Sunday 12 June 2011

STEROIDS


CORTICOSTEROIDS


Overview
-     corticosteroids are steroid hormones synthesized and secreted by the adrenal cortex
-     the adrenal cortex consists of 3 layers (listed from outermost to innermost)


LAYER                                   DESCRIPTION
ZONA GLOMERULOSA      - synthesize mineralocorticoids (primarily aldosterone)


ZONA FASCICULATA        - synthesize glucocorticoids (primarily hydrocortisone
(“cortisol”))


ZONA RETICULARIS          - synthesize and store sex hormones (primarily testosterone and oestradiol)




-     all the corticosteroids are steroid hormones synthesized from cholesterol in a complex meshwork


MINERALOCORTICOIDS                GLUCOCORTICOIDS                                 SEX HORMONES


CHOLESTEROL                           
      
               
              PREGNONELONE           
                                              3-dehydrogenase               17-HYDROXYPREGNONELONE                 DEHYDROEPIANDROSTERONE                                                                           
                                                                                                                                                                                           3dehydrogenas
PROGESTERONE                                                                                                
                                                                                       17-HYDROXYPROGESTERONE
                                               21-hydroxylase                                                                                                       ANDROSTENEDIONE
                                                                                                                                                                                                       ↓17-dehydrogenase

           11-DEOXYCORTICOSTERONE                                      11-DEOXYCORTISOL                                   TESTOSTERONE
                                                                                                                                                                           aromatase                                
            
                                              11- hydroxylase                                                                                                                      OESTRADIOL

 HYDROCORTISONE
                                                                                                                                                            OESTRIOL
CORTICOSTERONE



ALDOSTERONE                                                                                                                                            OESTRONE


MINERALOCORTICOIDS                GLUCOCORTICOIDS                                 SEX HORMONES

 CHOLESTEROL                           
      
               
              PREGNONELONE           
                                              3-dehydrogenase               17-HYDROXYPREGNONELONE                 DEHYDROEPIANDROSTERONE                                                                           
                                                                                                                                                                                           3dehydrogenas
PROGESTERONE                                                                                                
                                                                                       17-HYDROXYPROGESTERONE
                                               21-hydroxylase                                                                                                       ANDROSTENEDIONE
                                                                                                                                                                                                       ↓17-dehydrogenase

           11-DEOXYCORTICOSTERONE                                      11-DEOXYCORTISOL                                   TESTOSTERONE
                                                                                                                                                                           aromatase                                
            
                                              11- hydroxylase                                                                                                                      OESTRADIOL

 HYDROCORTISONE
                                                                                                                                                            OESTRIOL
CORTICOSTERONE



ALDOSTERONE                                                                                                                                            OESTRONE

   






MINERALOCORTICOIDS                GLUCOCORTICOIDS                                 SEX HORMONES


CHOLESTEROL                           
      
               
              PREGNONELONE
                                 3-dehydrogenase          17-HYDROXYPREGNONELONE        DEHYDROEPIANDROSTERONE                                                                           
                                                                                                                                             3dehydrogenas
PROGESTERONE                                                                                                
    17-HYDROXYPROGESTERONE
                   21-hydroxylase                                                                                           ANDROSTENEDIONE
                                                                                                                                                           17-dehydrogenase

 11-DEOXYCORTICOSTERONE                11-DEOXYCORTISOL                                   TESTOSTERONE
                                                                                                                                 aromatase                                
            
    11- hydroxylase                                                                                                                      OESTRADIOL


 HYDROCORTISONE
                                                                                                                         OESTRIOL
CORTICOSTERONE



ALDOSTERONE                                                                                                        OESTRONE

   




-     though this meshwork might seem overly complex to memorize, please notice that the enzymes in each row (see above) essentially are the same (!)



 MINERALOCORTICOIDS





Overview
-     mineralocorticoids are synthesized by the zona glomerulosa of the adrenal cortex
-     the main mineralocorticoid is aldosterone
-     aldosterone acts on aldosterone receptors exclusively found in the late distal tubule of the kidney nephrons
-     consequences of aldosterone stimulation, see 24
-     regulation of aldosterone secretion is done by the renin angiotensin aldosterone system


Relevant Drugs
-     3 groups

1) ALDOSTERONE RECEPTOR AGONISTS
-     aldosterone receptor agonists agonizes aldosterone receptors, thus causing
increased water/sodium retention and increased potassium/hydrogen ion excretion
-     2 types

DRUG NAME                    DESCRIPTION ALDOSTERONE                                             General information
- not used clinically


FLUDROCORTISONE     General information
- administered orally


Medical uses
- treatment of hypoadrenocorticism
(“addison’s disease”)




2) ALDOSTERONE RECEPTOR ANTAGONISTS
-     “potassium-sparing diuretics”
-     aldosterone receptor antagonists antagonize the action of aldosterone on
aldosterone receptors, thus causing decreased water/sodium retention and decreased potassium/hydrogen ion excretion



3) CORTICOSTEROID SYNTHESIS INHIBITORS
-     corticosteroid synthesis inhibitors inhibit enzymes responsible corticosteroid synthesis (see above), thus causing decreased synthesis of aldosterone, hydrocortisone and sex hormones
-     2 types


DRUG NAME                     DESCRIPTION TRILOSTANE                                             General information
- 3-dehydrogenase inhibitor



Medical uses
- treatment of hyperaldosteronism (“cushing’s syndrome”)
- treatment of hypercortisolism (“conn’s syndrome”)


METYRAPONE                  General information
- 11-hydroxylase inhibitor
- same as trilostane (see above)




GLUCOCORTICOIDS

Overview
-     glucocorticoids are synthesized by the zona fasciculata of the adrenal cortex
-     the main glucocorticoid is hydrocortisone (“cortisol”)
-     hydrocortisone acts on glucocorticoid receptors found in most cells
-     hydrocortisone also has a strong action on aldosterone receptors (see above)
-     consequences of hydrocortisone stimulation include

CONSEQUENCE                                     DESCRIPTION CARBOHYDRATE METABOLISM     - decreased glucose uptake
- decreased glycolysis
- increased gluconeogenesis


FAT METABOLISM                                - increased deliberation of free fatty acids from adipose tissue
- increased beta-oxidation


PROTEIN METABOLISM                      - decreased protein uptake
- decreased protein synthesis
- increased protein catabolism


CALCIUM HOMEOSTASIS                   - decreased calcium absorption from the GI
tract
- decreased osteoblast activity
- increased osteoclast activity
- increased calcium excretion by the kidneys


IMMUNE DEFENSE SYSTEM              - decreased synthesis of COX-2 (see 51/52)
- decreased synthesis of eicosanoids (due to decreased COX-2 synthesis)
- decreased edema, pain and fever (due to decreased eicosanoid synthesis)


- decreased synthesis of nitric oxide synthase
- decreased vasodilation (due to decreased nitric oxide synthase synthesis)


- decreased synthesis of GM-CSF
- decreased proliferation of granulocytes and monocytes/macrophages in the bone marrow (due to decreased GM-CSF synthesis)


- decreased synthesis of TNF-gamma
- decreased synthesis of VCAM-1 and ICAM-1 cell adhesion molecules (due to decreased
TNF-gamma synthesis)
- decreased migration of granulocytes and monocytes/macrophages (due to decreased VCAM-1/ICAM-1 synthesis)


- decreased activation of helper T-cells
- decreased secretion of IL-2 from helper T- cells (due to decreased activation of T-helper cells)
- decreased activation of cytotoxic T-cells (due to decreased IL-2 secretion from helper T- cells)


- decreased activation of fibroblasts
- decreased deposition of collagen and glycosaminoglycans (due to decreased activation of fiboblasts)
- decreased wound healing and fibrosis (due to decreased deposition of collagen/glycosaminoglycans)


- decreased activation of mast cells
- decreased secretion of histamine (due to decreased activation of mast cells)
- decreased bronchoconstriction (due to decreased histamine release)


- decreased synthesis of complement factors by the liver




-     regulation of hydrocortisone secretion is done by ACTH (see 54)




- 12 -

Relevant Drugs
-     1 group

1) GLUCOCORTICOID RECEPTOR AGONISTS
-     6 types

DRUG NAME                   DESCRIPTION HYDROCORTISONE     General information
- cortisol itself
- administered orally, IV, intramuscularly,
intra-articularly, by inhalation, and/or dermally


Medical uses
- treatment of adrenal hypofunction
(“addison’s disease”)


Side effects
- cushing’s syndrome-like syndrome (due to negative feedback on the anterior lobe of the pituitary gland, see 54)
- hyperglycemia (due to altered carbohydrate metabolism)
- diabetes (due to hyperglycemia)
- inhibition of growth in children (due to
altered protein metabolism and altered calcium homeostasis)
- osteoporosis in adults (due to altered calcium homeostasis)
- increased susceptibility to infections (due to immunosuppression)
- generalized edema (due to sodium/water retention by action on aldosterone receptors)
- adrenal hypofunction (if withdrawn rapidly)


CORTISONE                    General information
- pro-drug
- activated to hydrocortisone in the body
- same as hydrocortisone (see above)


Medical uses
- treatment of adrenal hypofunction
(“addison’s disease”)
- treatment of inflammations (including exophthalmus of hyperthyroidism)
- treatment of hypersensitivity reactions




(including asthma)


Side effects
- same as hydrocortisone (see above)


PREDNISOLONE            General information
- synthetic hydrocortisone derivative
- same as hydrocortisone (see above)


Medical uses
- treatment of inflammations
- treatment of hypersensitivity reactions
(including asthma)


Side effects
- same as hydrocortisone (see above)


PREDNISONE                  General information
- pro-drug
- activated to prednisolone in the body
- same as prednisolone (see above)


BETAMETHASONE        General information
- same as prednisolone (see above)


DEXAMETHASONE       General information
same as prednisolone (see above)




SEX HORMONES

Overview
-     sex hormones are synthesized by the zona reticularis of the adrenal cortex
-     the main sex hormones of the zona reticularis are testosterone and oestrogens
-     however, the zona reticularis only maintains a basal level of testosterone and oestrogens in
childhood and menopause, with the gonads synthesizing the bulk of the testosterone and oestrogens in puberty and adulthood (see 56/57/58)
-     regulation of sex hormone secretion by the zona reticularis is done by ACTH

1 comment:

Post a Comment