adrenal hyperplasia.
Can you stop taking cortisol suddenly?
No. Abruptly stopping cortisol after prolonged use (more than 2–3 weeks) can cause life-threatening adrenal crisis due to HPA axis suppression. The adrenal glands stop producing endogenous cortisol during exogenous therapy and require time to recover. Always taper glucocorticoids gradually over weeks to months. Patients may need stress-dose steroids for up to a year after stopping chronic therapy.
Cortisol vs prednisone — what is the difference?
Cortisol (hydrocortisone) is the endogenous hormone with equal glucocorticoid and weak mineralocorticoid activity, preferred for adrenal replacement. Prednisone is a synthetic glucocorticoid with four times the glucocorticoid potency, minimal mineralocorticoid activity, and longer duration of action. Prednisone is used for anti-inflammatory and immunosuppressive therapy, while hydrocortisone is the gold standard for physiologic replacement.
Conditions it is used for
Related drugs
Sources and further reading
DailyMed (FDA labels)StatPearls (NCBI Bookshelf)MedlinePlusWHO ATC/DDD index: A01AC03WHO ATC/DDD index: A07EA02
Educational content for medical students, prepared by the WhiteCoat Pro editorial team with AI assistance; every page is reviewed by a second AI model for factual errors. It is not medical advice and does not replace the product label, local guidelines or a clinician.