What are the causes of low Adrenocorticotropic Hormone (ACTH) levels?

Causes of Low ACTH

Low ACTH levels indicate secondary (central) adrenal insufficiency, where the problem originates in the pituitary gland or hypothalamus rather than the adrenal glands themselves. 1

Primary Causes of Low ACTH

Secondary Adrenal Insufficiency (Pituitary/Hypothalamic Disorders)

Low ACTH with low cortisol is the hallmark of secondary adrenal insufficiency, distinguishing it from primary adrenal insufficiency where ACTH is elevated. 1, 2

• Pituitary tumors (adenomas, craniopharyngiomas) that compress or destroy ACTH-producing cells 3
• Pituitary surgery or radiation therapy causing damage to corticotroph cells 2, 3
• Pituitary hemorrhage (Sheehan syndrome, pituitary apoplexy) 2
• Inflammatory/infiltrative conditions including hypophysitis, sarcoidosis, and hemochromatosis 2, 3
• Cranial trauma or head injury affecting the hypothalamic-pituitary axis 3, 4
• Infections involving the pituitary or hypothalamus 2, 3

Glucocorticoid-Induced (Iatrogenic) Adrenal Insufficiency

This is the most common cause of low ACTH in clinical practice. 2

• Exogenous glucocorticoid administration (prednisone, dexamethasone, hydrocortisone) suppresses the hypothalamic-pituitary-adrenal axis, leading to low ACTH and secondary adrenal insufficiency 5, 1, 2
• Inhaled corticosteroids (particularly fluticasone at high doses) can also suppress the HPA axis 1
• Patients taking ≥20 mg/day prednisone or equivalent for ≥3 weeks are at high risk 1
• The suppression can persist for months after discontinuation, requiring gradual tapering 1

Isolated ACTH Deficiency

This is a rare condition characterized by selective loss of ACTH production with preservation of other pituitary hormones. 6, 4

• Autoimmune lymphocytic hypophysitis targeting corticotroph cells 4
• Genetic causes in neonatal or childhood presentations 4
• Post-traumatic injury in adults 4
• Diagnosis requires demonstrating low cortisol with low ACTH, absent responses to hypothalamic/pituitary stimulation, intact adrenal response to exogenous ACTH, and normal secretion of other pituitary hormones 6

Medication-Induced ACTH Suppression

• Opioids (chronic use) suppress corticotropin production 2
• Checkpoint inhibitors can cause hypophysitis with selective or multiple pituitary hormone deficiencies including ACTH 5

ACTH-Independent Cushing Syndrome (Suppressed ACTH)

When adrenal tumors autonomously produce cortisol, the elevated cortisol suppresses ACTH production via negative feedback. 5

• Benign adrenal adenomas producing cortisol cause ACTH-independent Cushing syndrome with undetectable or very low ACTH 5
• Adrenal carcinomas (malignant tumors >5 cm with irregular margins) producing cortisol 5
• Bilateral multinodular adrenal hyperplasia with autonomous cortisol production 5
• In these conditions, ACTH is suppressed because the adrenal glands are producing excess cortisol independently, not because of pituitary/hypothalamic disease 5

Diagnostic Approach to Low ACTH

Morning (8 AM) paired measurements of serum cortisol and plasma ACTH are the first-line diagnostic tests. 1, 2

• Low cortisol (<5 µg/dL or <140 nmol/L) with low or inappropriately normal ACTH confirms secondary adrenal insufficiency 1, 2
• Intermediate cortisol levels (5-10 µg/dL or 140-275 nmol/L) with low ACTH require ACTH stimulation testing for confirmation 1, 2, 3
• High cortisol with low/undetectable ACTH suggests ACTH-independent Cushing syndrome from an adrenal source 5

Confirmatory Testing

• Cosyntropin stimulation test (250 mcg IV/IM) with cortisol measurements at baseline, 30, and 60 minutes is the gold standard when morning cortisol is indeterminate 1, 3
• Peak cortisol <500 nmol/L (<18 µg/dL) confirms adrenal insufficiency 1, 3
• Peak cortisol >550 nmol/L (>18-20 µg/dL) excludes adrenal insufficiency 1, 3

Critical Clinical Pitfalls

• Hyponatremia without hyperkalemia is typical of secondary adrenal insufficiency (unlike primary AI where both are common), because mineralocorticoid production is preserved 1, 4
• Never delay treatment of suspected adrenal crisis to perform diagnostic testing—give IV hydrocortisone 100 mg immediately if the patient is unstable 1, 2
• Exogenous steroids confound testing—hydrocortisone must be held for 24 hours and other steroids longer before accurate HPA axis assessment 1
• Use dexamethasone 4 mg IV instead of hydrocortisone if you need to treat suspected adrenal crisis but still want to perform diagnostic testing later, as dexamethasone doesn't interfere with cortisol assays 1
• ACTH stimulation testing can give false-negative results early in hypophysitis as adrenal reserve declines slowly after pituitary stimulation is lost 5