What is Adrenocorticotropic Hormone (ACTH)?

Adrenocorticotropic Hormone (ACTH): Definition and Function

Adrenocorticotropic hormone (ACTH) is a peptide hormone produced by the pituitary gland that plays a pivotal role in regulating adrenal gland function, particularly the production of glucocorticoids such as cortisol.

Key Characteristics of ACTH

• ACTH is the primary regulator of adrenal glucocorticoid production, making it a critical component of the hypothalamo-pituitary-adrenal axis 1
• ACTH is produced from proopiomelanocortin (POMC) in the anterior pituitary gland 1
• Normal ACTH levels are typically >5 pg/mL, with levels >29 pg/mL having 70% sensitivity and 100% specificity for diagnosing Cushing's disease (pituitary source of ACTH) 2

Physiological Functions

• ACTH stimulates steroidogenesis and steroid secretion from the adrenal cortex 1
• ACTH has differential acute vs chronic effects on aldosterone and glucocorticoid secretion 1
• ACTH influences adrenal growth, acting as both a mitogenic and differentiating factor 1
• ACTH activates multiple signaling cascades beyond the classical cyclic adenosine monophosphate (cAMP) pathway 1

Clinical Significance

Diagnostic Applications

• ACTH levels are used to determine whether Cushing's syndrome is ACTH-dependent or ACTH-independent 3
• Elevated ACTH levels indicate ACTH-dependent Cushing's syndrome (pituitary adenoma or ectopic source) 3
• Low or undetectable ACTH levels indicate ACTH-independent Cushing's syndrome (adrenal source) 3

ACTH Testing

• The high-dose (250-μg) ACTH stimulation test is recommended over the low-dose (1-μg) test for diagnosing critical illness-related corticosteroid insufficiency (CIRCI) 4
• The 250-μg ACTH stimulation test is preferred over evaluating hemodynamic response to hydrocortisone for diagnosing CIRCI 4

Pathological Conditions

• Genetic defects in the ACTH receptor (melanocortin 2 receptor) can cause familial glucocorticoid deficiency 5
• Overexpression of the ACTH receptor can lead to adrenal adenomas or hyperplasia associated with Cushing syndrome 5
• Isolated ACTH deficiency can occur as an immune-related adverse event following immune checkpoint inhibitor therapy 6

Management of ACTH-Related Disorders

• For primary adrenal insufficiency (high ACTH, low cortisol), replacement therapy with prednisone (5–10 mg daily) or hydrocortisone (10–20 mg orally every morning, 5–10 mg orally in early afternoon) is recommended 4
• Patients with adrenal insufficiency may require fludrocortisone (0.1 mg/d) for mineralocorticoid replacement 4
• For severe symptoms of adrenal insufficiency, IV stress-dose corticosteroids (hydrocortisone 100 mg or dexamethasone 4 mg) and normal saline (at least 2 L) are recommended 4

Emerging Therapeutic Approaches

• Novel long-acting monoclonal antibodies to ACTH (such as ALD1613) are being developed to control ACTH-driven pharmacology in conditions with elevated ACTH levels 7
• These antibodies can neutralize ACTH-induced signaling and reduce plasma corticosterone/cortisol levels 7

Important Clinical Considerations

• Primary and secondary adrenal insufficiency can be distinguished by the relationship between ACTH and cortisol 4
• All patients with adrenal insufficiency need education on stress dosing and a medical alert bracelet 4
• Endocrine consultation is recommended prior to surgery or any procedure for stress-dose planning 4