What is the treatment for Cushing's disease?

Treatment of Cushing's Disease

Transsphenoidal surgery is the first-line treatment for Cushing's disease, with medical therapy reserved for patients with persistent or recurrent disease after surgery or those who are not surgical candidates. 1

Diagnosis and Confirmation

Before initiating treatment, proper diagnosis is essential:

1. Confirm hypercortisolism using:

   • 24-hour urinary free cortisol (UFC) measurements (3 collections)
   • Late-night salivary cortisol (≥2 samples)
   • Overnight 1-mg dexamethasone suppression test
   • Midnight (sleeping) serum cortisol levels 1

2. Determine ACTH dependency:

   • Normal or elevated 09:00h plasma ACTH confirms ACTH dependency 1
   • MRI of the pituitary to identify adenoma
   • Inferior petrosal sinus sampling (IPSS) if MRI is negative or equivocal 1

Treatment Algorithm

First-Line Treatment

• Transsphenoidal surgery (TSS) to remove the ACTH-secreting pituitary adenoma
  • Success rates: ~80% for microadenomas (<1 cm)
  • Lower success rates (~30%) for macroadenomas (>1 cm) 2
  • Long-term recurrence rate: approximately 25% 1

Second-Line Options (for persistent or recurrent disease)

1. Repeat transsphenoidal surgery

   • Consider if tumor is visible on MRI
   • Higher success when performed at a Pituitary Tumor Center of Excellence 1

2. Medical therapy:

   • Adrenal steroidogenesis inhibitors:

     • Ketoconazole: 400-1200 mg/day (divided doses)

       • Efficacy: ~65% UFC normalization
       • Monitor for hepatotoxicity and drug interactions 1

     • Osilodrostat: 2-7 mg/day (BID dosing)

       • Efficacy: 86% UFC normalization
       • FDA approved for CD when surgery is not an option or has failed
       • Monitor for hyperandrogenism in women 1

     • Metyrapone: 500 mg/day to 6 g/day

       • Mechanism: Inhibits 11-beta-hydroxylation in adrenal cortex 3
       • Can cause increased androgenic and mineralocorticoid precursors 1

     • Mitotane: For severe cases

       • Monitor for adrenal insufficiency
       • Can cause CNS toxicity when plasma levels exceed 20 mg/L 4

   • Pituitary-directed therapies:

     • Pasireotide: Somatostatin analog

       • Consider for mild-to-moderate disease with visible tumor
       • High rate of hyperglycemia limits use 1

     • Cabergoline: Dopamine agonist

       • For mild disease
       • Less effective but requires less frequent dosing
       • Avoid in patients with history of bipolar or impulse control disorders 1

3. Radiation therapy:

   • Conventional or stereotactic radiotherapy
   • Slow onset of action (months to years)
   • Risk of hypopituitarism 1

4. Bilateral adrenalectomy:

   • Last resort for severe hypercortisolism unresponsive to other treatments
   • Results in permanent adrenal insufficiency requiring lifelong replacement 1

Special Considerations

Children and Adolescents

• Male predominance in pediatric Cushing's disease (63% boys vs. 79% women in adult series)
• Microadenomas account for 98% of cases in children/adolescents
• Growth failure with subnormal growth velocity is a key diagnostic feature
• Consider ketoconazole or metyrapone if medical therapy needed 1

Monitoring During Treatment

• UFC and late-night salivary cortisol to assess treatment efficacy
• For steroidogenesis inhibitors: monitor for adrenal insufficiency
• For osilodrostat and metyrapone: monitor for hyperandrogenism and hypokalemia
• For ketoconazole: regular liver function tests 1

Complications and Comorbidities

• Hypertension (present in 70-90% of patients)
• Diabetes mellitus and insulin resistance
• Obesity and abnormal fat deposition
• Osteoporosis
• Psychiatric disturbances
• Increased cardiovascular risk 1, 5

Early diagnosis and prompt treatment are critical to reduce mortality and improve long-term quality of life in patients with Cushing's disease 5, 6.