What is the best approach to assess adrenal function?

Assessment of Adrenal Function

The best approach to assess adrenal function involves a stepwise diagnostic algorithm starting with morning serum cortisol measurement, followed by stimulation testing with cosyntropin when indicated. 1, 2

Initial Evaluation

Clinical Assessment

• Evaluate for symptoms and signs of specific adrenal disorders:
  • Hypercortisolism (Cushing's syndrome): Weight gain, central obesity, easy bruising, severe hypertension, diabetes, proximal muscle weakness, facial plethora, purple striae 1
  • Primary aldosteronism: Hypertension, hypokalemia, muscle cramping 1
  • Pheochromocytoma: Headaches, anxiety attacks, sweating, palpitations, severe hypertension 1
  • Adrenal insufficiency: Weight loss, fatigue, hyperpigmentation (primary), electrolyte abnormalities 2

First-Line Laboratory Testing

1. Morning serum cortisol (8 AM):

   • Values ≥354 nmol/L (≥12.8 μg/dL) generally predict normal adrenal function with high specificity 3
   • Values <100 nmol/L (<3.6 μg/dL) strongly suggest adrenal insufficiency 4, 5
   • Intermediate values require further testing 4, 3

2. For suspected hyperfunction:

   • Cushing's syndrome: 1 mg overnight dexamethasone suppression test (DST) 1
     • Cortisol >138 nmol/L (>5 μg/dL) suggests cortisol hypersecretion
     • 51-138 nmol/L indicates possible autonomous cortisol secretion
     • <50 nmol/L excludes hypersecretion
   • Primary aldosteronism: Aldosterone/renin ratio (ARR) in morning after seated 5-15 minutes 1
     • ARR >20 ng/dL per ng/mL/hr has >90% sensitivity/specificity for hyperaldosteronism
   • Pheochromocytoma: Plasma free metanephrines 1

     • 2× upper limit of normal is diagnostic

Confirmatory Testing

ACTH Stimulation Test (Gold Standard)

• Indication: Suspected adrenal insufficiency or inconclusive morning cortisol 2, 6
• Procedure:
  1. Obtain baseline cortisol sample
  2. Administer cosyntropin:
     • Adults: 0.25 mg IV/IM 6
     • Children <2 years: 0.125 mg IV/IM 6
     • Children 2-17 years: 0.25 mg IV/IM 6
  3. Measure cortisol at 30 and 60 minutes post-administration 6
• Interpretation:
  • Normal response: Peak cortisol ≥18 μg/dL (≥500 nmol/L) 6
  • Note: Cutoff values may vary by assay method - newer assays may require lower thresholds (e.g., 13.3-13.7 μg/dL) 7

Additional Testing for Specific Conditions

• Primary vs. Secondary Adrenal Insufficiency:

  Type	ACTH Level	Cortisol Level	Electrolytes	Hyperpigmentation
  Primary	High	Low	↓Na, ↑K	Present
  Secondary	Low	Low	Usually normal	Absent
  2

• For suspected adrenocortical carcinoma or virilization: DHEAS, testosterone, 17β-estradiol, 17-OH progesterone 1

Important Considerations

Medication Interference

• Stop before testing:
  • Glucocorticoids and spironolactone: Stop on day of testing (may cause falsely elevated cortisol) 6
  • Estrogen-containing drugs: Stop 4-6 weeks before testing (increases cortisol binding globulin) 6
  • Long-acting glucocorticoids: May need longer washout period 6

Assay Variability

• Cortisol measurements vary significantly between different assays 7
• Modern assays (especially LC-MS/MS) yield lower values than older immunoassays 7
• Laboratory-specific reference ranges should be considered when interpreting results 7

Testing Pitfalls

• Morning cortisol alone may miss up to 75% of cases requiring dynamic testing 5
• Conditions affecting cortisol binding globulin (pregnancy, cirrhosis, nephrotic syndrome) may affect total cortisol levels 6
• Consider measuring cortisol binding globulin when interpreting total cortisol in these conditions 6

Algorithm for Adrenal Function Assessment

1. Initial screening: Morning serum cortisol (8 AM)
2. If morning cortisol is indeterminate: Proceed to ACTH stimulation test
3. For specific suspected disorders: Add targeted testing (DST, ARR, metanephrines)
4. For confirmed adrenal insufficiency: Determine if primary or secondary with ACTH level measurement

This approach allows for efficient diagnosis while minimizing unnecessary testing, as approximately 25-37% of patients may avoid dynamic testing based on morning cortisol results alone 3, 5.