Endocrinology 8- HPA Axis pt 2 Flashcards
Purpose of mineralocorticoids
Steroid hormones which regulate sodium and water balance - most common is aldosterone although 11 deoxycortisone and others have mineralocorticoid action
where does aldosterone act
distal tubule of kidney
colon
salivary ducts
sweat ducts
Main target of aldosterone is what organ, and what does it do?
Kidney- main function is to stimulate reabsorption of sodium and in turn – increase water reabsorption and increase potassium secretion
Renin angiotensin aldosterone system –
Renin is secreted in response to decrease in blood volume and blood pressure – sensed by JGA in kidney – renin is produced. Renin cleaves angiotensinogen to angiotensin I, then angiotensin I is converted by ace to angiotensin II. Angiotensin II stimulates the zona glomerulosa to release aldosterone – stimulates a specific enzyme called aldosterone synthase. Angiotensin II causes vasoconstriction on its own, so once you also have aldosterone you take up sodium again and also increase plasma volume as a result.
What enzyme does angiotensin II stimulate for aldosterone synthesis
aldosterone synthase
Is aldosterone or AVP the primary regulator of extracellular volume?
Aldosterone
Aldosterone does what?
stimulates sodium and water reabsrption in kidney, stimulates potassium excretion, and net result is increased extracellular fluid volume and blood pressure sodium in EC space retains water)
Aldosterone is the primary regulator of what?
free water balance
AVP does what?
stimulates distal nephron water permeability which leads to increased water retention - decreases lasma osmolarity which secondarily affects sodium concentration in blood. It does not target sodium and potassium directly.
Cortisol binds to what two receptors?
MR and GR – it is very high in concentration as well. This does not happen because of CBG and tissue specific enzymes, including 11b-HSD2
Why does cortisol not bind to random mineralocorticoid receptors
because of cbg which has a way higher affinity for cotisol than aldosterone, and will drop it off with tissue specific enzymes.
11b HSD2
Enzyme - when cortisol enters the cell, enzyme will deactivate it to something called cortisone. Cortisone has no biological action. Then aldosterone is free, no strong binding protein (mostly binds to albumin). It binds to the MR and does the response. Cortisone can be released back to blood stream
Licorice effect on cortisol
Impacts 11b HSD2- excessive consumption can lead to increased sodium and water retention
DHEA/S; metabolite = what?
androstendione
What is androsteinedione
precursor for more potent androgen testosterone, and for estrogens converted in reproductive tissues
Where does 50% of total androgen precursors in male prostate come from?
adrenal gland
Where do the androgens that initate and maintain pubic and axillary hair growth come from?
adrenal glands
Why are the androgens from the adrenal gland called “weak”
weak affinity for androgen receptors
What enzyme does ACTH activate that initiates steroid hormone synthesis
STAR (steroidogenic acute regulatory protein) –
what does STAR do?
helps free cholesterol get from outer to inner mitochondrial membrane - rate limiting step – has a cytochrome p450 enzyme known as desmolase that converts cholesterol to pregnenolone
What is the precursor for all steroid hormones
pregnenolone
Zona glomerulosa main hormone
mineralocorticoids (aldosterone)
zona fasiculata main hormones
glucocorticoids (cortisol)
zona reticularis main hormone
weak androgens (dhea)
Congenital adrenal hyperplasia (CAH) – most commonly 21a hydroxylase deficiency – signs and symptoms
Results in excess DHEA, no minearlocorticoids, or glucocorticoids (most common cause of CAH) – indicated clinically by virilization and ambiguous genetalia at birth, as well as sodium loss. You get hypotension, hyperkalemia, high plasma renin, masculinziation, and high ACTH.
Mechanism of action 21 a hydroxylase deficiency
21 hydroxylase is only expressed glomerulosa and fasiculata - but not in reticularis. So you get a block - after progesterone, you can’t convert anymore, you get no more glucocorticoids or mineralocorticoids. The reticularis cells are not affected though. And without cortisol, we get no negative feedack so ACTH remains very high, so all the processes are stimulated including adrenal growth. Because of the way blood flows, precursors flow to third zone –> get excess androgens being made. Masculinzation then happens because of high androgens.
CYP11B1 / 11 hydroxylase deficiency - signs and symptoms
No cortisol
No aldosterone– but high MR activity
Increased androgens
Clinical presentation - hypertension and hypokalemia, masculinzation and high ACth
Mechanism of action 11 hydroxylase / CYP11B1 deficiency
Mutation in zona fasiculata but not CYP11B in glomerulosa– you dn’t have 11 hydroxylase to make cortisol, so you lose negative feedback and have extremely high ACTH. You get no cortisol or aldosterone but high MR activity clinically speaking. We do have the precursr to 11DOC normally converted very quickly to aldosterone. But in this case, because there’s so much of it, it’s released into the bloodstream. It will bind to and activate mineralocorticoid receptor. Therefore, we get hypertension, hypokalemia, and no aldosterone because this enzyme for aldosterone synthesis responds to angiotensin II, and in this case, you are hypertensive and not producing renin
CYP17/ 17-a-hydroxylase deficiency signs and symptoms
No cortisol, no aldosterone but increased MR activity, decreased androgens
clinical presentation:
Hypertension, hypokalemia, feminization and ambiguous genetalia, high ACTH
17-a-hydroxylase / CYP17 deficiency mechanism of action
This enzyme will be missing in two zones - firstly you will lose cortisol so you get high ACTH due to lack of negative feedback. And again, here we have no androgens which results in feminization and ambiguous genetalia in a male child. You get hypokalemia and hypertension, high MR activity due to the 11DOC activating but because bp is too high there’s no renin so aldosterone doesn’t exist.
Most cells in adrenal gland release epinephrine, or norepinephrine?
Epinephrine
What is rate limiting step in catecholamine synthesis
tyrosine hydroxylase
What hormone is required for synthesizing epinephrine from norepinephrine?
Cortisol
When is epinephrine released
in response to acute stress such as pain, perceived danger – mediated at level of hypothalamus
Epinephrine’s main action
Enhance state of arousal and awareness
receptors for epinephrine
adrenergic receptors
epinephrine effect on metabolism
glucose release increase, increased metabolic rate due to activation of b adrenergic receptors , cardiovascular b adrenergic receptors –> increased HR
3 main targets of metabolic functions of epinephrine
muscle, liver, fat (promotes glycogenolysis, gluconeogenesis, fat mobilization)
How does epinephrine release lead to changes in response to long term stress?
Stressors come in –> acute stress activates NE in SNS to be released on axon terminals at site. NE terminals in brain activate CRH neurons – this one input into HPA axis, then CRh will inhibit feeding behavior and sexual activity – and in even longer ter, when HPA axis is continued to be activated, cortisol mobilizes energy and enhances cardiovascular responsiveness to catecholamines due to upregulating the adrenergic receptrs, and you suppress inflamatin, etc.
Monoamine metabolism: COMT methylation
Major source of metanehrine and normetanephrine in adrenal gland, converts DHPG to MHPG (precursor of VMA) – excreted in urine and can be diagnostic for pheochromocytomas
Catecholamine overproduction from pheochromocytomas
Tumor originating from chromaffin cells
Symptoms - hypertension with no response to medication, headaches, tachycardia
diagnosis - measurements of urinary metanephrines (VMA)
treatment: SUrgery, and prior to this, beta and alpha blockers
what is the “10%” tumor
adrenal pheochromocytomas
aside from the adrenal gland, what are some extraadrenal places a catecholamine releasing pheochromocytoma could be?
SNS chain along spinal cord, overlaying distal aorta, within ureter, within urinary bladder
