Cushing Disease

Background

• Cushing disease (pituitary Cushing syndrome) is hypercortisolism caused by an adrenocorticotropic hormone (ACTH)-secreting pituitary tumor (usually a microadenoma).
  • Excessive ACTH hyperstimulates the adrenal glands, resulting in an overproduction of cortisol.
  • Inappropriately high circulating cortisol and loss of physiologic diurnal variation cause the variable symptoms and signs of Cushing syndrome.

Evaluation

• Suspect Cushing syndrome in a patient presenting with otherwise unexplained common features including weight gain, depression, muscle weakness, headache, osteoporosis, diabetes, easy bruising, facial plethora, and menstrual irregularity and in patients with unusual features for their age, such as hypertension or osteoporosis in younger persons, as well as in children exhibiting weight gain and stunted linear growth.
• Diagnosis is based on confirming cortisol excess, followed by additional testing to confirm adrenocorticotropic hormone (ACTH)-dependent hypercortisolism (Cushing syndrome) of pituitary origin.
• Do not test during an acute illness to minimize false-positive results.
• Perform testing to demonstrate inappropriately elevated cortisol levels in urine, blood, or saliva to confirm hypercortisolism first (Strong recommendation). Patients often get tested using different modalities to have more confidence in diagnosis and clarify any equivocal results.

Table 1. Tests to Measure Cortisol

• Consider additional testing if there are equivocal results with the above tests (Strong recommendation).
• If hypercortisolism is confirmed, measure the serum ACTH level (in the morning) to establish Cushing syndrome as either ACTH-dependent (if ACTH > 4.4 pmol/L [> 20 pg/mL]) or ACTH-independent (if ACTH < 1.1 pmol/L [< 5 pg/mL]). Patients with ACTH levels between these cutoffs can be evaluated with more testing guided by clinical impression and presentation.
  • If it is determined to be ACTH-independent, obtain a computed tomography (CT) image of the adrenal glands.
  • If it is determined to be ACTH-dependent, test for presence of pituitary adenoma.

Table 2. Tests for Pituitary Adenoma

• If there are equivocal localization test results with ACTH-dependent Cushing, perform bilateral inferior petrosal sinus sampling (IPSS) which tests the serum ACTH gradient between pituitary and peripheral samples to confirm a pituitary source.

Management

• Resection of pituitary tumor is the first-line treatment (Strong recommendation).
  • Surgical excision of pituitary adenoma is the optimal therapy if a discrete tumor is identified (the usual method is transsphenoidal endoscopic surgery).
• Options for persistence or recurrence of Cushing disease after pituitary surgery include:
  • repeat pituitary surgery
  • radiation therapy (including Gamma Knife radiosurgery)
  • medical therapy (may also be considered for preoperative management, or if surgery is contraindicated), options include:
    • adrenal enzyme inhibitors (steroidogenesis inhibitors), such as osilodrostat, levoketoconazole, ketoconazole, metyrapone, mitotane, or etomidate
    • inhibitors of ACTH-secretion (pituitary-directed drugs), such as pasireotide or cabergoline
    • glucocorticoid receptor antagonists suggested for patients with diabetes mellitus or glucose intolerance
  • for patients with treatment-resistant Cushing disease, consider referral for bilateral adrenalectomy.