Management of Normal Cortisol with Abnormal ACTH
Determine the Direction of ACTH Abnormality
The critical first step is identifying whether ACTH is elevated or suppressed, as this fundamentally changes the diagnostic pathway and clinical significance. 1, 2, 3
High ACTH with Normal Cortisol
This pattern suggests compensated or early primary adrenal insufficiency where the adrenal glands are still producing adequate cortisol but only through excessive ACTH stimulation. 4
Measure morning (8 AM) paired cortisol and ACTH levels along with a basic metabolic panel to assess for hyponatremia (present in 90% of adrenal insufficiency cases) and hyperkalemia (present in only ~50% of cases). 1, 3
Calculate the cortisol:ACTH ratio—a ratio <3 has 100% sensitivity and specificity for primary adrenal insufficiency, even when baseline cortisol appears normal. 5
Proceed with cosyntropin stimulation test (0.25 mg IV or IM) with cortisol measurements at baseline, 30, and 60 minutes—peak cortisol <500 nmol/L (<18 mcg/dL) confirms adrenal insufficiency despite the normal baseline. 1, 3
If the stimulation test confirms impaired adrenal reserve, measure 21-hydroxylase autoantibodies first, as autoimmunity accounts for ~85% of primary adrenal insufficiency in Western populations. 1, 3
If autoantibodies are negative, obtain CT imaging of the adrenals to evaluate for hemorrhage, metastatic disease, tuberculosis, or other structural causes. 1, 3
Clinical Pearl: Patients with compensated hypoadrenalism may maintain normal cortisol through chronically elevated ACTH, resulting in striking skin hyperpigmentation as the only clinical manifestation for years. 4 These patients remain at high risk for acute decompensation during illness or stress.
Low or Inappropriately Normal ACTH with Normal Cortisol
This pattern indicates secondary (central) adrenal insufficiency with partial ACTH deficiency—the patient has decreased ACTH secretory reserve but sufficient baseline production to maintain normal resting cortisol. 2, 6, 7
Evaluate for other pituitary hormone deficiencies: TSH, free T4, LH, FSH, testosterone/estradiol, prolactin. 2
Consider MRI of the brain with pituitary/sellar cuts if multiple endocrine abnormalities are present or if there are new severe headaches. 2
Perform cosyntropin stimulation testing to assess adrenal reserve—patients with subnormal ACTH but normal cortisol responses have decreased ACTH secretory reserve and may decompensate during major stress. 6, 7
Morning cortisol between 5-18 mcg/dL (140-500 nmol/L) requires stimulation testing, as this indeterminate range cannot exclude secondary adrenal insufficiency. 3, 7
Important Caveat: The ACTH-cortisol relationship shows no sharp dividing line between normality and disease—patients with subnormal ACTH but normal cortisol responses in stimulation testing are unlikely to develop adrenal crisis during routine stress unless pituitary function deteriorates further. 6
Treatment Decision Algorithm
For Confirmed or High-Risk Compensated Primary Adrenal Insufficiency
Initiate glucocorticoid replacement with hydrocortisone 15-20 mg daily in divided doses (typically 10 mg at 7 AM, 5 mg at noon, 2.5-5 mg at 4 PM) plus fludrocortisone 0.05-0.1 mg daily for mineralocorticoid replacement. 1, 3
Educate patients to double or triple their usual dose during illness, fever, injury, or significant physical stress. 1, 3
Provide emergency injectable hydrocortisone 100 mg IM kit with self-injection training. 1, 3
All patients must wear a medical alert bracelet indicating adrenal insufficiency. 1, 3
For Partial Secondary Adrenal Insufficiency with Normal Baseline Cortisol
For asymptomatic patients with normal stimulation test results but subnormal ACTH responses, glucocorticoid replacement may not be required during unstressed periods—instead, provide stress-dose education and emergency hydrocortisone for use during major illness or surgery. 6, 7
For symptomatic patients (fatigue, weight loss, hypoglycemia tendency), initiate hydrocortisone 10-20 mg in the morning and 5-10 mg in early afternoon. 2, 7
If multiple pituitary hormone deficiencies are present, always start corticosteroids several days before thyroid hormone replacement to prevent precipitating adrenal crisis. 2, 3
Arrange endocrine consultation prior to any surgery or procedure for stress-dose planning. 2, 3
Critical Pitfalls to Avoid
Never assume normal baseline cortisol excludes adrenal insufficiency—compensated disease with high ACTH or partial secondary insufficiency with low ACTH can both present with deceptively normal resting cortisol levels. 6, 4, 5
Do not rely on electrolyte abnormalities to make or exclude the diagnosis—hyponatremia may be only marginally reduced and hyperkalemia is absent in ~50% of cases. 1
Exogenous steroids (including prednisone, dexamethasone, and inhaled fluticasone) suppress the HPA axis and confound interpretation—wait until sufficient washout time has elapsed before performing diagnostic testing. 1
If treating suspected adrenal crisis, never delay treatment for diagnostic procedures—administer IV hydrocortisone 100 mg immediately plus 0.9% saline infusion. 1, 3
Long-standing ACTH stimulation from any cause (including pituitary adenomas) can induce autonomous adrenal nodules with ACTH-independent cortisol production, creating confusing mixed patterns. 8