What labs should be ordered to evaluate pituitary function and the hypothalamus in secondary adrenal insufficiency?

Laboratory Evaluation for Secondary Adrenal Insufficiency

The comprehensive laboratory evaluation for secondary adrenal insufficiency should include morning ACTH and cortisol levels, thyroid function tests (TSH and free T4), gonadal hormones, and the 250-μg ACTH stimulation test, with MRI of the pituitary recommended for all patients with confirmed hormonal deficiencies.

Initial Laboratory Assessment

Core Laboratory Tests

• Morning ACTH and cortisol levels (8 am preferred) 1
  • Low ACTH with low cortisol suggests secondary adrenal insufficiency
  • Primary adrenal insufficiency shows high ACTH with low cortisol
• Thyroid function tests 1
  • TSH and free T4
  • Low free T4 with low/normal TSH suggests central hypothyroidism
• Electrolytes 1, 2
  • Typically normal in secondary adrenal insufficiency (unlike primary)

Confirmatory Testing

• 250-μg ACTH stimulation test (high-dose) 1
  • Preferred over low-dose (1-μg) test due to comparable accuracy and easier administration
  • Cortisol measured at baseline, 30 and 60 minutes after ACTH administration
  • Peak cortisol <500 nmol/L (18 μg/dL) is diagnostic of adrenal insufficiency

Additional Pituitary Hormone Evaluation

• Gonadal axis assessment 1
  • Males: LH, testosterone
  • Females: FSH, estradiol (in premenopausal women)
  • Consider in patients with fatigue, loss of libido, mood changes, or oligomenorrhea
• Consider DHEAS levels 2
  • Low levels are common in secondary adrenal insufficiency

Imaging Studies

• MRI of the brain with pituitary/sellar cuts with contrast 1
  • Recommended for all patients with confirmed hormonal deficiencies
  • Essential for patients with multiple endocrine abnormalities
  • Mandatory for patients with severe headaches or visual changes
  • May show pituitary enlargement, stalk thickening, or other abnormalities

Special Considerations

Alternative Testing When Needed

• Insulin Tolerance Test (ITT) 3, 4

  • Considered the gold standard as it tests the entire HPA axis
  • Contraindicated in patients with seizure disorders, cardiovascular disease, or elderly
  • Requires close monitoring due to risks associated with induced hypoglycemia

• CRH stimulation test 5

  • May help differentiate between hypothalamic and pituitary causes
  • Patients with hypothalamic dysfunction may show delayed but augmented ACTH response

Timing Considerations

• Perform testing before starting steroid therapy whenever possible 1
• If patient is already on steroids, testing should be done after appropriate withdrawal period (if safe)

Interpretation Pitfalls

• A normal response to ACTH stimulation does not completely rule out early or mild secondary adrenal insufficiency 4, 6
• Patients with recent onset of pituitary dysfunction may still respond normally to ACTH stimulation 4
• Multiple pituitary hormone deficiencies increase the likelihood of adrenal insufficiency 1
• Morning cortisol <3 μg/dL strongly suggests adrenal insufficiency, while >15 μg/dL makes it unlikely 1

Follow-up Management

• Patients with confirmed secondary adrenal insufficiency require:
  • Physiologic glucocorticoid replacement (typically hydrocortisone 15-20 mg daily in divided doses) 1, 2
  • Education on stress dosing for illness or procedures 2
  • Medical alert bracelet/card 1, 2
  • Regular monitoring of replacement therapy adequacy 2

Remember that secondary adrenal insufficiency can be subtle in presentation but potentially life-threatening during stress. Early endocrinology consultation is appropriate for all patients with suspected or confirmed secondary adrenal insufficiency 1.