What are the treatment options for managing Cushing's syndrome symptoms?

Treatment Options for Managing Cushing's Syndrome Symptoms

The first-line treatment for Cushing's syndrome is transsphenoidal pituitary surgery for Cushing's disease (pituitary-dependent), while medical therapy is indicated when surgery is not an option or has not been curative. 1, 2

Diagnostic Approach

Before treatment, proper diagnosis is essential:

1. Confirm hypercortisolism:

   • Late-night salivary cortisol (≥2 tests)
   • 24-hour urinary free cortisol (≥2-3 collections)
   • Overnight 1mg dexamethasone suppression test

2. Determine source:

   • Measure ACTH levels
   • Low ACTH: Adrenal-dependent (CT/MRI of adrenals)
   • Normal/high ACTH: ACTH-dependent (pituitary MRI)
   • If pituitary imaging inconclusive: Inferior petrosal sinus sampling

Treatment Algorithm

First-Line Treatment

• Cushing's disease (60-70% of cases): Transsphenoidal pituitary surgery 1, 3
• Adrenal adenoma/carcinoma: Surgical resection (laparoscopic for benign, open for suspected malignancy)
• Ectopic ACTH syndrome: Resection of primary tumor if possible

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

Medical Therapy Options

1. Adrenal steroidogenesis inhibitors:

   • Osilodrostat: FDA-approved, 86% UFC normalization, rapid onset, BID dosing 1, 2

     • Dose: 2-7 mg/day BID (max 30 mg/day)
     • Side effects: Increased androgens (hirsutism), hypertension, hypokalemia, GI issues

   • Ketoconazole: ~65% UFC normalization 1, 2, 4

     • Dose: 400-1200 mg/day (BID)
     • Side effects: Liver toxicity (requires monitoring), gynecomastia, GI disturbances
     • Better for women due to decreased testosterone effects

   • Metyrapone: ~70% UFC normalization, rapid onset 1, 2, 4

     • Dose: 500 mg/day to 6 g/day (q6-8h)
     • Side effects: Hyperandrogenism, hypertension, hypokalemia
     • Better for men and short-term use

2. Pituitary-directed therapies:

   • Pasireotide: FDA-approved, 15-26% UFC normalization 2

     • Side effects: Hyperglycemia (major concern), GI issues
     • Advantage: Potential tumor shrinkage

   • Cabergoline: ~40% UFC normalization 2

     • Avoid in patients with history of bipolar/impulse control disorders
     • May be preferred in young women desiring pregnancy

3. Glucocorticoid receptor antagonist:

   • Mifepristone: Improves hyperglycemia and weight gain 1
     • Challenge: No reliable biochemical markers for monitoring
     • Risk of adrenal insufficiency due to overtreatment

Combination Therapy

For inadequate response to monotherapy after 2-3 months on maximum tolerated doses:

• Ketoconazole + metyrapone (most common)
• Ketoconazole + osilodrostat
• Ketoconazole + cabergoline or pasireotide
• Pasireotide + cabergoline 1, 2

Radiation Therapy

• Consider for persistent/recurrent Cushing's disease after failed surgery
• Delayed effect (months to years)
• Risk of hypopituitarism

Bilateral Adrenalectomy

• Last resort for severe, refractory cases
• Requires lifelong glucocorticoid and mineralocorticoid replacement
• Risk of Nelson's syndrome (pituitary tumor growth)

Special Clinical Scenarios

Severe Disease

• Rapid cortisol normalization is critical
• Options: Osilodrostat or metyrapone (hours), ketoconazole (days)
• For hospitalized patients unable to take oral medications: IV etomidate
• Consider bilateral adrenalectomy if medical therapy fails 1, 2

Pregnancy

• No medications specifically approved
• Metyrapone may be considered with precautions in selected cases
• Use higher cortisol target (1.5× ULN) due to physiologically higher cortisol in pregnancy 1

Diabetes/Hyperglycemia

• Consider mifepristone (improves glucose control)
• Use pasireotide with caution (worsens hyperglycemia) 2

Visible Tumor with Persistent Disease

• Consider pituitary-directed therapies (pasireotide, cabergoline) 2

Monitoring Treatment Response

• Assess both clinical improvement (weight, BP, glucose) and biochemical control
• Measure 24-hour UFC (except with mifepristone)
• Consider treatment change if cortisol remains elevated after 2-3 months on maximum tolerated doses 1, 2

Key Pitfalls to Avoid

• Undertreatment leading to persistent hypercortisolism and complications
• Overtreatment causing adrenal insufficiency
• Inadequate monitoring of drug-specific side effects (e.g., LFTs with ketoconazole)
• Failing to recognize cyclical Cushing's syndrome (may require multiple tests)
• Ignoring drug interactions (especially with ketoconazole)
• Delaying definitive treatment in severe cases

Early diagnosis and prompt treatment are essential to reduce the substantial burden of illness associated with Cushing's syndrome, including cardiovascular complications, metabolic disorders, infections, and neuropsychiatric disturbances 5.