Management and treatment considerations

Early detection of hypercortisolism and initiation of treatment are essential for preventing or remedying the comorbidities linked to hypercortisolism as well as reducing the risk of death in these patients. Treatment options for patients with hypercortisolism include surgery, radiotherapy, and direct medical therapy.1
treatment grid

Surgery is generally the primary therapy for endogenous hypercortisolism. Transsphenoidal surgery (TSS), a type of surgery in which an endoscope and/or surgical instruments are directed through the nose to the bottom of the skull where the pituitary gland is located, remains the first-line treatment for Cushing Disease. Adrenalectomy is an additional surgical option that involves completely or partially removing one or both of the adrenal glands. This treatment results in immediate resolution of hypercortisolism and may involve lifelong hormone replacement therapy.2,3

Although surgery is generally the first-line therapy for endogenous hypercortisolism, for patients who have failed surgery or for those who are not candidates for surgery, medical therapy plays an important role in managing the effects of hypercortisolism.1,3

Treatment considerations


Transsphenoidal Surgery

  • Remains first-line treatment for Cushing Disease4
  • Surgery failure rates are reported as high as 30% and recurrence rates increase over time2,3


  • Irreversible3
  • Currently, there is no available long-term prospective data comparing adrenalectomy to medical therapy5
  • Improvement in many manifestations of disease up to 67% of patients6,7
    • Metabolic (blood pressure, weight, diabetes control)
    • Physical signs
  • Lifelong hormone replacement therapy may be needed3
  • Potential long-term complications3
  • Significant lifestyle changes3
Surgery is the preferred first-line treatment for patients with endogenous hypercortisolism. However, it is not right for everyone. Surgery may not be successful. Failure rates associated with surgery are reported to be as high as 30%. Recurrence rates of Cushing Disease increase over time and may reach as high as 46% more than 13 years after surgery.2,3
transsphenoidal surgery failures in patients with cushing disease
recurrence rate increase across time


  • Noninvasive
  • Takes a long time to produce results
  • Effective in controlling excess cortisol in up to 86% of patients
  • Prevents adenoma regrowth in approximately 90% to 100% of patients


  • May be useful for controlling symptoms of cortisol activity until the cause of increased levels is found
  • Noninvasive
  • Useful when surgery is not possible
  • Can be discontinued if not tolerated or no improvement seen

AACE/ACE surgery recommendations

Remission after surgery is indicated by postoperative adrenal insufficiency due to suppression of normal corticotropin cell production of Adrenocorticotropic hormone (ACTH) in the postoperative period; it may take years for the hypothalamic–pituitary–adrenal (HPA) axis to recover.4

Criteria for disease remission vary, but may include the following4:

  • Resolution of clinical symptoms related to hypercortisolism
  • Need for corticosteroid replacement for >6 months after TSS
  • Hypocortisolemia/Eucortisolemia
  • Presence of clinical and laboratory signs of low serum cortisol and adrenal adenomas

Assessing remission after TSS in Cushing Disease4

  • Postoperative cortisol <2 μg/dL (predictive of increased chance of long-term remission)
  • Most patients with postoperative cortisol 2 to 5 μg/dL a few days after TSS will also be in remission
  • Delayed remission in small numbers of patients with cortisol >5 to 10 μg/dL
  • Low, early postoperative ACTH levels may be predictive of early hypocortisolemia, but may not accurately predict long-term remission
  • Time needed to achieve recovery of the HPA axis was the only significant predictor of recurrence

Workup of recurrent hypercortisolism in patients in remission after TSS

Clinical suspicion of recurrent Cushing Disease

New onset or worsening of preexisting symptoms and comorbidities4

  • Type 2 diabetes mellitus
  • Hypertension
  • Osteoporosis
  • Weight gain
  • Easy bruising

Biochemical evaluation4

  • Collect late-night salivary cortisol (LNSC) 2 to 3 times; if high normal, additional LNSC testing is recommended
  • Overnight dexamethasone suppression test
  • Collect urinary-free cortisol (at least twice)
  • If discordant results, repeat testing

Salivary cortisol is the preferred initial test for recurrence4

New evidence of adenoma on magnetic resonance imaging or increase in size of previous residual adenoma will also require additional biochemical evaluation5

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