Download BCH 560 hormones (adrenal gland)

BCH 560 (ADRENAL GLAND)
Dr. Samina. Hyder Haq
Dept. Of biochemistry
King Saud university
ADRENAL GLAND

The adrenal glands are central components of the
endocrine system. They play an important role in
the regulation of the body's adaptive response to
stress, in the maintenance of body water and salt
balance, and in the control of blood pressure. The
main hormones produced by the human adrenal
glands are the steroid hormone cortisol, the
mineralocorticoid aldosterone, the androgen
dehydroepiandrosterone (DHEA), and the
catecholamines norepinephrine and epinephrine.
When studying the adrenal gland, it is important
to keep in mind that like the pituitary, it has 2
different embryologic origins.

The adrenal glands are located above the kidneys.
They are small, averaging 3–5 cm in length, and weigh
1.5–2.5 g. They are made of 2 different components
derived from 2 distinct embryologic origins: the cortex
and the medulla . The outer adrenal cortex is derived
from mesodermal tissue and accounts for about 90% of
the weight of the adrenals. The cortex synthesizes the
adrenal steroid hormones called glucocorticoids,
mineralocorticoids, and androgens (eg, cortisol,
aldosterone, and dehydroepiandrosterone [DHEA]) in
response to hormone stimulation . The inner medulla is
derived from a subpopulation of neural crest cells and
makes up the remaining 10% of the mass of the
adrenals. The medulla synthesizes catecholamines (eg,
epinephrine and norepinephrine) in response to direct
sympathetic stimulation
TABLE 14-1 -- HISTORY OF THE ADRENAL CORTEX:
IMPORTANT MILESTONES
 1563 Eustachius describes the adrenals (published by
Lancisi in 1714).
 1849 Thomas Addison, while searching for the cause of
pernicious anemia, “stumbles” on a bronzed appearance
associated with the adrenal glands—“melasma suprarenale.”
 1855 Thomas Addison describes the clinical features and
autopsy findings of 11 cases of diseases of the suprarenal
capsules, at least 6 of which were tuberculous in origin.
 1856 In adrenalectomy experiments, Brown-Séquard
demonstrates that the adrenal glands areb essential for life.
 1896 William Osler gives an oral glycerine extract derived
from pig adrenals and demonstrates clinical benefit in
patients with Addison's disease.
 1905 Bulloch and Sequeria describe patients with congenital
adrenal hyperplasia.
CONT





1929 Liquid extracts of cortical tissue are used to keep
adrenalectomized cats alive indefinitely (Swingle and Pfiffner).
Subsequently, this extract was used successfully to treat a patient
with Addison's disease (Rowntree and Greene).
1932 Harvey Cushing associates the “polyglandular syndrome” of
pituitary basophilism first described by him in 1912 with hyperactivity
of the pituitary-adrenal glands.
1936 Concept of stress and its effect upon pituitary-adrenal function
described by Seyle.
1937–1952 Isolation and structural characterisation of adrenocortical
hormones (Kendall, Reichstein).
1943 Li and colleagues isolate pure adrenocorticotropic hormone from
sheep pituitary.
1950 Hench, Kendall, and Reichstein share Nobel Prize in medicine for
describing the antiinflammatory effects of cortisone in patients with
rheumatoid arthritis.
CONT1953 Isolation and analysis of the structure of
aldosterone (Simpson and Tait).
 1956 Conn describes primary aldosteronism.
 1981 Characterization and synthesis of
corticotropin-releasing hormone (Vale).
 1980–present The “molecular era.” Cloning and
functional characterization of steroid receptors,
steroidogenic enzymes, and adrenal transcription
factors. Definition of the molecular basis for human
adrenaldiseases.

DIFFERENT REGIONS OF ADRENAL GLAND
Steroidogenic acute regulatory protein mediated uptake of
cholestrol into mitochondria within adrenocortical cells,
Aldosterone, glucocorticoid and androgens are synthesized
through the co-ordinated action of series of steroidogenic
enzymes in a zone specific fashion
Chemical structure of
Dehydroepiandrosterone
(DHEA)


The initial step in steroid hormone synthesis (steroidogenesis)
is the conversion of cholesterol to pregnenolone. Cholesterol
used for steroid hormone synthesis can be derived from the
plasma membrane or from the cytosolic pool known as the
steroidogenic cytoplasmic pool.
Cholesterol is released by the action of the enzyme cholesterol
esterase. Cholesterol is converted to pregnenolone by the action
of the cytochrome P450 side-chain cleavage enzyme (P450scc),
which is present in the inner mitochondrial membrane of all
steroidogenic cells. For cholesterol to be a substrate for
P450scc, free cholesterol must be transferred from the outer
mitochondrial membrane to the inner mitochondrial
membrane. This step is mediated by steroid acute regulatory
protein. This delivery of cholesterol from the outer
mitochondrial membrane to the inner mitochondrial
membrane, where the P450scc enzyme is located, is considered
the rate-limiting step in steroid hormone synthesis. This
conversion of cholesterol to pregnenolone is the first step in a
sequence of enzymatic reactions involved in the synthesis of
steroid hormones. Because the cells that constitute the
different sections of the adrenal cortex have specific enzymatic
features, the synthetic pathway of steroid hormones will result
in preferential synthesis of glucocorticoids, mineralocorticoids,
or androgens, depending on the region.
ADRENAL CORTEX
Consists of three zones.
 The zona glomerulosa contains abundant smooth
endoplasmic reticulum and is the unique source of the
mineralocorticoid aldosterone.
 The zona fasciculata contains abundant lipid droplets
and produces the glucocorticoids, cortisol and
corticosterone, and the androgens, DHEA and DHEA
sulfate (DHEAS).
 The zona reticularis develops postnatally and is
recognizable at about age 3; it also produces glucocorticoids
and androgens.
The products of the adrenal cortex can be
classified into 3 general categories:
glucocorticoids, mineralocorticoids, and
androgens
SCHEMATIC DIAGRAM OF THE STRUCTURE OF THE HUMAN
ADRENAL CORTEX, DEPICTING THE OUTER ZONA GLOMERULOSA
AND INNER ZONA
FASCICULATA AND ZONA RETICULARIS
SPECIFIC EFFECT OF GLUCOCORTICOIDS




Cortisol, the main glucocorticoid in humans, enters the cell by
passive diffusion and binds to the glucocorticoid receptor .
The hormone-receptor complex translocates to the nucleus,
where it binds to specific DNA sequences (glucocorticoid
response elements) and exerts its physiologic effects by
altering transcription of genes. Because virtually all cells
express glucocorticoid receptors, the physiologic effects are
multisystemic.
Glucocorticoids affect intermediary metabolism, stimulate
proteolysis and gluconeogenesis, inhibit muscle protein
synthesis, and increase fatty acid mobilization. At high levels,
glucocorticoids are catabolic and result in loss of lean body
mass. Their gluconeogenic effect increases blood glucose
concentrations, hence the name "glucocorticoids."
Glucocorticoids modulate the immune response by increasing
anti-inflammatory cytokine synthesis and decreasing
proinflammatory cytokine synthesis.
In the central nervous system, they modulate perception and
emotion and may produce marked changes in behavior.
GLUCOCORTICOID SYNTHESIS AND
RELEASE




The release of cortisol is pulsatile and is under direct stimulation by ACTH
released from the anterior pituitary.. An important feature in the release of
cortisol is that in addition to being pulsatile, it follows a circadian rhythm that
is exquisitely sensitive to light, sleep, stress, and disea. Release of cortisol is
greatest during the early waking hours, with levels declining as the afternoon
progresses.
The stimulation of cortisol release by ACTH is mediated by its binding to a Gs
protein–coupled plasma membrane melanocortin 2 receptor on adrenocortical
cells, resulting in activation of adenylate cyclase, an increase in cyclic
adenosine monophosphate, and activation of protein kinase A . Protein kinase
A phosphorylates the enzyme cholesterol ester hydrolase, increasing enzymatic
activity. This enzyme catalyzes the release of cholesterol from cholesterol
esters, providing the free cholesterol needed for steroid hormone synthesis. In
addition,
ACTH activates and increases the synthesis of steroid acute regulatory protein,
the enzyme involved in the transport of cholesterol into the inner mitochondrial
membrane, where cytochrome P450 converts cholesterol to pregnenolone.
Therefore, ACTH stimulates the 2 initial and rate-limiting steps in steroid
hormone synthesis.
The release of ACTH from the anterior pituitary is regulated by corticotropinreleasing hormone (CRH), produced by the hypothalamus and released in the
median eminence. Cortisol inhibits the biosynthesis and secretion of CRH and
ACTH in a classic example of negative feedback regulation by hormones
METABOLISM OF GLUCOCORTICOIDS




Because of their lipophilic nature, free cortisol molecules are mostly insoluble in water.
Therefore, cortisol is usually found in biologic fluids either in a conjugated form (eg, as
sulfate or glucuronide derivatives) or bound to proteins (noncovalent, reversible
binding). In the plasma, unconjugated steroids are usually bound to carrier proteins.
The half-life of cortisol is 70–90 minutes.
The majority of cortisol is bound to glucocorticoid-binding alpha2-globulin (transcortin
or cortisol-binding globulin), a specific carrier of cortisol. Normal levels of transcortin
average 3–4 mg/dL and are saturated with cortisol levels of 28 g/dL. The hepatic
synthesis of transcortin is stimulated by estrogen and decreased by hepatic disease
(cirrhosis). About 20–50% of bound cortisol is bound nonspecifically to plasma albumin.
Approximately 1–10% of total plasma cortisol circulates unbound and is referred to as
the free fraction. This is considered to represent the biologically active fraction of the
hormone that is directly available for action.
The major role of plasma-binding proteins is to act as a "buffer" or reservoir for active
hormones. Because of the noncovalent nature of the binding, protein-bound steroids are
released into the plasma in free form as soon as the free hormone concentration
decreases. Plasma-binding proteins also protect the hormone from peripheral
metabolism (notably by liver enzymes) and increase the half-life of biologically active
forms.
Because of their lipophilic nature, steroid hormones diffuse easily through cell
membranes and therefore have a large volume of distribution. In their target tissues,
steroid hormones are concentrated by an uptake mechanism that relies on their binding
to intracellular receptors. Interestingly, high concentrations of steroid hormones are
found in adipose tissue even though this tissue is not a target for the physiologic effects
of steroid hormones. However, adipose tissue contains enzymatic activity in the form of
aromatase (5-reductase), which converts circulating androgens to estrogens
METABOLISM OF GLUCOCORTICOIDS

Metabolism of glucocorticoids occurs in the liver and, to a lesser
extent, in the kidneys. In other words, the liver and kidney are the
2 major sites of hormone inactivation and elimination, or
catabolism. Inactive hormones are mainly eliminated as urinary
(mostly conjugated) metabolites. Usually, steroids are eliminated
once they have been inactivated. Urinary excretion of metabolic
products requires conversion from lipophilic to hydrophilic
compounds to ensure their solubility in biologic fluids at rather
high concentrations. Several pathways are involved in this process,
including reduction, oxidation, hydroxylation, and conjugation, to
form the sulfate and glucuronide derivatives of the steroid
hormones. Inactivation of cortisol to cortisone and to
tetrahydrocortisol and tetrahydrocortisone is followed by
conjugation and renal excretion. These metabolites are referred to
as 17-hydroxycorticosteroids, and their determination in 24-hour
urine collections is used to assess the status of adrenal steroid
production.
THE ANTIINFLAMMATORY
ACTION OF GLUCOCORTICOIDS.
GLUCOCORTICOID RECEPTOR
THROUGH
(GR). GLUCOCORTICOIDS
CORTISOL
BINDS TO THE CYTOPLASMIC
MEDIATE THEIR ANTIINFLAMMATORY EFFECTS
:
A:THE INHIBITORY PROTEIN
INDUCED.B
1KB, WHICH
THE GR–CORTISOL COMPLEX
INFLAMMATORY PROCESS.
BINDS AND INACTIVATES NUCLEAR FACTOR KB
IS ABLE TO BIND
NFKB AND THUS PREVENT
(NFKB), IS
INITIATION OF AN
EFFECT OF MINERALCORTICOIDS




The principal physiologic function of aldosterone is to regulate renal sodium
reabsorption, hence the name "mineralocorticoid." Aldosterone binds to the
mineralocorticoid receptor in the principal cells of the distal tubule and the
collecting duct of the nephron, producing an increase in sodium reabsorption
and potassium excretion .
Aldosterone also diffuses across the plasma membrane and binds to its
cytosolic receptor. The receptor-hormone complex is translocated to the
nucleus, where it interacts with the promoter region of target genes, activating
or repressing their transcriptional activity. Aldosterone-induced activation of
preexisting proteins and stimulation of new proteins mediate an increase in
transepithelial sodium transport. Aldosterone increases sodium entry at the
apical membrane of the cells of the distal nephron through the amiloridesensitive epithelial Na+ channel. The Na+/K+-adenosine triphosphatase
(ATPase), located in the basolateral membrane of the cells, maintains the
intracellular sodium concentration by extruding the reabsorbed sodium toward
the extracellular and blood compartments.
The increase in Na+ reabsorption leads to increased water reabsorption,
creating an electrochemical gradient that facilitates the transfer of
intracellular K+ from tubular cells into the urine. When most of the filtered
Na+ is reabsorbed in the proximal tubule, only a small amount of sodium
reaches the distal tubule (the site of aldosterone regulation)..
The role of aldosterone in regulation of blood pressure is considered central. By
regulating sodium transport across the tight epithelia of Na+-reabsorbing
tissues such as the distal nephron and colon, aldosterone is a major factor
determining total-body Na+ levels and thus long-term blood pressure
regulation.
MINERALOCORTICOID HORMONE ACTION.
The much higher concentrations of cortisol are inactivated by the type 2 isozyme of 11ß-hydroxysteroid
dehydrogenase (11ß-HSD2) to cortisone, permitting the endogenous ligand, aldosterone, to bind to the
mineralocorticoid receptor (MR). Relatively few mineralocorticoid target genes have been identified, but these
include serum and glucocorticoid-induced kinase (SGK), subunits of the epithelial sodium
channel (ENaC), and basolateral Na+,K+-adenosine triphosphatase
MINERALOCORTICOID SYNTHESIS AND
RELEASE

aldosterone synthesis and release in the adrenal zona
glomerulosa are predominantly regulated by
angiotensin II and extracellular K+ and, to a lesser
extent, by ACTH. Aldosterone is part of the reninangiotensin-aldosterone system, which is
responsible for preserving circulatory homeostasis in
response to a loss of salt and water (eg, with intense
and prolonged sweating, vomiting, or diarrhea). The
components of the renin-angiotensin-aldosterone
system respond quickly to reductions in intravascular
volume and renal perfusion. Angiotensin II is the
principal stimulator of aldosterone production when
intravascular volume is reduced.
RENIN –ANGIOTENSIN ALDOSTERONE
SYSTEM
CONTROL OF ALDOSTERONE SYNTHESIS

The main physiologic stimulus for aldosterone release is a
decrease in the effective intravascular blood volume . A
decline in blood volume leads to decreased renal perfusion
pressure, which is sensed by the juxtaglomerular
apparatus (baroreceptor) and triggers the release of renin.
Renin release is also regulated by NaCl concentration in
the macula densa, plasma electrolyte concentrations,
angiotensin II levels, and sympathetic tone. Renin
catalyzes the conversion of angiotensinogen, a liver-derived
protein, to angiotensin I. Circulating angiotensin I is
converted to angiotensin II by endothelial cells, primarily
in the lung. The increase in circulating angiotensin II
produces direct arteriolar vasoconstriction, but it also binds
to the angiotensin II receptor in the adrenocortical cells of
the zona glomerulosa, stimulating phospholipase C. This
results in an increase in intracellular Ca2+, leading to
stimulation of aldosterone synthesis and release
OTHER FORMS OF
MINERALOCORTICOID EXCESS OR
EFFECT
Hyperdeoxycorticosteronism(Congenital adrenal
hyperplasia (CAH)) is caused by enzymatic defects in
adrenal steroidogenesis that result in deficient secretion
of cortisol, A deficiency of both 11ß-hydroxylase
(CYP11B) and 17a-hydroxylase (CYP17)causes
hypertension and hypokalemia.
 Deoxycorticosterone-Producing Tumor; Primary Cortisol
Resistance Increased cortisol secretion and plasma
cortisol concentrations without evidence of Cushing's
syndrome are found in patients with primary cortisol
resistance (or glucocorticoid resistance), a rare familial
syndrome

ANDROGENS




DHEA is a crucial precursor of human sex steroid biosynthesis and exerts
androgenic or estrogenic activity following conversion by the activities of 3ßHSD, a superfamily of ß-HSD isozymes and aromatase, expressed in
peripheral target tisswhich is of clinical importance in many diseases.
Only desulfated DHEA is converted downstream and biologically active.
Serum DHEAS was previously thought to represent a circulating storage
pool for DHEA regeneration. However, recent work has suggested that
conversion of DHEAS to DHEA by steroid sulfatase plays a minor role in
adult physiology and that the equilibrium between serum DHEA and
DHEAS is mainly regulated by DHEA sulfotransferase
The physiologic effects of DHEA and DHEAS are not completely understood.
Current knowledge indicates that low levels of DHEA are associated with
cardiovascular disease in men and with an increased risk of premenopausal
breast and ovarian cancer in women.
In contrast, high levels of DHEA might increase the risk of postmenopausal
breast cancer. Exogenous administration of DHEA to the elderly increases
several hormone levels, including insulin-like growth factor-1, testosterone,
dihydrotestosterone, and estradiol. However, the clinical benefit of these
changes and the side effects of long-term use remain to be clearly defined.
Furthermore, the specific mechanisms through which DHEA exerts its
actions are not completely understood
GLUCOCORTICOIDS EXCESS
Glucocorticoid excess can be due to overproduction by an adrenal
tumor or to overstimulation of adrenal glucocorticoid synthesis
and release by ACTH produced by a pituitary tumor or an ectopic
tumor. Glucocorticoid excess, or Cushing syndrome, can be
separated into 2 categories depending on its etiology,
 In corticotropin-dependent Cushing syndrome, elevated
glucocorticoid levels are due to excess stimulation by ACTH. The
chronic elevation of ACTH causes bilateral enlargement
(hyperplasia) of the adrenal cortex. Corticotropin production may
also be ectopic (derived from extrapituitary tissue), most
frequently because of small cell lung carcinoma. Tumor secretion
of corticotropin is usually not suppressed by glucocorticoids, and
this feature is helpful in distinguishing the source of
corticotropin. The name "Cushing disease" is reserved for
Cushing syndrome caused by excess secretion of corticotropin by
pituitary corticotroph tumors and is the most common form of the
syndrome.
 In corticotropin-independent Cushing syndrome, excess cortisol
production is due to abnormal adrenocortical tissue regardless of
ACTH stimulation. In fact, the elevated circulating cortisol levels
suppress CRH and ACTH levels in plasma.
GLUCOCORTICOID DEFECIENCY


Glucocorticoid deficiency is less common than diseases due to
excess production of glucocorticoids. Glucocorticoid deficiency
can result from lack of ACTH stimulation of adrenal
glucocorticoid production (secondary deficiency) or from
adrenal dysfunction (primary deficiency). Exogenous
administration of synthetic analogs of glucocorticoids in the
chronic treatment of some diseases will also suppress CRH and
ACTH. Therefore, the sudden discontinuation of treatment
may be manifested as an acute case of adrenal insufficiency. It
is important to carefully taper the withdrawal of steroid
treatment from patients.
Most cases of ACTH deficiency involve deficiencies of other
pituitary hormones. Because aldosterone is mainly under the
regulation of angiotensin II and K+, individuals may not
necessarily have simultaneous mineralocorticoid deficiency
when impaired ACTH release is the causative factor.
Glucocorticoid deficiency due to adrenal hypofunction is known
as Addison disease, which can be the result of autoimmune
destruction of the adrenal gland or inborn errors of steroid
hormone synthesis
PRIMARY ALDOSTERONISM

Hypertension, suppressed plasma renin activity
(PRA), and increased aldosterone excretion
characterize the syndrome of primary aldosteronism,
first described in 1955. Aldosterone-producing
adenoma (APA) and bilateral idiopathic
hyperaldosteronism (IHA) are the most common
subtypes of primary aldosteronism
CLASSIFICATION AND
PATHOPHYSIOLOGY OF CUSHING'S
SYNDROME
ACTH-DEPENDENT
Cushing's disease (pituitarydependent)
Ectopic ACTH syndrome
Ectopic CRH syndrome
Macronodular adrenal hyperplasia
Iatrogenic (treatment with ACTH 1-24)

ACTH-INDEPENDENT
Adrenal adenoma and carcinoma
Primary pigmented nodular adrenal
hyperplasia and Carney's syndrome.
McCune-Albright syndrome
Aberrant receptor expression (gastric
inhibitory polypeptide,interleukin1ß).
Iatrogenic (e.g., pharmacologic doses of
prednisolone, dexamethasone

PSEUDOCUSHING'S
SYNDROMES
Alcoholism
Depression
Obesity

ACTH DEPENDENT CASES.
When iatrogenic causes are excluded, the commonest cause
of Cushing's syndrome is Cushing's disease, accounting for
approximately 70 percent of cases. The adrenal glands in
these patients show bilateral adrenocortical hyperplasia
with widening of the zona fasciculata and reticularis.
 Etiology
Cushing himself raised the question as to whether this disease
was a primary pituitary condition or secondary to an
abnormality in the hypothalamus, and there has been an
ongoing debate on this issue. The hypothalamic theory states
that ACTH-secreting adenomas arise because of
dysfunctional regulation of corticotrophs through chronic
stimulation by CRF (or arginine vasopressin), whereas other
studies provide data to support a primary pituitary defect as
the cause of the condition

ECTOPIC ACTH SYNDROME
In 15% of cases, Cushing's syndrome may be associated
with nonpituitary tumors secreting ACTH—the ectopic
ACTH syndrome. On clinical grounds, this can be
divided into two entities, cases occurring in the setting
of highly malignant tumors such as small cell
carcinoma of bronchus and more indolent cases
occurring in patients with underlying neuroendocrine
tumors such as bronchial carcinoids.
 Circulating ACTH concentrations and cortisol secretion
rates can be extremely high. As a result, duration of
symptoms from onset to presentation is short (<3
months); patients are commonly pigmented and the
metabolic manifestations of glucocorticoid excess are
often rapid and progressive. Weight loss, myopathy,
and glucose intolerance are prominent symptoms and
signs

PSEUDO-CUSHING'S SYNDROMES
A pseudo-Cushing's state can be defined as some or all of the clinical
features of Cushing's syndrome together with some evidence for
hypercortisolism. Resolution of the underlying cause results in
disappearance of the Cushingoid state. Several causes are described.
 Alcoholism:In the original description of this syndrome, urinary
and plasma cortisol levels were elevated and failed to suppress with
dexamethasone. Plasma ACTH has been found to be normal or
suppressed. The condition is rare but should be suspected in a
patient with an ongoing history of heavy alcohol intake and
biochemical/clinical evidence of chronic liver disease
 Depression:Although the cause is unknown, it is recognized that
patients with depression may exhibit the hormonal abnormalities of
patients with Cushing's syndrome.These abnormalities are
reversible on correction of the psychiatric condition.

Obesity: As one of the symptoms of this disease is extreme
waight gain. The most commont referrals to a clinical
endocrinologist is to exclude an underlying endocrine cause
in a patient with obesity, the diagnosis of Cushing's
syndrome in such patients should not cause difficulties.
Patients with obesity have mildly increased cortisol
secretion rates.
TREATMENT OF CUSHING'S DISEASE.
Surgical removal of the Adrenal adenomas by unilateral
adrenalectomy, with a 100% cure rate. Pituitary-Dependent
Cushing's Syndrome The treatment of Cushing's disease has been
significantly enhanced through transsphenoidal surgery
conducted by an experienced surgeon.
 Medical Treatment of Cushing's syndromeSeveral drugs have
been used in the treatment of Cushing's syndrome. Metyrapone
inhibits 11ßhydroxylase and has been most commonly given.
1. Aminoglutethimide is a more toxic drug, which in high dose blocks
earlier enzymes in the steroidogenic pathway and thus affects the
secretion of steroids other than cortisol
2. Trilostane, a 3ß-hydroxysteroid dehydrogenase inhibitor, is
ineffective in Cushing's disease.
3. Ketoconazole is an imidazole that has been widely used as an
antifungal agent but causes abnormal liver function tests in about
15% of patients. Ketoconazole blocks a variety of steroidogenic
cytochrome P450–dependent enzymes and thus lowers plasma
cortisol levels

HORMONES OF THE ADRENAL MEDULLA

The medulla is the central part of the adrenal
gland . It is extremely vascular and consists of
large chromaphil cells arranged in a network. It
is made of 2 cell types called pheochromocytes—
norepinephrine-producing and (more numerous)
epinephrine-producing cells—and synthesizes
and secretes the catecholamines
norepinephrineand epinephrine and, to a
lesser extent, dopamine. Epinephrine is
secreted in greater amounts than
norepinephrine;
.
1.
2.
3.
4.
Hydroxylation of tyrosine to L-dihydrophenylalanine (L-Dopa) by the
enzyme tyrosine hydroxylase. This enzyme is found in the cytosol of
catecholamine-producing cells and is the main control point for
catecholamine synthesis. The activity of this enzyme is inhibited by
noradrenaline, providing feedback control of catecholamine synthesis.
Decarboxylation of L-Dopa to dopamine by the enzyme dopa
decarboxylase in a reaction that requires pyridoxal phosphate as a
cofactor. This end product is packaged into secretory vesicles.
Hydroxylation of dopamine to norepinephrine by the enzyme
dopamine -hydroxylase, a membrane-bound enzyme found in
synaptic vesicles that uses vitamin C as a cofactor. This reaction occurs
inside the secretory vesicles.
Methylation of norepinephrine to epinephrine by the enzyme
phenylethanolamine N-methyltransferase. The activity of this
adrenal medullary enzyme is modulated by adjacent adrenal steroid
production, underscoring the importance of arterial flow from the cortex
to the medulla
RELEASE OF CATECHOLAMINE
Stressful stimuli (e.g., myocardial infarction, anesthesia,
hypoglycemia) trigger adrenal medullary catecholamine
release.
The release is a direct response to sympathetic nerve
stimulation of the adrenal medulla. Acetylcholine released
from the preganglionic sympathetic nerve terminals binds to
nicotinic cholinergic receptors in the plasma membrane of
the chromaffin cells, depolarizing the cells. Depolarization of
the cells leads to activation of voltage-gated Ca2+ channels,
producing an influx of Ca2+. The synaptic vesicles containing
the preformed catecholamines are docked beneath the
synaptic membrane and are closely associated with voltagegated Ca2+ channels. The influx of Ca2+ triggers the
exocytosis of secretory granules, which release their
contents (catecholamines, chromogranins, ATP,
adrenomedullin, proopiomelanocortin products, and other
peptides) into the interstitial space, from where they are
transported in the circulation to their target organs

CATECHOLAMINE PHYSIOLOGIC EFFECTS


Catecholamines are released as part of the stress response to a
physical or psychological insult such as severe blood loss, decrease
in blood glucose concentration, traumatic injury, surgical
intervention, or a fearful experience. Because catecholamines are
part of the "fight or flight" response, their physiologic effects include
arousal, alerting, papillary dilation, piloerection, sweating,
bronchial dilation, tachycardia, inhibition of smooth muscle activity
in the gastrointestinal tract, constriction of the sphincters, and
relaxation of the uterine muscles. Most of the events involved in
coping with a stressful situation require the expenditure of energy.
Catecholamines ensure substrate mobilization from the liver,
muscle, and fat by stimulating the breakdown of glycogen
(glycogenolysis) and fat (lipolysis). Thus, an increase in circulating
catecholamines is associated with elevations in plasma glucose and
free fatty acid levels. Some of the most important effects of
catecholamines are exerted in the cardiovascular system, where
they increase heart rate (tachycardia), produce peripheral
vasoconstriction, and elevate vascular resistance.
CATECHOLAMINE TRANSPORT & METABOLISM


The half-life of circulating catecholamines is short and is estimated to range
from 10 seconds to 1.7 minutes. A fraction of the catecholamines released
circulate bound to albumin with low affinity. Their elimination rate varies
depending on the site of release. Catecholamine metabolism occurs mainly in
the cytoplasm of the same cells where they are synthesized following leakage
from cytoplasmic vesicles. In humans, vanilmandelic acid (VMA) is the major
end product of norepinephrine and epinephrine metabolism. Monoamine
oxidase (MAO) catalyzes the first step of oxidative deamination of
catecholamines, followed by reduction to dihydroxyphenylglycol (DHPG) by
aldehyde reductase in sympathetic nerves.
Catechol-o-methyl transferase (COMT) catalyzes conversion of norepinephrine
to normetanephrine and of DHPG to 3-methoxy-4-hydroxyphenylglycol
(MHPG) in extraneuronal tissues. Catecholamines of neuronal or glandular
origin are degraded by COMT at their target cells. Circulating catecholamines
can undergo reuptake by extraneuronal sites and degradation by COMT or
MAO, especially in the liver (>94%), producing the metabolites metanephrine
and normetanephrine. The joint action of MAO and COMT on norepinephrine
and epinephrine produces the metabolite vanillylmandelic acid, which is then
excreted in the urine; dopamine metabolized through this pathway yields
homovanillic acid. Because these metabolites are water soluble and have high
levels of urinary excretion, they play an important role in the clinical detection
of tumors that produce excess catecholamines. Circulating catecholamines can
also undergo direct filtration into urine,
ADRENERGIC RECEPTOR AND SIGNALLING
PATHWAYS

The adrenergic receptors are classified as
predominantly stimulatory receptors (α) or
predominantly inhibitory receptors (β). For many of
these receptors, their precise physiologic functions
and their therapeutic potential have not been fully
elucidated. Only for the -adrenergic receptors have
subtype-selective ligands been developed that have
helped to identify the physiologic significance of β1, β2,
andβ 3 receptors, some of which are now used in
clinical medicine. Selective agonists for theβ 2adrenergic receptor play an important role in asthma
therapy, whereas β1-receptor antagonists are first-line
medication for patients with hypertension, coronary
heart disease, or chronic heart failure.
ALPHA-ADRENERGIC RECEPTORS


Alpha-adrenergic receptors have greater affinity for
epinephrine than for norepinephrine or for isoproterenol, a
synthetic agonist. They are subdivided into α 1- and α 2receptors.
Alpha1-adrenergic receptors are further subdivided into α
1A, α 1B, and α 1D. These are G protein–coupled receptors
(Gq/11) that activate phospholipase C, resulting in activation
of protein kinase C via diacylglycerol . This reaction
produces an increase in intracellular Ca2+ (via inositol
1,4,5-trisphosphate) and phospholipase A2. The increase in
intracellular Ca2+ calmodulin kinase–mediated
phosphorylation of myosin light-chain kinase in smooth
muscle produces contraction in vascular, bronchial, and
uterine smooth muscle. Alpha1-adrenergic receptors play
important roles in the regulation of several physiologic
processes, including myocardial contractility and
chronotropy and hepatic glucose metabolism
BETA-ADRENERGIC RECEPTORS




Beta-adrenergic receptors have been subclassified as 1, 2, and 3
receptors. They have greater affinity for isoproterenol than for
epinephrine or norepinephrine. All 3 receptor subtypes are
associated with Gs proteins, and their stimulation leads to an
increase in cyclic adenosine monophosphate .
Theβ 1-adrenergic receptor plays an important role in
regulating contraction and relaxation of cardiac myocytes .
Several mechanisms are thought to be involved, including the
phosphorylation of L-type Ca2+ channels in the sarcolemma,
ryanodine-sensitive Ca2+ channels in the sarcoplasmic
reticulum, troponin I, and phospholamban. The overall
physiologic effect is an increase in contractility.
β2-adrenergic receptor mediates several physiologic responses,
including vasodilatation, bronchial smooth muscle relaxation,
and lipolysis, in various tissues. Abnormalities in the function
of this adrenergic receptor may lead to hypertension.
The β3-adrenergic receptor plays an important role in
mediating catecholamine-stimulated thermogenesis and
lipolysis.
PHEOCHROMOCYTOMA AND
PARAGANGLIOMA
Catecholamine-secreting tumors that arise from
chromaffin cells of the adrenal medulla and the
sympathetic ganglia are pheochromocytomas and
extraadrenal catecholamine-secreting paragangliomas
(extraadrenal pheochromocytomas),
respectively.[Because the tumors have similar clinical
presentations and are treated with similar approaches,
many clinicians use the term pheochromocytoma to
refer to both adrenal pheochromocytomas and extra
adrenal catecholamine-secreting paragangliomas.
 However, the distinction between pheochromocytoma
and paraganglioma is an important one because of
implications for neoplasms, risk for malignancy, and
genetic testing. Catecholamine-secreting tumors are
rare, with an annual incidence cases per million people.

SYMTEMS OF PHEOCHROMOCYTOMA
Pheochromocytomas produce catecholamines,
and patients present with signs of excess
catecholamine effects, such as sustained or
paroxysmal hypertension associated with
headache, sweating, or palpitations.
 Weight Loss
 High blood pressor
 Anxiety
 Skin sensation

GENETIC AND SYNDROMIC FORMS OF
PHEOCHROMOCYTOMA AND
PARAGANGLIOMA

Approximately 15% to 20% of patients with
catecholamine-secreting tumors have germline
mutations (inherited mutations all cells of the
body) in genes associated with genetic disease .
Hereditary catecholamine-secreting tumors
typically present at a younger age than sporadic
neoplasms
AUTOSOMAL DOMINANT SYNDROMES
ASSOCIATED WITH PHEOCHROMOCYTOMA
syndrome
Gene
Protein product
Protein function
SDHD (familial
paraganglioma type 1
SDHD
SDHD subunit
ATP production
Familial paraganglioma
type 2
unknown
unknown
ATP production
SDHC (familial
paraganglioma type 3)
SDHC
SDHC-subunit
ATP production
SDHB (familial
paraganglioma type 4)
SDHB
SDHB-subunit
MEN-1
MENIN
menin
Transcriptional regulation
MEN-2A and -2B
RET
RET
Tyrosine kinase Receptor
Neurofibromatosi
s type 1
NF1
neurofibromin
GTP -hydrolysis
von HippelLindau disease
VHL
VHL
Transcription
elongation
suppression
ORALLY ADMINISTERED DRUGS USED
TO TREAT PHEOCHROMOCYTOMA
a-ADRENERGIC BLOCKING AGENTS
 COMBINED a- AND ß-ADRENERGIC
BLOCKING AGENT
 CALCIUM CHANNEL BLOCKERS
 CATECHOLAMINE SYNTHESIS INHIBITOR
