Drugs Causing Medical (Pharmacological) Adrenalectomy

1. Mitotane (o,p'-DDD)

• Class: Adrenolytic agent; chemically related to DDT/DDD insecticides
• Mechanism: Selectively destroys adrenocortical cells (both normal and neoplastic) - its exact mechanism is not fully elucidated, but it causes a rapid and profound reduction in adrenocorticosteroids and their urinary metabolites. This is the drug that most closely mimics a true surgical adrenalectomy.
• Uses: Inoperable adrenocortical carcinoma (primary indication); Cushing syndrome from adrenal tumor or hyperplasia; can be used to induce medical adrenalectomy during or after pituitary radiation
• Dosing: Initial 2-6 g/day orally in 3-4 divided doses; max up to 16 g/day
• Key point: ~40% oral absorption; drug persists in fat for 6-9 weeks after stopping. Because it damages the adrenal cortex, corticosteroid replacement is mandatory during therapy.
• Note: Do NOT co-administer spironolactone - it interferes with mitotane's adrenal suppression
• ADRs: Anorexia/nausea (majority), somnolence/lethargy (~34%), dermatitis (~15-20%), adrenal insufficiency requiring replacement

2. Metyrapone

• Class: Adrenal enzyme inhibitor
• Mechanism: Inhibits 11β-hydroxylase (CYP11B1), the final step in cortisol synthesis (conversion of 11-deoxycortisol to cortisol). This leads to accumulation of 11-deoxycortisol (compound S) and reduced cortisol output.
• Uses: Medical management of Cushing syndrome; also used diagnostically (the metyrapone test for pituitary ACTH reserve)
• Combination therapy: Metyrapone + aminoglutethimide together can cause a total adrenal enzyme block, necessitating full corticosteroid replacement

3. Aminoglutethimide

• Class: Adrenal enzyme inhibitor
• Mechanism: Inhibits the first step of steroidogenesis - the side-chain cleavage of cholesterol (CYP11A1/desmolase), blocking conversion of cholesterol to pregnenolone. This blocks synthesis of ALL adrenal steroids (cortisol, aldosterone, androgens, estrogens).
• Uses: Cushing syndrome; formerly used in metastatic breast/prostate cancer (estrogen deprivation); adrenocortical hyperfunction
• Key point: Its broad blockade means mineralocorticoid replacement is also required

4. Ketoconazole

• Class: Imidazole antifungal (used off-label for adrenal suppression)
• Mechanism: Inhibits adrenal steroid biosynthesis at two points: (a) cholesterol side-chain cleavage (CYP11A1) and (b) 11β-hydroxylation (CYP11B1). This creates a dual block in the steroidogenic pathway.
• Uses: Long-term control of hypercortisolism in Cushing syndrome of either pituitary or adrenal origin
• Dosing: 600-800 mg/day for 3 months to 1 year for adrenal suppression
• Note: FDA-approved as antifungal; its adrenal-suppressive effect was initially a recognized side effect

5. Etomidate

• Class: IV anesthetic agent
• Mechanism: Inhibits 11β-hydroxylase (CYP11B1) and to a lesser extent side-chain cleavage enzyme. Even a single induction dose can suppress the adrenal cortex for 4-8 hours; prolonged infusion causes sustained adrenal suppression.
• Uses: Rapid control of severe hypercortisolism in critically ill patients (e.g., florid Cushing syndrome awaiting surgery); also used in emergency management of adrenal crisis precipitated by Cushing
• Key point: The only agent available for IV/parenteral adrenal suppression - important when oral therapy is not feasible

6. Trilostane

• Class: Competitive enzyme inhibitor
• Mechanism: Inhibits 3β-hydroxysteroid dehydrogenase (3β-HSD), which is needed for the conversion of pregnenolone to progesterone (and DHEA to androstenedione). This blocks synthesis of all downstream steroids.
• Uses: Cushing syndrome; also veterinary use (canine hyperadrenocorticism)

Summary Table

Clinical Pearls

• Combination of metyrapone + aminoglutethimide causes a complete adrenal enzyme block and requires full corticosteroid (and often mineralocorticoid) replacement
• Mitotane is unique in being adrenolytic (destroys cells) rather than just an enzyme inhibitor - hence it most closely resembles a true surgical adrenalectomy
• All of these drugs risk precipitating adrenal insufficiency - patients must be monitored and replacement therapy prepared
• Nelson syndrome is a risk after bilateral surgical adrenalectomy (not medical adrenalectomy); medical adrenalectomy is sometimes preferred to avoid this complication