Adrenal Glands Part 3 Adrenal Medulla The adrenal

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 (2018) 2

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 (2018) 3

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 (2018) 4

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 (2018) 5

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 (2018) 6

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 (2018) 7

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 (2018) Epinephrine Norepinephrine 8

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 (2018) 9

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 (2018) 10

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 (2018) 11

DISORDERS OF ADRENOCORTICAL INSUFFICIENCY 12

Adrenocortical Insufficiency Decreased hormonal secretion is indicated by a dotted line and increased secretion by a dark solid line 13

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 (2018) 14

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 Dr. M. Alzaharna (2018) 15

• 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) 16

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 (2018) 17

Metyrapone blocks the synthesis of cortisol & rapid fall of cortisol • Evaluation of suspected primary or secondary adrenocortical insufficiency. • Boxes enclose clinical decisions, • Circles enclose diagnostic tests Dr. M. Alzaharna (2018) 18

• Thus, in healthy individuals, the fall in serum cortisol conc. leads sequentially to decreased negative feedback at hypothalamic and pituitary levels, • This increases CRH and ACTH secretion and adrenal steroidogenesis; the resultant secretion of cortisol precursors, in particular, • 11 -deoxycortisol, can be measured by different techniques in blood or its metabolites in urine Metyrapone 19

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 (2018) 20

HYPERSECRETION 21

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 (2018) 22

Cushing’s Syndrome • ACTH-dependent – Pituitary adenoma (Cushing’s disease) – Nonpituitary neoplasm • ACTH-independent – Adrenal neoplasm (adenoma, carcinoma) – Nodular adrenal hyperplasia Dr. M. Alzaharna (2018) 23

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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 (2018) 25

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 (2018) 26

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+/H 2 O 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 (2018) 27

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 H 2 O 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 (2018) 28

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 H 2 O loss during diuretic therapy (most common cause) or dietary Na+ deprivation; • Congestive heart failure Dr. M. Alzaharna (2018) 29

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, androgen receptors ) for long-term management Dr. M. Alzaharna (2018) 30

DISORDERS OF ADRENAL MEDULLARY FUNCTION 31

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 (2018) 32

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 (2018) 33

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 131 I-MIBG (metaiodobenzylguanidine) therapy for patients with MIBG -avid tumors Dr. M. Alzaharna (2018) 34