Adrenocorticotropic hormone (
ACTH), also known as 'corticotropin', 'Adrenocorticotrophic hormone', is a
polypeptidePeptides 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 hormoneTropic 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 glandA 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 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 ,...
and is often produced in response to biological stress (along with
corticotropin-releasing hormoneCorticotropin-releasing hormone , originally named corticotropin-releasing factor , and also called corticoliberin, is a polypeptide hormone and neurotransmitter involved in the stress response...
from the
hypothalamusThe 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,
cortisolCortisol 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 cortexSituated 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
peptidePeptides 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
translationTranslation 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
phosphorylationPhosphorylation is the addition of a phosphate group to a protein or other organic molecule. Phosphorylation activates or deactivates many protein enzymes....
and
glycosylationGlycosylation 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
corticotropeCorticotropes 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 lobeA 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 glandIn 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 hormoneCorticotropin-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
hypothalamusThe 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
transcriptionTranscription 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 rhythmA 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-lifeHalf-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 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 skinIn 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 hormoneThe 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 unitThe 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 receptorThe 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 cortexSituated 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 receptorG 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
cAMPCyclic 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 lipoprotein
A 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 cholesterolCholesterol 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 pregnenolone
Pregnenolone 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 PittsburghThe 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
cosyntropinCosyntropin 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 insufficiencyAdrenal 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 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...
.
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 disease
Addison’s disease is a rare, chronic endocrine disorder in which the adrenal glands do not produce sufficient steroid hormones...
- Small cell carcinoma
Small 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)
- Adrenoleukodystrophy
Adrenoleukodystrophy 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 hyperplasia
Congenital 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 syndrome
Cushing'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 syndrome
Nelson'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 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 ,...
- 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...