How to manage Pseudo Cushing's (Cushing's) syndrome?

Management of Pseudo-Cushing's Syndrome

The primary approach to managing Pseudo-Cushing's syndrome (non-neoplastic hypercortisolism) is to identify and treat the underlying condition causing the hypercortisolism, which will restore normal hypothalamic-pituitary-adrenal axis function. 1

Diagnosis and Differentiation from True Cushing's Syndrome

• Pseudo-Cushing's syndrome covers various conditions causing mild-to-moderate ACTH-dependent hypercortisolism not related to an ACTH-secreting tumor, but rather to hypothalamic CRH and/or AVP secretion 1

• Main conditions implicated in Pseudo-Cushing's include:

  • Neuropsychiatric disorders
  • Alcohol abuse
  • Insulin-resistant obesity
  • Polycystic ovary syndrome
  • End-stage kidney disease 1

• Diagnostic approach should include:

  • Thorough clinical history focusing on duration of symptoms 2
  • Screening for catabolic signs (muscle atrophy, skin fragility, etc.) 1
  • Late night salivary cortisol measurements (multiple tests) 2
  • 24-hour urinary free cortisol (multiple collections) 2
  • Dexamethasone suppression test 2

• Advanced testing to differentiate from mild Cushing's disease:

  • Dex-CRH test (at expert centers with dexamethasone level measurement) 2
  • Serial late night salivary cortisol measurements over time 2
  • Desmopressin stimulation test 2

Management Algorithm

1. Identify and treat the underlying condition 1, 3:

   • For alcohol-induced Pseudo-Cushing's: alcohol withdrawal 4
   • For depression/neuropsychiatric disorders: appropriate psychiatric treatment 5
   • For obesity-related Pseudo-Cushing's: weight management interventions 3
   • For PCOS: specific PCOS management 3

2. Monitor cortisol levels:

   • Repeat testing after 3-6 months of treating the underlying condition 2
   • Use late night salivary cortisol or dexamethasone suppression test to assess improvement 2

3. Manage symptoms while awaiting resolution:

   • For hypertension: consider spironolactone or eplerenone 2
   • For hyperglycemia: appropriate glucose-lowering therapy 2
   • For hypokalemia: potassium supplementation 2

4. Psychiatric support:

   • Psychiatric or psychological monitoring should be offered throughout management 5
   • Depression is the most common psychiatric manifestation (up to 55% of patients) 4, 5
   • Psychiatric symptoms often improve with normalization of cortisol levels 4

Special Considerations

• Diagnostic uncertainty: In some cases, definitive differentiation between mild Cushing's disease and Pseudo-Cushing's may require prolonged follow-up 1
• Bilateral inferior petrosal sinus sampling (IPSS) should not be used to diagnose hypercortisolism as the central-to-peripheral ACTH gradient in healthy controls and Pseudo-Cushing's overlaps with that seen in patients with Cushing's disease 2
• Pituitary MRI has limitations in both sensitivity and specificity for differentiating Pseudo-Cushing's from mild Cushing's disease 1

Common Pitfalls

• Misdiagnosing Pseudo-Cushing's as true Cushing's syndrome can lead to unnecessary and potentially harmful treatments 3
• Single cortisol measurements are unreliable; multiple tests over time provide more accurate assessment 2
• Failure to address the underlying condition will result in persistent hypercortisolism 1
• Psychiatric symptoms may persist even after normalization of cortisol levels, requiring ongoing psychiatric support 5

Follow-up

• Regular monitoring of cortisol levels until normalization 2
• Continued management of metabolic complications until resolution 2
• Long-term psychiatric follow-up as needed 5
• Patient education about the condition and importance of addressing underlying causes 5