adrenal glands part 3. dr. m. alzaharna (2014) adrenal medulla the adrenal medulla accounts for...

Adrenal Glands

Part 3

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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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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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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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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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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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)

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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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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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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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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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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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

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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

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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 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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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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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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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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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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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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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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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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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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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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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