What drugs affect serum cortisol levels?

Drugs That Affect Serum Cortisol Levels

Multiple drug classes significantly alter serum cortisol levels through various mechanisms, including CYP3A4 enzyme induction/inhibition, direct adrenal suppression, and interference with cortisol metabolism—requiring careful monitoring and dose adjustments in clinical practice.

Exogenous Corticosteroids

Direct Cortisol Suppression

• Oral corticosteroids (prednisolone, dexamethasone) and inhaled steroids (fluticasone) directly suppress endogenous cortisol production and confound interpretation of low serum cortisol levels 1
• Dexamethasone at doses as low as 0.1 mg can suppress basal cortisol, DHA, and DHAS levels, with ACTH-stimulated responses showing even greater suppression 2
• Topical hydrocortisone, even when applied topically or ingested inappropriately, can cause systemic absorption leading to elevated serum cortisol and suppressed ACTH 3
• High-dose dexamethasone therapy (≥12 mg daily) may not maintain cortisol suppression 8-12 hours after intake due to rapid dexamethasone elimination, despite initial suppression 4

CYP3A4 Enzyme Inducers (Decrease Cortisol Levels)

These drugs enhance corticosteroid metabolism, requiring increased replacement doses:

• Antiepileptic drugs: Barbiturates, phenytoin, carbamazepine, topiramate 1, 5
• Antituberculosis drugs: Rifampin 1, 5
• Phenytoin specifically increases hepatic metabolism of corticosteroids, resulting in decreased therapeutic effect 5
• These medications may necessitate increasing hydrocortisone/cortisone acetate doses in patients with adrenal insufficiency 1

CYP3A4 Enzyme Inhibitors (Increase Cortisol Levels)

These drugs decrease corticosteroid clearance, potentially increasing cortisol levels and side effects:

• Azole antifungals: Ketoconazole (decreases metabolism by up to 60%), itraconazole 1, 5
• Macrolide antibiotics: Erythromycin and other macrolides cause significant decrease in corticosteroid clearance 1, 5
• Protease inhibitors: Ritonavir, indinavir 5
• Ketoconazole has the dual effect of both inhibiting cortisol metabolism AND directly inhibiting adrenal corticosteroid synthesis, potentially causing adrenal insufficiency during corticosteroid withdrawal 5

Drugs Affecting Cortisol Binding and Clearance

Increase Cortisol Levels

• Estrogens and oral contraceptives decrease hepatic metabolism of corticosteroids by increasing corticosteroid-binding globulin (CBG), thereby increasing total serum cortisol 5
• Pregnancy-related estrogen increases cause physiologic elevation in CBG and total serum cortisol 1

Decrease Cortisol Levels

• Cholestyramine increases the clearance of corticosteroids 5

Drugs Affecting Mineralocorticoid Activity (Indirect Effects)

While not directly affecting cortisol measurement, these alter the clinical interpretation:

• Liquorice and grapefruit juice potentiate the mineralocorticoid effect of hydrocortisone and should be avoided in patients on replacement therapy 1
• Carbenoxolone has similar mineralocorticoid-potentiating effects 1

Anesthetic Agents

• Etomidate can suppress adrenal function and may require increased corticosteroid dosing 1

Clinical Implications for Interpretation

Key Pitfalls to Avoid

• When interpreting low serum cortisol, always inquire about all forms of steroid use including oral, inhaled, and topical preparations 1
• In patients with adrenal insufficiency on replacement therapy, failure to adjust doses when starting CYP3A4 inducers can lead to adrenal crisis 1
• Conversely, starting CYP3A4 inhibitors without dose reduction can cause iatrogenic Cushing's syndrome 5
• Dexamethasone levels should be measured concomitantly with cortisol during suppression testing to reduce false-positive results from drug interactions affecting dexamethasone metabolism 6

Diagnostic Testing Considerations

• CYP3A4 inducers, rapid dexamethasone absorption/malabsorption, and increased CBG levels can cause false-positive results on dexamethasone suppression testing 6
• CYP3A4 inhibitors and decreased CBG levels can cause false-negative results 6
• Post-dexamethasone cortisol concentrations correlate with the degree of autonomous cortisol secretion in adrenal adenomas, with higher levels associated with lower ACTH and DHEAS 7