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T H E A D R E N A L G L A N D

These are paired suprarenal glands

Embryologically:

Cortex forms first Gonadal Ridge

Medulla forms second Neural Crest Origin

Histologically, It’s quite easy to see the difference between CORTEX and MEDULLA

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The adrenal gland is formed of two completely separate glands :

1- The adrenal cortex .

2- The adrenal medulla.

1- The Adrenal Medulla

The adrenal medulla is a modified sympathetic ganglion i.e. the chromaffin cells of the gland are modified to secrete catecholamines instead of giving postganglionic sympathetic fibers. The adrenal medulla receives preganglionic sympathetic fibers running in the greater splanchnic nerve and secrete acetylcholine. The catecholamines secreted by the adrenal medulla potentiate

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the sympathetic nervous system stimulation and prepares the organism for emergency situations . BIOSYNTHESIS OF ADRENOMEDULLARY HORMONES :

In the cytoplasm of the chromaffin cells the following reactions take place:

Tyrosinase dopa decarboxylase

Tyrosine ----------- Dihydroxy-phenyl alanine (DOPA) -------------- Dopamine Dopamine oxidase N-methyl transferase

enter the secretory granules ----------------------- Noradrenaline -------------

Adrenaline reenter the secretory granules to be stored until secreted.

The cells of the adrenal medulla are specified to secrete either Adrenaline

or Noradrenaline but never the two by one cell. Biosynthesis of catecholamines is under control of the preganglionic nerve supply of the adrenal medulla. METABOLISM OF CATECHOLAMINES :

(1) Ortho - methylation and conjugation in the Liver : lt is the most rapid and main metabolic route.

Catecholamine Ortho - Methyl

Adrenaline ------------------------------------- Metanephrine Transferase (COMT)

COMT

Noradrenaline ----------------------------- Normetanephrine

Metanephrine and Normetanephrine are next conjugated with glucuronic

acid and excreted in urine as inactive metabolite . (2) Oxidation by Mono Amino Oxidase enzyme (MAO)

lt is a slower route of inactivation.

MAO

Adrenaline & Noradrenaline -------Vanillyl Mandelic Acid (VMA, excreted in urine)

PHYSIOLOGICAL EFFECTS OF CATECHOLAMUNES :

The adrenomedullary hormones prepare the body for fight or flight. They have the following effects: 1) Effects on the C.N.S.:

Epinephrine enhances the activity of the reticular activating system

increases cortical alertness and awareness.

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2) Effects on the heart :

Most of the cardiac effects are produced by epinephrine which has a effect:

lt increases all properties of the cardiac muscle; the heart rate, contractility, conductivity, metabolism and O2 consumption.

Vasodilatation of the coronary vessels. 3) Effects on the blood vessels :

Noradrenaline produces generalized vasoconstriction marked

increase in the peripheral resistance marked hypertension (-adrenergic stimulant).

Adrenaline (-and -adrenergic effects) produces: 1. Constriction of the cutaneous and splanchnic blood vessels. 2. Dilatation of the skeletal muscle blood vessels as well as the

coronaries. The net effect on the peripheral resistance is usually a slight increase with

moderate increase in blood pressure. i.e. Noradrenaline is a powerful hypertensive than Adrenaline . 4) Effects on respiration :

Both hormones produce initial apnea (adrenaline apnea) followed by hyperventilation (increased rate and depth of respiration).

Mechanism of adrenaline apnea:

Catecholamines increased blood pressure stimulate the

baroreceptors in the carotid sinus and aortic arch reflex inhibition of the

respiratory centers apnea. Mechanism of hyperventilation: Hyperventilation is secondary to the stimulatory effects of catecholamines on the brain centers including the respiratory.

5) Effects on smooth muscles:

Motor to the dilator pupillae muscle (-effect) dilatation of the pupil.

Relaxation of the smooth muscles of the bronchi bronchodilatation

(-effect).

Relaxation of the smooth muscles in the wall of the GIT (-effect ) but

motor to the sphincters (- effect ) delay emptying of the GIT.

Relaxation of the smooth muscles in the wall of the urinary bladder (-

effect) but motor to the internal urethral sphincter (-effect ) urine retention.

Motor to piloerector muscle erection of hairs.

Motor to the smooth muscles in the capsule and trabeculae of the spleen.

The response of the smooth muscles of the uterus varies according to

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the species of animals and pregnancy: Epinephrine stimulates the non pregnant uterus. lt relaxes the pregnant uterus.

6)- Effect on the skeletal muscles: Catecholamines decrease the onset of fatigue in the skeletal muscles

and facilitate neuroumscular transmission. Catecholamines enhance glycogenolysis and glycolysis in the skeletal

muscles accumulation of lactic acid dilatation of the skeletal muscle blood vessels.

7) Metabolic effects of catecholamines :

Catecholamines have a glycogenolytic effect on the liver increase the blood glucose level (this effect is mediated mainly by adrenaline).

Catecholamines produce lipolysis increase free fatty acids in plasma

oxidized to supply energy. By these mechanisms the fuel for increased muscular exercise during

fight or flight is provided. N.B.

Adrenaline has a predominant metabolic effect, while Noradrenaline has a predominant vasoconstrictor effect.

CONTROL OF CATECHOLAMINES SECRETION : - The adrenal medulla is under control of the nervous system. - There is an adrenaline secreting center in the medulla. - The center gives descending fibers to end on the lateral horn cells of the

lower thoracic and upper lumber segments. - The axons of these L.H. Cs will form the preganglionic sympathetic fibers

that run in the splanchnic nerve and supply the adrenal medulla. They secrete acetylcholine.

- The adrenaline secreting center is stimulated by different impulses from different sources:

1. Stress hypothalamus and reticular formation stimulate the center.

2. Hypoglycaemia stimulate glucoreceptors in the hypothalamus stimulate the adrenaline center.

3. Drop of blood pressure stimulates volume receptors in the

circulatory system stimulate the adrenaline center. - The result of all these stimuli is increased release of catecholamines from

the adrenal medulla. However, the relative amounts of adrenaline and noradrenaline depends upon the type of stimulus:

Hypoglycaemia increases the secretion of adrenaline mainly. Hypotension increases the secretion of noradrenaline

mainly. - The following drugs stimulate the adrenal medulla:

Acetylcholine and choline esters.

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Anticholine esterases e.g. prostigmine. Ganglion stimulants e.g. small doses of nicotine.

- The adrenal medulla under normal condition secretes 80 % adrenaline and 20 % noradrenaline. This is the reverse to adrenergic nerve terminals

Disorders of Catecholamine Secretion: P H E O C H R O M O C Y T O M A:

lt is a secreting tumor of the adrenal medulla producing excess amounts of catecholaminrs either continuously or intermittently.

Manifestations:

1. Paroxysmal attacks of hypertension severe headache. 2. Tachycardia and palpitation.

3. Constriction of the blood vessels of the skin cold pale skin.

4. Excessive sweating. 5. Hyperglycaemia and emotional stability.

Diagnosis: By measuring the amount of VMA in 24 hrs urine. lf it is more than 12 mg / day, it is diagnostic.

By injecting an - adrenergic blocker (phentolamine) during the attack. lf the systolic blood pressure decreased more than 30 mm Hg, it is diagnostic.

Treatment: - Surgical removal of the tumour. - lf the tumour could not be removed or the patient is going to be

prepared for the operation; an and - adrenergic blockers must be given e.g. phentolamine and propranolol respectively.

N.B.

The -blocker must be given first otherwise, the blood pressure will rise

more severe hypertension.

THE ADRENAL CORTEX

The adrenal cortex is divided histologically into 3 zones: 1) An outer zone called (Zona Glomerulosa):

concerned with secretion of Mineralocorticods mainly Aldosterone. 2) A middle zone called (Zona Fasciculata):

concerned with secretion of Glucocorticoids mainly Cortisol. 3) An inner zone adjacent to the medulla called ( Zona Reticularis ):

concerned with secretion of sex hormones mainly androgens.

(1) Adrenal cortex - Glucocorticoids - cortisol - Mineralocorticoids - aldosterone - Androgens (including testosterone)

(2) Adrenal medulla - Epinephrine -Norepinephrine

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Biosynthesis of Mineralo and Glucocoeticoids: (1) All these adrenocrtical Hs are steroid in nature and derived from the

mother substance cholesterol. (2) Cholesterol is present in high concentrations in the adrenocortical cells. This cholesterol is derived from:

either plasma cholesterol that enter the cells by endocytosis and stored as cholesterol esters.

or synthesized de novo from acetyl CoA. (3) Cholesterol is transformed in the adrenocortical cells into pregnenolone and 17-Hydroxypregnolone; each of which will pass in a specific pathway:

Pregnenolone will finally form corticosterone and aldosterone (mineralocrticoids ).

Hydroxypregnenolone will form glucocorticoids (cortisol) and sex hormones.

The steps for the synthesis of these different types of hormones are shown in figure lt is to be noted that:

- ACTH is essential for the initial step of conversion of cholesterol to pregnenolone.

- The Zona Glomerulosa does not contain the 17-hydroxylase enzyme which catalyzes the conversion of pregnenolone to hydroxypergnenolone, and therefore it can not form glucocorticoid or sex hormones whereas the Zona Fasciculata contains this enzyme can therefore synthesize them.

Biosynthesis of adrenal steroids

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Secretion of Adrenal Steroids: - The main adrenal steroid secreted by the adrenal cortex is the

glucocorticoid cortisol at a rate of 15 mg / day. - The main mineralocorticoid secreted is aldosterone. - The main sex hormones secreted are Androgens;

Dehydroepiandrosterone (DHEA), androstenedione , and testosterone to a little extent.

- Very little amount of oestrogens is also secreted.

Transport of adrenal steroids in the blood: 75 % of adrenal steroids is carried in reversible combination with a

plasma glycoprotein (transcortin). 15 % is bound to albumin. 10 % is found in the free unbound state and responsible for the

biological effects of the hormones. Aldosterone, DHEA, and oestrogens have very little binding affinities to

transcortin and their plasma levels are very low.

Metabolism of Adrenal Steroids: Adrenal steroids are inactivated mainly in the liver.

They are subjected to double processes of enzymatic reduction converting them to dihydro-, and then tetrahydrosteroid derivative that is finally conjugated with glucuronic acid and then excreted.

e.g. - Cortisol is excreted in urine as tetrahydrocortisol glucuronide. - Aldosterone is excreted as tetrahydroaldosterone glucuronide.

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G L U C O C O R T I C O I D S

Biological Effects:

(1) Effects of glucocorticoids on body metabolism:

A - Effect on carbohydrate metabolism:

Glucocorticoids enhance the process of gluconeogenesis in the liver. i. e. increase the formation of glucose from non carbohydrate sources e.g. amino acids and glycerol.

They increase the blood glucose level.

They enhance glycogen deposition in the liver.

Through this process of hyperglycaemia glucocorticoids can provide the body with the fuel needed to face conditions of stress.

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B- Effects on lipid metabolism:

Glucocorticoids increase lipolysis (mobilization of fat stores free fatty acids and glycerol. Glycerol will serve gluconeogenesis, while F.F.As are oxidized by the peripheral tissues to conserve carbohydrates. Glucocorticoids when present in excess amounts may help the deposition of fat in certain sites e.g. the face, supraclavicular region and trunk as a result of increased appetite and food intake.

C- Effects on protein metabolism:

Glucocorticoids decrease protein synthesis in the different tissues of the body and increase protein breakdown as well.

Both effect increase the amount of amino acids provided to the liver for the process of gluconeogenesis.

Glucocorticoids increase the synthesis of the protein enzymes responsible for gluconeogenesis in the liver, as well as the synthesis of plasma proteins.

(2) Anti -inflammatory effects of glucocorticoids - Mechanism of inflammation:

Any inflammatory reaction in the body whatever the cause; an antigen-antibody reaction or infection is accompanied by tissue cell destruction with liberation of lysosomal lytic enzymes and chemicals such as histamine, bradykinin ...et.

Tissue products produce vasodilatation and increased capillary permeability leading to redness and oedema.

lncreased mobilization of leucocoytes towards the site of inflammation as well as phagocytosis.

Tissue healing follows by growth of fibrous tissue. - Mechanism of action of glucocorticoids to counteract inflammation:

Stabilization of lysosomal membrane decrease tissue

destruction and the liberated tissue products decrease vasodilatation and oedema.

Decrease the mobilization and phagocytic activity of leucocytes. Effect on the immune response:

- Glucocorticoids are lympholytic; They decrease the T-

lymphocytes decrease the cellular immune response. They

decrease the B- lymphocytes decrease antibody production. Both effects result in suppression of the immune response.

- Due to this effect, glucocorticoids diminish the size of lymph nodes, thymus and spleen.

(3) Effect on blood elements:

Glucocorticoids produce eosinopenia.

Glucocorticoids stimulate erythropoiesis increase the red cell count for

unknown reason.

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(4) Glucocorticoids e.g. Cortisol has a Na+ retaining effect:

i.e. a mineralocorticoid effect, yet they can produce diuresis through mobilization of water from the intracellular to the extracellular compartments with consequent increase in plasma volume and blood pressure. They also aid rapid inactivation of ADH in the liver. (5) Glucocorticoids suppress the synthesis and release of AC TH

by direct action on the anterior pituitary and through suppression of release of CRF.

CONTROL OF GLUCOCORTICOID SECRETION Glucocorticoids secretion is under control of the ACTH of the basophil cells of the anterior pituitary.

ACTH is in turn under control of a releasing factor from the hypothalamus called CR.

ln the normal unstressed subject, the hypothalamus exerts a circadian rhythm over CRF secretion being maximum in the early morning and minimum at midnight. Both ACTH and cortisol secretion follow that rhythm.

Glucocorticoids (Cortisol) exert a long loop feedback effect on both ACTH and CRF secretion inhibiting them.

ACTH has a negative short loop feedback inhibiting CRF.

Since glucocorticoids are anti-stress factors, therefore all stressful conditions e.g. severe trauma, hypoglycaemia, electroconvulsive treatment and acute anxiety stimulate the hypothalamus to release CRF

increase ACTH increase glucocorticoids to combat stress.

Catecholamines; adrenaline and noradrenaline of the adrenal medulla released during stress can stimulate ACTH release both directly and through CRF release. Catecholamines do not act directly on the adrenal cortex.

Mechanism of action of ACTH:

ACTH is necessary for maintaining the structure and function of the adrenal cortex and synthesis of glucocorticoids through:

1. lncreased glucose uptake by the adrenocrtical cells increased oxidation and liberation of ATP for cAMP synthesis.

2. Activation of adenyl cyclase with increased cAMP activation of a

protein kinase within the cells activates 2 enzymes necessary for glucocorticoid synthesis:

i. Cholesterol esterase for liberation of free cholesterol. ii. The enzyme required for the conversion of cholesterol to

pregnenolone (the rat limiting step in steroid H synthesis).

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Disorders of glucocorticoid secretion: C U S H I N G’S S Y N D R O M E: Cause: Excessive secretion of glucocorticoids due to:

1) Adenoma in the adrenal cortex (primary cause).

2) Secondary to excessive ACTH or CRF secretion hyperplasia of the adrenal tissue.

General Manifestations:

1) Disturbance of lipid metabolism: Excessive food intake due

increased appetite deposition of fat in particular sites of the body give the characteristic features of cushing's syndrome; ln the

face Moon face, ln the trunk and girdle areas Buffalo Obesity.

2) Hyperglycaemia (Adrenal diabetes):

Cortisol gluconeogenesis blood glucose level. This type of diabetes is insulin resistant. There is failure of the blood glucose level to return to the fasting

level 2-3 hrs after meals.

3) lncreased protein catabolism: ln the skin: - The skin becomes thin and fragile. - lt is easily bruised. - lt becomes characterized by the presence of pink or purple

striae formed by the apparent capillaries. - There is delayed wound healing. ln the muscle:

- There is marked wasting severe muscle weakness. ln bones:

- increased mobilization of the organic bone matrix osteoporosis (weakness of bones). This leads to:

Kyphosis. Pathological fractures. Backache.

- lncreased mobilization of the inorganic bone matrix moderate

hypercalcaemia increased Ca2+ excretion in urine renal stones.

4) Hypertension:

Cortisol mineralocorticoid action of its own salt and water

retention blood volume hypertension.

5) There is an associated increased androgen secretion hirsutism and amenorrhea in females.

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6) Effects on blood components:

- Erythrocytosis. - Lyphocytopenia. - Eosinopenia.

N.B.

lymphocytes cellular and humoral (antibody) immunity, therefore the body resistance is markedly suppressed and the patient is liable to infection.

7) Most of these patients suffer from psychological diseases in the

form of psychosis and / or schizophrenia.

M I N E R A L O C O R T I C O I D S

- The mineralocorticoids have gained their name because they especially

affect the electrolytes of the extracellular fluid and in particular Na+ & K+. - The mineralocorticoids of the adrenal cortex are secreted by the zona

glomerulosa and include Aldosterone (The most potent), Corticosterone, and 11 deoxycorticosterone.

- Cortisol (glucocorticoid) possesses also a weaker mineralocorticoid action. Functions of Mineralocrticoids (Aldosterone):

Aldosterone plays an important role to keep the concentrations of Na+, K+, Cl- and water within their normal levels in the extracellular fluid (ECF).

The actions of aldosterone are exerted on the kidney, on the ducts of sweat and salivary glands, and on the intestine. (1) Effects on the kidney:

Aldosterone causes Na+ reabsorption in exchange for both K+ and H+ in the distal as well as the collecting tubules of the kidney.

Secondary water reabsorption occurs by osmosis following Na+

reabsrpition the extracellular fluid (ECF) volume. Mechanism Of Exchange Of Ions Across The Tubular Cells And The Role Of Aldosterone: (1) At the base and lateral borders of the tubular cells active pumping out of

Na+ occurs coupled to a little extent with active pumping of K+ into the

cell (more Na+ out than K+ in). This creates - ve potential inside the cell. the concentration of Na+ inside the cell is less

than in the lumen. So, Na+ diffuses from the tubular lumen into the cell according to both a concentration and electric gradients while K+ diffuses into the lumen from

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the cell by a conc. Gradient. (2) The active pump mechanism at the base is aided by an enzyme Na+ - K+

ATPase. (3) The net result is Na+ reabsorption in exchange for K+. The Role of Aldosterone:

Similar to other steroids, Aldosterone enters the target cell and binds to a cytoplasmic receptor (aldosterone binding protein) forming a complex. The

complex diffuses into the nucleus enhance DNA transcription to increase mRNA formation. mRNA returns back to the cytoplasmic ribosomes where translation occurs and results in increased synthesis of an aldosterone induced protein ( AIP) Effects of AIP: 1. lncreases ATP regeneration for the active Na+ pump through enhancing

oxidative mechanisms inside the cells. 2. lt has a permease effect, increasing the rate of passive Na+ entry into the

cell by: (A) increasing the permeability of the cell wall to Na+. (B) acting as a carrier facilitating Na+ transport .

3. Activating the Na+-K+ pump mechanism by enhancing the Na+-K+ ATPase activity.

4. Aldosterone also promotes K+ secretion directly and independent of Na+

reabsorption . (2) Effects On The Sweat And Salivary Glands:

Aldosterone exerts an effect on the duct cells of these glands similar to its

effect on the Kidney tubules enhances Na+ reabsorption in exchange for K+ decreases Na+ and increases K+ concentrations in their secretions.

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(3) Effect On The Intestine And Colon: Aldosterone also produces Na+ retention and K+ excretion in the GIT.

(4 ) All mineralocorticoids promote Mg 2+ excretion.

Regulation of Mineralocorticoid Secretion (1) RENIN -ANGIOTENSIN SYSTEM:

it is the most important regulatory mechanism of aldosterone secretion.

Renin is a proteolytic enzyme produced by the juxta-glomerular apparatus of the nephron.

Renin Angiotensinogen (Renin substrate, plasma globulin) ------- Angiotensin I (decapeptide).

Converting enzyme (in the lung)

Angiotensin 1 --------------------------------------- Angiotensin ll (octapeptide).

Angiotensin ll:

has a potent vasoconstrictor affect.

stimulates aldosterone synthesis and release. Factors Affecting Renin Release: (a) Decreased renal blood flow: Renal ischaemia e.g. in atherosclerosis or generalized decrease in plasma

volume stimulate baroreceptors in the juxtaglomerular apparatus increases renin secretion. (b) lncreased Na+ concentration in the tubular fluid at the macula densa cells

increases renin secretion finally increases aldosterone to reabsorb excess Na+ and to prevent its loss in urine.

(c) The juxtaglomerular apparatus contains -adrenergic receptors; when stimulated they increase renin secretion.

(d) Angiotensin ll has a direct inhibitory effect on renin secretion (short loop

feedback ). (2) CHANGES IN Na+ and K+ CONCENTRATIONS LN PLASMA:

- Na+ concentration in plasma aldosterone secretion more Na+

loss returns the plasma Na+ concentration to normal (and vice versa).

- K+ concentration in plasma aldosterone secretion more K+

retention elevates plasma K+ back to normal.

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(3) VOLUME RECEPTORS :

plasma volume and blood pressure stimulates volume receptors in

the large neck veins and atria reflex secretion of ADH and aldosterone Na+

and H2O retention correct the plasma volume. (4) ACTH: - lt has a permissive effect on aldosterone secretion i.e. very small amounts

are needed for normal aldosterone secretion.

- Absence of ACTH (totally) total atrophy of the whole adrenal cortex

except the zona glomerulosa partial atrophy mild to moderate degree of aldosterone deficiency .

(5) ALDOSTERONE STIMUL ATING HORMONE:

lt is also called adrenoglomerulotropin and is supposed to be secreted

by the anterior pituitary or the pineal gland aldosterone secretion (not verified )

DISORDERS OF MINERALOCORTICOID SECRETION: ALDOSTERONISM: Definition: lt is a condition of abnormal increased secretion of aldosterone. Types: 1) Primary Aldosteronism: - lt is also called Conn's Disease.

- lt is due to an adenoma of the zona glomerulosa increased aldosterone release.

- The manifestations are:

(1) Na+ retention and water reabsorption hypernatraemia and

plasma volume hypertension. However, the hypertension is limited by

the increased glomerular filtration rate some in plasma volume.

(2) K+ excretion hypokalaemia hyperpolarization in muscles

muscle excitability muscle weakness. Prolonged hypokalaemia

damage of the kidney hypokalaemic nephropathy.

(3) Na+ retention in exchange for H+ H+ loss alkalosis precipitates

Ca2+ ionized Ca2+

tetany. 2) Secondary Aldosteronism: - lt is due to increased aldosterone secretion in association with various

types of oedema e.g. Congestive heart failure. Nephrotic Syndrome. Hepatic cirrhosis. Toxaemia of pregnancy.

- Aldosterone is not the primary cause of oedema, but it can aggravate the

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condition. Aldosterone secretion is increased in cardiac and in renal diseases

secondary to renal ischaemia and increased renin secretion. ln liver diseases,

Aldosterone inactivation is impaired increased aldosterone. A D R E N A L I N S U F F I C I E N C Y ADDISSON'S Disease: - Cause: Adrenal insufficiency due to atrophy of the adrenal cortex for an

unexplained cause most probably an autoimmune disease both mineralo and glucocorticoids.

- Manifestations:

1. Aldosterone Na+ loss + water loss plasma volume hypotension.

2. Aldosterone K+ retention hyperkalaemia + hyponateraemia muscle weakness.

3. Glucocorticoids (cortisol) ACTH + MSH activity bronze pigmentation of the skin.

4. Glucocorticoids hypoglycaemia.

5. Na+ and water reabsorption from the GIT gastro-intestinal disturbances.

6. ADDISSONIAN CRISIS: occurs if the patient is exposed to stress

acute shock with marked hypotension and hypoglycaemia. Treatment: lntravenous glucocorticoids + glucose-saline + an antibiotic umbrella to prevent the possible infection due to lowered resistance.

A D R E N A L S E X H O R M O N E S

- They are secreted mainly by the zone reticularis. - The gland secretes Androgens mainly e.g. Dehydroepiandrosterone

(DHEA), Androstenedione and Testosterone. - Very small amounts of oesterogens are also secreted e.g. Oestradiol and

Oestrone.

D I S O R D ER S O F S E X H O R M O N E S E C R E T I O N THE ADRENOGENTITAL SYNDROME - It is due to a pathologic excess production of adrenal Androgens (very

very rarely Oestrogens). - The clinical picture varies according to: sex, age of onset and associated

adrenocortical hormonal disorders: A) During lntra - uterine life : - lt is due to:

Congenital defect in C-21, or C-11 hydroxylases which convert 17-

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hydroxypregnenolone into cortisol. So, there is increased 17-

hydroxypregnenolone androgenic pathway increased androgens.

Also, cortisol ACTH adrenal hyperplasia synthesis and release of androgens.

- Effects: I) The Female Foetus Develops Female Pseudohermaphroditism.

Pseudohermaphroditism: lt means the presence of the gonads of one sex only, while the external

genitalia are abnormal and simulates the opposite sex. True hermaphroditism:

lt is an embryonic defect not related to cortical dysfunction. lt is characterized by the presence of the gonads of both sexes in the same patient and an abnormal genital apparatus and sex characters. Female Pseusohermaphroditism:

The ovaries, tubes, uterus and vagina are normal since they develop early independent of the adrenal cortex.

The external genitalia develop later under the influence of adrenal androgens which produce:

Fused labia minora with persistence of cloacal plate. Enlarged clitoris simulating a small penis. So, the female foetus at birth has the female gonads

(ovaries) but the external genitals simulates the male.

II) The Male Foetus shows enlarged external genitals i.e. Macrogenitosomia. - Fate after birth :

The newborn baby may die from hypocorticism. The newborn may live if the associated cortical dysfunction

is not severe. B) During infancy: - ln Male children: They show early growth of the accessory sex organs

and development of the male sex characters at the age of 2-4 years (mention the secondary male sex characters that occur at puberty but without sperm production).

- ln Female children: They develop musculine secondary characteristics

Virilism ; in the form of: Growth of pubic and axillary hair of the musculine pattern or even

hirsutism. The voice deepens and hair grows on the face (beard) and there is

increased growth of muscles. The clitoris enlarges.

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The ovaries do not function and the uterus remains infantile and fails to menstruate.

- ln Both Sexes:

There is premature closure of the epiphysis short stature.

- Treatment: Suitable doses of cortisol inhibit ACTH suppresses

cortical hyperplasia androgens. - Plastic surgery for the external genitalia in females. C ) Before Puberty: - The onset of the syndrome occurs after infancy but before the onset of

puberty.

- Cause: Adenoma of the adrenal cortex androgens. - N.B. lt does not respond to cortisol treatment but surgical removal of the

tumour must be done. - Manifestations:

ln the male: Precocious puberty with early development of the male secondary sexual characters.

ln the Female: lt leads to virilism i.e. the development of musculine secondary characteristics.

D) ln the Adult: - Cause : Adenoma of the cortex secreting excess androgens. - Manifestations:

ln the adult Male: There is increased musculinisation. ln the adult Female: There is virilism. The woman develops male

characters in the form of : 1. Hair grows over the face and cheeks and all over the body

(hirsuitism). 2. The voice deepens. 3. The muscles increase in bulk. 4. The breasts and the external genitalia atrophy with the

exception of the clitoris which enlarges. 5. Amenorrhea is present.

- Treatment: Surgical removal of the tumour.

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T H E P A N C R E A S

The pancreas serves both an endocrine and an exocrine function. The

exocrine part is formed of the pancreatic acini which secrete the pancreatic digestive juice. The endocrine part is formed of the islets of Langerhans which consist of three types of cells:

Islets contain:

o Alpha Cells - Glucagon (15-20%) o Beta Cells - Insulin (65-80%) o Delta Cells - Somatostatin (3-10%) o PP Cells - Pancreatic Polypeptide (< 1%)

o Epsilon Cells – Ghrelin? (<0.5%)

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I N S U L I N

CHEMISTRY OF INSULIN: lt is a polypeptide hormone formed of 2 polypeptide chains A and B.

The A chain is formed of 21 amino acids.

The B chain is formed of 30 amino acids.

The 2 chains are connected by 2 disulfide bonds between cysteine

amino acids at (A7 B7 ) and (A20 B19 ).

The A chain contains also a disulfide bond between cysteine amino

acids at( A6 A11.

lnsulin is synthesized in the ribosomes of the -cells as a single polypeptide chain (81 amino acids) called proinsulin.

Proinsulin is subjected to hydrolysis and a C peptide chain of 30 amino acids is removed converting proinsulin into lnsulin.

lnsulin is stored inside vesicles complexed with Zn2+.

The C-peptide can be estimated by radio-immunoassay (RIA) and can be taken as a measure of endogenous insulin production since it is secreted in equimolar amounts with insulin.

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TRANSPORT AND METABOLISM: The rate of insulin secretion is 1-2 mg/day. lnsulin is carried in the blood partially bound to plasma proteins (inactive) and partially free (active). lnsulin is inactivated in the liver by an enzyme; insulin-glutathione transhydrogenase, or by a proteolytic enzyme insulinase in most tissues. Insulin has a half life time of 4 minutes.

BIOLOGICAL FUNCTIONS:

Effects on Carbohydrate Metabolism: lnsulin increases glucose utilization in most tissues through:

1. lt increases glucose transfer across the cell membrane in the skeletal muscles, heart and adipose cells. Mechanism: - Glucose transfer across the cell membranes occurs by facilitated

diffusion mediated by a carrier protein. - lnsulin binds to specific receptors on the cell membrane and activate

the carrier protein. - Glucose transport is not affected by lnsulin in the following tissues:

The brain. The renal tubules. The R.B. Cs. The liver. The intestinal mucosa.

Glucose transport through the cell membrane of skeletal muscles is enhanced by exercise by an unknown mechanism. 2. lnsulin increases the oxidation of glucose through increasing the activity of

the following enzymes: Hexokinase - Phosphofructinase - and Pyruvic kinase.

N.B. The conversion of glucose to glucose-6-P by the hexokinase prevents

back diffusion of glucose from the cells into the blood stream after its entry. 3. lnsulin increases glycogenesis in the skeletal muscles by stimulating the

enzyme glycogen synthetase. 4. lnsulin also increases glycogensis in the liver by stimulating the enzyme

glucokinase and reduces glycogenolysis by inhibiting the enzyme

phosphatase blood glucose. 5. lnsulin also inhibits gluconeogenesis. Effects on Protein Metabolism

lnsulin increases protein synthesis through: 1- lt increases amino acid transport the cells. 2- lt increases oxidation of carbohydrates and thus preserves amino acids for

protein synthesis. 3- lt decreases gluconeogenesis and thus decreases protein catabolism.

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Effect on Lipid Metabolism

1- glucose utilization will spare fats lipolysis.

2- glucose oxidation acetyl Co A and glyceraldehyde-3-P fatty acid synthesis.

3- Both effects will increase fat accumulation. Effect on the Resting Membrane Potential:

lnsulin activates Na+-K+ ATPase in skeletal muscles and fat cells

activate the Na+-K+ pump extracellular Na+ and intracellular K+ hyperpolarisation.

R E G U L A T I O N O F I N S U L I S E C R E T I O N (1) The most important factor increasing the insulin release is

hyperglycaemia. Glucose is the most effective hexose. However, other hexoses can contribute in the following order: Glucose > Mannose > Fructose >Galactose.

(2) The following GlT hormones stimulate insulin release: Gastrin, Secretin, Pancreozymin, G l P.

(3) Glucagon can stimulate insulin release indirectly: mechanism: Glucagon

blood glucose stimulate insulin release. (4) Amino acids: Several amino acids stimulate insulin release as Arginine,

Lysine and phenyl alanine.

(5) Catecholamines inhibit insulin release (- adrenergic effect). (6) The parasympathetic cholinergic fibers (vagal) stimulate insulin

secretion. (7) Growth hormone stimulates insulin secretion. (8) Sulphonylureas stimulate insulin secretion and are used as oral

antidiabetic drugs.

(9) Fasting blood glucose level stimulates catecholamines inhibit

insulin secretion (-effect).

(10) Plasma K+ inhibits insulin secretion.

(11) Somatostatin inhibits insulin secretion.

GLUCAGON HORMONE

It is a polypeptide hormone formed of 29 amino acid residues and

secreted by the alpha cells of the pancreas.

BIOLOCAL EFFECTS: 1) Glucagon increases the glucose level through :

i. Stimulation of glycogenolysis in the liver, an action which is more powerful than adrenaline and is mediated via cAMP.

ii. lncreased gluconeogenesis in the liver.

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2) Glucagon increases lipolysis in fat cells and in the liver. 3) Excess doses (pharmacological doses) stimulate myocardiac contractility

and increases the heart rate through stimulation of adenyl cyclase cAMP.

REGULATION OF GLUCAGON SECRETION: 1. Hypoglycaemia stimulates directly the alpha cells glucagon release. 2. Catecholamines stimulate glucagon secretion. 3. Somatostatin stimulates glucagon secretion. 4. Some plasma amino acids as arginine stimulate glucagon secretion.

DIABETES MELLITUS

lt is due to:

Absolute lack of lnsulin as a result of degeneration of the beta cells of the pancreas which may be due to an autoimmune process or genetic defect.

Relative lack of lnsulin e.g. when there is hormonal imbalance with excess production of one or more hyperglycaemic hormone e.g.

Growth H in acromegaly or gigantism pituitary diabetes.

Cortisol in cushing's syndrome adrenal diabetes.

Therefore: Conditions of absolute insulin lack are called insulin sensitive

diabetes since injection of insulin in those patients will lower much the blood glucose level.

Conditions of relative insulin lack are called insulin resistant

diabetes sine injection of insulin in those patients no significant lowering of the blood glucose level in the presence of the hormonal imbalance.

MANIFFSTATIONS OF DIABETES MELLITUS:

They are produced by the metabolic defects which are : 1. Decreased glucose utilization. 2. Hyperglycaemia. 3. lncreased protein catabolism. 4. lncreased lipolysis . Effects of Hyperglycaemia:

(1) blood glucose level exceeds the renal threshold glucose loss in

urine Glucosuria.

(2) glucose loss in urine osmotic diuresis polyuria.

(3) polyuria plasma volume hypotension + cardiac output tissue hypoxia.

(4) Polyurea plasma volume plasma osmotic pressure and

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dehydration of hypothalamic osmoreceptors Thirst. Effects Of Lncreased Protein Catabolism: (1) Generalized muscle weakness, delayed wound healing and in; the

young; growth retardation. (2) The patient becomes in a state of -ve N2 balance. Effects of lncreased lipolysis:

(1) lipolysis blood fatty acids -oxidation acetate

formation of ketone bodies in the liver (aceto - acetic and -

hydroxybutyric acids) ketone bodies in the blood (ketosis and

ketonaemia) blood pH (acidosis) synaptic transmission in the

brain hyperglycaemic coma and death (in untreated patients).

(2) acetate cholesterol synthesis blood cholesterol atherosclerosis and hypertension.

Effects of Decreased Glucose Utilization:

The feeding center in the hypothalamus is not saturated food intake

hyperphagia.

TREATMENT: 1. When the onset is in young age (Juvenile type), insulin administration is

a must. 2. When the onset is in old age (Old onset type), the beta cells are usually

present but their function is weak and needs stimulation by oral hypoglycaemic drugs.

3. lnsulin resistant cases must be discovered and correction of the hormonal disturbance is necessary .