What is ACTH (Adrenocorticotropic Hormone)?
Endocrinology
ACTH (adrenocorticotropic hormone) is a 39-amino-acid peptide made by the anterior pituitary that tells the adrenal cortex to make cortisol. It is the middle link of the hypothalamic-pituitary-adrenal (HPA) axis, and it is cut from a larger precursor protein that also yields other well-known peptides such as alpha-MSH.
What is ACTH?
ACTH is a peptide hormone released by corticotroph cells of the anterior pituitary. In UniProt’s annotation of the human precursor, pro-opiomelanocortin (POMC, entry P01189), ACTH corresponds to residues 138 to 176, which is 39 amino acids. UniProt notes that specific enzymatic cleavages at paired basic residues of POMC yield the different active peptides: alpha-MSH sits at the N-terminal end of ACTH (POMC 138-150) and CLIP at the C-terminal end (POMC 156-176). The entry also records modifications of the ACTH region, including an acetylated N-terminal serine and a phosphorylated serine. Calculated from its sequence, ACTH(1-39) has an average mass of roughly 4.5 kDa.
Because several peptides come from the same precursor, ACTH is a good example of how one gene can produce a family of related signals. The melanocortin family (ACTH and the MSH peptides) is covered further in our guide to melanocortin receptors, and POMC is also the source of beta-endorphin, discussed in endogenous opioid peptides.
How ACTH works on the adrenal cortex
ACTH acts through a G-protein-coupled receptor and raises intracellular cAMP in its target cells. According to the StatPearls physiology review, it acts mainly on the zona fasciculata and zona reticularis of the adrenal cortex, driving the conversion of cholesterol into cortisol and supporting adrenal androgen production. The receptor itself is the melanocortin 2 receptor (MC2R). Metherell and colleagues showed in 2005 that MC2R works together with a small accessory protein, MRAP, which may help the receptor reach the cell surface, and that mutations in MRAP cause familial glucocorticoid deficiency type 2.
ACTH is not the main controller of aldosterone. The same review states that although ACTH can influence mineralocorticoid secretion, the renin-angiotensin-aldosterone system is the primary regulator of that pathway (see our RAAS explainer).
ACTH and the HPA axis feedback loop
Hypothalamic corticotropin-releasing hormone (CRH) stimulates the pituitary to release ACTH, ACTH stimulates the adrenal cortex, and the cortisol that results suppresses both CRH and ACTH release. Low cortisol does the opposite. This negative feedback keeps the circuit in balance. ACTH secretion also follows a daily rhythm, peaking in the early morning before waking. More on the upstream signal is in CRH and the urocortins.
ACTH in medicine and diagnostics
Two uses of ACTH-related products are worth separating. The first is diagnostic. Cosyntropin is a synthetic fragment made of the first 24 of the 39 amino acids of ACTH. Its prescribing information (Cortrosyn) gives a molecular weight of 2934 g/mol and describes it as a diagnostic agent, used with other tests, to screen for adrenocortical insufficiency in adults and children.
The second is therapeutic. Acthar Gel is a repository corticotropin injection derived from porcine pituitary extract; its 2021 FDA label lists N-25 deamidated porcine ACTH(1-39) among its major components. Its labelled indications include infantile spasms in infants and children under 2 years, acute exacerbations of multiple sclerosis in adults, and short-term adjunctive use in certain rheumatic, collagen, dermatologic, allergic, ophthalmic, respiratory and edematous conditions. Indications change over time, so the current label is the authority.
ACTH also matters when the body makes too much of it. The StatPearls review defines Cushing disease as pituitary overproduction of ACTH, notes that night-time ACTH stays elevated in it, and lists the tests used to sort ACTH-dependent causes, including high-dose dexamethasone suppression, desmopressin stimulation and inferior petrosal sinus sampling.
Frequently asked questions
Is ACTH the same as cortisol?
No. ACTH is a peptide made in the pituitary; cortisol is a steroid made in the adrenal cortex in response to it.
Is cosyntropin the same as ACTH?
Not exactly. Cosyntropin is the first 24 amino acids of the 39-residue ACTH, made synthetically.
Why is ACTH highest in the morning?
ACTH release follows a daily rhythm that peaks in the early morning before waking, which drives the morning cortisol rise.
Where does ACTH come from in the cell?
It is cleaved from the POMC precursor, which also yields alpha-MSH and CLIP.
References
- UniProt P01189 — Pro-opiomelanocortin (POMC), human
- Physiology, Adrenocorticotropic Hormone (ACTH), StatPearls
- Metherell LA et al. Mutations in MRAP, encoding a new interacting partner of the ACTH receptor, cause familial glucocorticoid deficiency type 2. Nat Genet 2005
- Cortrosyn (cosyntropin) prescribing information
- Acthar Gel prescribing information (FDA, 2021)
Informational only — not medical advice. This article is for educational purposes. It does not recommend, sell or instruct personal human use of any compound. Consult a qualified healthcare professional for any health decision. Content is intended for adults 21+. Verify scientific details against the primary sources cited.