adrenal glands part 3. dr. m. alzaharna (2014) adrenal medulla the adrenal medulla accounts for...
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Adrenal Glands
Part 3
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2Dr. M. Alzaharna (2014)
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
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3Dr. M. Alzaharna (2014)
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
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4Dr. M. Alzaharna (2014)
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-N-methyltransferase (PNMT) is at least partly inducible by cortisol – determine the ratio of epinephrine to
norepinephrine production
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5Dr. M. Alzaharna (2014)
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 voltage-sensitive channels triggering the secretion of catecholamines
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6Dr. M. Alzaharna (2014)
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
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7Dr. M. Alzaharna (2014)
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”
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Dr. M. Alzaharna (2014)
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
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EpinephrineNorepinephrine
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9Dr. M. Alzaharna (2014)
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
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10Dr. M. Alzaharna (2014)
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
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11Dr. M. Alzaharna (2014)
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
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DISORDERS OF ADRENOCORTICAL INSUFFICIENCY
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Adrenocortical Insufficiency
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14Dr. M. Alzaharna (2014)
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
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15Dr. M. Alzaharna (2014)
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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17Dr. M. Alzaharna (2014)
Disorders of Adrenocortical Insufficiency
• Secondary adrenocortical insufficiency– Secondary to deficient pituitary ACTH secretion– Glucocorticoid therapy is the most common cause
of secondary adrenocortical insufficiency
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18Dr. M. Alzaharna (2014)
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19Dr. M. Alzaharna (2014)
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
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HYPERSECRETION
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21Dr. M. Alzaharna (2014)
Hypersecretion of Glucocorticoids
• The resultant condition of hypercortisolism is called Cushing’s syndrome– More prevalent in women
• Its symptoms may also be induced after long-term 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
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22Dr. M. Alzaharna (2014)
Cushing’s Syndrome
• ACTH-dependent– Pituitary adenoma (Cushing’s disease)– Nonpituitary neoplasm
• ACTH-independent– Adrenal neoplasm (adenoma, carcinoma)– Nodular adrenal hyperplasia
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24Dr. M. Alzaharna (2014)
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
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25Dr. M. Alzaharna (2014)
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
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26Dr. M. Alzaharna (2014)
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)
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27Dr. M. Alzaharna (2014)
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
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28Dr. M. Alzaharna (2014)
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
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29Dr. M. Alzaharna (2014)
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
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DISORDERS OF ADRENAL MEDULLARY FUNCTION
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31Dr. M. Alzaharna (2014)
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
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32Dr. M. Alzaharna (2014)
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
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33Dr. M. Alzaharna (2014)
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