Adrenocorticotropic hormone (ACTH)
Also known as: ACTH, corticotropin, corticotrophin
A 39-amino-acid peptide cleaved from POMC in corticotrophs that stimulates cortisol and adrenal androgen secretion and maintains the size of the zona fasciculata and reticularis.
Overview
Corticotrophs synthesise pro-opiomelanocortin (POMC), which prohormone convertase 1 cleaves into ACTH, β-lipotropin and β-endorphin (other tissues further process ACTH to α-MSH). ACTH is released in a circadian pattern — peaking before waking — and in bursts with stress.
In the adrenal cortex ACTH binds the melanocortin-2 receptor (MC2R), a Gs-coupled GPCR that requires the accessory protein MRAP. Within minutes cAMP/PKA increases cholesterol delivery to mitochondria (StAR) and side-chain cleavage, raising cortisol; over days it increases expression of steroidogenic enzymes, LDL receptors and adrenal blood flow, and maintains the size of the fasciculata and reticularis (trophic effect). ACTH has only a small, transient effect on aldosterone. At high concentrations ACTH also binds MC1R on melanocytes, causing pigmentation.
- Location
Source: corticotrophs of the anterior pituitary. Target: zona fasciculata and reticularis of the adrenal cortex (melanocytes at high levels).
Function
- Stimulates cortisol synthesis and secretion.
- Stimulates adrenal androgen secretion.
- Maintains adrenocortical growth (trophic).
- Physiology
Class: peptide (39 aa) from POMC. Receptor: MC2R — Gs/cAMP. Half-life ≈10 min. Reference (08:00–09:00) roughly 2–11 pmol/L (≈10–50 ng/L), assay-dependent.
- Regulation
Stimulated by CRH and ADH (V1b), stress, hypoglycaemia, circadian rhythm; inhibited by cortisol (fast and delayed negative feedback at pituitary and hypothalamus).
Clinical significance
ACTH-dependent Cushing syndrome
Pituitary adenoma (Cushing disease) or ectopic ACTH (small-cell lung carcinoma, bronchial carcinoid) — ectopic sources often produce very high ACTH with hypokalaemia, pigmentation and rapid onset.
Nelson syndrome
After bilateral adrenalectomy for Cushing disease, loss of cortisol feedback allows the corticotroph adenoma to grow aggressively, with very high ACTH and marked hyperpigmentation.
Short Synacthen test
Tetracosactide (synthetic ACTH 1–24) 250 µg; failure of cortisol to rise above a laboratory cut-off (≈430–550 nmol/L at 30–60 min, assay-dependent) indicates adrenal insufficiency.
Test yourself
A patient with ACTH-dependent Cushing syndrome shows suppression of cortisol with high-dose dexamethasone. The most likely source is:
- Adrenal cortical adenoma
- Pituitary corticotroph adenoma
- Ectopic ACTH from small-cell lung carcinoma
- Exogenous prednisolone
Answer: Pituitary corticotroph adenoma
Pituitary corticotroph adenomas retain partial glucocorticoid feedback and usually suppress at high dexamethasone doses; ectopic ACTH tumours do not. Adrenal tumours and exogenous steroids are ACTH-independent (ACTH suppressed).
Hyperpigmentation in primary adrenal insufficiency (Addison disease) results from:
- Loss of aldosterone
- Excess POMC-derived peptides (ACTH, MSH) acting on melanocortin-1 receptors
- Excess adrenal androgens
- Hypoglycaemia
Answer: Excess POMC-derived peptides (ACTH, MSH) acting on melanocortin-1 receptors
Low cortisol removes feedback, so corticotrophs overproduce POMC. ACTH and α-MSH stimulate melanocyte MC1 receptors. Secondary (pituitary) insufficiency has low ACTH and no pigmentation.
Which zone of the adrenal cortex is primarily controlled by angiotensin II and serum potassium rather than ACTH?
- Zona glomerulosa
- Zona fasciculata
- Zona reticularis
- Adrenal medulla
Answer: Zona glomerulosa
Zona glomerulosa cells express aldosterone synthase (CYP11B2) and respond mainly to angiotensin II (AT1, Gq) and hyperkalaemia (depolarisation). ACTH has only a minor, transient effect, which is why pituitary failure spares aldosterone.
Compiled from standard anatomy and physiology references — see the Endocrine System sources. For education only; not medical advice.