Treatment of Cushing's Disease
Transsphenoidal pituitary surgery is the first-line treatment for Cushing's disease, with medical therapy indicated when surgery is not an option or has not been curative. 1
Treatment Algorithm
First-line Treatment
- Transsphenoidal selective pituitary surgery
- Gold standard initial approach
- Success rate: ~78% remission in the first 10 years post-surgery
- ~13% experience relapse during this period 2
Second-line Options (for persistent or recurrent disease)
Medical Therapy
Medical therapy is indicated when:
- Surgery is not an option
- Surgery has not been curative
- As bridging therapy before, during, or after radiotherapy
- As presurgical treatment for severe disease
Adrenal Steroidogenesis Inhibitors:
Ketoconazole: First choice for many clinicians
- Dosage: 400-1200 mg/day in divided doses
- Efficacy: ~65% UFC normalization
- Monitoring: Liver function tests, drug interactions
- Rapid onset of action (days)
Osilodrostat:
- Dosage: 2-7 mg/day (BID)
- Efficacy: 86% UFC normalization
- FDA approved for CD when surgery not an option/not curative
- Rapid onset of action (hours)
- Monitor for hyperandrogenism, hypokalemia, QTc prolongation 1
Metyrapone:
- Dosage: 500 mg/day to 6 g/day
- Efficacy: ~70% UFC normalization
- Rapid onset of action (hours to days)
- Monitor for hyperandrogenism, hypokalemia
Pituitary-directed Drugs:
Pasireotide (somatostatin analog):
Cabergoline (dopamine agonist):
- Dosage: 0.5-7 mg weekly
- Efficacy: ~40% UFC normalization
- Potential for tumor shrinkage
- Not FDA approved for CD (off-label use)
Glucocorticoid Receptor Antagonist:
- Mifepristone:
- Dosage: 300-1200 mg/day
- Particularly useful when CD is associated with diabetes mellitus
- Cannot monitor cortisol levels; monitor clinical response
- Watch for hypokalemia and adrenal insufficiency
- Mifepristone:
Radiation Therapy
- Indicated when surgery and medical therapy fail
- Effective in controlling cortisol excess in many patients
- Drawback: High risk of hypopituitarism
- Delayed effect (months to years)
Bilateral Adrenalectomy
- Rapid and definitive control of cortisol excess
- Induces permanent adrenal insufficiency requiring lifelong replacement
- Consider when other treatments have failed or urgent control is needed
Treatment Response Monitoring
Assess both clinical and biochemical endpoints:
- Clinical: Improved phenotype, weight, hypertension, glucose metabolism, quality of life
- Biochemical: 24-hour urinary free cortisol (UFC), late-night salivary cortisol
Consider treatment change if:
- Cortisol levels remain elevated after 2-3 months on maximum tolerated doses
- If cortisol is reduced but not normalized with some clinical improvement, consider combination therapy
- If clear resistance to treatment despite dose escalation, switch to different therapy 1
Combination Therapy Approaches
When monotherapy is insufficient, consider these combinations:
- Ketoconazole + metyrapone (maximizes adrenal blockade)
- Ketoconazole + osilodrostat
- Ketoconazole + cabergoline or pasireotide (if visible tumor present)
- Pasireotide + cabergoline (if visible tumor present)
- Triple therapy options: cabergoline + pasireotide + ketoconazole, or ketoconazole + metyrapone + mitotane 1
Special Considerations
- Severe disease: Prioritize rapid cortisol normalization with osilodrostat, metyrapone, or ketoconazole; consider hospitalization with IV etomidate if oral medications not possible
- Pregnancy: No medications specifically approved; metyrapone may be considered with precautions in selected cases
- Diabetes: Mifepristone may be preferred; use pasireotide with caution due to hyperglycemic effects
- Visible tumor with persistent disease: Consider pituitary-directed therapies (pasireotide, cabergoline)
Early diagnosis and prompt treatment are critical to reduce mortality and morbidity associated with Cushing's disease, as the condition is associated with significant cardiovascular complications, metabolic disorders, skeletal problems, infections, and neuropsychiatric disturbances 4, 5.