What is the treatment for Cushing syndrome?

Treatment of Cushing Syndrome

The first-line treatment for Cushing syndrome is surgical resection of the underlying cause of hypercortisolism, with medical therapy reserved for cases where surgery is not possible or has failed. 1, 2

Etiology-Based Treatment Approach

ACTH-Dependent Cushing Syndrome (70-80% of cases)

Cushing Disease (Pituitary Source)

• Transsphenoidal surgery to remove the pituitary adenoma is the primary treatment 1, 3
• Postoperative corticosteroid supplementation is required until recovery of the hypothalamus-pituitary-adrenal axis 1
• For children and adolescents, early definitive treatment is crucial to normalize growth and puberty 1

Ectopic ACTH Syndrome

• Surgical removal of the ectopic tumor (commonly in lung, thyroid, pancreas, or bowel) is recommended when possible 1
• If the primary tumor is unresectable, bilateral laparoscopic adrenalectomy or medical management is recommended 1, 3

ACTH-Independent Cushing Syndrome (20-30% of cases)

Adrenal Adenoma

• Laparoscopic adrenalectomy of the affected gland is the treatment of choice 1
• Minimally invasive surgery should be performed when feasible 1

Adrenal Carcinoma

• Open adrenalectomy is recommended for suspected malignant lesions (tumors >5 cm, irregular margins, local invasion) 1
• Imaging of chest, abdomen, and pelvis is required to evaluate for metastases 1

Bilateral Adrenal Hyperplasia

• Medical management is indicated if cortisol production is symmetric 1
• If cortisol production is asymmetric, unilateral adrenalectomy of the most active side is recommended 1

Medical Therapy Options

Medical therapy is indicated when:

1. Surgery is not an option or has failed
2. As a bridge to definitive treatment
3. For recurrent disease

First-Line Medical Options

• Steroidogenesis inhibitors are the most effective pharmacological options 4:
  • Ketoconazol (400-1200 mg/day) - normalizes cortisol in approximately 64% of patients 4
  • Metyrapone (15 mg/kg every 4h or 300 mg/m² every 4h) 1, 4
  • Osilodrostat - a potent inhibitor of cortisol synthesis 4

Second-Line Medical Options

• Pasireotide (0.6 mg or 0.9 mg subcutaneously twice daily) - FDA-approved for Cushing disease when surgery is not an option or has not been curative 5
• Mitotane - particularly useful in severe cases or as part of combination therapy 4

Management of Complications

• For hypertension associated with Cushing syndrome, mineralocorticoid receptor antagonists (spironolactone or eplerenone) are recommended 1, 4
• For hyperglycemia, anti-diabetic therapy should be optimized 5

Monitoring Treatment Response

• Cortisol free urine (UFC) is the most commonly used measure to monitor treatment response 4
• Clinical improvement in symptoms and signs should also be assessed 4
• For medical therapy, if no adequate response after 2-3 months with maximum tolerated doses, consider changing agents or initiating combination therapy 4

Special Considerations

Mild Autonomous Cortisol Secretion (MACS)

• Adrenalectomy could be considered for select patients, particularly younger individuals with progressive metabolic comorbidities attributable to cortisol excess 1
• Patients not managed surgically should undergo annual clinical screening for new or worsening comorbidities 1

Bilateral Adrenalectomy

• Should be reserved for severe refractory cases or life-threatening emergencies 1
• Risk of corticotroph tumor progression (Nelson syndrome) is higher in children than adults 1

Treatment Complications and Monitoring

• Hypocortisolism - Monitor for signs of adrenal insufficiency during medical treatment (weakness, fatigue, anorexia, nausea, vomiting, hypotension) 5
• Hyperglycemia - Weekly monitoring for the first 2-3 months of treatment, especially after dose increases 5
• QT prolongation and bradycardia - Baseline ECG recommended before initiating therapy with certain medications like pasireotide 5
• Hepatotoxicity - Monitor liver function with ketoconazole treatment 1

The treatment of Cushing syndrome requires a multidisciplinary approach with careful consideration of the underlying etiology, patient characteristics, and potential complications of both the disease and its treatment 3, 6.