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HORMONES OF THE ADRENAL CORTEX Prof.Dr.Arzu SevenHORMONES OF THE ADRENAL KORTEX

The adrenal cortex makes 3 kinds of hormones:MineralocorticoidsGlucocorticoidsAndrogens

There is an overlap of biological activity, all natural glucocorticoids have mineralocoticoid activity and vice varsaH + R (intracellular)gene expression

Chemical structure of steroid hormones:17-C cyclopentanoperhydrophenanthrene structure with four rings labeled A_DAdditional carbons can be added at positions 10 or 13 or a side chain attached to C17Asymetric carbon atoms allow for stereoisomerism

Glucocorticoids21CMineralocorticoids21CAndrogens19CEstrogens18C

Synthesis of glucocorticoids C17C21C11

1721

11hydroxylationsEndoplasmic reticulummitochondriaCortisol is the major glucocorticoid , synhesized in the adrenal cortex It is under the direct control of pituitary ACTHCholestrol is the precursor for all seroid hormones The conversion of cholestrol to pregnenolone is the rate limiting stepCleavage 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

Plazma concentration shows a pronounced diurnal rhythm, being 10 times higher at 08.00 hr than at 24.00 hrThis parallels the marked diurnal rhythm of ACTH secretion 95% of cortisol in plasma is bound to proteins, mainly corticosterid binding globulin(CBG) or transcortin CBG is produced in liver Its synthesis , like TBG, is increased by estrogensFree fraction represents the biologically active cortisolHalf life ~ 100 minutesIn plasma :80% 17-OH corticoids, 20% cortisone and 11-deoxycortisol metabolized in the liver by reduction, side chain cleavage and conjugation reactionslipophilic steroid molecule becomes water soluble and excretable

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 urine20%in the fecesskinGlucocorticoid hormones affect basal metabolism, host defence mechanism, blood pressure and response to stress

Cortisol works in tandem with insulin and GH in regulating intermediary metabolismClinical disorders of cortisol secretionhypofunction:Hyposecretion of cortisol may occur as a result of hypothalamic ,pituitary or adrenal failure Diagnosis:Clinical presentationTimed measurement of cortisol and ACTHExtent of cortisol response to synthetic ACTH(synacthen)Addison disease(adrenal insufficiency)Primary adrenal failure autoimmune/infection(tbc or cytomegalivrus)Secretion of all adrenal hormones

Biochemical features HyponatremiaHyperkalemiaAcidosisUreampaired cortisol response to synacthen, together with ACTHDarkening of skin and mucous membranes Hypovolemia and hypotension stimulate AVP secretionwater retentionSynacthen tests(short or long)Synacthen is a synthetic, 1-24 analogue of ACTH, adminstered IV at a dose of 250gCortisol is measured at 0,30,60 minEquivocal 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 (1mg) is given IM for 3 days SST repeated on the 4th day

A normal response makes primary adrenal insufficiency unlikely LST may not be needed when ACTH is measured

Therapy:cortisol replacament , usually together with a mineralocorticoidAddisons disease can be associated with elevated TSH which revolves with glucocorticoid therapy

hyperfunctionHypersecretion of cortisol results in Cushings syndrome Prolonged use of exogenous glucocorticoids (iatrogenic)Disorders the hypothalamus, pituitary (80%) or adrenal gland(15%)Ectopic ACTH syndrome

Cortisol excess produces DM and hypertension, and usually suppresses the hypothalamic gonadal axis (amenorrhea)diagnosis

Random measurement of cortisol is of little use because of the pronounced circadian variation24 hour urinary free cortisol or cortisol/creatinine ratio in an early sample is a common screening testRepeatedly high early morning urine cortisol /creatinine ratios indicate further investigations If the test is negative on 3 occasions exclude Cushings syndrome from differential diagnosis

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 syndromeFailure 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 Failure of serum cortisol to rise after insulin_induced hypoglycaemia (0.15 units insulin /kg) is a characteristic feature of Cushings syndromeIn 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