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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 considerations

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

Transsphenoidal Surgery (TSS)

  • First-line treatment for those eligible for surgery2
  • Surgery may not be successful, nor its impact sustained2
close up of pituitary gland

TSS Considerations2,3,7

  • Failure rates are reported to be as high as 30%
  • Recurrence of Cushing disease after surgery is common
  • Recurrence rates increase over time and may reach as high as 46% at 5 to 13 years after surgery
Transsphenoidal Surgery Failures in Patients With Cushing Disease3
A portion of screened adrenal adenomas are found to be cortisol secreting
Bar chart showing that up to 30% of transsphenoidal surgeries have failed in patients with Cushing disease.
Recurrence Rate Increase Across Time2

Chart showing recurrence rates post surgery when used as treatment for hypercortisolism after 5 and 13 years.
Bar chart showing that after transsphenoidal surgery, the recurrence rate of Cushing disease was 26% at 5 years and increased to 46% between 5-13 years.


  • Evidence is best established in moderate to severe hypercortisolism4
  • Long-term prospective data vs medical therapy is unavailable in less severe hypercortisolism4
close up of kidneys

Adrenalectomy Considerations3,5-7

  • Considerable improvement of hypercortisolism
  • Improvement in many manifestations of disease in up to 67% of patients
    • Metabolic (blood pressure, weight, diabetes control)
    • Physical signs
  • Lifelong hormone replacement therapy may be needed
  • Irreversible
  • Significant lifestyle changes
  • Potential long-term complications


  • 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

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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.9

Criteria for disease remission vary, but may include the following9:

  • 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 disease9

  • 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

Cushing disease recurrence9

AACE/ACE recommended workup for recurrence post-TSS

New onset or worsening of preexisting symptoms and comorbidities, including ...

  • Diabetes mellitus
  • Hypertension
  • Osteoporosis
  • Weight gain
  • Easy bruising

Biochemical evaluation

  • Collect LNSC 2 to 3 times; if high normal, additional LNSC is recommended
  • Collect 1-mg overnight DST
  • Collect UFC 2 times

Collect additional or repeated biochemical testing when ...

  • Results are discordant
  • New evidence of a tumor is discovered
  • A previous residual tumor increases in size

DST=overnight dexamethasone suppression test; LNSC=late night salivary cortisol; UFC=urinary free cortisol.Urinary-free cortisol may lack sensitivity. Sixty-one percent of patients displayed normal UFC levels at the time of proven early-stage recurrence. Among the patients with elevated UFC levels, 39% were found to be only mildly elevated.

All patients will need lifelong, yearly evaluation for recurrance.* Late night salivary cortisol is the preferred initial test and best predictor of recurrence.9

*The timeline of repeat testing will depend on clinical circumstances.

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