Adrenal Glands
Part 3
Adrenal Medulla
• The adrenal medulla accounts for about 10% of the
mass of the adrenal gland
• Distinct embryologically and physiologically from the
cortex, although cortical and medullary hormones
often act in a complementary manner
• Cells of the adrenal medulla
have an affinity for chromium
salts in histological preparations
and hence are called chromaffin
cells
• Chromaffin cells are innervated
by neurons from the spinal cord
Dr. M. Alzaharna (2014)
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Secretory Products
• The principal secretory products:
– epinephrine and norepinephrine,
• are derivatives of the amino acid tyrosine
• and belong to a class of compounds called
catecholamines
• are stored in membrane-bound granules within
chromaffin cells
• The adrenal medulla also produces and
secretes several neuropeptides but their
physiological role is incompletely understood
Dr. M. Alzaharna (2014)
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Biosynthesis of Medullary
Catecholamines
• Hydroxylation of tyrosine to form
dihydroxyphenylalanine (DOPA) is the rate
determining reaction and is catalyzed by the
enzyme tyrosine hydroxylase
• Activity of this enzyme is inhibited by
catecholamines (product inhibition) and
stimulated by phosphorylation
• The enzyme phenylethanolamine-Nmethyltransferase (PNMT) is at least partly
inducible by cortisol
– determine the ratio of epinephrine to
norepinephrine production
Dr. M. Alzaharna (2014)
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Storage, Release, and Metabolism of
Medullary Hormones
• All the epinephrine in blood originates in the
adrenal glands
• However, norepinephrine may reach the blood
either by adrenal secretion or by diffusion from
sympathetic synapses
• Catecholamines are stored in secretory granules
Acetylcholine released during neuronal
stimulation increases the influx of sodium ions
which depolarizes the plasma membrane
• This leads to an influx of calcium through voltagesensitive channels triggering the secretion of
catecholamines
Dr. M. Alzaharna (2014)
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Storage, Release, and Metabolism of
Medullary Hormones
• The half-lives of medullary hormones in the
peripheral circulation have been estimated to
be less than 10 seconds for epinephrine and
less than 15 seconds for norepinephrine
• Epinephrine and norepinephrine that are
cleared from the circulation are either stored
or degraded
Dr. M. Alzaharna (2014)
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Physiological Actions of Medullary
Hormones
• The sympathetic nervous system and adrenal
medullary hormones, like the cortical
hormones, act on a wide variety of tissues to
maintain the integrity of the internal
environment
• Catecholamines enable us to cope with
emergencies and equip us for “fright, fight, or
flight”
Dr. M. Alzaharna (2014)
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Physiological Actions of Medullary
Hormones
• Cells in virtually all
tissues of the body
express G-protein
coupled receptors for
epinephrine and
norepinephrine on
their surface
membranes
• They are called
adrenergic receptors
originally were divided
into two categories, α
and β
Dr. M. Alzaharna (2014)
Epinephrine
Norepinephrine
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Physiological Actions of Medullary
Hormones
• Cardiovascular effects:
– maximize cardiac output and ensure perfusion of the brain
and working muscles
• Metabolic effects:
– ensure an adequate supply of energy-rich substrate
• Respiratory System:
– Relaxation of bronchial muscles facilitates pulmonary
ventilation.
• Ocular effects:
– increase visual acuity
• Effects on skeletal muscle:
– increase muscular performance,
– and quiescence of the gut permits diversion of blood flow,
oxygen, and fuel to reinforce these effects
Dr. M. Alzaharna (2014)
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Regulation of Adrenal Medullary
Function
• The sympathetic nervous system, including its
adrenal medullary component, is activated by
any actual or threatened change in the
internal or external environment
• Input reaches the adrenal medulla through its
sympathetic innervation
• Signals arising in the hypothalamus and other
integrating centers activate both the neural
and hormonal components of the sympathetic
nervous system
Dr. M. Alzaharna (2014)
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Regulation of Adrenal Medullary
Function
• Norepinephrine- or
epinephrine-secreting cells can
be preferentially and
independently stimulated
• In response to hypoglycemia
detected by glucose monitoring
cells in the central nervous
system:
– the concentration of
norepinephrine in blood may
increase threefold
– whereas that of epinephrine,
which tends to be a more
effective hyperglycemic agent,
may increase 50-fold
Dr. M. Alzaharna (2014)
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DISORDERS OF ADRENOCORTICAL
INSUFFICIENCY
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Adrenocortical Insufficiency
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Adrenocortical Insufficiency
• Deficient adrenal production of glucocorticoids or
mineralocorticoids results in adrenocortical
insufficiency which is either the consequence of:
• Primary adrenocortical insufficiency
– Destruction or dysfunction of the cortex (Addison’s
disease )
• Autoimmune disease
– deficiency in both cortisol and aldosterone production
• As a consequence of metastatic infiltration
• Infectious
• Congenital unresponsiveness to ACTH
– A rare defect in the adrenal ACTH receptor protein
• Congenital adrenal hyperplasia
Dr. M. Alzaharna (2014)
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Adrenocortical Insufficiency
Congenital (virilizing) adrenal hyperplasia,
• Inherited enzymatic defects in cortisol biosynthesis
– any of the steroidogenic enzymes may be affected
• Deficiency of 21β-hydroxylase, one of the key enzymes
in the cortisol (and aldosterone) synthetic pathway,
leads to:
– a reduction in cortisol secretion
– with a compensatory rise in plasma ACTH
– and a build up of adrenal androgenic steroid precursors
(androstenedione and ultimately testosterone)
– The excess production of ACTH leads to an excessive
growth (hyperplasia) of the adrenal cortex
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• There are general
symptoms of
glucocorticoid/mineralo
-corticoid deficiency
• Female infants may
show symptoms of:
– abnormal sexual organs
– or later in life
(precocious puberty,
hirsutism or
amenorrhoea in
adulthood)
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Disorders of Adrenocortical
Insufficiency
• Secondary adrenocortical insufficiency
– Secondary to deficient pituitary ACTH secretion
– Glucocorticoid therapy is the most common cause
of secondary adrenocortical insufficiency
Dr. M. Alzaharna (2014)
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Dr. M. Alzaharna (2014)
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Treatment
• In patients with chronic adrenal insufficiency
combination replacement therapy with both
glucocorticoid and mineralocorticoid
compounds is necessary
• A combination of hydrocortisone and
fludrocortisone (a synthetic
mineralocorticoid) administered by mouth, is
recommended
Dr. M. Alzaharna (2014)
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HYPERSECRETION
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Hypersecretion of Glucocorticoids
• The resultant condition of hypercortisolism is
called Cushing’s syndrome
– More prevalent in women
• Its symptoms may also be induced after longterm therapy with glucocorticoids
– (e.g. for asthma, rheumatoid arthritis or
inflammatory bowel disease)
• The condition of excess pituitary ACTH
secretion is traditionally referred to as
Cushing’s disease
Dr. M. Alzaharna (2014)
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Cushing’s Syndrome
• ACTH-dependent
– Pituitary adenoma (Cushing’s disease)
– Nonpituitary neoplasm
• ACTH-independent
– Adrenal neoplasm (adenoma, carcinoma)
– Nodular adrenal hyperplasia
Dr. M. Alzaharna (2014)
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Cushing’s Syndrome
• The classical features of Cushing’s
syndrome are:
– Muscle weakness and wasting
• thin arms and legs- due to increased protein
breakdown
– Back pain (due to osteoporosis)
• Excess cortisol (or glucocorticoid treatment) interferes
with bone metabolism
– Redistribution of body fat tissue
• rounded (moon) face
Dr. M. Alzaharna (2014)
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Treatment
• This is usually by removal of the pituitary, ectopic
(usually in lung) or adrenal tumor if possible, coupled
with corticosteroid replacement therapy
• When tumors are not easily located or inoperable,
patients may undergo therapy with a steroid
synthesis inhibitor
– Metyrapone is a competitive inhibitor of the enzyme
involved in the final step of cortisol synthesis in the
adrenal cortex;
– this drug may also be used in the treatment of Cushing’s
syndrome arising from an ectopic ACTH-secreting tumor
Dr. M. Alzaharna (2014)
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Mineralocorticoid Hyposecretion
• Isolated deficiency in aldosterone
production (hypoaldosteronism) may be due to
adrenal enzyme defects (very rare)
– It may occur for example, as a consequence of renal
disease due to diabetes mellitus
• The general symptoms of mineralocorticoid
deficiency:
– i.e. increased Na+/H2O excretion,
– hyperkalaemia (high plasma K+),
– hypotension and metabolic acidosis would also be seen in
conjunction with those of glucocorticoid lack in cases of
adrenal insufficiency (e.g. Addison’s disease)
Dr. M. Alzaharna (2014)
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Mineralocorticoid Hypersecretion
• Aldosterone excess (hyperaldosteronism) may be divided into
two types:
– Primary Hyperaldosteronism (Conn’s Syndrome):
•
•
•
•
•
•
caused by a bilateral adrenal hyperplasia (abnormal enlargement)
or small tumour (adenoma) of the adrenal zona glomerulosa.
Patients exhibit hypertension (due to Na+ and H2O retention)
and a low plasma K+ level
Plasma renin levels are characteristically low in this condition
Diagnosis is made by demonstration of:
– a high plasma or urine aldosterone level,
– in conjunction with a low level of plasma renin
– blood volume expansion by saline loading, would fail to suppress the high
aldosterone level
Dr. M. Alzaharna (2014)
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Mineralocorticoid Hypersecretion
– Secondary Hyperaldosteronism:
• This is caused by an abnormally
increased renin release, and therefore raised levels
of angiotensin II
• Some possible causes include:
– Poor renal perfusion e.g. in renal artery stenosis;
– Malignant hypertension (i.e. hypertension associated with
progressive renal failure due to renal arteriolar necrosis);
– Renal tumour of the juxtaglomerular cells;
• Excessive Na+ and H2O loss during diuretic therapy
(most common cause) or dietary Na+ deprivation;
• Congestive heart failure
Dr. M. Alzaharna (2014)
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Treatment
• Hypoaldosteronism
– treated by replacement therapy
• Hyperaldosteronism
– should involve the treatment of the underlying cause of
the abnormal renin/angiotensin system activation
– This is coupled with administration of Spironolactone
(antagonist of the mineralocorticoid , aldosterone, and
androgen receptors ) for long-term management
Dr. M. Alzaharna (2014)
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DISORDERS OF ADRENAL
MEDULLARY FUNCTION
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Adrenal Medullary Hypofunction
(Epinephrine Deficiency)
• Epinephrine is the major catecholamine
secreted by the normal adrenal medulla and
its secretion is unique to the adrenal medulla
• Epinephrine deficiency is caused by:
– bilateral adrenalectomies,
– tuberculosis,
– Hemorrhage
– autonomic insufficiency
• autonomic nervous system (ANS) malfunctions
– Or Cortisol deficiency
Dr. M. Alzaharna (2014)
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Adrenal Medullary Hyperfunction
• The adrenal medulla is not known to play a
significant role in essential hypertension
• Norepinephrine can increase blood pressure
by increasing:
– increasing cardiac output,
– increasing peripheral resistance through their
vasoconstrictive action on the arteriole,
– and increasing renin release from the kidney
leading to increased circulating levels of
angiotensin II
Dr. M. Alzaharna (2014)
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Pheochromocytoma
• Rare, usually noncancerous (benign) tumor that develops in
cells in the center of an adrenal gland
• Are usually unilateral
• Symptoms include:
–
–
–
–
Headaches
Palpitations
Diaphoresis
Severe hypertension
• Treatment of malignant tumors consists of surgery,
chemotherapy, external beam radiation to skeletal
metastases, and high-dose 131I-MIBG
(metaiodobenzylguanidine) therapy for patients with
MIBG-avid tumors
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