What are the treatment and management options for Cushing's (Cushing's) syndrome?

Treatment and Management of Cushing's Syndrome

Transsphenoidal surgery is the first-line treatment for Cushing's disease, while medical therapy is indicated when surgery is not an option or has not been curative, with specific treatment approaches determined by the underlying cause of hypercortisolism. 1

Diagnostic Approach Before Treatment

Before initiating treatment, proper diagnosis is essential:

1. Confirm hypercortisolism through:

   • Late-night salivary cortisol (≥2 tests)
   • 24-hour urinary free cortisol (≥2 tests)
   • Overnight 1mg dexamethasone suppression test 2, 1

2. Determine the source by measuring ACTH levels:

   • Low ACTH: ACTH-independent (adrenal causes)
   • Normal/high ACTH: ACTH-dependent (pituitary or ectopic sources) 2

3. Localize the source with appropriate imaging:

   • Pituitary MRI for suspected Cushing's disease
   • Adrenal CT/MRI for adrenal causes
   • Inferior petrosal sinus sampling (IPSS) when needed 2

Treatment Algorithm

First-Line Treatment

• Cushing's disease (60-70% of cases): Transsphenoidal surgery by an experienced neurosurgeon 2, 1

  • Success rates: 75-80% in adults
  • Early post-operative remission in children associated with adenoma identification at surgery 2
  • Lifelong follow-up essential due to potential recurrence (up to 15 years after apparent cure) 2

• Adrenal causes: Surgical resection of adrenal tumor(s) 2, 1

• Ectopic ACTH syndrome: Surgical removal of the ACTH-secreting tumor 2, 1

Second-Line Treatments (When Surgery Fails or Is Contraindicated)

1. Repeat transsphenoidal surgery for Cushing's disease 2

   • Early biochemical remission in 93% of pediatric patients undergoing repeat surgery 2

2. Radiotherapy for Cushing's disease 2

   • Focal external beam radiotherapy (more rapidly effective in children)
   • Stereotactic radiotherapy, fractionated proton beam, or gamma knife approaches
   • Typically initiated 2-4 weeks after unsuccessful surgery 2
   • Cure rates: 70-80% within 9-18 months in children 2

3. Medical therapy options:

   a. Adrenal steroidogenesis inhibitors:

   • Osilodrostat: Highest efficacy (86% UFC normalization) 1
   • Metyrapone: ~70% UFC normalization 1
     • Dosing: 15 mg/kg every 4h or 300 mg/m² every 4h (usual dose 250-750 mg every 4h) 2
     • Side effects: Hirsutism, dizziness, arthralgia, fatigue, hypokalaemia, nausea 2
   • Ketoconazole: ~65% UFC normalization 1
     • Dosing (>12 years): 400-600 mg/day in 2-3 divided doses, increased to 800-1,200 mg/day until cortisol normalizes 2
     • Side effects: Hepatotoxicity (requires liver function monitoring) 2

   b. Pituitary-directed drugs:

   • Pasireotide: 15-26% UFC normalization 1, 3
     • Dosing: 0.6-0.9 mg subcutaneously twice daily 3
     • Side effects: Hyperglycemia (use with caution in diabetic patients) 1, 3
   • Cabergoline: ~40% UFC normalization 1

   c. Glucocorticoid receptor antagonist:

   • Mifepristone: Improves hyperglycemia and weight gain but lacks reliable biochemical markers for monitoring 1

4. Bilateral adrenalectomy 2

   • Reserved for severe refractory Cushing's disease or life-threatening emergencies 2
   • Risk of Nelson syndrome (corticotroph tumor progression) is higher in children than adults 2

Combination Therapy Approaches

For inadequate response to monotherapy, consider combinations:

• Ketoconazole + metyrapone
• Ketoconazole + osilodrostat
• Pasireotide + cabergoline 1

Special Considerations

In Children and Adolescents

• Medical therapies (metyrapone, ketoconazole) should be used primarily to reduce cortisol burden while awaiting definitive surgery or radiotherapy effects 2
• Long-term medical therapy has limited role due to adverse effects 2
• GH deficiency assessment should be done soon after definitive therapy in children who have not completed linear growth 2
• Prompt GH replacement for those with GH deficiency or failing to show catch-up growth 2

In Severe Disease

• Rapid cortisol normalization should be prioritized with osilodrostat, metyrapone, or ketoconazole
• Consider hospitalization with IV etomidate if oral medications are not possible 1

Monitoring and Follow-up

1. Treatment efficacy monitoring:

   • 24-hour UFC (except with mifepristone)
   • Morning cortisol and/or late-night salivary cortisol
   • Clinical symptoms and comorbidities (weight, glycemia, blood pressure) 2, 1

2. Consider treatment change if:

   • Cortisol levels remain elevated after 2-3 months on maximum tolerated doses
   • Cortisol is reduced but not normalized with some clinical improvement 1

3. Long-term follow-up:

   • Lifelong follow-up essential due to potential recurrence 2
   • BMD assessment prior to adult transition in patients at high risk for bone fragility 2

Potential Pitfalls

• Undertreatment or overtreatment of hypercortisolism
• Inadequate monitoring of medication side effects
• Failure to recognize cyclical Cushing's syndrome 1
• Misinterpreting insufficient disease control due to under-dosing as treatment resistance 1

By following this structured approach to treatment and management, outcomes for patients with Cushing's syndrome can be optimized with reduced morbidity and mortality.