What are the treatment guidelines for Cushing syndrome?

Treatment Guidelines for Cushing Syndrome

The first-line treatment for Cushing syndrome is surgical resection of the causative tumor, with specific medical therapy options for persistent disease or non-surgical candidates. 1

Diagnostic Confirmation Before Treatment

• Determine the cause of Cushing syndrome by measuring plasma ACTH:

  • ACTH-dependent: Cushing's disease (pituitary) or ectopic ACTH syndrome
  • ACTH-independent: adrenal causes

• Localization studies:

  • Pituitary MRI for suspected Cushing's disease
  • Inferior petrosal sinus sampling to distinguish pituitary from ectopic sources
  • Adrenal CT or MRI for adrenal causes

Treatment Algorithm by Etiology

1. ACTH-dependent Cushing's Disease (Pituitary)

• First-line: Transsphenoidal surgery (60-80% remission for microadenomas) 1
• For persistent/recurrent disease:
  • Second transsphenoidal surgery
  • Medical therapy
  • Pituitary radiation
  • Bilateral adrenalectomy (last resort)

2. ACTH-independent (Adrenal)

• First-line: Unilateral adrenalectomy of affected gland, preferably minimally invasive 1

3. Ectopic ACTH Syndrome

• First-line: Surgical removal of the source tumor
• If surgery not possible: Medical therapy to control hypercortisolism

Medical Therapy Options

For Severe Disease

• Rapid normalization of cortisol is critical 2
• Options include:
  • Osilodrostat: Response within hours
  • Metyrapone: Response within hours
  • Ketoconazole: Response within days
  • Etomidate: For hospitalized patients unable to take oral medications
  • Combinations of steroidogenesis inhibitors for severe cases

Adrenal Steroidogenesis Inhibitors

1. Ketoconazole:

   • Dose: 400-1200 mg/day in 2-3 divided doses 1
   • Advantages: Ease of dose titration
   • Monitor: Liver function tests regularly
   • Efficacy: ~65%

2. Metyrapone:

   • Dose: 500 mg/day to 6 g/day 1
   • Advantages: Rapid control
   • Side effects: Hirsutism, hyperandrogenism
   • Efficacy: ~70%

3. Osilodrostat:

   • Dose: 2-7 mg/day 1
   • Advantages: High efficacy, twice-daily dosing
   • Monitor: Adrenal insufficiency, androgen effects
   • Efficacy: 86%

4. Mitotane:

   • Slower onset of action
   • Rarely used for Cushing's disease in most centers 2

Other Medical Options

1. Cabergoline:

   • Contraindicated in patients with history of bipolar or impulse control disorder
   • Preferred in young women desiring pregnancy 2

2. Mifepristone:

   • Improves hyperglycemia and weight gain
   • Challenges: No reliable biochemical markers for monitoring, risk of adrenal insufficiency
   • Should only be used by clinicians with extensive experience 2

3. Pasireotide:

   • Pituitary-targeted drug
   • Monitor for hyperglycemia

Special Considerations

Severe Disease

• Combination therapy may be necessary:
  • Ketoconazole + metyrapone (common)
  • Steroidogenesis inhibitor + tumor-targeting agent (e.g., ketoconazole + cabergoline)
  • Triple therapy in some cases 2

Pediatric Patients

• Medical therapy should be confined to normalizing cortisol levels in preparation for surgery or while awaiting response to radiotherapy 2
• Metyrapone dosing: 15 mg/kg every 4h or 300 mg/m² every 4h
• Ketoconazole (for patients >12 years): 400-600 mg/day initially in 2-3 divided doses 2

Pregnancy

• None of the drugs specifically approved for use in pregnancy
• Metyrapone may be considered with precautions
• Higher cortisol target (1.5 × ULN) due to normally higher cortisol during pregnancy 2

Monitoring Treatment

• Measure urinary free cortisol and late-night salivary cortisol
• Monitor for specific side effects:
  • Adrenal insufficiency
  • Hypokalemia (especially with mifepristone)
  • Liver function abnormalities (with ketoconazole)
  • Hyperglycemia (with pasireotide)

Management of Comorbidities

• Hypertension: Mineralocorticoid receptor antagonists (spironolactone, eplerenone) as cornerstone therapy 1
• Thromboprophylaxis: Recommended in perioperative period and up to 30 days post-op 1
• Adrenal insufficiency: Hormone replacement therapy with dose adjustments during stress

Common Pitfalls to Avoid

1. Underdosing ketoconazole due to fear of hepatotoxicity
2. Failing to monitor for adrenal insufficiency with rapid cortisol normalization
3. Using mifepristone without extensive experience
4. Not providing stress-dose glucocorticoid education to patients
5. Inadequate monitoring for QTc prolongation with combination therapy

Long-term Follow-up

• Lifelong monitoring for recurrence
• Management of persistent comorbidities
• In pediatric patients: monitor growth, pubertal progression, and consider GH deficiency testing 2