Adrenocorticotropic hormone
Adrenocorticotropic hormone is a polypeptide tropic hormone produced by and secreted by the anterior pituitary gland. It is also used as a medication and diagnostic agent. ACTH is an important component of the hypothalamic-pituitary-adrenal axis and is often produced in response to biological stress. Its principal effects are increased production and release of cortisol by the cortex of the adrenal gland. ACTH is also related to the circadian rhythm in many organisms.
Deficiency of ACTH is a sign of secondary adrenal insufficiency or tertiary adrenal insufficiency. Conversely, chronically elevated ACTH levels occur in primary adrenal insufficiency when adrenal gland production of cortisol is chronically deficient. In Cushing's disease a pituitary tumor is the cause of elevated ACTH and an excess of cortisol – this constellation of signs and symptoms is known as Cushing's syndrome.
Production and regulation
, ACTH and β-lipotropin are secreted from corticotropes in the anterior lobe of the pituitary gland in response to the hormone corticotropin-releasing hormone released by the hypothalamus. ACTH is synthesized from pre-pro-opiomelanocortin. 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 |
| NPP | NPP | 27–102 | |
| melanotropin gamma | γ-MSH | 77–87 | |
| potential peptide | 105–134 | ||
| corticotropin | adrenocorticotropic hormone | ACTH | 138–176 |
| melanotropin alpha | melanocyte-stimulating hormone | α-MSH | 138–150 |
| corticotropin-like intermediate peptide | CLIP | 156–176 | |
| lipotropin beta | β-LPH | 179–267 | |
| lipotropin gamma | γ-LPH | 179–234 | |
| melanotropin beta | β-MSH | 217–234 | |
| beta-endorphin | 237–267 | ||
| met-enkephalin | 237–241 |
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.
The half-life of ACTH in human blood is about ten minutes.
Structure
ACTH consists of 39 amino acids, the first 13 of which may be cleaved to form α-melanocyte-stimulating hormone. After a short period of time, ACTH is cleaved into α-melanocyte-stimulating hormone and CLIP, a peptide with unknown activity in humans.Human ACTH has a molecular weight of 4,540 atomic mass units.
Function
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 bioavailability 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.
, showing adrenocorticotropic hormone among the hormones with smallest concentration in the blood
ACTH receptors outside the adrenal gland
As indicated above, ACTH is a cleavage product of the pro-hormone, proopiomelanocortin, 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.History
While working on her dissertation, Evelyn M. Anderson co-discovered ACTH with James Bertram Collip and David Landsborough Thomson and, in a paper published in 1933, explained its function in the body.An active synthetic form of ACTH, consisting of the first 24 amino acids of native ACTH, was first made by Klaus Hofmann at the University of Pittsburgh.
Associated conditions
- 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
- Addison's disease, the primary adrenal insufficiency
- 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, a disease where ACTH is used as a therapy
- Postorgasmic illness syndrome, through production of tyrosine hydroxylase and dopamine β-hydroxylase, which two enzymes comprise the biochemical mechanism by which norepinephrine and epinephrine are produced.