Adrenocorticotropic hormone
Encyclopedia
Adrenocorticotropic hormone (ACTH), also known as 'corticotropin', 'Adrenocorticotrophic hormone', 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 corticotropin-releasing hormone
from the hypothalamus
). Its principal effects are increased production and release of corticosteroids and, as its name suggests, cortisol
from the adrenal cortex
.
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 NPP, Melanotropin Gamma (γ-MSH), Potential Peptide, Corticotropin (Adrenocorticotropic Hormone, or ACTH), Melanotropin Alpha (Melanocyte-Stimulating Hormone, or α-MSH), Corticotropin-like Intermediate Peptide (CLIP), Lipotropin Beta (β-LPH), Lipotropin Gamma (γ-LPH), Melanotropin Beta (β-MSH), Beta-Endorphin, and Met-Enkephalin. POMC, ACTH and β-lipotropin are secreted from corticotrope
s in the anterior lobe
(or adenohypophysis) of the pituitary gland
in response to the hormone corticotropin-releasing hormone
(CRH) released by the hypothalamus
.
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 is also related to the circadian rhythm
in many organisms. The half-life
of ACTH in human blood is about ten minutes.
s, 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.
Human ACTH has a molecular weight of 4,540 atomic mass unit
s (Da).
s, which are located primarily on adrenocortical cells of the adrenal cortex
. This results in the synthesis and secretion of gluco- and mineralo-corticosteroids and androgenic steroids. 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. This ultimately results in stimulation of steroidogenesis.
ACTH acts at several key steps to influence the steroidogenic pathway in the adrenal cortex:
.
ACTH is available as a synthetic derivative in the forms of cosyntropin
, tradename Cortrosyn, and synacthen (synthetic ACTH). Both are very rarely used in place of glucocorticoids to treat secondary adrenal insufficiency
in a hospital setting, but are used primarily 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 $47,000.
Peptide
Peptides are short polymers of amino acid monomers linked by peptide bonds. They are distinguished from proteins on the basis of size, typically containing less than 50 monomer units. The shortest peptides are dipeptides, consisting of two amino acids joined by a single peptide bond...
tropic hormone
Tropic hormone
Tropic hormones are hormones that have other endocrine glands as their target. Most tropic hormones are produced and secreted by the anterior pituitary...
produced and secreted by the anterior pituitary gland
Anterior pituitary
A major organ of the endocrine system, the anterior pituitary, also called the adenohypophysis, is the glandular, anterior lobe of the pituitary gland...
. It is an important component of the hypothalamic-pituitary-adrenal axis
Hypothalamic-pituitary-adrenal axis
The hypothalamic-pituitary-adrenal axis , also known as thelimbic-hypothalamic-pituitary-adrenal axis and, occasionally, as the hypothalamic-pituitary-adrenal-gonadotropic axis, is a complex set of direct influences and feedback interactions among the hypothalamus, the pituitary gland ,...
and is often produced in response to biological stress (along with corticotropin-releasing hormone
Corticotropin-releasing hormone
Corticotropin-releasing hormone , originally named corticotropin-releasing factor , and also called corticoliberin, is a polypeptide hormone and neurotransmitter involved in the stress response...
from the hypothalamus
Hypothalamus
The Hypothalamus is a portion of the brain that contains a number of small nuclei with a variety of functions...
). Its principal effects are increased production and release of corticosteroids and, as its name suggests, cortisol
Cortisol
Cortisol is a steroid hormone, more specifically a glucocorticoid, produced by the adrenal gland. It is released in response to stress and a low level of blood glucocorticoids. Its primary functions are to increase blood sugar through gluconeogenesis; suppress the immune system; and aid in fat,...
from the adrenal cortex
Adrenal cortex
Situated along the perimeter of the adrenal gland, the adrenal cortex mediates the stress response through the production of mineralocorticoids and glucocorticoids, including aldosterone and cortisol respectively. It is also a secondary site of androgen synthesis.-Layers:Notably, the reticularis in...
.
Production and regulation
ACTH is synthesized from pre-pro-opiomelanocortin (pre-POMC). The removal of the signal peptidePeptide
Peptides are short polymers of amino acid monomers linked by peptide bonds. They are distinguished from proteins on the basis of size, typically containing less than 50 monomer units. The shortest peptides are dipeptides, consisting of two amino acids joined by a single peptide bond...
during translation
Translation
Translation is the communication of the meaning of a source-language text by means of an equivalent target-language text. Whereas interpreting undoubtedly antedates writing, translation began only after the appearance of written literature; there exist partial translations of the Sumerian Epic of...
produces the 241-amino acid polypeptide POMC, which undergoes a series of post-translational modifications such as phosphorylation
Phosphorylation
Phosphorylation is the addition of a phosphate group to a protein or other organic molecule. Phosphorylation activates or deactivates many protein enzymes....
and glycosylation
Glycosylation
Glycosylation is the reaction in which a carbohydrate, i.e. a glycosyl donor, is attached to a hydroxyl or other functional group of another molecule . In biology glycosylation refers to the enzymatic process that attaches glycans to proteins, lipids, or other organic molecules...
before it is proteolytically cleaved by endopeptidases to yield various polypeptide fragments with varying physiological activity. These fragments include NPP, Melanotropin Gamma (γ-MSH), Potential Peptide, Corticotropin (Adrenocorticotropic Hormone, or ACTH), Melanotropin Alpha (Melanocyte-Stimulating Hormone, or α-MSH), Corticotropin-like Intermediate Peptide (CLIP), Lipotropin Beta (β-LPH), Lipotropin Gamma (γ-LPH), Melanotropin Beta (β-MSH), Beta-Endorphin, and Met-Enkephalin. POMC, ACTH and β-lipotropin are secreted from corticotrope
Corticotrope
Corticotropes are basophilic cells in the anterior pituitary that produce adrenocorticotropic hormone, melanocyte-stimulating hormone and lipotropin. These cells respond to corticotropin releasing hormone and make up about 20% of the cells in the anterior pituitary....
s in the anterior lobe
Anterior pituitary
A major organ of the endocrine system, the anterior pituitary, also called the adenohypophysis, is the glandular, anterior lobe of the pituitary gland...
(or adenohypophysis) of the pituitary gland
Pituitary gland
In vertebrate anatomy the pituitary gland, or hypophysis, is an endocrine gland about the size of a pea and weighing 0.5 g , in humans. It is a protrusion off the bottom of the hypothalamus at the base of the brain, and rests in a small, bony cavity covered by a dural fold...
in response to the hormone corticotropin-releasing hormone
Corticotropin-releasing hormone
Corticotropin-releasing hormone , originally named corticotropin-releasing factor , and also called corticoliberin, is a polypeptide hormone and neurotransmitter involved in the stress response...
(CRH) released by the hypothalamus
Hypothalamus
The Hypothalamus is a portion of the brain that contains a number of small nuclei with a variety of functions...
.
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
Transcription (genetics)
Transcription is the process of creating a complementary RNA copy of a sequence of DNA. Both RNA and DNA are nucleic acids, which use base pairs of nucleotides as a complementary language that can be converted back and forth from DNA to RNA by the action of the correct enzymes...
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 is also related to the circadian rhythm
Circadian rhythm
A circadian rhythm, popularly referred to as body clock, is an endogenously driven , roughly 24-hour cycle in biochemical, physiological, or behavioural processes. Circadian rhythms have been widely observed in plants, animals, fungi and cyanobacteria...
in many organisms. The half-life
Half-life
Half-life, abbreviated t½, is the period of time it takes for the amount of a substance undergoing decay to decrease by half. The name was originally used to describe a characteristic of unstable atoms , but it may apply to any quantity which follows a set-rate decay.The original term, dating to...
of ACTH in human blood is about ten minutes.
Structure
ACTH consists of 39 amino acidAmino acid
Amino acids are molecules containing an amine group, a carboxylic acid group and a side-chain that varies between different amino acids. The key elements of an amino acid are carbon, hydrogen, oxygen, and nitrogen...
s, 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
Hyperpigmentation
In dermatology, hyperpigmentation is the darkening of an area of skin or nails caused by increased melanin.-Causes:Hyperpigmentation may be caused by sun damage, inflammation, or other skin injuries, including those related to acne vulgaris...
in Addison's disease.) After a short period of time, ACTH is cleaved into α-melanocyte-stimulating hormone
Melanocyte-stimulating hormone
The melanocyte-stimulating hormones are a class of peptide hormones that are produced by cells in the intermediate lobe of the pituitary gland...
(α-MSH) and CLIP, a peptide with unknown activity in humans.
Human ACTH has a molecular weight of 4,540 atomic mass unit
Atomic mass unit
The unified atomic mass unit or dalton is a unit that is used for indicating mass on an atomic or molecular scale. It is defined as one twelfth of the rest mass of an unbound neutral atom of carbon-12 in its nuclear and electronic ground state, and has a value of...
s (Da).
Function
ACTH acts through the stimulation of cell surface ACTH receptorACTH receptor
The ACTH receptor is a type of melanocortin receptor , properly known as MC2, which is specific for ACTH.It is found in the zona fasciculata of the human adrenal cortex. Binding of the receptor by ACTH stimulates the production of cortisol...
s, which are located primarily on adrenocortical cells of the adrenal cortex
Adrenal cortex
Situated along the perimeter of the adrenal gland, the adrenal cortex mediates the stress response through the production of mineralocorticoids and glucocorticoids, including aldosterone and cortisol respectively. It is also a secondary site of androgen synthesis.-Layers:Notably, the reticularis in...
. This results in the synthesis and secretion of gluco- and mineralo-corticosteroids and androgenic steroids. The ACTH receptor is a seven-membrane-spanning G protein-coupled receptor
G protein-coupled receptor
G protein-coupled receptors , also known as seven-transmembrane domain receptors, 7TM receptors, heptahelical receptors, serpentine receptor, and G protein-linked receptors , comprise a large protein family of transmembrane receptors that sense molecules outside the cell and activate inside signal...
. Upon ligand binding, the receptor undergoes conformation changes that stimulate the enzyme adenylyl cyclase, which leads to an increase in intracellular cAMP
Cyclic adenosine monophosphate
Cyclic adenosine monophosphate is a second messenger important in many biological processes...
and subsequent activation of protein kinase A. This ultimately results in stimulation of steroidogenesis.
ACTH acts at several key steps to influence the steroidogenic pathway in the adrenal cortex:
- ACTH stimulates lipoproteinLipoproteinA lipoprotein is a biochemical assembly that contains both proteins and lipids water-bound to the proteins. Many enzymes, transporters, structural proteins, antigens, adhesins, and toxins are lipoproteins...
uptake into cortical cells. This increases the bio-availability of cholesterolCholesterolCholesterol is a complex isoprenoid. Specifically, it is a waxy steroid of fat that is produced in the liver or intestines. It is used to produce hormones and cell membranes and is transported in the blood plasma of all mammals. It is an essential structural component of mammalian cell membranes...
in the cells of the adrenal cortex. - ACTH increases the transport of cholesterol into the mitochondria and activates its hydrolysis.
- ACTH Stimulates cholesterol side-chain cleavage enzyme, which makes the rate-limiting step in steroidogenesis. This results in the production of pregnenolonePregnenolonePregnenolone is a steroid hormone involved in the steroidogenesis of progesterone, mineralocorticoids, glucocorticoids, androgens, and estrogens. As such it is a prohormone. Pregnenolone sulfate is a GABAA antagonist and increases neurogenesis in the hippocampus.-Chemistry:Like other steroids,...
.
Synthetic ACTH
An active synthetic form of ACTH, consisting of the first 23 amino acids of native ACTH, was first synthesized by Klaus Hofmann at the University of PittsburghUniversity of Pittsburgh
The University of Pittsburgh, commonly referred to as Pitt, is a state-related research university located in Pittsburgh, Pennsylvania, United States. Founded as Pittsburgh Academy in 1787 on what was then the American frontier, Pitt is one of the oldest continuously chartered institutions of...
.
ACTH is available as a synthetic derivative in the forms of cosyntropin
Cosyntropin
Cosyntropin is a synthetic derivative of adrenocorticotropic hormone that is used in the ACTH stimulation test to evaluate and diagnose cortisol disorders...
, tradename Cortrosyn, and synacthen (synthetic ACTH). Both are very rarely used in place of glucocorticoids to treat secondary adrenal insufficiency
Adrenal insufficiency
Adrenal insufficiency is a condition in which the adrenal glands, located above the kidneys, do not produce adequate amounts of steroid hormones , primarily cortisol, but may also include impaired aldosterone production which regulates sodium, potassium and water retention...
in a hospital setting, but are used primarily to conduct the ACTH stimulation test
ACTH stimulation test
The ACTH stimulation test is a medical test usually ordered and interpreted by endocrinologists to assess the functioning of the adrenal glands stress response by measuring the adrenal response to adrenocorticotropic hormone...
.
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 $47,000.
Associated conditions
- Addison's diseaseAddison's diseaseAddison’s disease is a rare, chronic endocrine disorder in which the adrenal glands do not produce sufficient steroid hormones...
- Small cell carcinomaSmall cell carcinomaSmall cell carcinoma is a type of highly malignant cancer that most commonly arises within the lung, although it can occasionally arise in other body sites, such as the cervix and prostate....
(a common cause of ACTH secreted ectopically) - AdrenoleukodystrophyAdrenoleukodystrophyAdrenoleukodystrophy is a rare, inherited disorder that leads to progressive brain damage, failure of the adrenal glands and eventually death. ALD is a disease in a group of genetic disorders called leukodystrophies, whose chief feature is damage to myelin...
- Congenital adrenal hyperplasiaCongenital adrenal hyperplasiaCongenital adrenal hyperplasia refers to any of several autosomal recessive diseases resulting from mutations of genes for enzymes mediating the biochemical steps of production of cortisol from cholesterol by the adrenal glands ....
- Cushing's syndromeCushing's syndromeCushing's syndrome is a hormone disorder caused by high levels of cortisol in the blood. This can be caused by taking glucocorticoid drugs, or by tumors that produce cortisol or adrenocorticotropic hormone or CRH...
- Nelson's syndromeNelson's syndromeNelson's syndrome is the rapid enlargement of a pituitary adenoma that occurs after the removal of both adrenal glands.-Pathophysiology:Removal of both adrenal glands, or bilateral adrenalectomy, is an operation for Cushing's syndrome...
- Infantile spasms
See also
- Pituitary-adrenal axisHypothalamic-pituitary-adrenal axisThe hypothalamic-pituitary-adrenal axis , also known as thelimbic-hypothalamic-pituitary-adrenal axis and, occasionally, as the hypothalamic-pituitary-adrenal-gonadotropic axis, is a complex set of direct influences and feedback interactions among the hypothalamus, the pituitary gland ,...
- ACTH stimulation testACTH stimulation testThe ACTH stimulation test is a medical test usually ordered and interpreted by endocrinologists to assess the functioning of the adrenal glands stress response by measuring the adrenal response to adrenocorticotropic hormone...