What causes low Adrenocorticotropic hormone (ACTH) levels?

Causes of Low ACTH (Adrenocorticotropic Hormone) Levels

Low ACTH levels are most commonly caused by exogenous glucocorticoid administration, pituitary disorders (especially hypophysitis), or secondary adrenal insufficiency. 1

Primary Causes of Low ACTH

1. Exogenous Glucocorticoid Administration

   • Medication-induced suppression of the hypothalamic-pituitary-adrenal (HPA) axis
   • Common with prednisone, dexamethasone, or other corticosteroids 2
   • Duration and dose-dependent effect

2. Pituitary Disorders

   • Hypophysitis (inflammation of the pituitary)

     • Immune checkpoint inhibitor-related hypophysitis 1
     • Lymphocytic hypophysitis (possibly autoimmune) 3
     • Characterized by low ACTH with low cortisol levels

   • Pituitary tumors

     • Compressive effects on ACTH-producing cells
     • May present with other hormonal deficiencies

   • Radiation-induced damage

     • Following treatment for pituitary tumors or brain malignancies 4
     • Can cause discordance between basal ACTH secretion and response to stimulation tests

   • Pituitary surgery

     • Post-surgical damage to ACTH-producing cells

3. Isolated ACTH Deficiency

   • Rare disorder with normal secretion of other pituitary hormones 3, 5
   • May have genetic etiology in neonatal/childhood cases
   • Can present with non-specific symptoms like fatigue, anorexia, weight loss

4. Traumatic Brain Injury

   • Damage to pituitary or hypothalamus affecting ACTH production

Secondary Causes

1. Adrenal Hyperfunction

   • Primary adrenal tumors producing excess cortisol (Cushing's syndrome) 1
   • Adrenal adenomas or carcinomas causing autonomous cortisol production
   • Bilateral adrenal hyperplasia

2. Hypothalamic Dysfunction

   • Defective corticotropin-releasing hormone (CRH) secretion 4
   • May result from tumors, inflammation, or radiation damage

Clinical Presentation of Low ACTH

• Fatigue and weakness
• Anorexia and weight loss
• Hypoglycemia (especially during stress)
• Hyponatremia with normal or slightly elevated potassium
• Mild anemia, lymphocytosis, and eosinophilia
• Hypotension and orthostatic changes
• Gastrointestinal symptoms (nausea, vomiting, abdominal pain) 5
• Cognitive changes and mood disturbances

Diagnostic Approach

1. Initial Laboratory Testing

   • Morning cortisol and ACTH levels (8am)
   • Low ACTH with low cortisol is diagnostic of central adrenal insufficiency 1

2. Confirmatory Testing

   • Insulin tolerance test (gold standard) 6
   • Low-dose (1 μg) ACTH stimulation test 6
   • Standard ACTH stimulation test may give false normal results in recent onset secondary adrenal insufficiency

3. Additional Evaluation

   • Other pituitary hormone assessment (TSH, FT4, LH, FSH, testosterone/estradiol)
   • MRI of pituitary with contrast if multiple hormone deficiencies or new severe headaches 1

Important Clinical Pitfalls

• Morning cortisol <3 μg/dL with low ACTH is virtually diagnostic of secondary adrenal insufficiency 3
• Patients on corticosteroids will have low morning cortisol and ACTH as a result of iatrogenic suppression 1
• ACTH stimulation can give false-negative results early in hypophysitis as adrenal reserve declines slowly after pituitary stimulation is lost 1
• Laboratory confirmation of adrenal insufficiency should not be attempted in patients on high-dose corticosteroids until treatment is ready to be discontinued 1
• Hydrocortisone needs to be held for 24 hours (and other steroids for longer) before endogenous function is assessed 1

Remember that untreated secondary adrenal insufficiency can lead to life-threatening adrenal crisis during stress, so prompt diagnosis and appropriate replacement therapy are essential for reducing morbidity and mortality.