What is the difference between cortisone and synthetic corticosteroids?

Cortisone vs. Synthetic Corticosteroids: Key Differences

Cortisone is a naturally occurring glucocorticoid, while synthetic corticosteroids (like dexamethasone, prednisone, and methylprednisolone) are chemically modified derivatives designed to be more potent and have different pharmacologic properties. 1

Fundamental Chemical and Pharmacologic Distinctions

Natural vs. Synthetic Origin

• Cortisone (and hydrocortisone/cortisol) are naturally occurring glucocorticoids produced by the adrenal cortex with both glucocorticoid and mineralocorticoid (salt-retaining) properties 1
• Synthetic corticosteroids are chemically modified versions created to enhance anti-inflammatory potency while often reducing mineralocorticoid effects 2

Potency Differences

The potency hierarchy is critical for dosing equivalence:

• Cortisone/Hydrocortisone: Least potent (baseline reference) 2
• Prednisone/Methylprednisolone: 4-5 times more potent than hydrocortisone 3, 2
• Dexamethasone: Approximately 25 times more potent than hydrocortisone 3, 2

This means 0.5 mg/kg/day of dexamethasone equals 15-20 mg/kg/day of hydrocortisone—a massive difference with significant clinical implications 3

Receptor Binding Characteristics

A crucial mechanistic difference exists in how these agents interact with cellular receptors:

• Cortisone/Hydrocortisone: Binds to both mineralocorticoid AND glucocorticoid receptors, mimicking native cortisol 3
• Synthetic corticosteroids (especially dexamethasone): Bind ONLY to glucocorticoid receptors 3

This selective binding has profound consequences—dexamethasone's exclusive glucocorticoid receptor binding causes hippocampal neuronal degeneration and necrosis in animal models, an effect blocked by simultaneous corticosterone (cortisol equivalent) administration 3

Half-Life and Duration of Action

• Short-acting (hydrocortisone, cortisone): Shortest duration 2
• Intermediate-acting (prednisone, methylprednisolone): Moderate duration 2
• Long-acting (dexamethasone): Prolonged biological half-life, resulting in much higher relative potency even at equivalent glucocorticoid doses 3

Clinical Implications of These Differences

Neurodevelopmental Safety Profile

The most striking clinical difference emerges in neonatal populations:

• Dexamethasone: Multiple RCTs demonstrate adverse neurodevelopmental outcomes, decreased hippocampal volume, altered hippocampal synaptic plasticity, and impaired memory formation in later life 3
• Hydrocortisone: Neither multicenter RCTs nor cohort studies reveal adverse effects on functional or structural neurologic outcomes; no decrease in hippocampal volume, no adverse hippocampal metabolism, and no memory impairment at school age 3

Replacement Therapy vs. Pharmacologic Suppression

• Cortisone/Hydrocortisone: Preferred for physiologic replacement in adrenocortical deficiency states because they replicate native hormone function with both glucocorticoid and mineralocorticoid activity 1, 3
• Synthetic analogs: Primarily used for potent anti-inflammatory effects in pathologic conditions, not for replacement therapy 1

For adrenal insufficiency, hydrocortisone 15-25 mg/day (or cortisone acetate 25-37.5 mg/day) in divided doses mimics physiologic cortisol secretion patterns 3

Dose Equivalence for Anti-Inflammatory Use

When prescribing for inflammatory conditions, understanding equivalence prevents under- or over-dosing:

• Cortisone acetate 25 mg = Hydrocortisone 20 mg = Prednisone 5 mg = Methylprednisolone 4 mg = Dexamethasone 0.75 mg 3

First-Pass Metabolism

• Budesonide (a synthetic corticosteroid): 90% first-pass hepatic clearance with rapid degradation, resulting in potent topical effects with reduced systemic exposure 3
• Conventional corticosteroids: More complete systemic absorption 3

Common Clinical Pitfalls

Assuming All Corticosteroids Are Interchangeable

They are not. The choice between cortisone/hydrocortisone versus synthetic agents should be deliberate:

• Use cortisone/hydrocortisone for replacement therapy in adrenal insufficiency 3, 1
• Use synthetic agents when maximal anti-inflammatory potency is needed 1, 2
• In neonates requiring postnatal corticosteroids, hydrocortisone (not dexamethasone) should be strongly considered given the neurodevelopmental safety profile 3

Ignoring Mineralocorticoid Activity

• Cortisone and hydrocortisone retain salt and water; synthetic agents generally do not 1
• In primary adrenal insufficiency, separate mineralocorticoid replacement (fludrocortisone 50-200 mcg/day) is required when using synthetic glucocorticoids 3

Underestimating Potency Differences

High-dose dexamethasone (0.5 mg/kg/day) has been associated with numerous short- and long-term adverse outcomes including neurodevelopmental impairment, with no evidence that high doses confer additional benefit over lower-dose therapy 3

Duration-Dependent Adrenal Suppression

All corticosteroids suppress the hypothalamic-pituitary-adrenal axis with prolonged use (>2 weeks), but longer-acting agents like dexamethasone may cause more profound suppression 4, 3. Patients receiving >14 days of treatment require tapering and potentially HPA axis evaluation 3