What is the treatment for hypercortisolism?

Treatment of Hypercortisolism

Transsphenoidal surgery is the first-line treatment for Cushing's disease, achieving remission in 75-88% of patients, while medical therapy with adrenal steroidogenesis inhibitors (ketoconazole, osilodrostat, or metyrapone) is reserved for persistent/recurrent disease, surgical non-candidates, or as a bridge to definitive therapy. 1, 2

Treatment Algorithm Based on Etiology and Clinical Context

For Cushing's Disease (Pituitary Source)

Initial Treatment:

• Perform transsphenoidal surgery at a high-volume pituitary center as first-line therapy 1, 2
• Remission rates range from 37-88% depending on surgeon experience, tumor characteristics, and remission criteria used 1

For Recurrent or Persistent Disease:

• Consider repeat transsphenoidal surgery if tumor is visible on MRI, especially if initial surgery was not performed at a specialized center 1, 2
• Reoperation may be appropriate even without visible tumor if positive pathology or central ACTH gradient on inferior petrosal sinus sampling was documented initially 1
• Critical caveat: Repeat surgery carries higher risk of CSF leak, meningitis, and hypopituitarism, though serious morbidity is less likely with experienced surgeons 1

Medical Therapy Selection Strategy

For Mild Disease Without Visible Tumor:

• First-line options: Ketoconazole, osilodrostat, or metyrapone 2, 3
• Osilodrostat and metyrapone work within hours; ketoconazole works within days 2
• Ketoconazole normalizes urinary free cortisol in 64.3% of patients at mean dose of 673.9 mg/day, but 23% experience escape phenomenon 1
• Monitor weekly liver function tests with ketoconazole due to hepatotoxicity risk (10-20% of patients), which typically appears within first 6 months 1

For Mild-to-Moderate Disease With Visible Tumor:

• Consider cabergoline or pasireotide due to potential for tumor shrinkage 2, 3
• Cabergoline is less effective but requires less frequent dosing 2
• Warning: Pasireotide has high rate of hyperglycemia and requires baseline ECG and gallbladder ultrasound monitoring 2

For Severe Hypercortisolism:

• Prioritize rapid cortisol normalization with osilodrostat, metyrapone, ketoconazole, or intravenous etomidate 3, 4
• Severe disease is defined by random serum cortisol >1000 nmol/L or 24-hour urinary free cortisol >4× upper limit of normal, plus severe hypokalemia (<3.0 mmol/L) and/or acute complications (sepsis, psychosis, uncontrolled hypertension, heart failure) 4
• Etomidate is rapidly effective when parenteral therapy is required but requires careful supervision 4

Combination Therapy Approach

When Monotherapy Fails:

• Combine ketoconazole with metyrapone to maximize adrenal blockade 2, 3
• Monitor for overlapping toxicities, particularly QTc prolongation 2
• For visible tumor, combine steroidogenesis inhibitor (ketoconazole) with tumor-targeting agent (cabergoline or pasireotide) 2, 3

Alternative Glucocorticoid Receptor Blockade

Mifepristone:

• Effective regardless of hypercortisolism etiology 3
• Improves hyperglycemia, weight gain, blood pressure, insulin resistance, and quality of life 2, 3
• Should only be used by clinicians with extensive Cushing's disease experience 2
• Monitor thyroid function and adjust thyroid hormone replacement as needed 3

Bilateral Adrenalectomy

Indications:

• Medical therapy fails to control severe hypercortisolism 2
• Provides immediate control of cortisol excess 2
• Results in long-term clinical improvement in BMI, diabetes, hypertension, and muscle weakness in >80% of patients 2
• Requires lifelong glucocorticoid and mineralocorticoid replacement plus monitoring for pituitary hormone deficiencies 2

Treatment for Adrenal Source Hypercortisolism

• Laparoscopic adrenalectomy for benign adenomas 2
• Open adrenalectomy with lymph node removal for suspected adrenal carcinomas 2

Treatment for Ectopic ACTH Source

• Surgical removal of ectopic tumor as first-line treatment 2
• Medical therapy or bilateral adrenalectomy when surgery is not possible 2

Monitoring During Treatment

Biochemical and Clinical Monitoring:

• Define response by both clinical endpoints (improved phenotype, weight, hypertension, glucose metabolism, quality of life) and biochemical endpoints (urinary free cortisol levels) 3
• Consider changing treatment if cortisol remains persistently elevated after 2-3 months on maximum tolerated doses 3
• Monitor for adrenal insufficiency with steroidogenesis inhibitors due to overtreatment risk 1, 3

Tumor Surveillance:

• Obtain MRI 6-12 months after initiating treatment and repeat every few years 2, 3
• Monitor ACTH levels as significant elevations may indicate tumor growth 2, 3
• Reassess medical treatment if progressive tumor growth is observed 3

Critical Pitfalls to Avoid

• Escape phenomenon: Up to 23% of initially responsive patients on ketoconazole lose biochemical control 1, 2
• Preoperative medical therapy may make it difficult to assess surgical remission 2
• Hypopituitarism occurs in 25-50% of patients after radiation therapy and generally increases over time 2
• Patients with cirrhosis may have impaired response to metyrapone 3, 5
• Risk of inappropriate glucocorticoid over-replacement with block-and-replace regimen if blockade is incomplete 1