1. 2008 BIOM 463 Dr. Nasser Rizk

2.  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)

4.  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.

7.  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

8.  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.

10.  Cortisol Metabolic Stress response Mineralocorticoid activity Excretion of water Immune response CVS role Pharmacological effects Immunosuppressive actions Anti-allergic effect Anti-inflammatory effect

11.  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 GLUT1&4 activity.

12.  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.

13.  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.

14.  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.

15.  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.

16.  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

17. 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

18.  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.

19.  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.

20. Physiologically: It has a role in regulating the immune response and prevent damage to body. How? Via interaction between the hypothalamo- hypophyseal- 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

21. Adrenal cortex Macrophages Cortisol CRH VP +VE Interleukins (e.g. IL-1) TNF-  ( and other toxic substances) ACTH Hypothalamus Ant. pit. gland - Ve Immune challenge Interactions between Hypothalamo-hypophyseal Adrenocortical axis And immune system

22.  4- Effect on blood cells:  Decrease number of: Eosinophils, Basophils, and lymphocytes.  Increase: total count of RBCs, WBCs, platelets, Monocytes and PMNs.CellNormalCortisol-effect WBCs Total PMNs Lymphocytes Eosinophils Basophils MonocytesRBCs90005760237027060450 5 million 10.000830010802030540 5.2 million

23.  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

24.  6- Other effects:  Gastric secretion: increases, increase incidence of gastric & peptic ulcers.  Nervous system: change in personality.  ACTH secretion: inhibited

26.  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.

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

28.  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.

32.  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.

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

35.  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.

36.  Excess secretion:  1- Excess androgen: adrogenital syndrome and masculinization in females.  2- Excess glucocorticoids:  Cushing’s syndrome:  moon face, plethoric appearance,  trunk obesity, purple abdominal striae,  hypertension, osteoporosis,

37.  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.

40.  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.

42.  C/p:  Hyperkalemia  Salt wasting  Hypotension  Metabolic acidosis

43.  End of this gland  Dr. Nasser Rizk  2008