What are the treatment options for high cortisol levels?

Treatment Options for High Cortisol Levels

The treatment of high cortisol levels should be targeted based on the underlying cause, with surgical intervention as first-line therapy for most cases of Cushing's disease (pituitary adenoma) and adrenal adenomas, while medical therapy is reserved for cases where surgery is not possible or has failed. 1

Diagnostic Approach Before Treatment

• Before initiating treatment, determine the source of hypercortisolism through appropriate testing, including 24-hour urinary free cortisol, late night salivary cortisol, or overnight 1 mg dexamethasone suppression test 1
• Measure ACTH levels to differentiate between ACTH-dependent (pituitary or ectopic source) and ACTH-independent (adrenal) causes 1
• Imaging studies (pituitary MRI for ACTH-dependent, adrenal CT/MRI for ACTH-independent) should be performed to localize the source 1

Treatment Algorithm Based on Etiology

ACTH-Dependent Cushing's Disease (Pituitary Source)

1. First-line: Transsphenoidal Surgery (TSS)

   • Preferred initial treatment for corticotroph adenomas 1
   • Offers immediate control of cortisol excess with potential for cure
   • Should be performed at centers with experienced pituitary surgeons

2. Second-line: Radiation Therapy

   • Used for persistent hypercortisolism after incomplete tumor resection 1
   • Stereotactic radiosurgery (SRS) is preferred when feasible (fewer sessions required) 1
   • Requires 3-5 mm distance between tumor and optic chiasm to avoid damage 1
   • Effects may take months to years, necessitating interim medical therapy 1
   • Long-term monitoring for hypopituitarism (occurs in 25-50% of patients) is essential 1

3. Third-line: Bilateral Adrenalectomy (BLA)

   • Offers immediate control of cortisol excess in patients with persistent disease 1
   • Associated with 10-18% complication rate and <1% mortality 1
   • Results in adrenal insufficiency requiring lifelong glucocorticoid and mineralocorticoid replacement 1
   • May be considered earlier in patients with severe hypercortisolism requiring rapid control 1
   • Often recommended earlier for females with CD desiring pregnancy 1
   • Requires monitoring for corticotroph tumor progression (occurs in 25-40% after 5-10 years) 1

ACTH-Independent Cushing's Syndrome (Adrenal Source)

1. Adrenal Adenoma

   • Laparoscopic adrenalectomy is the treatment of choice 1
   • Postoperative corticosteroid supplementation required until HPA axis recovery 1

2. Adrenal Carcinoma

   • Open adrenalectomy with lymph node dissection for complete resection 1
   • May require removal of adjacent structures for complete tumor excision 1

3. Bilateral Adrenal Hyperplasia

   • If cortisol production is asymmetric, unilateral adrenalectomy of the most active side 1
   • If cortisol production is symmetric, medical management is indicated 1

Ectopic ACTH Syndrome

• Surgical removal of the ectopic tumor when possible 1
• If primary tumor is unresectable, bilateral adrenalectomy or medical management 1

Medical Therapy Options

Medical therapy is used when surgery is contraindicated, delayed, or unsuccessful, or as adjunctive therapy while awaiting effects of radiation.

1. Steroidogenesis Inhibitors

   • Ketoconazole

     • Most commonly used (doses 400-1200 mg/day) 1
     • Relatively tolerable toxicity profile compared to alternatives 1
     • Potential side effects include hepatotoxicity, gastrointestinal symptoms, and adrenocortical insufficiency 2

   • Metyrapone

     • Inhibits 11-beta-hydroxylation in adrenal cortex 3
     • Reduces cortisol and corticosterone production 3
     • Side effects include gastrointestinal symptoms, hyponatremia, hypertension, and hirsutism 3
     • Requires monitoring for adrenal insufficiency 3

   • Mitotane

     • Used particularly in adrenal carcinoma 1
     • Has adrenolytic effects 1

2. Neuromodulators of ACTH Release

   • Cabergoline (dopamine agonist)
     • May be temporarily withheld during radiation therapy 1
     • Less effective than steroidogenesis inhibitors for most patients 1

3. Somatostatin Analogs

   • Octreotide can be considered for ectopic Cushing syndrome if the tumor is Octreoscan-positive 1
   • May be less effective for ectopic ACTH secretion than in other contexts 1

Non-Pharmacological Interventions

• Stress management interventions have shown medium positive effects on cortisol levels (g = 0.282) 4
• Mindfulness/meditation (g = 0.345) and relaxation techniques (g = 0.347) are most effective at reducing cortisol levels 4
• These should be considered as adjunctive approaches, not primary treatment for pathological hypercortisolism 4

Monitoring and Follow-up

• After bilateral adrenalectomy, monitor plasma ACTH and serial pituitary imaging starting 6 months after surgery 1
• After radiation therapy, lifelong monitoring for pituitary hormone deficiencies and recurrence is required 1
• Periodic imaging for secondary neoplasia in the radiation field should be considered 1
• For medical therapy, regular assessment of cortisol levels and monitoring for side effects is essential 3, 2

Clinical Considerations

• High cortisol levels are associated with increased mortality risk 5, 6, cardiovascular disease 7, hypertension, diabetes mellitus, and susceptibility to infections 5
• Prompt treatment is essential to reduce morbidity and mortality associated with chronic hypercortisolism 5, 7
• Treatment decisions should consider the severity of hypercortisolism, presence of comorbidities, and patient-specific factors such as desire for pregnancy 1