What is the treatment approach for a patient diagnosed with Cushing syndrome?

Treatment of Cushing Syndrome

Surgical resection of the underlying source of hypercortisolism is the first-line treatment for all forms of endogenous Cushing syndrome, with the specific surgical approach determined by whether the disease is ACTH-dependent or ACTH-independent. 1

Initial Treatment Strategy Based on Etiology

For ACTH-Dependent Cushing's Disease (Pituitary Source)

Transsphenoidal surgery to remove the pituitary adenoma is the primary treatment, with postoperative corticosteroid supplementation required until recovery of the hypothalamus-pituitary-adrenal axis 1. This approach is recommended by the American College of Surgeons and should be performed by an expert neurosurgeon 2.

• For children and adolescents with Cushing disease, early definitive treatment is particularly crucial to normalize growth and puberty 1
• Approximately 60-70% of endogenous Cushing syndrome cases are due to Cushing disease 3

For ACTH-Independent Cushing's Syndrome (Adrenal Source)

Adrenalectomy is the treatment of choice, with the specific approach depending on the underlying pathology 1:

• Adrenal adenoma: Laparoscopic unilateral adrenalectomy 1, 2
• Adrenal carcinoma: Open adrenalectomy with extended resection by an expert surgeon, with possible adjuvant therapy 1, 2
• Bilateral macronodular hyperplasia: Medical management or unilateral/bilateral adrenalectomy depending on the clinical scenario 1, 2

For Ectopic ACTH Syndrome

Surgical removal of the ectopic tumor when possible is the primary treatment 4. If the tumor is unresectable, bilateral adrenalectomy or medical management should be considered 4.

Medical Therapy Options

Medical therapy is reserved for cases where surgery is not possible, has failed, or as a bridge to surgery 1, 3.

Steroidogenesis Inhibitors (Most Effective Pharmacological Options)

Ketoconazole is the medical treatment of choice, normalizing cortisol in approximately 64% of patients 1, 5:

• Liver function monitoring is required to minimize hepatotoxicity risk 1
• Other steroidogenesis inhibitors include metyrapone and osilodrostat 1

Pituitary-Targeted Therapy

Pasireotide (SIGNIFOR) is FDA-approved for adult patients with Cushing's disease when pituitary surgery is not an option or has not been curative 6:

• Initial dosing: 0.6 mg or 0.9 mg subcutaneously twice daily 6
• Maximum UFC reduction typically seen by two months of treatment 6
• Critical monitoring requirements: Weekly glycemic monitoring for the first 2-3 months, as nearly all patients develop worsening glycemia in the first two weeks 6
• Baseline assessments required: fasting plasma glucose, HbA1c, liver tests, serum potassium/magnesium, ECG, and gallbladder ultrasound 6

Glucocorticoid Receptor Blockers

Mifepristone can be considered for severe cases of hypercortisolism, though it requires careful monitoring as cortisol levels remain elevated and only clinical features can assess treatment response 7.

Second-Line and Salvage Therapies

Radiation Therapy

Pituitary radiotherapy (with or without steroidogenesis inhibitors) is an option for Cushing disease when surgery has failed 8, 2.

Bilateral Adrenalectomy

Bilateral adrenalectomy should be reserved for severe refractory cases or life-threatening emergencies 1:

• This carries a higher risk of corticotroph tumor progression (Nelson syndrome) in children than adults 1
• It is appropriate for ACTH-dependent causes of Cushing syndrome when other treatments have failed 8

Special Considerations for Exogenous Cushing's Syndrome

The primary treatment is immediate discontinuation of the causative glucocorticoid if medically feasible, followed by gradual tapering to prevent adrenal insufficiency 7:

• Stop all sources: oral glucocorticoids, injectable steroids, inhaled corticosteroids, and topical preparations 7
• Avoid concomitant azole antifungals (itraconazole, voriconazole) with inhaled budesonide or fluticasone, as this significantly increases risk 7
• Monitor for clinical features of adrenal insufficiency during tapering: fatigue, weakness, nausea, hypotension, hyponatremia, hypoglycemia 7

Monitoring Treatment Response

Urinary free cortisol (UFC) is the most commonly used measure to monitor treatment response, along with clinical improvement in symptoms and signs 1:

• For patients on ketoconazole, monitor liver function regularly 1
• For patients on pasireotide, intensive glycemic monitoring is essential, with weekly checks for 2-3 months 6
• Monitor for hypocortisolism signs: weakness, fatigue, anorexia, nausea, vomiting, hypotension, hyponatremia, hypoglycemia 6

Adjunctive Management

Hypertension Control

Mineralocorticoid receptor antagonists (spironolactone or eplerenone) are recommended for hypertension associated with Cushing syndrome, as these block mineralocorticoid receptor activation from excess cortisol 1, 7.

Hyperglycemia Management

Appropriate glucose-lowering therapy should be initiated, with consideration of GLP-1 receptor agonists or DPP-4 inhibitors if pasireotide is used 7.

Critical Pitfalls to Avoid

• Do not use bilateral inferior petrosal sinus sampling (BIPSS) to diagnose hypercortisolism—it should only be used for localization after Cushing syndrome is confirmed 9
• Do not assume complete reversibility of all clinical features after treatment—some signs may have incomplete reversibility, underscoring the need for timely intervention 2
• Do not overlook monitoring for pituitary hormone deficiencies in patients who have undergone transsphenoidal surgery or pituitary irradiation, as they are at increased risk 6
• For select patients with mild autonomous cortisol secretion (MACS), particularly younger individuals with progressive metabolic comorbidities, adrenalectomy may be appropriate 1