Adrenal Gland PDF

Adrenal Cortex ● Cholesterol→ precursor for all steroid hormones ○ Cholesterol is NOT soluble!! → needs to be transported into the cell by LDL (LDL= bad cholesterol) ■ Cholesterol is NOT lipophilic (even though steroid hormones are) ○ Cholesterol enters cell→ goes into mitochondria to get converted...

Adrenal Cortex ● Cholesterol→ precursor for all steroid hormones ○ Cholesterol is NOT soluble!! → needs to be transported into the cell by LDL (LDL= bad cholesterol) ■ Cholesterol is NOT lipophilic (even though steroid hormones are) ○ Cholesterol enters cell→ goes into mitochondria to get converted to pregnenolone ■ This only happens if you need more steroid H’s. if you don't cholesterol is stored as cholesterol esters in lipid droplets until it is needed ■ Production of steroids: mitochondria, cytoplasm, smooth ER ● Transport proteins ○ cortisol= CBG (90%) and transcortin ■ CBG= corticosteroid binding protein ■ Less than 5% is free→ 60-90 minute half life ● Small amount free, but it has a long half life ■ Plasma concentration= 5-20 micrograms/dL ○ aldosterone= albumin ■ 50% bound to albumin (and CBG) with low affinity ■ Half life= 20 minutes ● Half life is shorter bc only 50% is bound to albumin and loosely→ so it is more easily degraded bc its not protected by the protein ● Short half life= short term effect on body ● Main hormones secreted by adrenal cortex→ all are steroid hormones ○ Cortisol ■ glucocorticoid ○ Aldosterone ■ Mineralocorticoid ○ Androgens ● Zona glomerulosa= aldosterone ○ Outermost layer ○ Cholesterol→ cytochrome p450→ pregnenolone→ 3B- hydroxysteroid dehydrogenase→ progesterone→ 21- hydroxylase→ DOC→ 11B- hydroxylase→ corticosterone→ aldosterone synthase→ aldosterone ○ Mechanism of aldosterone ■ Diffuses into kidney (bc lipophilic) ■ Activates MR receptor→ releases HSP→ can now dimerize and enter nucleus ● MR= mineralocorticoid receptor ■ Increases expression of Na and K channels, and Na/ K pump in kidney ● Na channel and K channel on side of lumen (urine) ○ Passive diffusion ● Na/K pump on side with blood ○ Pumps Na into blood, pumps K into cell ○ ● This keeps intracell K high so it diffuses down into urine, and intracell Na low so it diffuses from urine, back into the cell to be then pumped back into the blood ■ Water follows Na so it is also retained→ increases blood volume and increases blood pressure ○ Low blood volume→ kidney releases renin→ converts angiotensin→ angiotensin I→ ACE converts it into angiotensin II→ increases aldoesterone release ○ If you block aldosterone secretion→ hyperkalemia (too much K in blood) ○ If you are in a stress-related environment→ increased retention of Na and water Zona fasciculata= cortisol ○ Middle layer ○ Mechanism: ■ Brought to the (liver) by CBG/ transcortin ■ Diffuses into cell ■ Interacts with nuclear receptor (glucocorticoid R= GR) ● GR is bound to heat shock protein (HSP), when cortisol binds it releases HSP ● Now the GR receptor can dimerize and enter the nucleus ■ Binds to specific DNA sequences called glucocorticoid response elements… eventually increases glucose production in the liver ○ Role of cortisol= increase blood glucose by increasing gluconeogenesis ■ Adipose tissue→ free fatty acids released ■ Muscles→ breaks down proteins into amino acids→ goes to liver for gluconeogenesis ■ Anti- insulin action ● Insulin moves the GLUT4 receptor to the membrane (to bring glucose into the cells, reducing blood glucose levels) ● Cortisol blocks GLUT4 from getting to the membrane→ no glucose can go into the cells→ keeps blood glucose levels high ■ Inhibits inflammatory and immune responses ● Ex. prescribe a pt corticosteroids to reduce inflammation ■ Minor role: increases vascular tone in the heart ○ Regulation of cortisol ■ stress/ trauma→ hypothalamus releases CRH (NOT a steroid) → makes anterior pituitary release ACTH→ adrenal cortex makes cortisol ■ Increased cortisol levels have negative feedback to both hypothal to stop CRH and to anterior pituitary to stop ACTH ■ *ACTH levels will always peak BEFORE cortisol levels* ● Bc ACTH triggers cortisol release ● During sleep= low ACTH/ cortisol, but they peak just before waking up ○ How ACTH controls cortisol synthesis: ■ ● ● ● ACTH binds to the melanocortin 2 receptor= GPCR that activates adenyl cyclase/ increases cAMP→ cAMP activates PKA→ triggers releases of cholesterol esters from lipid droplets (storage) → they get hydrolyzed back into cholesterol ■ ACTH stimulates transfer of cholesterol into the outer mitochondrial membrane, and then also into the inner mitochondrial membrane ■ ACTH stimulates P450 to convert cholesterol into pregnenolone Zona reticularis= androgens ○ innermost layer MR receptor (aldosterone) binds both aldosterone and cortisol with the same affinity= bad ○ MR is in the kidneys→ you need to prevent cortisol from getting into the kidneys or else it would always be activated→ always retain Na→ always have high BP= BAD ○ Solution→ kidney cells have 11 beta hydroxysteroid dehydrogenase (11BOHSD) ■ Converts cortisol→ cortisone ● Cortisone can’t bind to MR ■ Inhibited by liquorice ● Pts who eat a lot of liquorice have high blood pressure ● Bc licorice inhibits 11B- OHSD→ cortisol doesn’t get converted→ cortisol binds to MR→ constant retention of Na Cushing’s syndrome= excess glucocorticoids ○ Causes ■ Most common: exogenous therapeutic glucocorticoids (ex. Using steroids to treat inflammation) → syndrome ■ Tumor of anterior pituitary→ causes excess ACTH secretion→ too much cortisol made AND excess androgens→ called cushing’s disease ■ Tumor of adrenal cortex→ making too much cortisol ○ Symptoms ■ Red cheeks ■ Receding hairline ■ Striae (stretch marks) → bc no elasticity in the skin ■ Moon face ■ Pendulous abdomen ■ Poor muscle development ■ Poor wound healing ■ Bruisability ○ Clinical features ■ Weight gain and central obesity ■ Hypertension ● Bc excess cortisol→ cant all be converted to cortisone in kidney→ stimulates MR aldosterone receptor→ increases blood pressure ● Also bc it increases vascular tone ■ ● Diabetes mellitus= impaired glucose tolerance ● Bc cortisol has anti-insulin factor ■ Striae ● Loss of elasticity in skin→ bc cortisol decreases fibroblast formation and synthesis ■ osteopenia/ osteoporosis ● Bc cortisol decreases osteoblast formation ■ Proximal myopathy ● Bc cortisol stimulates protein break down into amino acids→ excess cortisol can cause muscle wasting Hypoadrenalism ○ Adrenal cortex is not making enough cortisol ○ Causes ■ 99% of cases: abruptly stop taking glucocorticoid medication ● Need to taper off glucocorticoids→ bc high levels of exogenous glucocorticoids the adrenal cortex basically shuts off bc the high levels inhibit ACTH production→ need to taper so adrenal cortex has enough time to start working again ■ 1% of cases: ● Primary adrenal insufficiency (Adrenal cortex destruction= Addison’s disease) ○ High levels of ACTH bc there is no cortisol being produced so there is no negative feedback to stop it ○ Symptoms ■ Weakness ■ Weight loss ■ Increased pigmentation ● High ACTH→ ACTH also contain melanocyte stimulating hormone (MSH) → so you also have high levels of MSH ● *pigmentation will go away with tx of glucocorticoids* ■ Postural hypotension ■ Anorexia ● Secondary adrenal insufficiency→ any pituitary or hypothalamic disease causes hypopituitarism→ CRH or ACTH deficiency ○ Bc there won’t be enough stimulation to increase cortisol production Adrenal Medulla ● Adrenal medulla ○ In the center of the gland ○ 10-20% of the gland ○ Neuronal origin ○ ○ ● ● ● ● ● ● Made of chromaffin cells Secretes catecholamines ■ Made from tyrosine ■ Catecholamines are stored in granules→ can be quickly released when needed ● Diff than steroid H’s that are secreted by diffusion/ not stored ○ **stimulated by sympathetic nervous system** Biosynthetic pathway ○ SCRIBE NOTES ○ Limiting step= tyrosine hydroxylase (TH) ■ Tyrosine→ DOPA ○ Requires ATP→ bc moving things into the granules from cytoplasm Adrenergic receptors ○ Epinephrine→ Beta 1 and Beta 2 ■ Gs→ increases adenyl cyclase→ increases cAMP ○ Norepinephrine→ Alpha 1 and Alpha 2 ■ Alpha 1= Gq→ PLC→ DAG/IP3→ increased calcium levels ■ Alpha 2= Gi→ inhibits adenylyl cyclase→ decreases cAMP Effects of epi/ norep ○ Increase glucose production (E>NE) ■ Increase gluconeogenesis in liver ■ Release of lactate from muscle via glycogen breakdown (glycogenolysis) ○ Increase lipolysis in fat cells→ Epi ○ Dilation of bronchioles→ Epi ■ Smooth muscle relaxation ○ Increase rate and force of contraction in heart (E>NE) ○ Constriction of blood vessels→ increases BP (NE>E) ■ Smooth muscle contraction in arterioles Regulation of secretion ○ Short half lives ○ Exocytosis of granules is calcium dependent ○ Triggers: ■ Fear ■ Hypoglycemia stimulus pregang sym. Neurons→ increases Ach release Pheochromocytoma ○ Tumor of adrenal medulla→ produces too much catecholamines ○ Symptoms ■ Headaches ■ Chest pain ■ Extreme anxiety ■ Cold perspiration ■ High BP ■ Tachycardia Epinephrine is a vasoconstrictor ○ ○ Beta-blockers→ antagonists of epi (compete with catecholamines for binding to adrenergic receptor, but they dont actually stimulate it) ■ Used to tx hypertension Amphetamines→ agonists of epi→ stimulate the adrenergic receptor ■ Mimics effects of epi