The Adrenal Gland Flashcards
What is the adrenal gland?
a hybrid gland consisting of a cortex and a medulla
What is important about the hormones of the adrenal gland?
regulators of metabolism and adaptation to stress
What is cortisol?
glucocorticoid which increases plasma glucose levels
What is aldosterone?
mineralocorticoid promotes salt and water retention by the kidney
What else is secreted by the adrenal cortex?
weak androgens which can be converted to testosterone
What are the products of chromaffin cells?
epinephrine but also produces small amounts of norepinephrine
What are steroid hormones derived from?
cholesterol - different ring structures and side chains
What is the common features of steroid hormones?
lipid soluble so are freely permeable
How are steroid hormones are carried in the blood ?
complexed to binding globulins - corticosteroid binding globulin binds cortisol
Where are the enzymes that produce steroids from cholesterol?
in the mitochondria and smER
What are the sources of free cholesterol in the cell is maintained relatively constant?
cellular synthesis of cholesterol from acetate
LDL -> esterified cholesterol from LDL droplets inside the cell
What is the rate limiting step in steroidogenesis?
the transport of free cholesterol from the cytoplasm to the mitochodria
How is cholesterol carried into the mitochondria?
Steroidgenic Acute Regulatory Protein (StAR)
What is cholesterol converted to in the inner membrane?
pregnenolone by CYP450scc -side chain cleavage aka desmolase
Where does cholesterol conversion occur?
in the adrenal, ovary and testis
What converts pregnenolone to 17a-hydroxypregnenolone?
CYP17
What converts pregnenolone and pregesterone to mineralocorticoids?
CYP11B2
Where is CYP17 found?
not in glomerulosa
Where is CYP11B2 found?
only in the glomerulosa
What is synthesised in the fasiculata?
cortisol
Which enzyme esterifies free cholesterol?
acyl coA cholesterol transferase
Which enzyme turns lipid droplets back into cholesterol?
hormone sensitive lipase
What increases the activity of hormone sensitive lipase?
ACTH
How many reactions modify cholesterol to cortisol?
5
What is the first enzyme in the modification of cholesterol to cortisol and where is it located?
CYP11A1
inner mitochondrial membrane
How is the activity of StAR increased?
ACTH stimulates Gs -> cAMP-> PKA which phosphorylates StAR
How is cortisol predominantly transported in the blood?
CBG - 90%
albumin - 5-7%
What does the unbound form of cortisol do?
exerts its effects on tissues and feedsback on the pituitary and hypothalamus
What does the liver conjugate cortisol with?
gluconoride or sulfate
What is the circulating half life of cortisol?
70mins
How does cortisol act?
through glucocorticoid receptor which bind the Glucocorticoid response Element and regulates gene transcription
What happens to GR in the absence of cortisol?
resides in cytoplasm in complex with chaperones including heat shock protein 90 and cyclophillins
What happens to GR in the presence of cortisol?
moves to the nucleus and binding GRE near basal promotors of cortisol regulated genes
recruits co-activator or co-repressor proteins followed by covalent modification of chromatin
How is c-GR complex turned off?
phosphorylation and nuclear export or degradation of the GR
How is cortisol inactivated?
by 11b-HSD2
Why would cortisol be inactivated?
to prevent it binding and activating MR
What is the enzyme that activates cortisol?
11b-HSD1
Where is 11bHSD1 found?
in cells that express the GR including liver, adipose, skin and CNS
What can happen with natural black liquorice?
inactivates 11b-HSD2 which results in MR activation by cortisol, Na retention, increased BP and muscle spasms
What are the actions of cortisol essential for?
gluconeogenesis
suppression of inflammatory and immune responses
modulation of CNS function
vascular responsiveness to catecholamines
surviving fasting
What does cortisol stimulate?
protein and triglyceride catabolism
gluconeogenesis in the liver
What does cortisol inhibit?
glucose uptake by the body - goes to brain
elevates blood glucose - diabetogenic
bone formation
non-essential function i.e. growth
How is cortisol secretion regulated by the HP-axis?
CRH and ADH secretion are controlled by the supraoptichiasmatic nucleus and retina - circadian rhythm which thus regulates ACTH and cortisol
What happens if there is no ACTH?
fasciculata and reticularis atrophy and no cortisol production - dependent on exogenous glucocorticoids
What happens in excess ACTH?
enlarged adrenals, excess steroids
What does adrenal hyperplasia do in men and women?
women - virilism, hirsutism, clitoral hyperplasia
men - precocious puberty
What causes adrenal hyperplasia?
21-hydroxylase deficiency
What happens when the body cannot cope with the demand for cortisol?
ACTH might be used to stimulate androgen production pathway
What is the difference between ACTH independent and dependent Cushings Syndrom?
dependent - pituitary tumour - Cushings disease
independent - adrenal tumour
What are the 2 primary consequences of Cushings syndrome?
Salt and Water retention with renal loss of K - results in moon face and cardiac hypertrophy due to increased BP and peripheral oedema and glucocorticoid induced diabetes
Catabolism causes muscle wasting, fat accumulation, osteoporosis, kyphosis, buffalo hump, fracture, ulcered skin and poor wound healing§
What is Addisons disease?
a rare, chronic endocrine disorder in which the adrenal glands do not produce sufficient steroid hromones
What are the symptoms of addisons disease?
over production of ACTH
skin hyperpigmentation
What are the glucocorticoid deficiency symptoms?
hypglycaemia, hypotension, changes in mood, muscle weakness, anemia, decreased GI motility and appetite
What are the mineralocorticoid deficiency symptoms?
loss of Na, craving salt, loss of fluids and retention of K, hypotension, muscle fatigue and pain due to increased EC K+
What does aldosterone govern?
EC volume due to action on Na retention
Where is aldosterone produced?
zona glomerulosa
What are the two integrated systems for balancing salt and water?
ADH and aldosterone
What enzyme converts cholesterol to aldosterone?
aldosterone synthase
What limits the rate of Aldosterone secretion?
there is no storage pool of the hormone
What stimulates the production of aldosterone?
ACTH, EC K, and angiotensin II
How much aldosterone is free in the plasma?
37%
What is aldosterone bound to in the plasma?
GBG and albumin
Where does aldosterone act?
mainly kidney
colon, salivary glands, sweat
How does aldosterone act?
binds mineralocorticoid receptor and regulates gene transcription
What ensures cortisol does not activate the MR?
11b-HSD2
What does aldosterone stimulate transcription of?
ROMK channel
ENaC
Na-K pump
SGK-1
What is the function of the ROMK?
increases K secretion on apical membrane
What is the function of ENac?
brings Na into the cell on the apical membrane
What is the function of the Na-K pump?
takes Na into the blood and K into the cell on the basolateral membrane
What is the function of SGK-1 expression?
enhances ROMK, ENaC and Na-K pump
decreases degradation fo ENac
serine/threonine kinase
What can loss of aldosterone result in?
hyperkalaemia, hypotension
What sort of change does a 2% change in Na excretion cause?
3L change in ECV
How is aldosterone regulated by Na and water levels?
Feedback through the RAS system AngII binds to AT1 receptor Gaq -> PLC -> DAG and IP3 Ca increases depolarising cell and increasing Ca further Ca stimulates production of P450scc delivery of cholesterol aldosterone synthase
What does Ca stimulate in glomerulosa cells?
production of P450scc
delivery of cholesterol
aldosterone synthase
What other two systems increase and regulate aldosterone synthesis?
High EC K+
ACTH
How does BP regulate aldosterone synthesis?
low BP is detected by baroreceptors in the kidney which release renin from Juxtaglomerular cells and cause activation of sympathetic fibers and innervate JG cells through b1-adrenergic receptors
what prevents chromaffin cells from developing into post-ganglionic sympathetic neurons?
cortisol inhibits neuronal differentiation
What does cortisol induce in the chromaffin cells?
the expression of PNMT which converts norepinephrine to epinephrine
where are adrenal medullary catecholamines secreted?
into the blood where they act as hormones
What does ACTH stimulate in the adrenal medulla?
the conversion of tyrosine to DOPA
What enzyme converts tyrosine to DOPA?
tyrosine hydroxylase
What is DOPA converted to and by what?
dopamine by amino acid decarboxylase
How is dopamine stimulated to convert to norepinephrine?
ACTH stimulates dopamine b-hydroxylase
Where does norepinephrine go?
diffuses out of the granule
Where does epinephrine go?
back to the granule by vesicular monoamine transporters VMATS
What is epinephrine stored in the chromaffin granule with?
ATP, Ca, chromogranins
What is the difference between the needs for epinephrine and norepinephrine?
all of the epinephrine is derived from the medulla
only 30% of circulating norepinephrine is derived from the medulla
Where does the rest of the norepinephrine come from?
the postganglionic sympathetic nerve terminals
Where does the rest of the norepinephrine come from?
the postganglionic sympathetic nerve terminals
Where are the autonomic centres that initiate the sympathetic response?
hypothalamus and brain stem
Where do the hypothalamus and brain stem recieve inputs from?
the cerebral cortex, limbic system and other regions of the hypothalamus and brain stem
What are the general signals which stimulate secretion of epinephrine and norepinephrine?
various forms of stress, including exercise, hypoglycaemia and surgery
What is the chemical signal for catecholamine release?
ACh -> nAChR on the chromaffin cells
What enzymes does ACh increase the rate of?
tyrosine hydroxylase
dopamine b-hyrdoxylase
exocytosis of chromaffin granules
How does cortisol regulated catecholamine secretion?
maintaining adequate expression of PNMT
what are the primary enzymes involved in degrading catecholamines?
MAO - neuronal mitochondria
COMT
What is the fate of catecholamines in non-neuronal tissues?
methylation to metanephrine and metanorepinephrine
What does MAO convert metanephrine to?
VMA - vanillylmandelic acid
What does the liver and gut do to metanephrine?
conjugates them to sulfate or glucuronide
Where is epinephrine more potent than norepinephrine?
the liver where it activates b2 increaseing cAMP
where do catecholamines decrease cAMP?
pancreatic b cells on a2
Where do catecholamines increase IP3 and DAG?
a1 on vascular smooth muscle
Where are b1 and b3 found?
heart and adipose tissue respectively
What are the physiologic actions of catecholamines?
fatty acids broken down blood glucose increased HR and force increases digestion slows respiratory passages dilate bronchiole dilation occurs BP goes up from vasoconstriction
What is pheochromocytoma?
uncommon tumour caused by hyperlasia of the adrenal medulla or other chromaffin tissues
What does pheochromocytoma cause?
sudden hypertension headaches episodes of sweating anxiousness tremor glucose intolerance
How is pheochromocytoma diagnosed?
urinary catecholamines are detected for diagnosis
