What are the treatment options for elevated cortisol levels?

Treatment Options for Elevated Cortisol Levels

The treatment of elevated cortisol levels depends on the underlying cause, with surgical removal of the source being first-line for most cases of Cushing syndrome, while medical therapy is recommended for patients who are not surgical candidates or when surgery has not been curative. 1

Diagnostic Approach

Before initiating treatment, it's crucial to determine the cause of hypercortisolism:

1. Confirm hypercortisolism: 24-hour urinary free cortisol (UFC) measurement is recommended when cortisol levels are elevated 1

2. Determine the source:

   • Measure ACTH levels:
     • Elevated ACTH: Suggests pituitary tumor (Cushing's disease) or ectopic ACTH production
     • Low/normal ACTH: Suggests adrenal source (adenoma, carcinoma, or bilateral hyperplasia)

3. Imaging:

   • MRI of pituitary (for suspected Cushing's disease)
   • CT/MRI of chest, abdomen, pelvis (for suspected ectopic source or adrenal tumors)
   • Adrenal protocol imaging to determine size, heterogeneity, lipid content, and margins 1

Treatment Algorithm Based on Source

1. ACTH-Dependent Cushing Syndrome (Pituitary or Ectopic Source)

Pituitary Source (Cushing's Disease):

• First-line: Transsphenoidal pituitary surgery
• For non-surgical candidates or persistent disease after surgery:
  • Medical therapy with:
    • Pasireotide (0.6-0.9 mg SC twice daily) 2
    • Cabergoline (for mild disease, especially in young women planning pregnancy) 1
    • Ketoconazole (400-1200 mg/day) 1
    • Osilodrostat (for rapid control) 1
    • Metyrapone (for rapid control) 1

Ectopic ACTH Source:

• First-line: Surgical removal of the ectopic tumor if possible 1
• If unresectable:
  • Bilateral laparoscopic adrenalectomy 1
  • Medical management with adrenostatic agents 1
  • Consider octreotide if tumor is Octreoscan-positive 1

2. ACTH-Independent Cushing Syndrome (Adrenal Source)

Adrenal Adenoma:

• First-line: Laparoscopic adrenalectomy 1
• Post-operative: Corticosteroid supplementation until recovery of HPA axis 1

Adrenal Carcinoma:

• First-line: Open adrenalectomy with removal of adjacent lymph nodes 1
• Consider: Adjuvant radiation therapy for high-grade carcinoma 1

Bilateral Adrenal Hyperplasia:

• If cortisol production is asymmetric: Unilateral adrenalectomy of most active side 1
• If cortisol production is symmetric: Medical management 1

Medical Management Options

For Rapid Control (Severe Hypercortisolism):

1. Osilodrostat or Metyrapone: Response within hours 1
2. Ketoconazole: Response within days 1
3. Etomidate: For hospitalized patients who cannot take oral medications 1
4. Combination therapy: For severe hypercortisolism not responsive to monotherapy 1

For Mild-to-Moderate Disease:

1. Without visible tumor: Ketoconazole, osilodrostat, or metyrapone 1
2. With visible residual tumor: Cabergoline or pasireotide (potential for tumor shrinkage) 1

Combination Therapy Options:

• Ketoconazole + metyrapone (most common) 1
• Steroidogenesis inhibitor + tumor-targeting agent (e.g., ketoconazole + cabergoline) 1
• Triple therapy: cabergoline + pasireotide + ketoconazole, or ketoconazole + metyrapone + mitotane 1

Monitoring Treatment Response

• Evaluate UFC levels and clinical signs/symptoms 1
• Maximum UFC reduction typically seen by two months of treatment 2
• Consider changing treatment if cortisol levels remain elevated after 2-3 months on maximum tolerated doses 1
• Monitor for hypocortisolism (weakness, fatigue, anorexia, nausea, vomiting, hypotension) 2

Important Precautions and Monitoring

• Before starting medical therapy:

  • Baseline fasting plasma glucose and HbA1c 2
  • Liver function tests 2
  • Serum potassium and magnesium 2
  • ECG and gallbladder ultrasound 2

• During treatment:

  • Weekly glycemic monitoring for first 2-3 months with pasireotide 2
  • Regular monitoring of liver function with ketoconazole 1
  • Monitor for QTc prolongation with combination therapy 1

Special Considerations

• Pregnancy: Metyrapone may be considered with precautions in selected pregnant women 1
• Hepatic impairment: Adjust dosage of medications like pasireotide 2
• Diabetes: Optimize anti-diabetic therapy before starting pasireotide 2
• Immunotherapy-induced hypophysitis: Requires specific management approach with steroids 1

Non-Pharmacological Approaches

For mild elevations in cortisol related to stress rather than Cushing syndrome, stress management interventions may be beneficial:

• Mindfulness and meditation practices 3
• Relaxation techniques 3

These approaches have shown medium positive effects on reducing cortisol levels (g = 0.282) 3.