What are the management options for elevated cortisol levels?

Management Options for Elevated Cortisol Levels

The management of elevated cortisol levels should be tailored to the underlying cause, with surgical intervention being the first-line treatment for most cases of endogenous hypercortisolism, while medical therapy is reserved for patients who are not surgical candidates or have persistent disease after surgery. 1

Diagnostic Approach

• First determine the source of cortisol excess through appropriate testing, as management differs based on etiology 1:
  • Measure ACTH levels - elevated ACTH indicates pituitary or ectopic source, while suppressed ACTH suggests adrenal source 1
  • 24-hour urinary free cortisol to confirm hypercortisolism 1
  • Imaging studies (pituitary MRI, adrenal CT/MRI) to localize the source 1

Management Based on Etiology

1. Cushing's Disease (Pituitary Source)

• First-line treatment: Transsphenoidal surgery (TSS) for removal of pituitary adenoma 1
• For persistent or recurrent disease:
  • Radiation therapy (RT), particularly stereotactic radiosurgery (SRS) for incomplete tumor resection 1
  • SRS achieves biochemical control in approximately 80% of patients with durable hypercortisolism control in 57% 1
  • Medical therapy is needed during the latency period until RT achieves remission 1

2. Adrenal Source (Adenoma or Carcinoma)

• For benign adrenal adenoma: Laparoscopic adrenalectomy with postoperative corticosteroid supplementation until HPA axis recovery 1
• For adrenal carcinoma: Open adrenalectomy with removal of adjacent lymph nodes 1
• For bilateral adrenal hyperplasia:
  • If cortisol production is asymmetric: unilateral adrenalectomy of the most active side 1
  • If cortisol production is symmetric: medical management 1

3. Ectopic ACTH Source

• First-line: Surgical removal of the ectopic tumor if possible 1
• If unresectable: Bilateral laparoscopic adrenalectomy or medical management 1

Medical Management Options

• Adrenostatic agents:
  • Ketoconazole (400-1200 mg/day) - most commonly used due to relatively tolerable toxicity profile 1
  • Mitotane - effective but has more side effects 1
• For ectopic Cushing syndrome:
  • Octreotide can be considered if the tumor is Octreoscan-positive 1

Bilateral Adrenalectomy (BLA)

• Often considered a treatment of last resort after other options have failed 1
• Provides immediate control of cortisol excess but results in adrenal insufficiency requiring lifelong glucocorticoid and mineralocorticoid replacement 1
• May be warranted earlier in:
  • Patients with severe hypercortisolism requiring rapid cortisol control 1
  • Female patients with Cushing's disease desiring immediate pregnancy 1
• Long-term clinical improvement in BMI, diabetes, hypertension, and muscle weakness is reported in more than 80% of patients 1
• Requires monitoring for corticotroph tumor progression (25-40% after 5-10 years) 1

Monitoring After Treatment

• For patients who undergo bilateral adrenalectomy:
  • Monitor plasma ACTH and perform serial pituitary imaging, starting 6 months after surgery 1
  • More frequent evaluation if clinical suspicion of corticotroph tumor progression 1
• For patients treated with radiation therapy:
  • Lifelong monitoring for pituitary hormone deficiencies 1
  • Regular imaging to detect recurrence and secondary neoplasia 1

Management of Complications

• Patients with hypercortisolism often have cardiovascular and metabolic comorbidities that require management 2:
  • Hypertension
  • Impaired glucose metabolism
  • Dyslipidemia
  • Obesity

Special Considerations

• Perioperative management for patients with adrenal insufficiency (following treatment):
  • Hydrocortisone 100 mg IV at the start of surgery, followed by infusion of 200 mg/24h 1
  • Double the regular oral replacement dose for 48h and up to a week following major surgery 1

Pitfalls and Caveats

• Even after successful treatment of hypercortisolism, cardiovascular risk remains elevated though reduced 2
• Hypopituitarism is the most common side effect of radiation therapy (25-50% of patients) and generally increases over time 1
• When using SRS, maintain distance of at least 3-5 mm between tumor and optic chiasm and limit chiasm dose to <8 Gy to prevent damage 1
• Long-term clinical relapse of hypercortisolism after BLA due to adrenal rest stimulation is uncommon (<10%) 1