Steroids of the adrenal cortex Flashcards
(19 cards)
explain adrenal blood flow and functional zonation
-blood flows from outer cortex to inner medulla.
-enzymes are expressed in a layer-specific way (3 cellular levels of cortex). This means steroid sythesis in one layer can inhibit different enzmes in subsequent layers.
-this results in functional zonation of cortex with different hormones being made in each layer.
explain steroid synthesis in the adrenal cortex
-steroids such as aldosterone, cortisol and androgens are synthsised from cholesterol but by through different CYP enzyes (chytochrome oxidase superfamily) in the 3 layers of the cortex.
-deficiency of these enzymes can lead to congenital adrenal hyperplasia where aldosterone and cortisol production is reduced whilst androgen production is increased.
explain mineralocorticoid (aldosterone) function
-Na+ retention (whole body Na+ volume increased not concentration- osmotically equal amount of water also retained);
* active reabsorption of Na+ (with associated passive reabsoprtion of water)
* active secretion of K+
-volume regulation (part of RAAS)
explain control of aldosterone secretion
-reduced perfusion pressure, salt delivery and sympathetic activity and increased K+ is detected by the JGA and causes RAAS activation.
-angiotensinogen is released from the liver and converted into angiotension II which increases aldosterone secretion.
discuss aldosterone action on the PCT, DCT, and cortical collecting duct
-Aldosterone stimulates and increases the number of ENAC channels (more Na+ enters cell) on the plasma membrane when it binds to its receptor)
-it also increaes Na/K ATPase which means Na+ enters the circulation.
-cortisol has some cross reactivity with the aldosterone receptor so can activate it and cause hypernatremia
Explain how cortisol and aldosterone have similar affinity for the aldosterone receptor
Cortisol and aldosterone have a similar affinity for the aldosterone receptor:
-cortisol is rapidly metabolised to inactive cortisone in the kidney by the enzyme 11beta- hydroxysteroid dehydrogenase type 2.
-rare inactivating mutation of 11B-HSD2 leads to syndrome of apparant mineralcorticoid excess (AME) where the effects of aldosterone seem to be higher but aldosterone is low
-Liquorice contains a compound that blocks this enzyme
Explain a glcorticoid receptor (nuclear receptor)
-characteristic 3 domain structure; ligand binding, DNA binding, and N-terminal transcription cofactor-binding
-receptors dimerize on ligand binding and translocate to nucleus to change transcription.
-alternative splicing of the 9th exon gives rise to 2 different major isoforms from one gene
discuss regulation of genomic and non-genomic effects in target cells by the glucocorticoid receptors
-transactivation; glucocorticoid receptor enhances transcription of target gene
-transrepressin; glucocorticoid receptor represses transcription of target gene.
-anti inflammatory effects of glucocorticoids is due to transgression
-due to the large range of pathways the receptor affects, its suppression/activation can lead to many side effects so drugs have to be specific to a pathway
give the functions of glucocorticoids
-decreased glucose utilization (glucose sparing/conserving); decreased glucose uptake, proteolysis, gluconeogenesis (mainly from amino acids) and lipolysis.
-stress (e.g. fasting)
-without stress- this causes hyperglycaemia which increases insulin levels
-as insulin promotes lipogenesis and cortisol lipolysis, fat is being laid down and broken at the same tie. This causes central obesity and peripheral wasting
explain hypocortisolism and hypercortisolism in the cardiovascular system
-required for vascular integrity and maintenance of blood pressure by interacting with the NO system.
-hypocortisolism; inappropiate vasodilation, hypotension
-hypercortisolism (overwhelms enzymes all isn’t converted into inactive form); hypertension
explain anti inflammatory, immunosuppressive
-60 years of glucocorticoid therapy
-highly profitable industry
-extremely effective drugs but with many side effects
what is the effect of glucocorticoids on inflammatory mediators derived from arachidonic acid
-phospholipids form arachidonic acid via phospholipase A2
-this then forms different products such as thromboxane’s, prostaglandins and leukotrienes which act as messangers on local and distant tissues.
-glucocorticoids increases annexin which inhibits phospholipase A2 and also inhibits the COX enzymes (reducing thromboxane production)
explain the control of glucocorticoid and androgen production
1) VP; vasopressin (ADH)
2) Corticotropin-releasing hormone (CRH)
3) Adrenocorticotropic hormone (ACTH)
4) ACTH receptor; G protein coupled receptor stimulates cholesterol uptake and steroid synthesis via cAMP.
5) If cholesterol is low, there is a lack of negative feedback which causes more ACTH and ADH release. This is very important pathophysiologically
explain adrenal insufficiency
-Addison’s disease; primary adrenal insufficiency
-Primary doesn’t reduce aldosterone because aldosterone is controlled by the RAAS system
-secondary (hypopituitirism which is secondary to failure in RAAS)
-enzyme defect in steroid synthesis pathways
explain clinical features of Addison’s disease (primary adrenal insufficiency)
-low circulating adrenal steroids (cortisol and aldosterone) cause negative feedback that produces more ACTH.
-the plasma [Na+] is normal to low and the plasma [K+] is normal to high as aldosterone usually retains Na+ and excretes K+.
-elevated plasma renin due to low aldosterone signalling it.
-may be unmasked by significant stress or illness- shock, hypotension, volume depletion.
Explain Addison’s disease ; primary adrenal failure
-Increased CRH or signifcant hypotension causes ADH secretion which leads to plasma dilution and increased blood volume.
-this is why its associated with hyponatremia.
-ACTH is synthesised from the pro-opiomelanocortin prohormone (POMC) which also synthesises the a-MSH.
-MSH bind to melanocortin receptors to release melanin however there is cross-talk so ACTH can also bind to these receptors.
-this is why excess circulating ACTH may cause skin pigmentation
explain hypercortisolism and clinical features of hypercortisolism
Hypercortisolism:
-Cushing’s syndrome; excess glucocorticoid
-ACTH dependent;
* Cushing’s disease, due to increased ACTH secreion from a pituitary adenoma or an ectopic ACTH-secreting tumour
-ACTH-independent;
* adrenal adenoma or carcinoma
* Iatrogenic
Hypercortisolism Clinical features:
-hypertension, hyperglycarmia, truncal obesity, fatigue, muscle weakness, Virilization and depression, mood or psychiatric disturbances
explain dexamethasone suppression test
Low dose:
-normal; suppresses ACTH secretion via negative feedback
-Cushing’s; fails to supress ACTH.
High dose;
-suppression; in Cushing’s (pituitary gland tumour) as the gland needs a ‘kick’
-no suppression; adrenal tumour (low ACTH) or ectopic source of ACTH
explain the diagnosis of hypercortisolism
1) confirm the hypersecretion of cortisol by conducting a 24hr urinary cortisol test or take samples at the lowest of secretion
2) Determine the cause; measure the plasma cortisol and ACTH by doing short and long dexamethasone suppression tests.
3) exogenous glucocorticoids; ACTH and CRH reduce due to negative feedback;
* slow witdrawal required because the adrenal cortex has shut down and stopped synthesising cortisol due to the negative feedback
* it can’t restart production immediately as it takes a few days for the adrenal gland to recover.
-secondary (pituitary tumour); high ACTH and high cortisol will reduce CRH but ACTH will remain high as it can’t be changed by negative feedback so cortisol production will remain high.
