Endocrinology 8- HPA Axis pt 2

Question 1

Purpose of mineralocorticoids

Answer 1

Steroid hormones which regulate sodium and water balance - most common is aldosterone although 11 deoxycortisone and others have mineralocorticoid action

Question 2

where does aldosterone act

Answer 2

distal tubule of kidney
colon
salivary ducts
sweat ducts

Question 3

Main target of aldosterone is what organ, and what does it do?

Answer 3

Kidney- main function is to stimulate reabsorption of sodium and in turn – increase water reabsorption and increase potassium secretion

Question 4

Renin angiotensin aldosterone system –

Answer 4

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.

Question 5

What enzyme does angiotensin II stimulate for aldosterone synthesis

Answer 5

aldosterone synthase

Question 6

Is aldosterone or AVP the primary regulator of extracellular volume?

Answer 6

Aldosterone

Question 7

Aldosterone does what?

Answer 7

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)

Question 8

Aldosterone is the primary regulator of what?

Answer 8

free water balance

Question 9

AVP does what?

Answer 9

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.

Question 10

Cortisol binds to what two receptors?

Answer 10

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

Question 11

Why does cortisol not bind to random mineralocorticoid receptors

Answer 11

because of cbg which has a way higher affinity for cotisol than aldosterone, and will drop it off with tissue specific enzymes.

Question 12

11b HSD2

Answer 12

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

Question 13

Licorice effect on cortisol

Answer 13

Impacts 11b HSD2- excessive consumption can lead to increased sodium and water retention

Question 14

DHEA/S; metabolite = what?

Answer 14

androstendione

Question 15

What is androsteinedione

Answer 15

precursor for more potent androgen testosterone, and for estrogens converted in reproductive tissues

Question 16

Where does 50% of total androgen precursors in male prostate come from?

Answer 16

adrenal gland

Question 17

Where do the androgens that initate and maintain pubic and axillary hair growth come from?

Answer 17

adrenal glands

Question 18

Why are the androgens from the adrenal gland called “weak”

Answer 18

weak affinity for androgen receptors

Question 19

What enzyme does ACTH activate that initiates steroid hormone synthesis

Answer 19

STAR (steroidogenic acute regulatory protein) –

Question 20

what does STAR do?

Answer 20

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

Question 21

What is the precursor for all steroid hormones

Answer 21

pregnenolone

Question 22

Zona glomerulosa main hormone

Answer 22

mineralocorticoids (aldosterone)

Question 23

zona fasiculata main hormones

Answer 23

glucocorticoids (cortisol)

Question 24

zona reticularis main hormone

Answer 24

weak androgens (dhea)

Question 25

Congenital adrenal hyperplasia (CAH) – most commonly 21a hydroxylase deficiency – signs and symptoms

Answer 25

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.

Question 26

Mechanism of action 21 a hydroxylase deficiency

Answer 26

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.

Question 27

CYP11B1 / 11 hydroxylase deficiency - signs and symptoms

Answer 27

No cortisol
No aldosterone– but high MR activity
Increased androgens

Clinical presentation - hypertension and hypokalemia, masculinzation and high ACth

Question 28

Mechanism of action 11 hydroxylase / CYP11B1 deficiency

Answer 28

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

Question 29

CYP17/ 17-a-hydroxylase deficiency signs and symptoms

Answer 29

No cortisol, no aldosterone but increased MR activity, decreased androgens

clinical presentation:
Hypertension, hypokalemia, feminization and ambiguous genetalia, high ACTH

Question 30

17-a-hydroxylase / CYP17 deficiency mechanism of action

Answer 30

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.

Question 31

Most cells in adrenal gland release epinephrine, or norepinephrine?

Answer 31

Epinephrine

Question 32

What is rate limiting step in catecholamine synthesis

Answer 32

tyrosine hydroxylase

Question 33

What hormone is required for synthesizing epinephrine from norepinephrine?

Answer 33

Cortisol

Question 34

When is epinephrine released

Answer 34

in response to acute stress such as pain, perceived danger – mediated at level of hypothalamus

Question 35

Epinephrine’s main action

Answer 35

Enhance state of arousal and awareness

Question 36

receptors for epinephrine

Answer 36

adrenergic receptors

Question 37

epinephrine effect on metabolism

Answer 37

glucose release increase, increased metabolic rate due to activation of b adrenergic receptors , cardiovascular b adrenergic receptors –> increased HR

Question 38

3 main targets of metabolic functions of epinephrine

Answer 38

muscle, liver, fat (promotes glycogenolysis, gluconeogenesis, fat mobilization)

Question 39

How does epinephrine release lead to changes in response to long term stress?

Answer 39

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.

Question 40

Monoamine metabolism: COMT methylation

Answer 40

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

Question 41

Catecholamine overproduction from pheochromocytomas

Answer 41

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

Question 42

what is the “10%” tumor

Answer 42

adrenal pheochromocytomas

Question 43

aside from the adrenal gland, what are some extraadrenal places a catecholamine releasing pheochromocytoma could be?

Answer 43

SNS chain along spinal cord, overlaying distal aorta, within ureter, within urinary bladder