Lecture 15: Adrenal Physiology

Question 1

What is the set-up of adrenal gland structure?

Answer 1

1. Capsule
2. Zona glomerulosa
3. Zona Fasciculata
4. Zona Reticularis
5. Adrenal medulla
   GFR is the mnemonic
   Salt, Stress, Sex
   Salt, sugar, sex

Question 2

What do the adrenocortical hormones come from?

Answer 2

Cholesterol

Synthesized by cytochrome P450 enzymes in mitochondria and smooth ER

Question 3

What is the rate-limiting step in cholesterol to adrenocortical hormones?

Answer 3

Side chain cleavage of cholesterol to pregnenolone by CYP11A1 in the mitochondria

Question 4

How do adrenalcortical hormones affect their action?

Answer 4

They are lipid soluble so they pass through cell membrane and binds to receptors that enter the nucleus

Question 5

What is aldosterone released in response to?

Answer 5

1. Increased angiotensin II
2. Increased potassium
3. Increased ACTH (lesser stimulus)

Question 6

What does aldosterone regulate?

Answer 6

Blood volume
Salt/water homeostasis
Binds to mineralocorticoid receptor

Question 7

What is the Renin angiotensin system?

Answer 7

Renin is released in response to
i. decreased afferent arteriole volume (low renal perfusion)
ii. decreased distal tubule sodium concentration (tubuloglomerular feedback)
Renin is DECREASED in response to
i. increased arteriole volume (high renal perfusion pressure)
ii. Increased distal tubule sodium concentration (tubuloglomerular feedback)

Question 8

What does renin do?

Answer 8

Converts angiotensinogen to angiotensin I
Angiotension converting enzyme (ACE) then takes angiotensin I and converts to angiotensin II
Leads to aldosterone release
So renin —- aldosterone

Question 9

What does aldosterone bind to?

Answer 9

Mineralocorticoid receptor in the DISTAL cortical collecting duct principal cells
-moves to nucleus to stimulate transcription of genes to increase number of Na and K channels
(increase blood sodium and decrease blood potassium)
Promotes K+ and H+ secretion

Question 10

What is cortisol released in response to?

Answer 10

1. Increased ACTH

2. Increased arginine VASOPRESSIN

Question 11

What does cortisol regulate?

Answer 11

Binds to glucocorticoid receptor
Regulates energy balance
Cardiovascular
Metabolic homeostasis
Immune homeostasis
GLUCOSE

Question 12

What regulates cortisol release?

Answer 12

Circadian rhythm
Physical stressors
Stimulates release of CRH

Question 13

What stimulates ACTH?

Answer 13

CRH
Arginine vasopressin
Inflammation

Question 14

What action does cortisol have on ACTH and CRH?

Answer 14

Cortisol inhibits both ACTH and CRH

Question 15

How is ACTH made?

Answer 15

From proopiomelanocortin (POMC)
ACTH is a 38 aa section of POMC

Question 16

How does ACTH function?

Answer 16

ACTH specific receptor is melanocortin 2 receptor on adrenal tissue and functions

i. to increase LDL recpetors to bring in more cholesterol as precursor for steroid hormones
ii. activate CYP11A1 enzyme for cholesterol side chain cleavage
iii. ACTH can function as MELANOCORTIN, activating the melanocortin 1 receptor expressed on melanocytes

Question 17

What are cortisol and ACTH levels like?

Answer 17

Cortisol and ACTH are pulsatile throughout the day
Look at cortisol at 7 or 8am (to check if there is too little cortisol)
At midnight, cortisol should be low…so if you get high levels, then the person might have cushing’s

Question 18

What are the actions of cortisol?

Answer 18

1. liver
   
   • gluconeogenesis
   • decrease glucose uptake
2. skeletal muscle
   
   • release of amino acids
   • blocks insulin dependent glucose uptake (insulin resistance)
3. Inflammatory and immune cells
   
   • potent immunosuppressant and anti-inflammatory effects
   • decrease macrophage, T cell and mast cell
4. peripheral adipose tissue
   
   • release of free fatty acids and glycerol
5. Heart
   
   • increases BP via vasoconstriction
   • increases adrenergic receptor responsiveness
6. Increases vasomotor tone
7. Increases osteoclast activity and decrease calcium absorption
8. Epinephrine synthesis (activates PNMT enzyme)

Question 19

What is the cortisol cortisone shunt?

Answer 19

In GCR rich tissues like kidney, cortisol is inactived into CORTISONE
Uses 11BHSD2 to inactivate cortisol to cortisone
To convert cortisone back to cortisol, use 11BHSD1 (lung, brain, adipose tissue)
Cortisol has higher affinity for mineralocorticoid receptor
This shunt is so that the cortisol does not hijack the mineralocorticoid receptors in kidney lmao

Question 20

What is the significance of 11(beta)HSD2?

Answer 20

It is the enzyme that converts cortisol to cortisone
So inhibitors to 11BHSD2 will lead to hyperALDOSTERONISM
Because cortisol is bound to the mineralocorticoid receptors

Question 21

Why does licorice cause hyperALDOSTERONISM?

Answer 21

Licorice (glycyrrhizic acid) inhibits 11BHSD2 which means that cortisol cant be inactivated into cortisone
This means cortisol binds the shit out of mineralocorticoid

Question 22

How is glucocorticoids converted to mineralocorticoids?

Answer 22

By aldosterone synthetase present only in glomerulosa

Question 23

What do androgens regulate?

Answer 23

Binds to androgen receptor

Regulates pubarche

Question 24

What are the different types of adrenal androgens?

Answer 24

DHEA
DHEAS
Androstenedione
Increase in production with age
Main site of androgen production for women and minor site of androgen production for men
Andrenarche begins before gonadarche
Timulates pubarche

Question 25

What are androgens released in response to?

Answer 25

1. increased ACTH

Question 26

What is norepinephrine and epinephrine released in response to?

Answer 26

Sympathetic nervouse system
Synthesis is dependent on highlocal concentrations of cortisol
Binds to adrenergic receptors

Question 27

What is PNMT?

Answer 27

Phenylethanolamine N-methyltransferase
Convers norepi to epi
Cortisol upregulates PNMT to make epinephrine

Question 28

How are adrenal medullary catecholamines formed?

Answer 28

Tyrosine enters chromaffin cells and converted by tyrosine hydroxylase to dopa (rate limiting)
Cortisol upregulates PNMT