Diagnostic Approach to Secondary Adrenal Insufficiency

Introduction to Diagnostic Rationale

The combination of low ACTH with normal cortisol is indeterminate and requires dynamic testing to establish whether the patient has true adrenal insufficiency or intact adrenal reserve, as stated by the American College of Endocrinology 1
Low ACTH with normal cortisol is not diagnostic of secondary adrenal insufficiency—it represents an indeterminate result that requires confirmatory testing, according to the Endocrine Society 1, 2
Morning cortisol levels alone cannot distinguish between adequate adrenal reserve and partial ACTH deficiency, as noted by the American Association of Clinical Endocrinologists 1, 2

The standard high-dose cosyntropin stimulation test should be performed, with administration of 0.25 mg (250 mcg) cosyntropin IV or IM, as recommended by the Endocrine Society 2
Peak cortisol <500 nmol/L (<18 mcg/dL) confirms adrenal insufficiency, while peak cortisol >550 nmol/L (>18-20 mcg/dL) excludes adrenal insufficiency, according to the American College of Endocrinology 1, 2

Assess for other pituitary hormone deficiencies beyond what has already been tested, including TSH and free T4 to evaluate for central hypothyroidism, as recommended by the Journal of Clinical Oncology 3, 1
IGF-1 should be screened for growth hormone deficiency, and morning testosterone (in men) or estradiol (in premenopausal women) should be evaluated if not already done, to fully characterize hypogonadotropic hypogonadism, according to the Endocrine Society 3, 1

If the ACTH stimulation test confirms secondary adrenal insufficiency, initiate glucocorticoid replacement therapy with hydrocortisone 15-20 mg in the morning and 5-10 mg in early afternoon, as recommended by the American Association of Clinical Endocrinologists 3, 1
Critical management principles include starting corticosteroids several days before initiating thyroid hormone replacement if concurrent central hypothyroidism is present, and providing mandatory patient education on stress dosing, according to the Journal of Clinical Oncology 3, 1

Never delay treatment if the patient develops symptoms of acute adrenal crisis—immediately administer IV hydrocortisone 100 mg and 0.9% saline infusion without waiting for test results, as recommended by the Endocrine Society 3, 1, 2
Do not rely on electrolyte abnormalities to make or exclude the diagnosis of secondary adrenal insufficiency, and do not diagnose SIADH in a patient with hyponatremia without first excluding adrenal insufficiency, according to the American College of Endocrinology 2, 4