endocrinology: steroids Flashcards
what stimulates steroid hormone production, where is site of production
CRH released by hypothalmus causes release of ACTH by anterior pituitary stimulates secretion of cortisol by adrenal cortex. Negative feedback by cortisol, ACTH formed by cleavage of POMC
how is ACTH synthesised
expression of pro-POMC driven by CRH
cleaveage of pro-POMC creates POMC
cleavage of POMC using prohormone convertase (PC) creates pro-ACTH
further PC/ endopeptidase action generates ACTH and beta endorphins
how do steroid hormones circulate, when are they produce
steroid hormones require transport proteins when in blood circulation.
most steroid hormones are made on demand and cant be stored since they are membrane permeable
transport proteins a hyrophillic globular proteins, steroid binding globulins are CBG (cortisol binding globulin, binds carbon 21 steroids) and SHBG (sex hormone binding globulin, binds 18-19 carbon steroids)
what forms all steroid hormones
cholesterol (all steroid hormones are cholesterol derivatives)
how is cholesterol first modified in steroid synthesis
cholesterol is first modified by cholesterol side chain cleavage enzyme which converts it to pregnenolone, this enzyme is located on the inner mitochondrial membrane surface
the steroid is then trapped here since the outer environment is aqueous till the transport protein StAR is produced, when transported it is modified in the smooth ER usually, some modification takes place in mitochondria (synthesis of cortisol and aldosterone)
what is aldosterone
aldosterone (21 carbon) is an end product in one of the steroid synthesis chains, controls sodium/potassium balance and water levels, level of aldosterone controlled by circulating potassium levels as well as sympathetic activity
what is rate determining step in steroid synthesis
for all steroids is the conversion of cholesterol (C27) to pregnenolone (C21) catalysed by P450 cscc
where is are steroids produced
aldosterone/mineralocorticoids is produced in zona glomerulosa in kidney
cortisol/glucocorticoids is produced in zona fasciculata in kidney
other steroids are produced in zona reticularis
what is congenital adrenal hyperplasia
causes adrenal cortex in kidney to be very oversized, a type of salt wasting hyperplasia due to lack of P450c21
aldosterone and cortisol cannot be produced and as a result a lot of salt is lost due to lack of aldosterone
causes lack of negative feedback of HPA axis so increases ACTH drive increasing amount of androgens, this leads to female sufferers possibly being born w male genetalia, male sufferers have no effect on sex characteristics
what is another type of hyperplasia, other than congenital adrenal hyperplasia
salt sparing hyperplasia, aldosterone and cortisol are still not produced however deoxycorticosterone (DOC) is produced, it has aldosterone like actions which helps balance sodium/potassium
there is still ACTH drive and so lots of androgens are still present, affects women the same
how do adrenal androgens in hyperplasias effect men
they do not effect men since DHEA is swamped by testosterone
what are corticosteroid receptors, what are agonists
mineralocorticoid receptor (MR), in vivo agonist is aldosterone and DOC
glucocorticoid receptor (GR) in vivo agonist is cortisol
MR has no inherent specificity for minerlocorticoids, since in vivo concentrations of cortisol are much higher than aldosterone if cortisol is present aldosterone does not work, body prevents cortisol agonising MR using 11betaHSD enzyme which oxidises glucocorticoids which converts cortisol to cortisone which is not an MR agonist, this enzyme is expressed in areas where aldosterone action is desired, NAD is reduced in the process
what are isofroms of 11betaHSD
11betaHSD1 is NADPH dependent, highly expressed in key metabolic tissues including liver, adipose tissues and CNS, reduces cortisone to active cortisol in these tissues, converts NADPH to NADP+, used to reactivate cortisol in some tissues such as liver
11betaHSD2 is NAD+ dependent, expressed in aldosterone selective tissues, oxidises cortisol and cortisone, prevents activation of MR receptor by cortisol
type 1 is a reductase, type 2 is a dehydrogenase
what is AME
apparent mineralocorticoid excess
11betaHSD2 is inhibited/deficient, even though aldosterone is not binding, since cortisol is effects of aldosterone occur which physiologically acts as if there is excess aldosterone
type 1 AME: due to mutations in 11betaHSD2 gene, either in coding sequence or regulatory region
type 2 AME: due to enzyme inhibition
if cortisol production is high possibly due to a tumour or glucocorticoid resistance symptoms of AME occur since cortisol concs exceed HSD capacity
what is barkers hypothesis
11betsHSD is also important in development to protect foetus from effects of cortisol
higher in utero concs of cortisol lead to increase risks of obesity, coranary heart disease and hypertension
