Adrenal Glands Part 3. Dr. M. Alzaharna (2014) Adrenal Medulla The adrenal medulla accounts for about 10% of the mass of the adrenal gland Distinct embryologically

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


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


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


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


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


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)


• 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



• 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


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


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



• 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



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)


Disorders of Adrenocortical Insufficiency

• Secondary adrenocortical insufficiency– Secondary to deficient pituitary ACTH secretion– Glucocorticoid therapy is the most common cause

of secondary adrenocortical insufficiency



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


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


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


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


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)


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


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


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


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


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


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

Documents

Adrenal Glands Part 3. Dr. M. Alzaharna (2014) Adrenal Medulla The adrenal medulla accounts for about 10% of the mass of the adrenal gland Distinct embryologically