Adrenocorticotropic hormone (ACTH), also known as corticotropin, is a polypeptide tropic hormone produced and secreted by the anterior pituitary gland. It is an important component of the hypothalamic-pituitary-adrenal axis and is often produced in response to biological stress (along with its precursor corticotropin-releasing hormone from the hypothalamus). Its principal effects are increased production and release of corticosteroids. Primary adrenal insufficiency, also called Addison's disease, occurs when adrenal gland production of cortisol is chronically deficient, resulting in chronically elevated ACTH levels; when a pituitary tumor is the cause of elevated ACTH (from the anterior pituitary) this is known as Cushing's Disease and the constellation of signs and symptoms of the excess cortisol (hypercortisolism) is known as Cushing's syndrome. A deficiency of ACTH is a cause of secondary adrenal insufficiency. ACTH is also related to the circadian rhythm in many organisms.
Production and regulation
POMC, ACTH and β-lipotropin are secreted from corticotropes in the anterior lobe (or adenohypophysis) of the pituitary gland in response to the hormone corticotropin-releasing hormone (CRH) released by the hypothalamus. ACTH is synthesized from pre-pro-opiomelanocortin (pre-POMC). The removal of the signal peptide during translation produces the 241-amino acid polypeptide POMC, which undergoes a series of post-translational modifications such as phosphorylation and glycosylation before it is proteolytically cleaved by endopeptidases to yield various polypeptide fragments with varying physiological activity. These fragments include:
|polypeptide fragment||alias||abbreviation||amino acid residues|
|melanotropin alpha||melanocyte-stimulating hormone||α-MSH||138–150|
|corticotropin-like intermediate peptide||CLIP||156–176|
In order to regulate the secretion of ACTH, many substances secreted within this axis exhibit slow/intermediate and fast feedback-loop activity. Glucocorticoids secreted from the adrenal cortex work to inhibit CRH secretion by the hypothalamus, which in turn decreases anterior pituitary secretion of ACTH. Glucocorticoids may also inhibit the rates of POMC gene transcription and peptide synthesis. The latter is an example of a slow feedback loop, which works on the order of hours to days, whereas the former works on the order of minutes.
ACTH consists of 39 amino acids, the first 13 of which (counting from the N-terminus) may be cleaved to form α-melanocyte-stimulating hormone (α-MSH). (This common structure is responsible for excessively tanned skin in Addison's disease.) After a short period of time, ACTH is cleaved into α-melanocyte-stimulating hormone (α-MSH) and CLIP, a peptide with unknown activity in humans.
ACTH stimulates secretion of glucocorticoid steroid hormones from adrenal cortex cells, especially in the zona fasciculata of the adrenal glands. ACTH acts by binding to cell surface ACTH receptors, which are located primarily on adrenocortical cells of the adrenal cortex. The ACTH receptor is a seven-membrane-spanning G protein-coupled receptor. Upon ligand binding, the receptor undergoes conformation changes that stimulate the enzyme adenylyl cyclase, which leads to an increase in intracellular cAMP and subsequent activation of protein kinase A.
ACTH influences steroid hormone secretion by both rapid short-term mechanisms that take place within minutes and slower long-term actions. The rapid actions of ACTH include stimulation of cholesterol delivery to the mitochondria where the P450scc enzyme is located. P450scc catalyzes the first step of steroidogenesis that is cleavage of the side-chain of cholesterol. ACTH also stimulates lipoprotein uptake into cortical cells. This increases the bio-availability of cholesterol in the cells of the adrenal cortex.
The long term actions of ACTH include stimulation of the transcription of the genes coding for steroidogenic enzymes, especially P450scc, steroid 11β-hydroxylase, and their associated electron transfer proteins. This effect is observed over several hours.
In addition to steroidogenic enzymes, ACTH also enhances transcription of mitochondrial genes that encode for subunits of mitochondrial oxidative phosphorylation systems. These actions are probably necessary to supply the enhanced energy needs of adrenocortical cells stimulated by ACTH.
ACTH receptors outside of the adrenal gland
As indicated above, ACTH is a cleavage product of the pro-hormone, proopiomelanocortin (POMC), which also produces other hormones including α-MSH that stimulates the production of melanin. A family of related receptors mediates the actions of these hormones, the MCR, or melanocortin receptor family. These are mainly not associated with the pituitary-adrenal axis. MC2R is the ACTH receptor. While it has a crucial function in regulating the adrenal, it is also expressed elsewhere in the body, specifically in the osteoblast, which is responsible for making new bone, a continual and highly regulated process in the bodies of air-breathing vertebrates. The functional expression of MC2R on the osteoblast was discovered by Isales et alia in 2005. Since that time, it has been demonstrated that the response of bone forming cells to ACTH includes production of VEGF, as it does in the adrenal. This response might be important in maintaining osteoblast survival under some conditions. If this is physiologically important, it probably functions in conditions with short-period or intermittent ACTH signaling, since with continual exposure of osteoblasts to ACTH, the effect was lost in a few hours.
An active synthetic form of ACTH, consisting of the first 24 amino acids of native ACTH, was first synthesized by Klaus Hofmann at the University of Pittsburgh. ACTH is available as a synthetic derivative in the forms of cosyntropin, tradename Cortrosyn, and Synacthen (synthetic ACTH). Synacthen is not FDA approved but is used in the UK and Australia to conduct the ACTH stimulation test.
ACTH was first synthesized as a replacement for Acthar Gel, a long-lasting animal product used to treat infantile spasms. Once relatively inexpensive, Acthar Gel is currently an extremely expensive pharmaceutical product. Prices per vial have been as high as $36,000. Acthar gel has been proposed as a therapy to treat refractory autoimmune diseases and refractory nephrotic syndrome due to a variety of glomerular diseases.
- Diseases of the pituitary, the gland that produces, among others, the hormone ACTH
- Hypopituitarism, the hyposecretion of ACTH in the pituitary, leading to secondary adrenal insufficiency (a form of hypocorticism)
- Addison's disease, the primary adrenal insufficiency (another form of hypocorticism)
- Cushing's syndrome, hypercorticism, one of the causes is hypersecretion of ACTH
- Small cell carcinoma, a common cause of ACTH secreted ectopically
- Congenital adrenal hyperplasia, diseases in the production of cortisol
- Nelson's syndrome, the rapid enlargement of the ACTH producing pituitary after the removal of both adrenal glands
- Adrenoleukodystrophy, can be accompanied by adrenal insufficiency
- West syndrome ("infantile spasms"), a disease where ACTH is used as a therapy
- POIS, through production of tyrosine hydroxylase and dopamine β-hydroxylase, which two enzymes comprise the biochemical mechanism by which norepinephrine and epinephrine are produced
- Dibner, Charna; Schibler, Ueli; Albrecht, Urs (2010). "The Mammalian Circadian Timing System: Organization and Coordination of Central and Peripheral Clocks". Annual Review of Physiology72: 517–549. PMID 20148687. doi:10.1146/annurev-physiol-021909-135821
- "Adrenocorticotropic Hormone (ACTH)".
- "Pro-opiomelocortin precursor". Retrieved 8 April 2013.
- Yalow RS, Glick SM, Roth J, Berson SA (November 1964). "Radioimmunoassay of human plasma ACTH". J. Clin. Endocrinol. Metab.24 (11): 1219–25. PMID 14230021. doi:10.1210/jcem-24-11-1219.
- PROOPIOMELANOCORTIN; NCBI --> POMC Retrieved on September 28, 2009
- Raikhinstein M, Zohar M, Hanukoglu I (February 1994). "cDNA cloning and sequence analysis of the bovine adrenocorticotropic hormone (ACTH) receptor". Biochim. Biophys. Acta1220 (3): 329–32. PMID 8305507. doi:10.1016/0167-4889(94)90157-0.
- Hanukoglu I, Feuchtwanger R, Hanukoglu A (November 1990). "Mechanism of corticotropin and cAMP induction of mitochondrial cytochrome P450 system enzymes in adrenal cortex cells". J. Biol. Chem.265 (33): 20602–8. PMID 2173715.
- Raikhinstein M, Hanukoglu I; Hanukoglu, I. (November 1993). "Mitochondrial-genome-encoded RNAs: differential regulation by corticotropin in bovine adrenocortical cells". Proc. Natl. Acad. Sci. U.S.A.90 (22): 10509–13. Bibcode:1993PNAS...9010509R. PMC 47806. PMID 7504267. doi:10.1073/pnas.90.22.10509.
- Isales CM, Zaidi M, Blair HC (March 2010). "ACTH is a novel regulator of bone mass". Ann. N. Y. Acad. Sci.1192: 110–6. PMID 20392225. doi:10.1111/j.1749-6632.2009.05231.x.
- Zhong Q, Sridhar S, Ruan L, Ding KH, Xie D, Insogna K, Kang B, Xu J, Bollag RJ, Isales CM (May 2005). "Multiple melanocortin receptors are expressed in bone cells". Bone36 (5): 820–31. PMID 15804492. doi:10.1016/j.bone.2005.01.020.
- Zaidi M, Sun L, Robinson LJ, Tourkova IL, Liu L, Wang Y, Zhu LL, Liu X, Li J, Peng Y, Yang G, Shi X, Levine A, Iqbal J, Yaroslavskiy BB, Isales C, Blair HC (May 2010). "ACTH protects against glucocorticoid-induced osteonecrosis of bone". Proc. Natl. Acad. Sci. U.S.A.107 (19): 8782–7. PMC 2889316. PMID 20421485. doi:10.1073/pnas.0912176107.
- "Simulated ACTH". Time. December 12, 1960.
- Gettig J, Cummings JP, Matuszewski K (May 2009). "H.P. Acthar gel and cosyntropin review: clinical and financial implications". P T34 (5): 250–7. PMC 2697107. PMID 19561871.
- Pollack A (2012-12-29). "Questcor Finds Profits, at $28,000 a Vial". New York Times.
- Bomback AS, Tumlin JA, Baranski J, Bourdeau JE, Besarab A, Appel AS, Radhakrishnan J, Appel GB (2011). "Treatment of nephrotic syndrome with adrenocorticotropic hormone (ACTH) gel". Drug Des Devel Ther5: 147–53. PMC 3063118. PMID 21448451. doi:10.2147/DDDT.S17521.
- * Adrenocorticotropic Hormone at the US National Library of Medicine Medical Subject Headings (MeSH)