What is ACTH? Adrenocorticotropic hormone is a 39-amino-acid peptide made in the anterior pituitary, and it is the signal that tells the adrenal cortex to make cortisol. It sits at the centre of the hypothalamic-pituitary-adrenal (HPA) axis, which sets the daily cortisol rhythm and the response to stress. It is also a peptide family tree: ACTH shares its precursor with α-MSH and β-endorphin, and one of its fragments is the core of the research peptide Semax.
This guide covers how ACTH is made and controlled, how the adrenal reads it, how labs measure it, the main ACTH disorders as physiology, the Montreal history of the stress concept, and what fragment research shows.
The short answer
- ACTH is a 39-residue peptide. Also called corticotropin, it is residues 138 to 176 of proopiomelanocortin (POMC), a 267-residue precursor that also yields α-MSH and β-endorphin.
- The hypothalamus sets the pace. Corticotropin-releasing hormone (CRH), a 41-residue peptide, and vasopressin trigger ACTH release; vasopressin potentiates CRH several times over.
- Cortisol applies the brake. Glucocorticoids feed back on the hypothalamus and the pituitary.
- The rhythm has two speeds. Fast ultradian pulses ride on a circadian rhythm that, in humans, peaks just before the active phase of the day.
- Its receptor needs a partner. MC2R, the only melanocortin receptor activated by ACTH but not by α-MSH, needs the accessory protein MRAP to reach the cell surface and work.
- The route to cortisol runs through cAMP, PKA and StAR. StAR rapidly delivers cholesterol into mitochondria; over the longer term, ACTH raises transcription of the steroid-making enzymes.
- Fragments without adrenal activity started a field. In David de Wied’s work, ACTH fragments devoid of corticotropic effects changed rat behaviour. Semax builds on ACTH(4–7); its evidence is mostly rodent and Russian clinical literature.
Adrenocorticotropic hormone
ACTH · corticotropin · ACTH(1–39)
- Molecule type
- Linear peptide hormone, 39 amino acids
- Human sequence
- SYSMEHFRWG KPVGKKRRPV KVYPNGAEDE SAEAFPLEF
- Precursor
- POMC, 267 residues; ACTH is residues 138–176
- Made by
- Corticotroph cells of the anterior pituitary, via prohormone convertase 1
- Receptor
- MC2R with its accessory protein MRAP, in the adrenal cortex
- Main outputs
- Cortisol and adrenal androgens
- Purified
- 1943, in parallel papers from Berkeley and Yale
Where the evidence stands
- Hormone structure and receptor biology
- Diagnostic use of synthetic ACTH(1–24)
- Fragment effects in rodents
- Fragment peptides in large human trials
ACTH physiology is textbook material. Peptides derived from its fragments, such as Semax, rest mainly on rodent work and a Russian clinical literature.
What is ACTH?
ACTH, or adrenocorticotropic hormone, is a single chain of 39 amino acids named for its target, the adrenal cortex. Searchers often write “ACTH hormone”, although the H already stands for hormone. It is cut from proopiomelanocortin (POMC), a 267-residue precursor that cells cleave at pairs of basic residues.
Which products a cell makes depends on its enzymes. In 1991, Michel Chrétien, Nabil Seidah and colleagues at the Clinical Research Institute of Montreal showed in cultured cells that the convertase PC1 cuts POMC into ACTH and β-lipotropin, while PC2, with a broader range, produces β-endorphin and α-MSH. In the anterior pituitary the main product is ACTH. Our guides to α-MSH and the melanocortin system and to peptide hormones cover the wider family.
| Peptide | Length; position in human POMC | Receptor | Main role |
|---|---|---|---|
| ACTH | 39 residues; 138–176 | MC2R, which responds to ACTH but not α-MSH; also MC1R, MC3R, MC4R, MC5R | Cortisol, adrenal androgens, adrenal growth |
| α-MSH | 13; 138–150, ACTH’s first 13 residues | MC1R, MC3R, MC4R, MC5R | Melanocyte signal; appetite suppression through MC4R |
| CLIP | 21; 156–176 | None established | No function annotated in the curated record |
| β-Lipotropin | 89; 179–267 | None established | Released with ACTH by PC1; contains β-MSH and β-endorphin |
| β-MSH | 18; 217–234 | MC1R, MC3R, MC4R, MC5R | Appetite suppression through MC4R |
| γ-MSH | 11; 77–87 | Mainly MC3R; also active at MC4R and MC5R | Melanocortin ligand from outside the ACTH region |
| β-Endorphin | 31; 237–267 | Opioid receptors | Endogenous opioid |
| Met-enkephalin | 5; 237–241 | Opioid receptors | Endogenous opioid |
ACTH activates its adrenal receptor through two separated regions: His-Phe-Arg-Trp at positions 6 to 9 and the basic cluster Lys-Lys-Arg-Arg-Pro at positions 15 to 19. In cultured adrenal cells, synthetic ACTH(1–24) matched the full hormone in stimulating glucocorticoid output, while ACTH(1–16) did not. That result underpins both the diagnostic peptide and the fragment research below.
The HPA axis: how ACTH is controlled
The hypothalamic-pituitary-adrenal (HPA) axis is a three-tier loop. Neurons of the hypothalamic paraventricular nucleus release CRH and arginine vasopressin into the pituitary’s portal blood supply; corticotroph cells of the anterior pituitary respond by releasing ACTH; ACTH drives cortisol production in the adrenal cortex; and cortisol feeds back to restrain both the hypothalamus and the pituitary.
Wylie Vale’s group at the Salk Institute characterized CRH in 1981 as a 41-residue peptide from sheep hypothalamus that releases both corticotropin and β-endorphin. A year later, a London group showed that vasopressin potentiates the corticotropin-releasing activity of CRH several times over.
Rhythm, pulses and stress
The master clock in the suprachiasmatic nucleus drives the paraventricular nucleus daily. In humans the glucocorticoid rhythm peaks just before the active phase, around waking; in night-active rats and mice it peaks before dark. Faster ultradian pulses ride on top. Stressors, relayed from the brainstem and limbic forebrain, add CRH and vasopressin release. ACTH and cortisol are also measured as off-target signals in growth hormone research (see our guide to secretagogues).
How the adrenal reads ACTH: MC2R, MRAP and the route to cortisol
ACTH acts through the melanocortin 2 receptor, MC2R, a G protein-coupled receptor on adrenal cortex cells and the only melanocortin receptor activated by ACTH but not by α-MSH. Our guide to GPCRs and peptide receptors explains the receptor family.
MRAP, the partner MC2R needs
MC2R needs the melanocortin 2 receptor accessory protein, MRAP, to be expressed and active at the cell surface. Louise Metherell, Adrian Clark and colleagues in London identified MRAP in 2005 in families with familial glucocorticoid deficiency type 2, whose adrenals ignored ACTH although their MC2R genes were normal. MRAP is a 19-kDa single-transmembrane protein that binds MC2R and appears to help move it to the cell surface. Defects in either gene give the same picture: low cortisol, high ACTH, normal aldosterone and renin.
From receptor to cortisol
MC2R stimulates adenylyl cyclase, cyclic AMP rises and protein kinase A is activated, as our cAMP and PKA guide describes. The rapid response mobilizes stored cholesterol and delivers it to the inner mitochondrial membrane, the step mediated by the steroidogenic acute regulatory protein, StAR. The slower response increases transcription of the genes for steroid-making enzymes, so sustained ACTH builds capacity as well as output; ACTH also supports adrenal growth.
Of the three cortical zones, the zona fasciculata makes cortisol and is the ACTH-responsive zone; the zona reticularis makes the androgen DHEA and its sulfate, and ACTH drives adrenal androgens too; the zona glomerulosa makes aldosterone under angiotensin II and potassium. ACTH has acute effects on aldosterone, but aldosterone does not need ACTH: it usually stays normal in familial glucocorticoid deficiency.
ACTH vs cortisol
ACTH is a pituitary peptide read by a cell-surface receptor; cortisol is an adrenal steroid built from cholesterol. ACTH is the signal, cortisol the response and also the brake, so when the adrenal cannot answer, cortisol falls while ACTH climbs.
Semax and N-Acetyl Semax, research peptides built on the ACTH(4–7) fragment, are stocked as laboratory reagents and priced in CAD.
Browse cognitive & neuroWhen the axis goes wrong: Addison’s, Cushing’s, ectopic ACTH and CAH
The main ACTH disorders are faults at different points in the same loop.
Physiology, not diagnosis. These conditions are described to show how the axis behaves when one part fails. Nothing here is a symptom guide, a testing guide or advice.
| Condition | Where the fault lies | ACTH | Cortisol |
|---|---|---|---|
| Primary adrenal insufficiency (Addison’s disease) | The adrenal cortex cannot make enough cortisol | Driven up as feedback is lost | Low |
| Cushing’s disease | An ACTH-secreting pituitary adenoma | Pituitary-driven: the excess is ACTH-dependent | High |
| Ectopic ACTH syndrome | A tumour outside the pituitary, such as a neuroendocrine tumour | High; some forms escape assays built on C-terminal antibodies | Often intensely high |
| Congenital adrenal hyperplasia | An inherited block in cortisol synthesis, usually 21-hydroxylase | Drive raised; the cortex is chronically overstimulated | Reduced; precursors accumulate before the block |
Cushing’s syndrome is the general term for chronic cortisol excess; Cushing’s disease is its pituitary, ACTH-dependent form. A 2020 expert review calls ectopic ACTH syndrome rare but frequently severe, since the cortisol excess can be intense and out of step with the tumour’s status. Congenital adrenal hyperplasia is a group of autosomal recessive disorders, most often from CYP21A2 mutations, in which the overstimulated cortex also produces excess androgens.
Because ACTH’s first 24 residues carry its adrenal activity, a synthetic peptide identical to ACTH(1–24), called cosyntropin or tetracosactide, is used as a diagnostic agent in tests of adrenal cortex function. This article does not describe how such tests are performed.
How ACTH is measured in research labs
ACTH is measured with two-site, or sandwich, immunometric assays: one antibody captures the molecule and a second, aimed at a different region, carries the signal, often read by chemiluminescence. Needing two binding sites makes these assays specific for intact ACTH, at a cost: a 2017 review notes that bioactive ACTH from ectopic tumours may be missed by assays built on C-terminal antibodies.
Why the sample is fragile
ACTH is a peptide exposed to plasma proteases, so time, temperature and storage are part of the method. In a 2022 study, ACTH in healthy-donor EDTA plasma stayed largely stable for 1.5 years at −20 °C or −70 °C, with changes under 11%, but patient samples stored at −20 °C retained about 75% after roughly four years and about 46% after six. For study design, record each sample’s clock time.
From McGill to the molecule: a short history
Canada’s part in this story is unusually large.
- 1933, McGill University, Montreal. James Bertram Collip, Evelyn Anderson and David Thomson described the adrenotropic hormone of the anterior pituitary in The Lancet, working in McGill’s Department of Biochemistry.
- 1936, the same department. Hans Selye’s short letter to Nature, “A syndrome produced by diverse nocuous agents”, described rats developing enlarged adrenals, a shrunken thymus and lymph nodes, and erosions of the stomach and gut whatever the harmful agent. He called it the general adaptation syndrome and later the stress response.
- 1943, Berkeley and Yale. Li, Evans and Simpson, and Sayers, White and Long, published purified ACTH in the same issue of the Journal of Biological Chemistry.
- 1954. P. H. Bell reported the purification and structure of β-corticotropin.
- 1981 and 1991. CRH was characterized at the Salk Institute, and PC1 and PC2 processing of POMC was mapped in Montreal.
- 2005, London. MRAP was identified.
Quebec adrenal research continues: one review cited here is by Nicole Gallo-Payet of the Université de Sherbrooke. Our history of Canada’s century of peptide discovery covers the wider story.
ACTH fragments, de Wied and Semax
Fragments that act on the brain, not the adrenal
From the 1960s, David de Wied’s group at the Rudolf Magnus Institute in Utrecht found that rats without a pituitary learned an avoidance task poorly, and that the deficit could be corrected with ACTH, with α-MSH and with ACTH and MSH fragments devoid of corticotropic effects; a 1973 paper studied ACTH(4–10) in such rats. De Wied concluded that these behavioural effects are not mediated through endocrine target tissues. His 1996 Heineken Prize for Medicine citation records his 1969 hypothesis that neuropeptides directly influence brain function and behaviour, and credits his neuropeptide concept with originating current neuropeptide research. ACTH(4–10) lacks the 15–19 basic cluster that MC2R activation needs.
Semax and N-acetyl Semax
Semax is Met-Glu-His-Phe-Pro-Gly-Pro: ACTH(4–7) plus a Pro-Gly-Pro tail that, according to the Moscow group that studies it, was added to resist peptidases. It is often called an ACTH(4–10) analogue, but Arg-Trp-Gly is absent (see how peptide names are built), and so is the basic cluster. Much of its literature comes from Moscow groups, prominently the Institute of Molecular Genetics of the Russian Academy of Sciences, whose authors report that Semax has been used in neurological practice for many years, including in ischemic stroke, citing Russian clinical studies. That is a sourced fact about one country’s practice, not evidence about a reagent and not a recommendation. In a 2020 rat study of transient middle cerebral artery occlusion, Semax changed the expression of 394 genes at 24 hours and none at 4.5 hours, broadly reversing the ischemia-induced pattern. Our Semax vs Selank comparison covers the rodent BDNF work.
N-acetyl Semax adds an N-terminal acetyl cap. Our N-acetyl peptides guide located one published study on it, about stability to proteolysis; the rodent findings often quoted for it used plain Semax.
How strong is this evidence? The behavioural findings come from rats, much of the Semax work from a few Moscow groups, and the human experience from a Russian clinical literature we did not find mirrored in large trials elsewhere in the sources reviewed. See how to read a peptide study.
What’s established and what isn’t
Reasonably well established
- ACTH is POMC residues 138 to 176.
- CRH and vasopressin drive ACTH release; vasopressin potentiates CRH.
- Glucocorticoid feedback, circadian rhythm and ultradian pulses shape secretion.
- MC2R needs MRAP; defects in either cause familial glucocorticoid deficiency.
- MC2R signals through cAMP and PKA; StAR delivers cholesterol.
- ACTH(1–24) matches the full hormone’s adrenal activity in cultured cells.
Open questions
- How ACTH engages MC2R: a stepwise docking model remains a hypothesis.
- How stable banked samples are: donor and patient samples differed in the 2022 study.
- Which ACTH forms assays miss in ectopic ACTH syndrome.
- Whether fragment effects in rats have a counterpart in people.
- Whether the Moscow Semax findings replicate independently.
- What acetylation changes in Semax’s activity; the one study located concerns stability.
Sourcing ACTH-family peptides in Canada
For research peptides in Canada built on ACTH fragments, names are loose and molecules differ by a few residues or one cap.
- Confirm the sequence, not the name. Semax is Met-Glu-His-Phe-Pro-Gly-Pro; ACTH(4–10) is Met-Glu-His-Phe-Arg-Trp-Gly. A certificate should identify the molecule by measured mass.
- Check the form. Plain and N-acetyl Semax differ by the mass of the acetyl group, and an acetate salt is not N-acetylation.
- Match the batch number to your vial using our COA guide, and keep lyophilized material cold, dry and dark, as the peptide storage guide describes.
- Choose paperwork you can check. Our guide to research peptides in Canada covers what to ask for.
SemaxACTH(4–7) extended with Pro-Gly-ProView product
N-Acetyl SemaxSemax with an N-terminal acetyl cap and a thinner literatureView product
Illumineuro BlendFour neuro research peptides in one vial, N-Acetyl Semax among themView product
Research use only. Pure Peptides Canada products are laboratory reagents for in-vitro research, not for human or veterinary use. This article explains published research for education; it is not medical, dietary or dosing guidance.
Frequently asked questions
What does ACTH stand for?
ACTH stands for adrenocorticotropic hormone, also called corticotropin, named for its target, the adrenal cortex. It is a 39-amino-acid peptide cut from the precursor POMC in the anterior pituitary, and its main job is to make the adrenal cortex produce cortisol.
What does ACTH do?
ACTH binds MC2R on adrenal cortex cells, a receptor that needs its partner protein MRAP, and signals through cyclic AMP and protein kinase A. The StAR protein then rapidly moves cholesterol into mitochondria, and over time production of the steroid-making enzymes rises. The results are cortisol, adrenal androgens and adrenal growth.
What is the difference between ACTH and cortisol?
ACTH is a 39-amino-acid peptide hormone from the anterior pituitary; cortisol is a steroid hormone made from cholesterol in the adrenal cortex. ACTH is the signal and cortisol the response, and cortisol also suppresses ACTH release. When the adrenal cannot respond, cortisol falls while ACTH rises.
What is the HPA axis?
The hypothalamic-pituitary-adrenal (HPA) axis is the hormonal loop that controls cortisol. The hypothalamus releases corticotropin-releasing hormone and vasopressin, the anterior pituitary answers with ACTH, and ACTH makes the adrenal cortex produce cortisol, which feeds back on both upper tiers. The axis follows a daily rhythm and responds to stress.
Why are ACTH and cortisol highest in the morning?
Their secretion follows a circadian rhythm driven by the brain’s master clock, the suprachiasmatic nucleus. In humans the glucocorticoid rhythm peaks just before the active phase of the day, around waking, with faster ultradian pulses on top. Night-active rats and mice peak before dark instead, which matters when timing rodent samples.
Is Semax made from ACTH?
Semax is a synthetic heptapeptide, Met-Glu-His-Phe-Pro-Gly-Pro: the ACTH(4-7) fragment plus a Pro-Gly-Pro tail added to resist peptidases. It is often called an ACTH(4-10) analogue, but residues 8 to 10 are missing, as is the basic cluster the adrenal receptor needs. Its evidence comes mostly from rodent studies and Russian clinical literature.
Neuro research peptides from the ACTH family
Semax, N-Acetyl Semax and the rest of the cognitive and neuro range are laboratory reagents, priced in Canadian dollars and shipped tracked from inside Canada. Pay by credit or debit card, Interac e-Transfer or cryptocurrency at checkout.
References
- Collip JB, Anderson EM, Thomson DL. The adrenotropic hormone of the anterior pituitary lobe. Lancet. 1933;222(5737):347–348. DOI
- Selye H. A syndrome produced by diverse nocuous agents. Nature. 1936;138(3479):32. DOI
- Li CH, Evans HM, Simpson ME. Adrenocorticotropic hormone. J Biol Chem. 1943;149(2):413–424. DOI
- Sayers G, White A, Long CNH. Preparation and properties of pituitary adrenotropic hormone. J Biol Chem. 1943;149(2):425–436. DOI
- Bell PH. Purification and structure of β-corticotropin. J Am Chem Soc. 1954;76:5565–5567. DOI
- Gispen WH, Bohus B, de Wied D. Effect of lysine vasopressin and ACTH4–10 on conditioned avoidance behavior of hypophysectomized rats. Neuroendocrinology. 1973;11:137–143. Bibliographic record consulted. Utrecht University Repository
- de Wied D. Pituitary neuropeptides and behavior. In: Fuxe K, Hökfelt T, Luft R, eds. Central Regulation of the Endocrine System. Nobel Symposia, vol 42. Springer; 1979:297–314. DOI
- Vale W, Spiess J, Rivier C, Rivier J. Characterization of a 41-residue ovine hypothalamic peptide that stimulates secretion of corticotropin and β-endorphin. Science. 1981;213(4514):1394–1397. DOI
- Gillies GE, Linton EA, Lowry PJ. Corticotropin releasing activity of the new CRF is potentiated several times by vasopressin. Nature. 1982;299(5881):355–357. DOI
- Benjannet S, Rondeau N, Day R, Chrétien M, Seidah NG. PC1 and PC2 are proprotein convertases capable of cleaving proopiomelanocortin at distinct pairs of basic residues. Proc Natl Acad Sci USA. 1991;88(9):3564–3568. DOI
- Metherell LA, Chapple JP, Cooray S, et al. Mutations in MRAP, encoding a new interacting partner of the ACTH receptor, cause familial glucocorticoid deficiency type 2. Nat Genet. 2005;37(2):166–170. DOI
- Castinetti F, Morange I, Conte-Devolx B, Brue T. Cushing’s disease. Orphanet J Rare Dis. 2012;7:41. DOI
- Szabo S, Taché Y, Somogyi A. The legacy of Hans Selye and the origins of stress research: a retrospective 75 years after his landmark brief letter to the editor of Nature. Stress. 2012;15(5):472–478. DOI
- Pihlajoki M, Dörner J, Cochran RS, Heikinheimo M, Wilson DB. Adrenocortical zonation, renewal, and remodeling. Front Endocrinol. 2015;6:27. DOI
- Dumbell R, Matveeva O, Oster H. Circadian clocks, stress, and immunity. Front Endocrinol. 2016;7:37. DOI
- Gallo-Payet N. 60 years of POMC: adrenal and extra-adrenal functions of ACTH. J Mol Endocrinol. 2016;56(4):T135–T156. Abstract consulted. DOI
- Ruggiero C, Lalli E. Impact of ACTH signaling on transcriptional regulation of steroidogenic genes. Front Endocrinol. 2016;7:24. DOI
- Ghaddhab C, Vuissoz J-M, Deladoëy J. From bioinactive ACTH to ACTH antagonist: the clinical perspective. Front Endocrinol. 2017;8:17. DOI
- Filippenkov IB, Stavchansky VV, Denisova AE, et al. Novel insights into the protective properties of ACTH(4-7)PGP (Semax) peptide at the transcriptome level following cerebral ischaemia–reperfusion in rats. Genes. 2020;11(6):681. DOI
- Young J, Haissaguerre M, Viera-Pinto O, Chabre O, Baudin E, Tabarin A. Management of endocrine disease: Cushing’s syndrome due to ectopic ACTH secretion: an expert operational opinion. Eur J Endocrinol. 2020;182(4):R29–R58. DOI
- Claahsen-van der Grinten HL, Speiser PW, Ahmed SF, et al. Congenital adrenal hyperplasia: current insights in pathophysiology, diagnostics, and management. Endocr Rev. 2022;43(1):91–159. DOI
- Hillebrand JJ, Zhou L, Marcinkus MA, et al. Instability of corticotropin during long-term storage: myth or reality? Clin Chem Lab Med. 2022;60(1):60–65. DOI
- Heineken Prizes. David de Wied, Dr A.H. Heineken Prize for Medicine 1996: prize citation and biography. Page
- UniProt Consortium. UniProtKB entry P01189 (POMC_HUMAN), pro-opiomelanocortin: peptide boundaries, processing notes and sequence. Record
- US National Library of Medicine. Medical Subject Headings descriptor D003366, Cosyntropin: scope note and synonyms, as displayed by CISMeF. Record
For laboratory research use only. Not for human or veterinary use. This article summarizes published research for educational purposes and is not medical advice.
