Glucocorticoids &androgens by blvqR2l

VIEWS: 5 PAGES: 43

									     2008
  BIOM 463
Dr. Nasser Rizk
  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)
   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.
   A- general: inactivation of corticosteroids by: 1-
    Enzymatic reduction to :

    Dihydrocortisol                Tetrahydrocortisol

 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.
    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.
                      Cortisol

Metabolic                                  Immune response


            Stress           Excretion
            response         of water

                  Mineralocorticoid         CVS role
                  activity

               Pharmacological effects
               Immunosuppressive actions
                  Anti-allergic effect
                Anti-inflammatory effect
 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.
 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.
  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.
 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.
   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.
   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
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
   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.
 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.
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
                      Hypothalamus
        +VE
                                               Interactions between
                 CRH VP                        Hypothalamo-hypophyseal
                                               Adrenocortical axis
          +VE
                                               And immune system

                Ant. pit.
Interleukins    gland
(e.g. IL-1)
                            ACTH

                                     Adrenal
                      Cortisol       cortex



                                                   ACTH
                              - Ve

                   Macrophages                    TNF-
                                                  ( and other toxic substances)
                   Immune challenge
    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              9000               10.000
    PMNs               5760               8300
    Lymphocytes        2370               1080
    Eosinophils        270                20
    Basophils          60                 30
    Monocytes          450                540
    RBCs               5 million          5.2 million
   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
6-   Other effects:
 Gastric secretion: increases,
  increase incidence of gastric &
  peptic ulcers.
 Nervous system: change in
  personality.
 ACTH secretion: inhibited
 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.
                         Actions ?        Autocrine effect
Cortisol                                  Via Lipocortin receptor ?




                                                    Phospholipase A

                           Lipocortin 1
Cortisol
receptor   New protein                              Arachidonic acid
           synthesis

            mRNA                                     Prostaglandins &
                                                     Leukotriens synthesis


                                                      Actions

           Mechanism of action of Cortisol
   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.
 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.
                    Stress
     Indirect -Ve
                             Hypothalamus

                    CRH VP
                                              Hypothalamo-
                                              Hypophyseal
                                              Portal system

      Direct - ve
                                     Adenohypophesis


                       Corticotrophin, ACTH




                         Adrenal                  Control of secretion
Cortisol                 Cortex                       of Cortisol
   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.
   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,
   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.
   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.
   C/p:
 Hyperkalemia
 Salt wasting

 Hypotension

 Metabolic acidosis
 End of this gland
 Dr. Nasser Rizk

       2008

								
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