What is the treatment approach for Cushing's syndrome?

Treatment Approach for Cushing's Syndrome

The first-line treatment for Cushing's syndrome is surgical resection of the causative tumor, with specific approaches determined by the underlying etiology. 1, 2

Diagnostic Workup

Before initiating treatment, proper diagnosis is essential:

• Initial screening tests (at least two positive tests needed):

  • 24-hour urinary free cortisol (UFC)
  • Late-night salivary cortisol (LNSC)
  • 1-mg overnight dexamethasone suppression test (DST) 1, 3

• Determine ACTH dependency:

  • Measure plasma ACTH levels
  • ACTH-dependent: Cushing's disease (pituitary) or ectopic ACTH syndrome
  • ACTH-independent: Adrenal causes 1

• Localization studies:

  • Pituitary MRI for suspected Cushing's disease
  • Bilateral inferior petrosal sinus sampling (IPSS) to distinguish pituitary from ectopic sources
  • Adrenal/chest imaging as appropriate 1

Treatment Algorithm by Etiology

1. Cushing's Disease (Pituitary-Dependent)

• First-line: Transsphenoidal surgery (TSS) 1, 3

  • Remission rates: 60-80% for microadenomas, lower for macroadenomas

• For persistent/recurrent disease after TSS:

  • Second TSS if visible tumor on MRI or positive pathology/central gradient on IPSS was seen before initial operation 1

  • Medical therapy options:

    • Adrenal steroidogenesis inhibitors:

      • Ketoconazole (400-1200 mg/day)
      • Metyrapone (500-6000 mg/day)
      • Osilodrostat (starting dose 2 mg twice daily, maximum 30 mg twice daily) 1, 3, 4

    • Pituitary-directed drugs:

      • Pasireotide (FDA-approved for Cushing's disease) 5
      • Cabergoline (for mild disease) 1

    • Glucocorticoid receptor antagonist:

      • Mifepristone (especially for patients with diabetes/glucose intolerance) 1, 3

  • Radiation therapy:

    • Stereotactic radiosurgery (SRS) preferred over conventional radiotherapy
    • Requires 3-5 mm distance between tumor and optic chiasm 1

  • Bilateral adrenalectomy:

    • Consider when other options have failed
    • Provides immediate control of hypercortisolism
    • Requires lifelong glucocorticoid and mineralocorticoid replacement
    • Risk of corticotroph tumor progression (Nelson's syndrome) in 25-40% 1

2. Adrenal Cushing's Syndrome

• Unilateral adrenal adenoma/carcinoma: Laparoscopic adrenalectomy 3
• Bilateral adrenal disease: Bilateral adrenalectomy with lifelong steroid replacement 1

3. Ectopic ACTH Syndrome

• Localized tumor: Surgical resection of the primary tumor 3, 2
• Unidentified or metastatic source: Medical therapy with steroidogenesis inhibitors 1

Medical Therapy Selection Guidelines

For patients requiring medical therapy, selection should be based on:

1. Disease severity:

   • Mild disease: Ketoconazole, osilodrostat, metyrapone, or cabergoline
   • Severe disease: Rapid-acting agents (osilodrostat, metyrapone, or ketoconazole) 1

2. Presence of visible tumor:

   • With residual tumor: Consider pasireotide or cabergoline for potential tumor shrinkage 1

3. Patient-specific factors:

   • Diabetes: Consider mifepristone
   • Pregnancy considerations: Metyrapone may be considered with precautions
   • Psychiatric history: Avoid cabergoline in patients with bipolar or impulse control disorders 1

Monitoring and Follow-up

• Monitor cortisol levels with UFC and LNSC during treatment 1
• For steroidogenesis inhibitors: Check for adrenal insufficiency, hypokalemia, and liver function
• For pasireotide: Monitor for hyperglycemia
• For mifepristone: Monitor for hypokalemia, endometrial changes in women 1
• After successful treatment: Lifelong monitoring for recurrence and management of persistent comorbidities 3

Important Caveats

• Risk of adrenal insufficiency: All treatments that lower cortisol carry this risk; patients need education about stress dosing of glucocorticoids 1
• Combination therapy: May be needed when monotherapy is insufficient; common combinations include ketoconazole with metyrapone or a steroidogenesis inhibitor plus a tumor-targeting agent 1
• QTc prolongation: Monitor ECG with medications like ketoconazole and pasireotide 1, 4
• Hypertension management: Mineralocorticoid receptor antagonists (spironolactone/eplerenone) are most effective for Cushing's-related hypertension 3

By following this structured approach based on the underlying etiology and individual patient factors, outcomes related to morbidity, mortality, and quality of life can be optimized in patients with Cushing's syndrome.