Adrenocorticotropic hormone

POMC polypeptideal chain demarcating the location of adrenocorticotropa hormone (ACTH)

The adrenocorticotropic hormone, corticotropin or corticotropin (ACTH) is a polypeptide hormone produced by the pituitary gland and stimulates the adrenal glands. It exerts its action on the adrenal cortex by stimulating the secretion of steroids and the growth of the adrenal cortex.

Its secretion is regulated by corticotropin-releasing factor (CRF) from the hypothalamus, it is pulsatile and has a characteristic circadian rhythm, maximum secretion occurs in the morning. Its secretion also increases in response to low circulating cortisol levels, along with stress, fever, acute hypoglycemia, and major surgical interventions.

Features

It is a hormone with a short and unstable half-life, used in corticosteroid treatments and vulnerable to cellular enzymes. To quantify it, immunoassays are performed, and its synthetic derivative (ACTH 1-24) is used as a pharmacological stimulus for the study of hypothalamic-pituitary-adrenal function.

Chemical structure of ACTH

ACTH is a 39 amino acid peptide hormone whose sequence does not change between species. It is secreted from the anterior pituitary within a large chain of amino acids called proopiomelanocortin (POMC), a 241 amino acid peptide whose gene is located on chromosome 22. Of the 39 amino acids, only 13 have known biological activity. The remainders of the carboxyl terminus are highly variable and determine immune activity.

From POMC by post-transcriptional processing, in addition to ACTH, melanotropin (MSH), lipotropin and beta-endorphin are produced. For example, the first thirteen amino acids counting from the amino group can be cleaved to form melanotropin (MSH). Therefore, after a short period of time, ACTH is cleaved to form melanotropin (MSH) along with CLIP, a peptide of unknown activity in humans.

In humans, the amino acid sequence is as follows:

Ser-Tyr-Ser-Met-Glu-His-Phe-Arg-Try-Gly-Lys-Pro-Val-Gly-Lys-Lys-Arg-Arg-Pro-Lys-Val-Tyr-Pro-Asp-Gly-Glu-Asp-Gln-Pla-Glu-

ACTH in humans has a molecular weight of 4,540 Daltons (Da).

Role of ACTH

ACTH stimulates two of the three zones of the adrenal cortex, which are the zona fasciculata, where glucocorticoids (cortisol and corticosterone) are secreted, and the zona reticularis, which produces 10% of total androgens such as dehydroepiandrosterone (DHEA) and androstenedione.

In the zona fasciculata, ACTH works by binding to ACTH receptors, which are found mainly on the adrenocortical cells of the adrenal cortex. The ACTH receptor is a membrane protein, the receptors are coupled to G proteins. Upon binding of the ligand, the receptor undergoes conformational changes that stimulate the enzyme adenylyl cyclase, which leads to an increase in cyclic adenosine monophosphate and a subsequent PKA activation.

ACTH influences steroid hormone secretion through rapid, short-term mechanisms lasting minutes, along with slow, long-term actions. ACTH's rapid actions include stimulating the release of cholesterol into the mitochondria, where the P450scc enzyme is found. This enzyme catalyzes the first step of steroidogenesis, which is the cleavage of the cholesterol side chain. ACTH also stimulates the uptake of lipoproteins in cortical cells, which increases the presence of cholesterol in the cells of the adrenal cortex. ACTH's long-term actions include stimulation of transcription of genes encoded by steroidogenic enzymes, especially P450scc. This effect is observed over a few hours. In addition to steroidogenic enzymes, ACTH also increases the transcription of mitochondrial genes that code for subunits of the mitochondrial oxidative phosphorylation systems. These actions are probably necessary to meet the increased energy requirement of cortical cells when stimulated by ACTH.

ACTH is permissive, but not necessary, on the synthesis and secretion of mineralocorticoids. These mineralocorticodes are secreted by the outermost layer of the adrenal cortex, that is, the glomerular layer. ACTH also has a lipolytic function.

ACTH synthesis

ACTH, POMC, and beta-lipotropin are secreted by basophilic cells of the anterior pituitary (adenohypophysis), in response to the action of corticotropin-releasing hormone (CRH) secreted by the hypothalamus.
ACTH is synthesized in the Adenohypophysis from pre-POMC. Elimination of the peptide signal during translation produces the 241 amino acid POMC polypeptide, which undergoes a series of post-translational modifications such as phosphorylation and glycosylation, before being cleaved, in a proteolysis process carried out by endopeptidases, to produce fragments of the polypeptide with different physiological activity, such as beta-endorphins and metencephalins, lipotropin (LPH) and melanocyte-stimulating hormone (MSH).

The regulation of ACTH secretion depends on multiple stimuli, the hypothalamic stimulating factor of corticotropine, corticoliberine (CRH), is the main regulator.

ACTH synthesis is regulated as follows: In situations of physical or psychological stress such as pain, fatigue, fear or temperature changes, the secretion of the hypothalamic factor CRH (from English corticotropin releasing hormone).

This is also known as CRF (corticotropin-releasing factor). The CRF, a neuropeptide, acts as a powerful stimulator of the anterior lobe of the hypophysis, which induces this gland to synthesize ACTH.

The interaction between the CRF and the protein (CRFR1), which has in its extracellular area a coupled receptor (type B GCR), initiates the ACTH secretion process. The CRFR1 protein has its N-terminal in the extracellular i area of the C-terminal in the intracellular zone. In addition to a 7-transmembrane helical domain that is common in all GPCRs, class B receptors have an N-terminal extracellular domain (ECD) of approximately 100-160 amino acids containing three disulfuous links and which is a very hydrophobic zone. When the CRF adopts a continuous helix alpha structure it is attached to the ECD. The generated union produces a change of conformation in the receptor protein in question which activates the hypothalamus-hypophysis-suprareal axis.

ACTH synthesis is also stimulated by other hormones such as arginine-vasopressin (AVP), catecholamines, angiotensin II, serotonin, oxytocin, atrial natriuretic peptide (ANF), cholecystokinin, and vasoactive intestinal peptide (VIP), among others.

Conversely, there is a negative retrocontrol (negative feedback) for glucocorticoids, which bind to receptors in the hypothalamus and inhibit CRH secretion. Glucocorticoids also act on the pituitary gland, blocking the release of ACTH into the bloodstream. When pharmacological amounts of cortisol or a synthetic derivative such as dexamethasone are administered, ACTH synthesis is decreased.

So the net synthesis of ACTh is the result of the relative potency of the stimulatory (CRH) and inhibitory (cortisol) signals.

One of the characteristics of ACTH's secretion is its circadian rhythm, regulated by light-dark cycles. The ACTH concentration is at its lowest point around midnight and gradually increases to a morning peak and slows down. It has a relatively reverse rate of GH secretion. Stress induced by pain, fear, fever, and hypoglycemia also stimulates ACTH secretion and can be used in the clinic to evaluate the axis' functionality.

In order to regulate ACTH secretion, many substances secreted in this axis present slow and/or fast feedback activity. Glucocorticoids secreted from the adrenal cortex work to inhibit CRH secretion from the hypothalamus, which consequently reduces ACTH secretion from the pituitary gland. Glucocorticoids can also inhibit POMC transcription gene levels and peptide synthesis. The latter is an example of slow feedback, it works from hours to days while the others last for minutes. The half-life of ACTH in human blood is ten minutes.

ACTH mode of action

ACTH binds to membrane receptors of the adrenocortical gland. This binding activates adenyl cyclase, which produces an increase in the intracellular concentration of cAMP, which in turn activates the enzymes (P450scc enzyme) responsible for the transformation of cholesterol into pregnenolone, a glucocorticoid precursor. ACTH also stimulates, among other proteins necessary for steroidogenesis, receptors for LDL lipoprotein, and in the fetal adrenal gland, hydroxymethyl glutaryl coenzyme reductase (HMG-CoA), necessary for the synthesis of new of cholesterol.

The plasma rate of ACTH presents a circadian cycle, with a higher secretion during the day and lower during the night. There is a peak of maximum secretion from 7 to 9 in the morning. This indicates that such hormone and glucorticoids are very important for normal monitoring activity. The lack of the circadian cycle of ACTH with the time of the place is the cause of physical and psychic discomfort arising after intercontinental travel, especially if they are from the east to the west.

The half-life of ACTH in human blood is about ten minutes.

ACTH receptors outside the adrenal gland

The MCR is a family of interrelated receptors that mediate the actions of hormones that have a common origin with ACTH, that is, hormones that come from the POMC (or pro-hormone). In the case of ACTH, this receptor is the MC2R. MC2R, in addition to having a basic function regulating the adrenal gland, is also present in the rest of the body, specifically in osteoblasts (which are responsible for creating new bone). The response of bone-forming cells to ACTH includes the production of VEGF, as it does in the adrenal. This response could be important for osteoblast survival under some conditions.

Usefulness of the analysis of ACTH levels

ACTH testing is used as an indicator of pituitary function and is useful in the differential diagnosis of:

• Addison's disease.

Addison's disease is the leading cause of adrenal insufficiency in the developed world. When the disease begins, Adison's Disease (AD) can be fatal in cases that are not detected and treated properly. It is for this reason that an early indicator can be very helpful.
Studies show that elevated ACTH levels are a useful indicator of AD in individuals who present with the 21OH-AA antibody (which precedes the disease). This statement is due to the fact that when analyzing individuals positive for the antibody, when their basal cortisol and ACTH levels and their plasma renin activity are studied, the clearest difference between individuals in whom the disease ends up progressing and in those who it is not an elevated level of the hormone ACTH in the former.

• Congenital adrenal hyperplasia.

Congenital adrenal (or suprarenal) hyperplasia consists of a group of alterations in adrenal steroidogenesis that cause a decrease in the biosynthesis of cortisol (which leads to an increase in ACTH levels and, consequently, an increase in the localized steroid synthesis prior to blockade). Through this, a series of clinical pictures determined by the cortisol deficit and the excess of hormones and related metabolites appear. Altered ACTH levels may be an indicator of the disease.

• Cushing syndrome.

It is also used as a treatment for West syndrome and Opsoclonus Myoclonus syndrome.

Effect of decreased ACTH secretion

If there is a decrease in ACTH, the absence of this will cause a decrease in cortisol secretion. This will induce the patient into a state of hypoglycemia and weakness. On the other hand, the decrease in ACTH secretion will cause a decrease in adrenal androgens. This mainly affects women and is seen in the form of decreased axial pubic hair and decreased libido. In the case of men, the decrease in adrenal androgens does not cause any visible condition or is clinically apparent, due to the high rate of testicular androgen secretion. In conclusion, decreased ACTH will lead to adrenal insufficiency. Through stimulation with 250 micrograms of ACTH, extracting blood after 60 minutes, determining the cortisol concentration, adrenal function and pituitary function can be studied.

Effect of excess ACTH

The formation of a tumor in the periphery of the pituitary gland (pituitary corticotroph adenoma) or, exceptionally, by an extrapituitary tumor (ectopic ACTH syndrome), such as small cell lung cancer, carcinoid tumor, or medullary thyroid cancer, it induces a tonic stimulation without circadian rhythm or regulation of the adrenal glands and produces a hyperplasia of these. As a consequence, a hypersecretion of cortisol and androgens is produced, which show a series of clinical manifestations. Most of the time these tumors co-secrete melanotropin. This produces a pigmentation of the skin. The main disease produced by excess corticotropin hypersecretion is known as Cushing's disease caused by excess cortisol in the blood due to hypersecretion of ACTH.

Biochemical diagnosis is based on the following tests:

• Determination of free urine cortisol
• Frenation with dexamethasone
• Nictameral rhyme of cortisol
• Quantification of Plasmatic ACTH
• CRH stimulation test
• Cateterization of the petrous breasts.

Diagnosis of Cushing's syndrome requires demonstration of elevated cortisol levels with at least two confirmatory tests. Among all these, determination of free cortisol in urine is the most effective method to demonstrate cortisol hypersecretion. A possible diagnostic test for excess ACTH secretion is dexamethasone restraint (a highly potent synthetic corticoid carbohydrate). This suppresses pituitary ACTH secretion through a mechanism of negative counterregulation of the hypothalamic-pituitary axis by corticosteroids. In the case of normal patients, a decrease in cortisol is observed to less than 5 micrograms per deciliter, while in patients with Cushing's disease it remains above 10 μg/dl.

Discovery

While working on her thesis, Evelyn M. Anderson co-discovered ACTH with B. Collip and D. L. Thomson. In a report published in 1933, they explained its role in the body.

Therapeutic uses of ACTH

Although anti-inflammatory drugs are probably the most common and most marketed drugs, today chronic inflammations such as rheumatoid arthritis, multiple sclerosis or inflammatory bowel disease still pose health problems to be solved. New drugs will be discovered in the future, but reconsidering the efficacy of old drugs is also important. This is the case of adrenocorticotropic hormone (ACTH), used in patients since 1952 but mostly considered the last therapeutic option, only used when other medications such as glucocorticoids cannot be used. However, a better understanding of the physiologic and pharmacologic mechanisms of ACTH along with new information on melanocortin receptors has revived interest in ACTH as a drug. ACTH not only induces cortisol production, it also exerts anti-inflammatory actions by attacking the melanocortin receptors on immune cells. These discoveries suggested the possibility of manufacturing new ACTH in the form of melanocortin drugs.

It should be remembered that adrenocorticotropic hormone is a melanocortin peptide that must now be recovered for therapeutic use. ACTH was approved by the FDA for use in humans in 1952, just three years after it was first tested to treat rheumatoid arthritis. At that time, ACTH was used to treat rheumatoid arthritis but also to treat gout, lupus, psoriasis, rheumatic fever or ulcerative colitis, thanks to its stimulating actions on the adrenal cortex for cortisol production.

Philip S. Hench, Edward C. Kendall, and Tadeus Reichstein were awarded the Nobel Prize in Physiology and Medicine in 1950 for their discoveries in ACTH and adrenal hormones. However, very efficient methods for the synthesis of glucocorticoids (GC) were discovered years later, causing a drop in prices, which, together with the availability of oral forms, made glucocorticoids the selected therapy to the detriment of ACTH.

50 years after its approval, the anti-inflammatory actions of ACTH were found to be independent of cortisol, mediated by the melinocortin MC3 receptor, which is found on immune cells and in the brain. These discoveries heightened interest in ACTH as a medical therapy, firstly to reconsider its use (and in particular, in cases where glucocorticoids cannot be used) and secondly, to propose new therapeutic targets, for example, the melanocortin system for development. of anti-inflammatory therapies.

Clinically, ACTH is formulated in two forms in the US. One is known as Acthar® Gel, an injectable drug composed of purified porcine ACTH from pituitary extracts. It is used to treat infantile spasms and also for multiple sclerosis, in addition, it is recommended to treat rheumatic, dermatological, allergic and respiratory problems. The second ACTH formula is called Cortrosyn™, it is synthetic ACTH and consists of the first 24 amino acids (tetracosactide), a sequence that is responsible for the steroidogenic action of the whole protein. This product is used only for the diagnosis of adrenal insufficiency. In the United Kingdom, ACTH is available under the name of Synacthen® Depot, a drug that also contains the structure of the first 24 amino acids, but in this case it has therapeutic and diagnostic use. Therefore, the drug is prescribed for patients who cannot tolerate glucocorticoids or when glucocorticoids have failed.

The most frequent uses of ACTH at the clinical level are the treatment of infantile spasms, multiple sclerosis, gout and nephrotic syndrome.