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Prof.Dr.Arzu Seven Slide 2 HORMONES OF THE ADRENAL KORTEX Slide 3 The adrenal cortex makes 3 kinds of hormones: Mineralocorticoids Glucocorticoids Androgens Slide 4 There is an overlap of biological activity, all natural glucocorticoids have mineralocoticoid activity and vice varsa H + R (intracellular) gene expression Slide 5 Chemical structure of steroid hormones: 17-C cyclopentanoperhydrophenanthrene structure with four rings labeled A_D Additional carbons can be added at positions 10 or 13 or a side chain attached to C 17 Asymetric carbon atoms allow for stereoisomerism Slide 6 Slide 7 Glucocorticoids 21C Mineralocorticoids 21C Androgens 19C Estrogens 18C Slide 8 Slide 9 Synthesis of glucocorticoids C17 C21 C11 17 21 11 hydroxylations Endoplasmic reticulum mitochondria Slide 10 Cortisol is the major glucocorticoid, synhesized in the adrenal cortex It is under the direct control of pituitary ACTH Cholestrol is the precursor for all seroid hormones The conversion of cholestrol to pregnenolone is the rate limiting step Slide 11 Cleavage of the cholestrol side chain liberates C-21 corticosteroids, further side chain cleavage yields C-19 androgens, aromatization of ring A results in C-18 estrogens Slide 12 Slide 13 Plazma concentration shows a pronounced diurnal rhythm, being 10 times higher at 08.00 hr than at 24.00 hr This parallels the marked diurnal rhythm of ACTH secretion 95% of cortisol in plasma is bound to proteins, mainly corticosterid binding globulin(CBG) or transcortin Slide 14 CBG is produced in liver Its synthesis, like TBG, is increased by estrogens Free fraction represents the biologically active cortisol Half life ~ 100 minutes Slide 15 In plasma :80% 17-OH corticoids, 20% cortisone and 11-deoxycortisol metabolized in the liver by reduction, side chain cleavage and conjugation reactions lipophilic steroid molecule becomes water soluble and excretable Slide 16 In humans most of the conjugated steroids,that enter the intestine by biliary excretion,are reabsorbed by the enterohepatic circulation Conjugated steroids are excreted : 70% in the urine 20%in the feces skin Slide 17 Glucocorticoid hormones affect basal metabolism, host defence mechanism, blood pressure and response to stress Slide 18 Slide 19 Cortisol works in tandem with insulin and GH in regulating intermediary metabolism Slide 20 Clinical disorders of cortisol secretion hypofunction: Hyposecretion of cortisol may occur as a result of hypothalamic,pituitary or adrenal failure Diagnosis: Clinical presentation Timed measurement of cortisol and ACTH Extent of cortisol response to synthetic ACTH (synacthen) Slide 21 Addison disease(adrenal insufficiency) Primary adrenal failure autoimmune/infection(tbc or cytomegalivrus) Secretion of all adrenal hormones Slide 22 Slide 23 Slide 24 Biochemical features Hyponatremia Hyperkalemia Acidosis Urea mpaired cortisol response to synacthen, together with ACTH Darkening of skin and mucous membranes Hypovolemia and hypotension stimulate AVP secretion water retention Slide 25 Synacthen tests(short or long) Synacthen is a synthetic, 1-24 analogue of ACTH, adminstered IV at a dose of 250g Cortisol is measured at 0,30,60 min Equivocal or inadequate responses to SST (short synacthen test) may require LST to be performed in order to establish whether adrenal insufficiency is primary or secondary to pituitary or hypothalamic disease.Depot Synacthen ( 1 mg) is given IM for 3 days SST repeated on the 4 th day Slide 26 A normal response makes primary adrenal insufficiency unlikely LST may not be needed when ACTH is measured Slide 27 Slide 28 Therapy:cortisol replacament, usually together with a mineralocorticoid Addisons disease can be associated with elevated TSH which revolves with glucocorticoid therapy Slide 29 Slide 30 hyperfunction Hypersecretion of cortisol results in Cushings syndrome Prolonged use of exogenous glucocorticoids (iatrogenic) Disorders the hypothalamus, pituitary (80%) or adrenal gland(15%) Ectopic ACTH syndrome Slide 31 Slide 32 Slide 33 Cortisol excess produces DM and hypertension, and usually suppresses the hypothalamic gonadal axis (amenorrhea) Slide 34 diagnosis Random measurement of cortisol is of little use because of the pronounced circadian variation 24 hour urinary free cortisol or cortisol/creatinine ratio in an early sample is a common screening test Repeatedly high early morning urine cortisol /creatinine ratios indicate further investigations If the test is negative on 3 occasions exclude Cushings syndrome from differential diagnosis Slide 35 Cortisol concentrations at 08.00 and 22.00 normally shows a circadian rhythm with evening sample having a lower value than in the morning Loss of this rhythm indicates Cushings syndrome Failure of 1 mg dexamethasone taken at 23.00 to supress serum cortisol level at 08.00 the following morning, or failure to supress urinary cortisol secretion overnight (cortisol/creatinine) is another indicator of Cushings syndrome Slide 36 Failure of serum cortisol to rise after insulin_induced hypoglycaemia (0.15 units insulin /kg) is a characteristic feature of Cushings syndrome In patients with pitiutary dependent Cushings disease, serum urinary cortisol will be partially supressed after 2 days of dexamethasone, 2.0 mg q.i.d. (synthetic glucocorticoid) Failure to supress suggests either ectopic ACTH production or autonomous secretion of cortisol by an adrenal tm Slide 37