What is the treatment for lowering cortisol levels?

Treatment for Lowering Cortisol Levels

For patients with elevated cortisol requiring medical therapy, adrenal steroidogenesis inhibitors (ketoconazole, osilodrostat, or metyrapone) are the first-line treatment, with selection based on disease severity and patient-specific factors. 1

Treatment Selection Algorithm

For Mild Disease (No Visible Tumor on MRI)

• First-line options: Ketoconazole, osilodrostat, or metyrapone are preferred due to their reliable effectiveness 1, 2
• Alternative option: Cabergoline may be used but is less effective with slower onset of action, though it requires less frequent dosing 1
• These agents work by inhibiting 11-beta-hydroxylation in the adrenal cortex, directly reducing cortisol production 3

For Mild-to-Moderate Disease (With Residual Tumor)

• Preferred agents: Cabergoline or pasireotide should be considered due to their potential for tumor shrinkage 1, 2
• Critical caveat: Pasireotide has a high rate of hyperglycemia, making patient selection essential 1
• Avoid cabergoline in patients with bipolar disorder or impulse control disorders 1

For Severe Disease (Rapid Control Required)

• Primary goal: Rapid normalization of cortisol is the most important objective 1, 2
• Fastest-acting agents:
  • Osilodrostat and metyrapone: Response typically within hours 1
  • Ketoconazole: Response within a few days 1
  • Etomidate: Works rapidly for hospitalized patients unable to take oral medications 1
• Combination therapy: Multiple steroidogenesis inhibitors may be necessary for severe hypercortisolism 1
• Last resort: If medical therapy fails, bilateral adrenalectomy (BLA) should be considered to avoid worsening outcomes 1

Combination Therapy Regimens

When monotherapy is insufficient:

• Ketoconazole + metyrapone: Maximizes adrenal blockade and allows lower doses of both drugs 1, 2
• Steroidogenesis inhibitor + tumor-targeting agent: Such as ketoconazole plus cabergoline, especially if visible tumor is present 1
• Triple therapy options: Cabergoline + pasireotide + ketoconazole, or metyrapone + ketoconazole + mitotane 1
• Important warning: Monitor for QTc prolongation with combination therapy 1

Special Considerations for Specific Agents

Osilodrostat

• Only steroidogenesis inhibitor approved in the United States 1
• High efficacy with twice-daily dosing 1
• Does not cause hypogonadism in men 1
• Monitor for adrenal insufficiency and effects on androgens 1

Ketoconazole

• Approved in Europe but not in the United States for Cushing's disease 1
• Often under-dosed due to fear of hepatotoxicity 1
• Monitor liver function tests regularly, but mild stable elevations do not necessarily require discontinuation 1

Metyrapone

• Approved in Europe but not in the United States 1
• May be considered in pregnant women with precautions, using a higher cortisol target of 1.5 × upper limit of normal 1
• Patients with cirrhosis may have impaired response 3

Mifepristone

• Unique mechanism: Blocks cortisol receptors rather than reducing cortisol production 1
• Improves hyperglycemia and weight gain specifically 1
• Major limitation: No reliable biochemical markers for monitoring cortisol levels, increasing risk of adrenal insufficiency 1
• Should only be used by clinicians with extensive experience in Cushing's disease 1
• Often worsens hypokalemia 1

Monitoring Treatment Response

Biochemical Monitoring

• Use multiple serial tests of 24-hour urinary free cortisol (UFC) and late-night salivary cortisol (LNSC) 1
• Consider changing treatment if cortisol levels remain persistently elevated after 2-3 months on maximum tolerated doses 1, 2
• Ensure insufficient disease control is not due to under-dosing before declaring treatment resistance 1

Tumor Monitoring

• Obtain MRI typically 6-12 months after initiating treatment, then repeat every few years 1, 2
• Monitor ACTH levels for significant elevations that may indicate tumor growth 1, 2
• Important caveat: ACTH has a short half-life and fluctuates, so elevations may not necessarily reflect tumor growth 1
• If progressive tumor size increase is seen, suspend treatment and reassess management 1, 2

Common Pitfalls to Avoid

• Under-dosing ketoconazole: Fear of hepatotoxicity leads to inadequate dosing; monitor liver function but don't automatically discontinue for mild stable elevations 1
• Misinterpreting treatment resistance: Ensure maximum tolerated doses are reached before switching therapies 1
• Inadequate monitoring for adrenal insufficiency: All steroidogenesis inhibitors carry this risk and require vigilant monitoring 1, 3
• Using mifepristone without expertise: This agent requires specialized knowledge due to inability to monitor cortisol levels reliably 1