Steroids of the Adrenal Cortex Flashcards
how is the adrenal gland divided?
cortex and medulla
what is the cortex?
outer layer
what does the cortex do?
secretes steroids
what is the medulla?
inner layers
what does the medulla do?
secrets catecholamines (mainly adrenaline)
what are three classes of cortex steroids?
glucocorticoids, mineralocorticoids, androgens
what are glucocorticoids?
mainly cortisol in mammals
what are mineral corticoids?
aldosterone
what are androgens?
have relatively minor effects, sex steroids
what is the condition for excess glucocorticoids?
cushings
what is the condition for adrenal insufficiency?
addisons
what is adrenal blood flow like?
arterial blood comes in at outer cortex, drains through network of capillaries and through medulla until draining out of venous end
what are the three zones in the cortical tissue?
zona glomerulosa, zona fasiculata, zona reticularis
what is layer/tissue specific enzyme expression?
adrenal cortex zones each act independently so different hormones are made in each layer
what can steroid synthesis in one layer cause?
inhibition of enzymes in subsequent layers
what does steroid synthesis begin from?
cholestrol
what do cytochrome enzymes do?
allow conversion of different substances
what happens when cholestrol enters a cell in the zona glomerulosa?
converted into pregnenolone
what are the three layers in the adrenal gland?
glomerulosa, faiculata, reticularis
what is the end result of the zone specific expression of enzymes?
only aldosterone is produced in the zona glomerulosa, cortisol in the zona fasiculata and androgens in zona reticularis
what is produced in the zona glomerulosa?
aldosterone
what is produced in the zone fasiculata?
cortisol
what is produced in the zona reticularis?
androgens
what is glucocorticoid?
cortisol
what are mineralocorticoids involved in?
salt and water balance
what does stress increase release of?
glucocorticoid
what do androgens do?
minimal function in humans with normal gonadal function
what effect does cortisol have?
glucose-conserving, prevents hypoglycaemia and stimulates gluconeogenesis in the liver
how does cortisol antagonise the effects of insulin?
counteracts the expression of GLUT-4 glucose transporter so uptake of glucose in adipose and muscle is inhibited so insulin levels increase
what is the effect of cortisol on lipids?
cortisol promotes lipolysis but the increased insulin promotes lipogenesis. so people with excess cortisol have hyperglycaemia, insulin resistant and extra fat storage.
what is the effect of cortisol in the immune response?
it depresses the inflammatory response
what is the function of glucocorticoids?
proteolysis lipolysis, decreased glucose utilisation
anabolic actions of glucocorticoids in the liver?
gluconeogenesis maintaining blood glucose during fasting
what is the effect of cortisol deficiency in cardiovascular function?
inappropriate vasodilation (low BP), hypertension in excess
what is arachidonic acid?
lipid derived substance that can be converted via phospholipase A2
what are prostaglandins?
lipid derived signalling molecules with paracrine effects
what do prostaglandins do?
mediate the inflammatory response, vasodilatation, increase in vascular permeability and attraction of leucocytes
what is the effect of cortisol on arachidonic acid?
inhibits its formation and cuts off the source of inflammatory signalling molecules
what type of receptor is the glucocorticoid receptor?
nuclear
how many forms of the glucocorticoid receptor are there?
two major isoforms due to alternate splicing
what type of binding do the glucocorticoid receptors have?
DNA binding and ligand binding domains
how will the receptor bind its cortisol ligand?
via the sequence in the ligand binding domain in the receptor dimerises and the bound receptor an bind to the DNA by the DNA binding domain to the hormone response element of the target gene
why are nuclear receptors controllers of transcription?
they can turn on or turn off the transcription of numerous target genes
what happens if the beginning of a gene, at the promotor region has the hormone response element?
the gene will be a target for the receptor
what are the two ways the glucocorticoid receptor can work?
transactivation and transrepression
what is transactivation?
where the glucocorticoid receptor enhances transcription of the target gene
what is transrepression?
where glucocorticoid receptor represses transcription of the target gene
what are anti-inflammatory effects of glucocorticoids thought to be due to?
transrepression of genes
what is the function of mineralocorticoid aldosterone?
retaining salt via the kidney and hence retaining water
what does the mineralocorticoid receptor do?
induced expression of genes for the Na+/K+/ATPase. increasing activity of Na+/K+ you increase the Na+ gradient between the cell and the tubular fluid so more Na+ moves into cell and circulation is retained
what network controls aldosterone?
renin-angiotensin network NOT hypothalamo-pituitary axis
what will drop in perfusion or Na+ conc or sympathetic activity cause?
activates the renin-angiotensin network
what does the renin enzyme do to angiotensinogen?
converts it into angiotensin I
what happens to angiotensin I in circulation?
converted to angiotensin II by ACE
what is ACE?
angiotensin converting enzyme
what does angiotensin II stimulate?
aldosterone secretion which is released according to need for sodium/water retention
what does enzyme 11B-HSD1 present in the kidney cause to happen to cortisol?
rapidly metabolises cortisol into inactive cortisone so that only aldosterone can activate the receptor
what does 11B-HSD2 do in mineralocorticoid responsive tissue?
inactivates cortisol into THE (tetrahydrocortisone)
in normal patients what is the ratio of THE:THR in the urine?
equal but if something interferes with the enzymes, THE will be less
what is glucocorticoid secretion controlled by?
hypothalamic-pituitary axis
how is ACTH released?
hypothalamus released CRH which stimulates anterior pituitary to release ACTH
what type of receptor is ACTH receptor?
GPCR and via cAMP stimulates cholesterol uptake and steroid synthesis
when does cortisol peak?
morning
what type of hormone is ACTH?
peptide. synthesised from the POMC prohormone gene
what can the POMC prohormone be spliced into?
ACTH and alpha MSH present in the skin promoting skin pigmentation by stimulating melanocytes
what type of receptor is the ACTH receptor?
melanocortin group
what happens when ACTH is high?
binds to melanocortin receptor for alpha MSH and stimulates melanocytes resulting in skin pigmentation
what is addisons disease?
primary adrenal insufficiency so adrenal cortex not functioning efficiently to produce enough cortisol and aldosterone
what will low levels of cortisol result in?
increased ACTH via negative feedback so increases skin pigmentation
what will loss of aldosterone result in?
hypotension due to water loss that usually maintains blood volume and pressure
what is the cause of addisons disease?
autoimmune destruction of the cells so ACTH has no effect on adrenal cortex and its the lack of adrenal cortex function that is the actual issue
symptoms of addisons?
weakness, weight loss, pigmentation, anorexia
what is cushings syndrome?
effects of excess glucocorticoids, most common cause is exogenous as a side effect of glucocorticoid drug treatment
why is cushing’s disease endogenous?
there is increased ACTH secretion due to pituitary adenoma
why are there high levels of ACTH in cushing’s disease?
there is an ACTH secreting pituitary tumour that is endogenous so high levels of ACTH so cortisol increases despite -ve feedback
symptoms of cushings?
central obesity, slim arms and legs, bruising, hirsuitism
diagnosis of cushings?
24 hr cortisol and dexamethasone suppression test
what is dexamethasone?
exogenous steroid that diagnoses cushings disease (shows ACTH coming from pituitary)
what do low loses of dexamethasone do?
suppress ACTH secretion via -ve feedback
what does it mean if a low dose of dexamethasone fails to sppress ACTH secretion?
there is Cushing’s disease
what will high doses of dexamethasone do?
suppress ACTH secretion in Cushings disease
what does it mean if neither high or low doses of dexamethasone suppress ACTH secretion?
there is an ectopic source of ACTH (tumour) or an adrenal tumour
what do you expect after giving dexamethasone?
low cortisol the next day due to -ve feedback system activating
why will ACTH not be affected if there is an ectopic source?
the tumour wont be under feedback control
what does the dexamethasone test allow you to distinguish between?
cushing’s disease ectopic source and cushing’s syndrom e
