Prof.Dr.Arzu Seven

HORMONES OF THE ADRENAL KORTEX

The adrenal cortex makes 3 kinds of hormones: Mineralocorticoids Glucocorticoids Androgens

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

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

Glucocorticoids  21C Mineralocorticoids  21C Androgens  19C Estrogens  18C

Synthesis of glucocorticoids C17 C21 C hydroxylations Endoplasmic reticulum mitochondria

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

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

Plazma concentration shows a pronounced diurnal rhythm, being 10 times higher at hr than at 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

CBG is produced in liver Its synthesis, like TBG, is increased by estrogens Free fraction represents the biologically active cortisol Half life ~ 100 minutes

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

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

Glucocorticoid hormones affect basal metabolism, host defence mechanism, blood pressure and response to stress

Cortisol works in tandem with insulin and GH in regulating intermediary metabolism

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)

Addison disease(adrenal insufficiency) Primary adrenal failure autoimmune/infection(tbc or cytomegalivırus) Secretion of all adrenal hormones

Biochemical features Hyponatremia Hyperkalemia Acidosis Urea İmpaired cortisol response to synacthen, together with ACTH Darkening of skin and mucous membranes Hypovolemia and hypotension stimulate AVP secretion  water retention

Synacthen tests(short or long) Synacthen is a synthetic, 1-24 analogue of ACTH, adminstered IV at a dose of 250µg 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

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

Therapy:cortisol replacament, usually together with a mineralocorticoid Addison’s disease can be associated with elevated TSH which revolves with glucocorticoid therapy

hyperfunction Hypersecretion of cortisol results in Cushing’s 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 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 Cushing’s syndrome from differential diagnosis

Cortisol concentrations at and normally shows a circadian rhythm with evening sample having a lower value than in the morning Loss of this rhythm indicates Cushing’s syndrome Failure of 1 mg dexamethasone taken at to supress serum cortisol level at the following morning, or failure to supress urinary cortisol secretion overnight (cortisol/creatinine) is another indicator of Cushing’s syndrome

Failure of serum cortisol to rise after insulin_induced hypoglycaemia (0.15 units insulin /kg) is a characteristic feature of Cushing’s syndrome In patients with pitiutary dependent Cushing’s 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