How to manage elevated cortisol levels?

Management of Elevated Cortisol Levels

For patients with elevated cortisol levels, medical therapy should be individualized based on the clinical scenario, severity of hypercortisolism, and underlying cause, with adrenal steroidogenesis inhibitors typically used as first-line treatment due to their reliable effectiveness. 1

Diagnostic Approach

• First confirm hypercortisolism with 24-hour urinary free cortisol test 2
• Determine if ACTH-dependent (pituitary or ectopic source) or ACTH-independent (adrenal source) 2
  • Normal/low ACTH with elevated cortisol suggests adrenal source
  • Elevated ACTH suggests pituitary or ectopic source
• Obtain appropriate imaging based on suspected source:
  • Adrenal imaging (CT or MRI with adrenal protocol) for suspected adrenal source 2
  • Pituitary MRI for suspected Cushing's disease 1

Treatment Algorithm Based on Severity and Source

1. Mild Disease

• For mild disease with no visible tumor on MRI:
  • First-line: Ketoconazole, osilodrostat, or metyrapone 1
  • Alternative: Cabergoline (less effective, slower onset, but requires less frequent dosing) 1

2. Mild-to-Moderate Disease with Residual Tumor

• Consider cabergoline or pasireotide due to potential for tumor shrinkage 1
• Note: Pasireotide has high rate of hyperglycemia, requiring careful patient selection 1

3. Severe Disease

• Rapid normalization of cortisol is the primary goal 1
• Options with rapid response:
  • Osilodrostat or metyrapone (response within hours) 1
  • Ketoconazole (response within days) 1
  • Etomidate (for hospitalized patients unable to take oral medications) 1
• For very severe hypercortisolism unresponsive to optimized medical therapy, consider bilateral adrenalectomy 1

Monitoring Treatment Response

• Response should be defined by both clinical and biochemical endpoints 1
  • Clinical: Improved phenotype, weight, hypertension, glucose metabolism, quality of life 1
  • Biochemical: Urinary free cortisol (UFC), except when using mifepristone 1
• Consider changing treatment if cortisol levels remain persistently elevated after 2-3 months on maximum tolerated doses 1
• If cortisol is reduced but not normalized and there is some clinical improvement, consider combination therapy 1
• If clear resistance to treatment despite dose escalation, switch to a different therapy 1

Combination Therapy Options

• Ketoconazole with metyrapone or osilodrostat to maximize adrenal blockade 1
• Ketoconazole plus cabergoline or pasireotide when visible tumor is present 1
• Pasireotide plus cabergoline may be rational for visible tumors 1
• More complex combinations include triplets of cabergoline, pasireotide, plus ketoconazole, or ketoconazole, metyrapone, plus mitotane 1

Special Considerations

Glucocorticoid Receptor Blocker (Mifepristone)

• Effective regardless of etiology of hypercortisolism 1
• Improves glucose tolerance, blood pressure, insulin resistance, weight, and quality of life 1
• Important monitoring considerations:
  • May cause increased blood pressure and hypokalemia (may require spironolactone) 1
  • Can cause endometrial hypertrophy and irregular menstrual bleeding 1
  • Cortisol levels remain high, so adrenal insufficiency must be diagnosed clinically 1
  • Monitor thyroid function and adjust thyroid hormone replacement as needed 1
  • Review all concomitant medications for drug-drug interactions 1

Tumor Monitoring

• MRI typically obtained 6-12 months after initiating treatment and repeated every few years 1
• Monitor ACTH levels, as progressive elevations may indicate tumor growth 1
• If progressive tumor growth is observed, medical treatment should be reassessed 1

Pregnancy Considerations

• Metyrapone crosses the placenta and may decrease fetal cortisol production 3
• Limited data on use during pregnancy, but may be considered with precautions in selected cases 1, 3
• There are reports of low cortisol levels at birth in infants exposed in utero following chronic use 3

Non-Pharmacological Approaches

• For mild elevations of cortisol related to stress rather than Cushing's syndrome, consider:
  • Mindfulness meditation has been shown to significantly reduce serum cortisol levels 4
  • Stress management interventions, particularly mindfulness/meditation and relaxation techniques, have demonstrated medium positive effects on cortisol levels 5

Cautions and Monitoring

• Monitor for adrenal insufficiency with steroidogenesis inhibitors 1
• Patients with cirrhosis may have an impaired response to metyrapone 3
• Metyrapone overdose can cause gastrointestinal symptoms and acute adrenal insufficiency 3
• For patients on insulin or oral antidiabetics, signs of metyrapone overdose may be aggravated 3