regulation of adrenal steroidogenesis Flashcards
types of steroid hormones 6
6 mineralocorticoids glucocorticoids vitamin d androgens oestrogen progesterones
how do steroids act 2 ways and difference in paths
- classical genomic mechanism via a steroid coupled receptor translocating to the nucleus causing transcription
- non genomic through intra-cellular signalling pathways eg calcium channels
number 2 is fast and 1 is slow
what is the percursor of steroid hormones
c27 cholesterol
how are steroids made in stages
- hydrophobic 6 carbon side chain removed off c27= c21 as steroids more water soluble
- most steroids then a varied substituent at c17
- extra specificity from side chain modification
2 enzymes involved in the steroid production
- cytochrome p450 family which is also involved in drug detoxification in liver as cleaves or modifies choelstrol side groups in MONO OXYGENASE REACTION
- STEROID DEHYDROGENASES interconvert from active to inactive forms of steroids ie coritsone and cortisol
which enzyme converts cortisol to cortisone and vice versa and in which organs
11b hsd1 converts cortisone to cortisol in liver and tissues to bind to gr and mr
11bhsd2 in kidney converts cortisol to cortisone
function of the adrenal glands 3
- make steroids/ catecholamines
- co-ordiate the body’s response to internal and environmental stimuli
- first line of defence to physiological stress
vertebral level of adrenal glands
t12
blood supply to cortex and medulla
cortex= short arteries penetrating capsule= subscapular plexus or arterioles and capillary sinusoids
medulla:long cortical arteries and capillaries from cortex and drains via central medullar vein
what level produces what in adrenals and what stimulates it
- symp ns acts on medulla= adrenaline and noradrenaline
- acth acts on zr= adrenal androgens
- acth acts on zf= cortisol
- angiotensin II from RAAS acts on zg= aldosterone
what enzymes does the zona glomerulosa have
aldosterone synthase
what enzymes does the zona fasciculata have
same as zg except has 11b hydroxylase and 17a hydroxylase but lacks alosterone synthase so produces cortisol
what enzymes does zr have
zr has 17a hydroxylase and 17,20 lyase but lower levels of 11b hydroxylase and no aldosterone synthase so produces adrenal androgens
3 ways in which 11b hydroxylase differs to alosterone synthase
- being expressed exclusively in zf
- having only 11b hydroxylase activities whilst AS has both 11 hydroxylase and 18 hydroxylase activities
- AS converts DOC via corticosterone and 18 hydroxycorticosterone in a 3 step reaction 11b hydroxylase converts
3 ways in which 11b hydroxylase differs to alosterone synthase
- being expressed exclusively in zf
- having only 11b hydroxylase activities whilst AS has both 11 hydroxylase and 18 hydroxylase activities
- AS converts DOC via corticosterone in a 3 stage reaction whilst 11 obhase converts in a single reaction to cortisol
what accumulates in CAH 11 obhase deficiency
both deoxycortisol and deoxycorticosterone as in zf a small quantity of deoxycorticosterone is also made which is then usuallly converted into corticosterone
describe the hypothalamic pit adrenal axis
crh released from the paraventricular
acth released from ant pituitary then act on zf to produce cortisol which then regulates its own function by negative feedback
the 3 stimulatory and 3 inhibitory factors of cortisol aka glucose
stimulatory
- serotonin
- acetylcholine
- encephalin
inhibitory
- alpha adrenergic agonist
- GABA, endorphin
- dopamine
how is acth made in the ant pituitary 2
what else is POMC cleaved into
- crh binds to gpcr, releasing 2ndary CAMP messenger
- POMC cleaved to ACTH and other peptides
- beta lipotrophin
- beta endorphin
- opioid enkephalin
how does acth act on zf cells
- acth attaches to gpcr releasing camp 2nd messenger
- causes cholesterol ester hydrolase to increase which increases transport to mitochondria via cholesterol ester being converted to free cholesterol
- acetyl coA by HMG coA reductase is converted into free cholesterol
- ssc p450 cleaves cholesterol to pregnenolone
how does cholesterol cross the mitochonrial membrane and what stimulates it and what gene is related
chaperoned by stAR steroid acute regulatory protein the rate limiting step -stimulated by aii or ACTH -congenital adrenal hyperplasia CAH
what are the catabolic and anabolic actions of cortisol and why elevated levels are bad
anabolic action
-increased gluconeogenesis
catabolic action
- reduced glucose uptake= muscle wasting
- immune system suppression= poor wound healing
- increased muscle protein breakdown
- increased fat breakdown
- increased bone resorption=osteoporosis
- increased appetite and central fat deposition
- excess mineralocorticoid action = hypertension
causes of cortisol excess and their blood levels
- cushing’s syndrome= adrenal or ectopic tumuors = low plasma acth but high cortisol
- cushing disease= pit tumour secretes acth causing high cortisol and high acth and hypertension leading to low aldosterone and raas
what binds to cortisol
transcortin and albumin
plasma ratio cortisol to cortisone
and plasma ratio free to bound cortisol
1: 2
1: 96
RAAS system
liver release angiotensinogen
converted by renin to angiotensin I then ACE released by lungs converts to angiotensin II
action of angiotensin II
-sympathetic activity
-tubular Na, Cl, K, excretion, H2O retention
-aldosterone secretion
-vasoconstriction
-ADH secretion
increase BP
what activates renin secretion
juxtaglomerula cells sense reduced perfusion
macula densa low sodium
low arterial pressure
long term effects of increased RAAS
- muscle hyperplasia
- cardiac fibrosis
- L.ventricular hypertrophy
- hypertension
- changes to adrenal, kidney and heart
