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10
Adrenocorticotropic Hormone
M.E. Rhodes
Saint Vincent College, Latrobe, PA, United States
O U T L I N E
Abstract INTRODUCTION
Adrenocorticotropic hormone (corticotropin; ACTH) is a 39
amino acid peptide hormone produced by cells of the ante- The anatomical structures that mediate the stress
rior pituitary gland and carried by the peripheral circulation response are found in both the central nervous sys-
to its effector organ, the adrenal cortex, where it stimulates
tem (CNS) and in the peripheral tissues. The principal
the synthesis and secretion of glucocorticoids and, to a more
modest extent, mineralocorticoids and adrenal androgens. endocrine effectors of the stress response are released
ACTH is secreted in response to corticotropin-releasing hor- from the hypothalamus, pituitary, and adrenal glands.
mone (CRH) from the hypothalamus. The actions of CRH on Corticotropin-releasing hormone (CRH) is released from
ACTH release are augmented by another hypothalamic hor- parvocellular neurons of the paraventricular nucleus
mone, arginine vasopressin. ACTH production and secretion
(PVN) of the hypothlamus into the hypophyseal pitu-
are regulated by glucocorticoid feedback, with ACTH at the
center of a homeostatic network involving the hypothala- itary portal system and this hypothalamic hormone is
mus and pituitary. Important brain areas influencing ACTH the principal regulator of anterior pituitary adrenocor-
release include the hypothalamus, amygdala, hippocampus, ticotropic hormone (ACTH) synthesis and secretion.
and prefrontal cortex. As well, ACTH release is modulated The principal target tissue for circulating ACTH is the
by several other stimulatory and inhibitory factors, includ-
adrenal cortex, where ACTH stimulates the synthesis
ing neurotransmitters, peptides, and immune factors. ACTH
release can become dysregulated by a number of factors and secretion of glucocorticoids (cortisol in humans and
including stressors, psychiatric illnesses, endocrine disor- corticosterone in rodents such as rats and mice) from
ders, and various diseases. the zona fasciculata by binding to melanocortin type 2
receptors (MC2-R). Glucocorticoids are the downstream beta-endorphin, a peptide known for its analgesic and
effectors of the hypothalamic–pituitary–adrenal (HPA) euphoric effects in the brain, are produced in the pitu-
axis and facilitate and regulate the vast array of physi- itary from the chemical enzymatic breakdown of a large
ological responses to stress. precursor protein POMC24,34,45 (Fig. 10.1).
Since the discovery of the sequence and processing
KEY POINTS of POMC by Shosaku Numa and his colleagues,38–40
the POMC gene has been shown to be expressed in the
• A drenocorticotropic hormone (ACTH) is a 39 brain and pituitary of essentially all species that have
amino acid peptide hormone produced following been studied to date.36 POMC is a large, 241 amino acid
cleavage of proopiomelanocortin (POMC). protein (prohormone) produced and processed within
• The principal target of circulating ACTH is anterior pituitary corticotropes that undergoes hydro-
the adrenal cortex, where ACTH stimulates lytic cleavage at the sites of basic amino acids, such as
glucocorticoid synthesis and secretion. arginine and lysine, resulting in the production of many
• The regulation of ACTH secretion primarily hormonally active peptides.3,21 POMC is also produced
involves the stimulatory effect of corticotropin- by hypothalamic neurons, the intermediate lobe of the
releasing hormone and arginine vasopressin, pituitary, as well as by the placenta, skin, pancreas, liver,
hypothalamic hormones released directly into kidney, heart, thymus, lungs, ovaries, testes, spleen, leu-
the portal blood supplying the anterior pituitary, kocytes, and gastrointestinal tract.3,36 Within the anterior
and the inhibitory effect of glucocorticoids via pituitary, POMC is processed to yield an N-terminal
feedback loops. peptide, whose function is unclear, and the peptides
ACTH and β-lipotropin (β-LPH). These peptides are
• Areas of the brain, including the amygdala,
generated by the proteolytic cleavage of POMC by pro-
hippocampus, hypothalamus, and prefrontal
hormone convertase 1 (PC1; also known as prohormone
cortex, regulate ACTH production and secretion.
convertase 3), prohormone convertase 2 (PC2), and car-
• Dysregulation of ACTH occurs in boxypeptidase E.5 The importance of the enzyme PC1 in
endocrinopathies such as Cushing syndrome
and Addison disease, as well as other psychiatric
illnesses and disease states.
• The emerging role of ACTH and its related
POMC-derived peptides in conditions other than
those involving the stress response provides
important opportunities to better understand
their mechanisms of action and to develop new
therapeutic uses of these agents.
ADRENOCORTICOTROPIC HORMONE
AND PROOPIOMELANOCORTIN FIGURE 10.1 Proopiomelanocortin (POMC) and its biologically
active peptide hormones following processing. Following transcrip-
tion and translation, POMC is cleaved in a tissue- and species-specific
Advances in the measurement of ACTH and its related manner by the prohormone convertases 1 and 2 (PC1 and PC2) and
peptides have elucidated their extensive distribution in by carboxypeptidase E. Products from initial processing include an
areas of the body outside the pituitary gland, with dif- N-terminal peptide, joining peptide (JP), adrenocorticotropic hormone
ferential processing in different tissues. Tissue-specific (ACTH1-39), and β-lipotropin (β-LPH). Bioactive products include:
ACTH; β-and γ-lipotropins (β-LPH, γ-LPH); α-, β-, and γ-melanocyte-
differences in the way the peptides are processed after stimulating hormones (α-MSH, β-MSH, γ-MSH); corticotropinlike inter-
translation give rise to differences in the final secre- mediate lobe peptide (CLIP), β-endorphin (β-End), and met-enkephalin
tory products. ACTH and other peptides, including (Met-Enk).
ADRENOCORTICOTROPIC HORMONE
PRODUCTION AND RELEASE FROM
PITUITARY CORTICOTROPES
predominantly at the level of de novo synthesis.45 ACTH are important in the regulation of the entire HPA axis.
activation of MC2-R and the cAMP-protein kinase A In the pituitary, Nur 77 and Nurr1 are involved in CRH-
pathway induces rapid phosphorylation of the steroid dependent induction of POMC mRNA27,29,41, CRH also
regulatory protein that facilitates transport of cholesterol stimulates the transcription of c-fos, FosB, and Jun-B, as
into the mitochondria for conversion into active steroid well as binding to the POMC activator protein-1 (AP-1)
hormones, and within the nucleus, induces the tran- site.29 The pituitary adenylate cyclase-activating protein
scription of several steroidogenic enzymes necessary also increases cAMP production and POMC transcrip-
for the short- and long-term stimulation of steroidogen- tion, perhaps via a common pathway with CRH.8
esis.49 Mutations in MC2-R account for approximately The participation of other regulators in addition
25% of the cases of familial glucocorticoid deficiency, a to CRH and AVP, that modulate ACTH secretion in
rare hereditary syndrome of ACTH resistance.45 the absence of or during stress, cannot be discounted
ACTH is secreted into the bloodstream in pulses (Fig. 10.3). A number of other factors, such as angiotensin
from pituitary corticotropes with approximately II, catecholamines, ghrelin, growth hormone–releasing
40 pulses/24 h, correlating with subsequent corticoste- hormone (GHRH), and immune factors have been shown
roid pulses.33 The development of immunoradiometric to stimulate ACTH secretion and/or augment cleavage
assays specific for intact human and rodent ACTH1-39 of POMC. Pancreatic vasoactive intestinal peptide (VIP)
has improved the reliability of ACTH measurement. also stimulates ACTH secretion, probably indirectly via
Radioimmunoassay and enzyme immunoassay of CRH secretion, a mechanism which may explain ACTH
plasma ACTH and its precursors also are accepted meth- increases following eating.33 Indeed, food intake and
ods for evaluating ACTH secretion, although the anti- feeding behaviors appear to be major regulators of HPA
bodies used also recognize some of the shorter ACTH axis hormone rhythms.50
fragments. Therefore, performance differs among the
various commercially available assays, and should be
considered when interpreting patient or bench work
results. Glucocorticoid concentrations in the blood also
can be measured as an index of ACTH secretion.
CONTROL OF SECRETION
by nongenomic (second messenger pathway) mecha- levels of circulating cortisol, as well as mineralocorti-
nisms13,14,26,29,50; As well, there is some evidence to sup- coids, and high levels of circulating ACTH. Symptoms of
port the involvement of endocannabinoids in producing Addison disease include muscle weakness, skin hyperpig-
this fast feedback.17,50 Intermediate feedback occurs mentation, loss of appetite, vomiting and diarrhea, fever,
within 2–10 h of initial stimulation, and involves inhibi- fatigue, difficulty concentrating, and lack of initiative.
tion of CRH synthesis and release, but does not directly Depression and stress intolerance also may be evident.21
influence ACTH synthesis. Slow feedback occurs over
longer intervals and results from inhibition of POMC
transcription and processing.26 Adrenocorticotropic Hormone
Resistance Syndromes
Inherited ACTH resistance diseases are rare and
CLINICAL PERSPECTIVES include triple A syndrome (Allgrove syndrome) and
familial glucocorticoid deficiency (FGD). Clinically,
Cushing Syndrome FGD is characterized solely by ACTH resistance
while triple A syndrome exhibits a variety of addi-
Cushing syndrome is a clinical condition resulting tional characteristics. FGD is caused by mutations
from chronic elevation of circulating glucocorticoids. of the MC2-R and melanocortin 2 receptor accessory
Clinical signs and symptoms of Cushing syndrome protein (MRAP) genes.12,32 Therefore, most patients
include obesity of the face and trunk, weakness and atro- with FGD and triple A syndrome will exhibit adre-
phy of limb muscles, increased blood pressure, imbal- nal insufficiency and high circulating ACTH levels,
ance of glucose metabolism, and psychological changes. while most patients will have no disruption of circu-
Psychiatric symptoms may include depression, mood lating mineralocorticoids.9 Other symptoms of triple
swings, mania, agitation, and memory disturbances.21 A syndrome include alacrima (no tear production),
There are two main types of Cushing syndrome, ACTH- achalasia (relaxation of the lower esophageal muscles,
dependent and ACTH-independent. ACTH-dependent preventing food from entering the stomach), and pro-
Cushing syndrome results from increased pituitary gressive neurological symptoms such as ataxia, spas-
secretion of ACTH, usually from a pituitary tumor ticity, myopathy, and peripheral neuropathy.32 Other
(Cushing disease), inappropriate ACTH secretion by symptoms of FGD typically present during childhood
nonpituitary tumors, often in the lungs or thyroid gland, and include hypoglycemia, hyperpigmentation of the
and inappropriate CRH secretion by nonhypothalamic skin, and in some cases, tall stature that may be caused
tumors, in turn stimulating excessive pituitary ACTH by high-circulating ACTH levels acting at MC1-R in
secretion. These conditions, all involving excess ACTH the bone and cartilage.9,32
production, cause enlargement of the adrenal glands and
excessive cortisol secretion from continuous stimulation.
ACTH-independent Cushing syndrome is caused by OTHER EFFECTS OF
primary tumors or abnormalities of the adrenal cortex ADRENOCORTICOTROPIC HORMONE
itself, resulting in excessive cortisol secretion and sup-
pression of ACTH production by the pituitary. Prolonged In addition to its endocrine activity, ACTH also influ-
administration of glucocorticoids for the treatment of ences neuronal activity. In higher animals, decades of
certain illnesses also may cause ACTH-independent research have shown that ACTH and its fragment pep-
Cushing syndrome. tides influence behavior, attention, and learning.6,15,25
The excessive pituitary production of ACTH and Increased ACTH secretion in Cushing syndromes can be
adrenal production of cortisol in Cushing disease are associated with deficits in memory; however, whether the
only partially suppressible by low-dose dexamethasone, memory impairments result solely from increases in cir-
a synthetic and potent glucocorticoid, but more sup- culating ACTH versus increases in circulating glucocorti-
pressible by higher doses. In contrast, patients with non- coids is unclear. ACTH administered into the brain leads
pituitary sources of ACTH production will rarely show to other, sometimes bizarre, behaviors not observed with
suppression of ACTH and cortisol by dexamethasone. peripheral administration. In this case, ACTH increases
penile erection and ejaculation, sexual receptivity, yawn-
ing, grooming behavior, and stretching.5 ACTH also has
Addison Disease been shown to increase slow-wave sleep and REM sleep
Addison disease is characterized by diminished glu- in rats.52 In addition to the adrenal cortex, MC2-R also
cocorticoid production by the adrenal cortex (resulting in are expressed in the adipose tissue of rodents, and ACTH
adrenal insufficiency) usually resulting from an autoim- affects adipocyte lipolysis and enhances insulin-induced
mune mechanism. Patients with this disease show low glucose uptake in adipose tissue.10
THERAPEUTIC USES to this regulation. The emerging role of ACTH and its
related POMC-derived peptides in conditions other than
There are currently two ACTH formulations avail- those involving the stress response are exciting avenues
able for use in the US. The first is H.P. Acthar Gel, an for exploration into mechanisms and potential therapeu-
injectable formulation used primarily for the treatment tic uses of these agents.
of infantile spasms and acute symptoms of multiple
sclerosis. However, this injectable formulation also is
indicated for rheumatic, allergic, and certain respira- Acknowledgment
tory diseases. The second is cosyntropin (Cortosyn), a This chapter is a revised and expanded adaptation from a previous
synthetic ACTH1-24 peptide that is used as a diagnostic chapter by Michael E. Rhodes, Encyclopedia of Stress, volume 1, pp.
agent when screening for adrenal insufficiency. In the 69–72, © 2007, Elsevier, Inc.
UK, ACTH1-24 (Synacthen Depot) is available for both
diagnostic and therapeutic uses, where it is indicated for
short-term conditions where glucocorticoids are indi-
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