What is ACTH?
ACTH (adrenocorticotropic hormone) is a peptide hormone secreted by the anterior pituitary gland that stimulates the adrenal cortex to produce and release cortisol, serving as the central regulator of the hypothalamic-pituitary-adrenal axis. 1
Physiological Function and Production
ACTH is derived from the precursor molecule proopiomelanocortin (POMC) through proteolytic cleavage by prohormone convertase-1 (PC1) in the anterior pituitary corticotrope cells 2
The hormone is released from the pituitary in response to corticotropin-releasing hormone (CRH) from the hypothalamus, which acts via CRH-R1 receptors on corticotrope cells 3
ACTH binds to melanocortin-2 receptors (MC2-R) on adrenal cortex cells, triggering cortisol synthesis and immediate release into systemic circulation 3
The hormone follows a circadian rhythm with peak levels in the morning (reference range 140–700 nmol/L at 0900h) and nadir at midnight 1
Clinical Significance in Diagnosis
Morning plasma ACTH levels >5 pg/mL indicate ACTH-dependent Cushing's syndrome, while levels <5 pg/mL indicate ACTH-independent (adrenal) disease 4, 5
ACTH levels >29 pg/mL provide 70% sensitivity and 100% specificity for diagnosing pituitary Cushing's disease specifically 4
In primary adrenal insufficiency, ACTH is elevated (high ACTH with low cortisol), whereas in secondary adrenal insufficiency from pituitary failure, both ACTH and cortisol are low 1
Broader Physiological Effects
Beyond steroidogenesis, ACTH has mitogenic effects on adrenal tissue and influences adrenal growth, acting as both a differentiating and proliferative factor 6
ACTH exerts extra-adrenal actions including lipolytic effects on adipocytes and differentiation signals in various cell types 6
The hormone demonstrates differential acute versus chronic effects: acutely stimulating both aldosterone and glucocorticoid secretion, but chronically favoring glucocorticoid over mineralocorticoid production 6
Key Clinical Pitfalls
ACTH must be measured in the morning (08:00-09:00h) for accurate diagnostic interpretation, as afternoon levels are physiologically lower and do not correspond to established diagnostic thresholds 4
Exogenous steroid administration suppresses ACTH secretion and confounds interpretation; patients must be off steroids for accurate testing 4
ACTH is unstable and requires proper specimen handling with immediate processing or freezing to prevent degradation 4