What pharmacotherapies (pharmacological treatments) are available to lower cortisol levels?

Pharmacotherapies for Lowering Cortisol Levels

Several effective pharmacological options are available to lower cortisol levels, with adrenal steroidogenesis inhibitors (ketoconazole, metyrapone, and osilodrostat) being the most reliable first-line medical therapies for hypercortisolism. 1

First-Line Medications

Adrenal Steroidogenesis Inhibitors

1. Metyrapone

   • Mechanism: Inhibits 11-beta-hydroxylation in the adrenal cortex 2
   • Dosing: 15 mg/kg every 4h or 300 mg/m² every 4h (usual dose 250-750 mg every 4h) 3
   • Efficacy: Rapid cortisol reduction (within hours) 1
   • Side effects: Hirsutism, dizziness, arthralgia, fatigue, hypokalemia, nausea, hyperandrogenism 3
   • Monitoring: Cortisol levels, electrolytes, blood pressure

2. Ketoconazole

   • Dosing: 400-600 mg/day in 2-3 divided doses, increased to 800-1,200 mg/day until cortisol normalizes 3
   • Efficacy: Response within days 1
   • Side effects: Hepatotoxicity (requires liver function monitoring), gastrointestinal disturbances 3
   • Monitoring: Liver function tests, cortisol levels

3. Osilodrostat

   • Efficacy: 86% UFC normalization, rapid cortisol reduction (within hours) 3, 1
   • Advantages: Twice-daily dosing, high efficacy 4
   • Side effects: Nausea, headache, fatigue, arthralgia, dizziness, prolonged QTc interval, hypokalemia 4
   • Monitoring: QTc interval, electrolytes, cortisol levels

Second-Line Options

Pituitary-Directed Medications

1. Pasireotide

   • Efficacy: 15-26% UFC normalization 3
   • Side effects: Hyperglycemia (significant), hypocortisolism 5
   • Best for: Patients with mild-to-moderate disease and visible tumor 1

2. Cabergoline

   • Efficacy: ~40% UFC normalization 3
   • Dosing: Up to 7 mg/week 1
   • Side effects: Impulse control disorders, hypersexuality, pathological gambling 1
   • Contraindications: History of bipolar or impulse control disorders 1
   • Best for: Mild disease, young women desiring pregnancy 1

Glucocorticoid Receptor Antagonist

1. Mifepristone
   • Effects: Improves hyperglycemia and weight gain 1, 3
   • Challenges: No reliable biochemical markers for monitoring, risk of adrenal insufficiency, worsens hypokalemia 1
   • Monitoring: Clinical features only (not cortisol levels) 1

Treatment Algorithm

1. For mild hypercortisolism:

   • Start with ketoconazole, osilodrostat, or metyrapone 1
   • Alternative: Cabergoline for mild disease with no visible tumor 1

2. For moderate hypercortisolism with visible tumor:

   • Consider cabergoline or pasireotide (potential for tumor shrinkage) 1
   • Monitor for hyperglycemia with pasireotide 1

3. For severe hypercortisolism:

   • Rapid cortisol normalization is critical
   • Use osilodrostat or metyrapone (response within hours) 1
   • Alternative: Ketoconazole (response within days) 1
   • For hospitalized patients unable to take oral medications: IV etomidate 1, 3

4. For inadequate response to monotherapy:

   • Combination therapy options:
     • Ketoconazole + metyrapone (maximizes adrenal blockade) 1
     • Ketoconazole + cabergoline (rational if visible tumor present) 1
     • Other combinations: cabergoline + pasireotide + ketoconazole, or metyrapone + ketoconazole + mitotane 1

Monitoring Recommendations

• Efficacy monitoring: 24-hour UFC, morning cortisol, late-night salivary cortisol 3
• Treatment adjustment: Consider changing therapy if cortisol levels remain elevated after 2-3 months on maximum tolerated doses 1
• For adrenal-targeting agents: Monitor ACTH levels and MRI for tumor growth (typically at 6-12 months and then every few years) 1
• For combination therapies: Monitor for overlapping toxicities, particularly QTc prolongation 1

Special Considerations

• In children and adolescents, medical therapies should primarily be used to reduce cortisol burden while awaiting definitive surgery or radiotherapy effects 1
• Long-term use of metyrapone and ketoconazole in children has limitations due to adverse effects 1
• For pregnant patients, metyrapone may be considered with precautions, using a higher cortisol target (1.5 × ULN) 1

Common Pitfalls

• Undertreatment leading to persistent hypercortisolism and associated comorbidities
• Overtreatment causing adrenal insufficiency
• Misinterpreting insufficient disease control due to under-dosing as treatment resistance 1
• Failing to monitor for drug-specific side effects (hepatotoxicity with ketoconazole, hyperandrogenism with metyrapone)
• Not recognizing drug-drug interactions, particularly with mifepristone 1

Remember that while medical therapy is effective for controlling hypercortisolism, the definitive treatment for Cushing's syndrome depends on the underlying cause, with surgery being the first-line approach in most cases.