Glucocorticoids

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Glucocorticoids androgens

• 2008
• BIOM 463
• Dr. Nasser Rizk

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Zona Fasciculate andCorticosteroids

• Secretion
• The human adrenal cortex secretes two main
  glucocorticoids
• 1- Cortisol
• 2- Corticosterone
• Transport
• 75 of Cortisol, bound to Globulin (transcortin),
  and Corticosterone.
• 15 bound to albumin
• 10 is free (active)

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Synthesis of glucocorticoids

• As shown before.
• 1- Uptake of cholesterol
• 2- side-chain- cleavage of cholesterol
• 3- Pregnenolone common precursor.
• 4- Hydroxylation reactions
• 5- 17-?-hydroxyprogestrone 17-?-hydroxypregenlone
  ,
• Give rise to 11-deoxycortisol..
  Glucocorticoid pathway.

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Metabolism of glucocorticoids

• A- general inactivation of corticosteroids by
  1- Enzymatic reduction to
• 2- Conjugation reaction, excreted by kidney.
• Major urinary metabolite of Cortisol is
• Tetrahydrocortisol glucuronide
  
• B- Liver is the main extra-adrenal site of
  metabolism. Cortisol is converted into Cortisone
• which is conjugated and reduced to be excreted.

Dihydrocortisol
Tetrahydrocortisol
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• Steroids with 17-? hydroxyl groups appear in
  urine in the form of
• 17- Ketosteroids (marker of corticosteroid
  secretion in humans)
• 3- Conversion in other extra-adrenal tissues
• Like muscles, skin, fibroblasts, intestine by
  oxidation-reduction reactions.

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Actions of glucocorticoids

• Cortisol

Immune response
Metabolic
Excretion of water
Stress response
Mineralocorticoid activity
CVS role
Pharmacological effects Immunosuppressive
actions Anti-allergic effect Anti-inflammatory
effect
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• Metabolic effects
• 1- Carbohydrate Hyperglycemic ?
• A- Gluconeogensis especially Sk.M, and
• B- Hepatic glycogenolysis, and
• C- Anti-insulin effect, decreasing glucose
  transport in Sk.M and adipose tissue by
  inhibiting GLUT14 activity.

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• 2- Protein Metabolism
• A- Enhance protein breakdown and release of A.A.
  in extrahepatic tissue esp. Sk.M Fat.
• B- Liver deals mobilized A.A by deamination,
  gluconeogensis, Ptn synthesis and Plasma protein
  formation
• It is catabolic hormone.

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• 3- Fat metabolism
• It is lipolytic hormone
• Increased mobilization of fatty acids.
• This effect is due to potenetiation by other
  lipolytic hormones as catecholamines and
  Somatotrophins.
• When large amounts of Cortisol are secreted,
  could lead to
• Centripetal Distribution of fat
• ( Increased deposition of fat in trunk, face
  and neck regions), as in Cushing's syndrome.

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2- Mineralocorticoid activity

• 1- Cortisol has a weak mineralocorticoid
  activity. It helps Na reabsorption and enhances
  excretion of K in urine.
• 2- This weak effect is due to presence of enzyme
  11-? hydroxysteroid dehydrogenase ( 11 ? HSD),
  which catalyses conversion of active Cortisol
  into inactive Cortisol.
• This enzyme is present in Aldosterone-sensitive
  tissues.

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• 3- Water metabolism
• Depends on the water content of the body
• 1- Dehydration Cortisol has antidiuretic effect
  secondary to increased Na reabsorption.
• 2- Hydration Cortisol has a diuretic effect by
• a- Increased renal blood flow and GFR
• b- Inhibit action of ADH on collecting tubules.
• 4- CVS effects Increase vascular tone by
  potenetiation the effects of catecholamines on
  blood vessels.

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• 5- Response to stress
• Stressors as trauma., hemorrhage, acute
  hypoglycemia, febrile stimuli, emotions.
• All these conditions characterized by marked
  increase in ACTH and glucocorticoid
  concentrations.
• This effect is due to
• 1- Increase vascular reactivity,
• 2- Mobilization of F.F.A. from adipose tissue,
  and its use as source of energy

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Pharmacological actions of glucocorticoids

• Inflammation is characterized by increased
  capillary permeability, edema, WBC infiltration
  release of proteolytic enzymes by WBCs, and
  increase collagen activity.
• 1-Anti-inflammatory actions
• 1- Decrease capillary permeability
• 2- Stabilize lysosomal membrane of WBCs, inhibit
  proteolytic enzymes
• 3- Decreased infiltration of WBCs into the
  inflamed area
• 4-Inhbited fibroblastic activity and collagen
  deposition

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• 2- Anti-allergic actions
• Allergy is characterized by histamine release
  from basophil and mast cell which produces
• edema, inflammation, V.D in capillaries, decrease
  B.P, bronchospasm and could lead to anaphylactic
  shock, also stimulates salivary, gastric
  secretions.
• Anti-allergic effects
• Cortisol inhibits the release of histamine.

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• 3- Immunosuppressive effects
• Therapeutic effect of large amounts of
  glucocorticoids, inhibit the normal immune
  response by
• 1- Gradual destruction of lymphoid tissues
  Decrease antibody production, Lymphocytes,
  Basophiles, and Esinophiles.
• This effect is used in tissue transplant , but
  decrease the ability of the body defense against
  infections.

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• Physiologically
• It has a role in regulating the immune response
  and prevent damage to body. How?
• Via interaction between the hypothalamo-hypophysea
  l- adrenal axis and the immune system as shown in
  the next fig.
• e.g., TNF-? released by macrophages is under
  control by increased production of Cortisol which
  in turn inhibits macrophages

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Hypothalamus
VE
Interactions between Hypothalamo-hypophyseal Adre
nocortical axis And immune system
CRH VP
VE
Ant. pit. gland
Interleukins (e.g. IL-1)
ACTH
Adrenal cortex
Cortisol
ACTH
- Ve
Macrophages
TNF-? ( and other toxic substances)
Immune challenge
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• 4- Effect on blood cells
• Decrease number of Eosinophils, Basophils, and
  lymphocytes.
• Increase total count of RBCs, WBCs, platelets,
  Monocytes and PMNs.

Cell Normal Cortisol-effect
WBCs Total PMNs Lymphocytes Eosinophils Basophils Monocytes RBCs 9000 5760 2370 270 60 450 5 million 10.000 8300 1080 20 30 540 5.2 million
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• 5- Effect on calcium and bone
• large amounts of glucocorticoids,
• 1- Antagonizes the effect of Vit D metabolites on
  calcium absorption of the gut
• 2- Increase excretion of Ca in urine via
  increase in GFR.
• 3- May inhibit the secretion of growth hormone
  from ant. Pituitary gland.
• All these effects lead to increase incidence of
• Osteoporosis

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• 6- Other effects
• Gastric secretion increases, increase incidence
  of gastric peptic ulcers.
• Nervous system change in personality.
• ACTH secretion inhibited

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Mechanism of action

• 1- Like other steroids affects gene
  transcription and translation
• 2- Rapid action via Lipocortin1 which causes
  rapid inhibition of ACTH secretion.
• The following Fig. show such mechanisms.

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Actions ?
Autocrine effect Via Lipocortin receptor ?
Cortisol
Phospholipase A
Lipocortin 1
Cortisol receptor
New protein synthesis
Arachidonic acid
mRNA
Prostaglandins Leukotriens synthesis
Actions
Mechanism of action of Cortisol
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Control of Cortisol release

• Synthesis and secretion of glucocorticoids is
  under control of ACTH released from ant.pit.gland
  (act via cyclic AMP).
• ACTH is under control of CRF (CRH) by the
  hypothalamus.
• ACTH is secreted in pulsatile manner.
• Pulses are more frequent early in morning, least
  in evening (circadian rhythm).
• Only Cortisol has a negative feedback effect on
  ACTH and CRH.

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• Hypothalamo-hypophyseal-adrenocortical axis are
  stimulated by a wide range of stress conditions
  including
• Trauma, infections, hypoglycemia
• Acute anxiety, exercise, pain,
• Surgery, shock, inflammation,
• Cold exposure and
• Psychological stress.

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Stress
Indirect -Ve
Hypothalamus
CRH VP
Hypothalamo- Hypophyseal Portal system
Direct - ve
Adenohypophesis
Corticotrophin, ACTH
Adrenal Cortex
Control of secretion of Cortisol
Cortisol
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Adrenal androgens

• Functions
• In males little effect compared to testosterone.
• In females
• 1- Appearance and maintenance of pubic and
  Axillary hair growth of clitoris.
• 2- Protein anabolism which promotes physical
  growth esp. in prepuberatl stage.
• 3- Increased secretion of sebaceous glands of the
  skin and acne formation.

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Disorders of adrenal cortex

• Excess secretion
• 1- Excess androgen adrogenital syndrome and
  masculinization in females.
• 2- Excess glucocorticoids
• Cushings syndrome
• moon face, plethoric appearance,
• trunk obesity, purple abdominal striae,
• hypertension, osteoporosis,

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• protein depletion, mental abnormalities, frequent
  diabetes mellitus.
• 3- Excess mineralcorticosteroids lead to
• 1- K depletion, Na retention
• 2- No edema
• 3- Weakness, hypertension, tetany, polyurea
• 4-Hypokalaemic alkalosis.

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Adrenal insufficiency

• Addison disease destruction of adrenal cortex by
  autoimmune diseases/T.B.
• C/P
• 1- weight loss, tired, hypotensive, hypoglycemia
• 2- response to stress leads to shock and collapse
  addisonian crisis
• 3- increase ACTH level which has MSH activity
  leads to tanning of the skin, pigmentation
• 4- Menstrual abnormalities.

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Decrease aldosterone

• C/p
• Hyperkalemia
• Salt wasting
• Hypotension
• Metabolic acidosis

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• End of this gland
• Dr. Nasser Rizk
• 2008