What is the initial treatment approach for a patient with Cushing's syndrome?

Initial Treatment Approach for Cushing's Syndrome

The first-line treatment for Cushing's syndrome is surgical resection of the causative tumor, regardless of etiology. 1, 2

Diagnostic Confirmation Before Treatment

Before initiating treatment, proper diagnosis must be established:

• Rule out exogenous glucocorticoid use as the cause of Cushing's syndrome 3, 1
• Confirm hypercortisolism with one or more of the following tests:
  • 24-hour urinary free cortisol (UFC) (≥2-3 collections) 3
  • Late-night salivary cortisol (LNSC) (≥2 tests on consecutive days) 3
  • 1mg overnight dexamethasone suppression test (DST) 3
• Determine ACTH dependency to identify the source:
  • Low ACTH: ACTH-independent (adrenal cause)
  • Normal/high ACTH: ACTH-dependent (pituitary or ectopic source) 3

Treatment Algorithm

Step 1: Surgical Management (First-Line)

• For Cushing's disease (pituitary source): Transsphenoidal surgery 3, 2
• For adrenal causes: Unilateral adrenalectomy (adenoma) or bilateral adrenalectomy (hyperplasia) 2
• For ectopic ACTH syndrome: Surgical resection of the ACTH-producing tumor 2

Step 2: Medical Therapy (When Surgery Is Not an Option or Has Failed)

For patients in whom surgery is not an option or has not been curative, medical therapy should be initiated:

• Steroidogenesis inhibitors (first choice for medical management):

  • Ketoconazol (initial dose 400-600 mg/day) - normalizes UFC in approximately 64.3% of patients 4
  • Metyrapone - effective alternative to ketoconazol 4
  • Osilodrostat - potent inhibitor of cortisol synthesis 4, 5
  • Mitotano - especially for severe cases or as part of combination therapy 4

• Pituitary-directed therapy (for Cushing's disease):

  • Pasireotide - FDA-approved for adult patients with Cushing's disease for whom pituitary surgery is not an option or has not been curative 6
  • Cabergoline - can be used alone or in combination with pasireotide 5

• Glucocorticoid receptor antagonists:

  • Mifepristone - blocks cortisol action at the receptor level 5

Step 3: Radiation Therapy or Bilateral Adrenalectomy

• Radiation therapy for pituitary-dependent Cushing's syndrome when surgery and medical therapy fail 2
• Bilateral adrenalectomy as last resort for ACTH-dependent causes 2

Monitoring Treatment Response

• Evaluate both clinical and biochemical parameters:
  • 24-hour UFC is the most commonly used measure 4
  • Monitor for signs of clinical improvement (reduction in cushingoid features) 4
  • Consider treatment modification if cortisol levels remain elevated after 2-3 months at maximum tolerated doses 4

Special Considerations

Potential Complications and Management

• Hypocortisolism: May require dose reduction, treatment interruption, or short-term glucocorticoid supplementation 6
• Hyperglycemia: Intensive glucose monitoring and antidiabetic treatment may be necessary, especially with pasireotide 6
• QT prolongation: ECG monitoring before and during treatment, especially with ketoconazole and pasireotide 6
• Liver function abnormalities: Regular monitoring of liver tests 6
• Cholelithiasis: Periodic ultrasound monitoring 6

Pediatric Considerations

• Ketoconazole or metyrapone are typically used with morning cortisol monitoring 3
• Growth hormone deficiency should be evaluated 3-6 months post-surgery 3
• Thromboprophylaxis should not be routinely used due to bleeding risk 3

Treatment of Comorbidities

• For hypertension associated with Cushing's syndrome, mineralocorticoid antagonists (spironolactone or eplerenona) are recommended 4
• Address metabolic abnormalities (diabetes, dyslipidemia) with appropriate medications 1