Adrenal

Question 1

Adrenal glands

1. Other term
2. Layers (which is the thickest?)
3. Zones

Answer 1

1. Suprarenal gl
2. Layers (outer -> inner): Capsule, Cortex (thickest), Medulla
3. Zones (outer to inner): GFR = Glomerulosa, Fasciculata, Reticularis
   >Each of these zones have diff sets of enzymes. This diff sets of enzymes are necessary to prod the hormones specific for each zone

Question 2

Hormones produced in each zone?

Answer 2

Glomerulosa -> produces aldosterone

Fasciculata -> cortisol

Reticularis -> androgen

Question 3

Adrenocortical hormones

1. Type of hormone?
2. Synthesized from? Majority comes from? (Be specific.)
3. Receptor of #2 (Majority)
4. General properties of #1

Answer 3

1. Steroid hormone
2. From cholesterol (80% from LDL which transports endogenously synthesized cholesterol)
3. LDL receptor
4. Non-polar so whenever in the blood, they require carrier proteins

Question 4

Carrier protein for:

1. Cortisol
2. Aldosterone
3. Androgens

Answer 4

1. Cortisol
   - Cortisol-binding globulin is the major carrier protein
   - Other: albumin
2. Aldosterone
   - Albumin
3. Androgens
   - Sex-hormone binding globulin

Question 5

Metabolism of steroid hormones?

Answer 5

SH inactivation can be done in 2 ways and both occur in the liver:

1. Conjugation (glucuronate/sulfate)
2. C-17 reduction

Question 6

How to regulate synthesis of SHs?

Answer 6

1. LDL receptor expression
2. Through the action of HSL which releases stored lipids leading to free cholesterol
3. Cholesterol desmolase activity

Question 7

Synthesis of the adrenocortisol hormones start with?

Answer 7

Cholesterol —> Pregnenolone

```
Via CYP11A1 (desmolase enzyme) removal of side chain
Location: mitochondria
~~~

Question 8

HPA axis

Answer 8

Hypth would release CRH which would stim your AP to release ACTH -> ACTH would stim your Adrenal Cortex to release corticosteroid

If cortisol is elevated, (-) feedback on CRH and ACTH release

Question 9

CRH

1. Type of hormone
2. What releases it? Where will it travel?
3. Receptor?
4. What cells express the receptor?
5. Precursor?

Answer 9

CRH

• peptide hormone (coming from mRNA) prod as an inactive hormone so prohormone
• After synthesis before it is stored into vesicles, it will be converted into its active form
• So in other words, pag nastore sila, it is already active
• This (from your hypothalamus) will reach your anterior through BVs
• Take note of receptors: CRH-R1 (Corticotrophin RH -receptor type 1)
• On your AP gland, the cells that would express CRH-R1 (w/c are your cortictrophs), it has this receptor. When CRH binds to this receptor results to cascade of events leading to inc intracellular Ca2+ causing exocytosis of vesicles resulting to release of ACTH

Question 10

ACTH

1. Type of hormone?
2. Precursor?
3. Receptor?
4. Effect?
5. Location of effect?
6. The release of these adrenocortical hormones is affected by ACTH.

Answer 10

ACTH is a peptide hormone

• What is special abt ACTH: Whenever it is synthesized, it’s precursor is a v big peptide (POMC: Proopiomelanocortin)
• ACTH whenever released from BVs and reaches adrenal cortex, it would bind to melanocortin-2 receptor (MC2R) when this GPCR is activated -> cascade of events -> inc in PKA activity which can phosphorylate sev enzymes which are necessary for SH synthesis
• Note: The effect of ACTH is only shown or will only be exhibited on zona fasciculata and reticularis (Or in other words, MC2R only found on cells in these two zones)
• So ACTH would only affect cortisol and androgen release or synthesis and not aldosterone

Effects of M2CR activation
Immediate
-Inc cholesterol esterase, chol transport, chol binding to P-450SCC, pregnenolone production, StAR protein
-Dec cholesterol ester synthetase

Subsequent
-Inc gene transcription of P-450, Adrenoxin, LDL & HDL receptor

Long-term

• Inc size and fxnal complexity of organelles
• Inc size and number of cells so hypertrophy

Question 11

Chronic elevation of ACTH would lead to?

Removal of ACTH for long periods of time would lead to?

Answer 11

• Chronic elevations on your ACTH lvls, your adrenal cortex becomes very big (hypertrophy) due to these effects
• And vice versa, if you remove ACTH for long periods of time, adrenal cortex would shrink naman

Question 12

Effect of __ on CRH and ACTH secretions

1. Cortisol
2. Pulsatile secretion of CRH and ACTH
3. Higher centers

Answer 12

1. Cortisol
   - exerts negative feedback on CRH and ACTH release
2. Pulsatile secretion of CRH and ACTH
3. Higher centers
   -Circadian rhythm
   >Early morning, you’ll have increase in ACTH release which will dictate your adrenal cortex to produce cortisol in preparation for the stressful day. During nighttime, ACTH goes down so cortisol would also be decreased.
   -Integrated signals in response to stress (you’ll produce cytokines which increases secretion of CRH and ACTH)

Question 13

Hormones from Zona Fasciculata?
1. Hormones?
2. Main hormone?
3. Effects?
>In terms of carbs, proteins, fats, bones, CNS, unique effect

Answer 13

1. Hormones: GCs (Cortisol, corticosterone, cortisone)
2. Main: Hydrocortisone/Cortisol
3. Effects:
   A. Carbs:
   >Stimulate gluconeogenesis
   >Dec glucose utilization of vells
   >Overall: elevate blood glucose lvl, antagonistic/opposite to insulin

B. Proteins
>For peripheral tissues, reduction in cellular protein (so dec in protein synthesis and inc proteolysis)
>In the liver, inc protein synthesis

C. Fats
>Causes mobilization of FAs so it will break down your stored lipids

D. Bones
>Decreases bone formation

E. CNS
>Alterations on cognition and mood

F. Unique effect of cortisol
>Reduces inflammation by decreasing number of immune cells through the induction of apoptosis
>Dec release of cytokines
>Inhibits PLA2 (so not free up ARA so no substrate for PG and LT synthesis)

Question 14

Synthesis of cortisol

1. Location
2. What happens?

Transport of cortisol

Inactivation and Excretion

Elimination rate from plasma

Answer 14

Location: Zona Fasciculata

> Decrease aldosterone synthase
Decrease 17, 20-lyase activity

So all pregnenolone and progesterone would be shunted to your cortisol synthesis

Take note:
21Beta-Hydroxylase - without this enzyme you can’t produce cortisol and aldosterone

——————
TRANSPORT
>Once produced, it diffuses out of the cell and into the blood where it will be transported by a carrier protein (Mainly ~90%: TRANSCORTIN or CBG; others: 7% albumin, 3% Free Cholesterol)

—————-
Inactivation: Conjugation and reduction

—————-
Slow elimination from plasma bc higher affinity to CBG than aldosterone

Question 15

Glucocorticoid receptor

1. Location
2. Mechanism

Answer 15

1. Cytoplasm (intracellular)
2. W/o binding of cortisol, GR is complexed with HSP preventing unnecessary activation of your GR.

Once cortisol binds to the GR —> there will be dissociation of GR w/ HSP —> Hormone-GR complex enters the nucleus and binds to GRE to start transcription -> prod mRNA -> prod protein -> physiologic effects

Question 16

Androgens in the adrenal gland?

1. Hormones. Main in the adrenal gl?
2. Compare with androgens from gonads
3. Zone location
4. Effect on sex characteristics?

Answer 16

1. 2 hormones: DHEA (main) and Androstenedione; the male sex hormones
2. Not the major androgens in our body; the major androgen is testosterone that is produced by your gonads
   >Also, these 2 hormones are less potent than the androgens formed from gonads
3. Zona reticularis

4.
>In males, does NOT contribute to male sex characteristics
>In females, provides 50% of androgens so xs can cause masculinization.

Question 17

Synthesis of DHEA

1. Location
2. What happens?

Inactivation of Adrenal Androgens? Elimination?

Answer 17

1. Zone reticularis
2.
>No 21Beta-hydroxylase
>Enhances 17,20-lyase activity
>DHEA sulfotransferase: (attaches a sulfate group to DHEA); impt to increase v short half-life

———
Inactivation: Conjugation and reduction
Elimination: Urine

Question 18

T or F. Testosterone is only produced by the gonads.

Answer 18

False!!! In the zona reticularis, a little bit of estrogen and testosterone can also be formed by converting DHEA to testosterone and testosterone to estrogen through aromatase. This conversion is applicable for both males and females.

Question 19

T or F. Adrenal androgens do not bind to albumin and globulins.

Answer 19

FALSE! Low affinity.

Question 20

Regulation of Adrenal Androgens?

Scenario 1: You have a px who has a tumor on pit gland that produces ACTH

Scenario 2: If there is a condition wherein your zona fasciculata is destroyed by drugs or immune system

Answer 20

> ”Loophole of HPA axis”
MC2R is expressed both on zona fasciculata and zona reticularis so both ACTH can act on these 2 zones causing an increase in cortisol and androgen release
HOWEVER, only cortisol exerts a negative effect on ACTH

E.g. You have a px who has a tumor on pit gland that produces ACTH (so masyadong mataas si ACTH). So what will happen? Both cortisol and androgens will be elevated.
-Another e.g. if there is a condition wherein your zona fasciculata is destroyed by drugs or immune system so body will not be able to produce cortisol and since cortisol is absent, no feedback exerted on your pituitary so your body will think that it needs more cortisol so more of your ACTH will be released but sira nga si fasciculata so your ACTH now will only activate reticularis to produce your androgens. That would be a problem if the px is a female (adrenal androgens doesn’t contrib to male sex char but in females contrib ~50% of androgens so any xs can have masculinizing fx in female, nagkakams sila, develop facial hair, voice becomes lower, etc)

Question 21

> What is adrenarche?
To whom does this occur?
Effect?

Answer 21

> Characterized as an increase in adrenal androgen 1-2 years before puberty SO even before development of 2’ sexual characteristics, you already have an increase in adrenal androgen; so nauuna si adenal gland madevelop
Occurs on both males and females
Effect: Masculinizing
Causes growth of pubic hair (pubarche)

Question 22

Aldosterone

1. Location
2. Other hormones in the same location
3. Function
4. Effect of the ff on aldosterone: ACTH, Angiotensin, Increased K+ in plasma/ECF

Answer 22

1. Zona Glomerulosa
2. Deoxycortisone, coritcosterone, cortisone, cortisol (May MC effect din si cortisol pero mahinang mahina; 1/30 of aldosterone)
3. Primary regulator of salt and ECV
4. ACTH, Angiotensin, Increased K+ in plasma/ECF
   ACTH: Has no effect on aldosterone synthesis

ANG II: Main regulator; increases aldosterone synthesis

Increased K+ in plasma/ECF (or hyperkalemia): Activate aldosterone release (Remember aldosterone causes secretion of K+)

Question 23

Aldosterone
1. Synthesis

2. Properties
   A. Once produced, what’ll happen?
   B. Compare affinity of cortisol to aldosterone to binding proteins? To MR? Effect?
3. Inactivation
4. Excretion

Answer 23

1. > On glomerulosa, no 17beta-hydoxysteroid activity
   SO pregnenolone and progesterone would not be shunted to androgen and cortisol synthesis
   You have aldosterone synthase
2. Properties
   - Same as cortisol, once prod -> diff out of adrenal cortex and into the blood and once in the blood, it will be transported by your carrier proteins
   - However, if we compare the affinity of cortisol with that of your aldosterone, you ald would have less affinity to your carrier proteins (so mas madali siyang nawawala) bc it is easily released from proteins, it can readily be inactivated kaya yung half-life niya is shorter compared to your cortisol kasi si cortisol 90% diba
   - It is also inactivated via conjugation and reduction and excreted through your urine
   - MR has similar affinity to cortisol and aldosterone

Question 24

Physiologic effects of aldosterone?

Answer 24

1. Increases blood Na+ lvls
   - Reabsorption from kidneys
   - Absorption from colon
2. Promotes K+ secretion so dec blood K+ lvl

-Cells on CD and Cells on distal colon, ito yung nangyayari:
-Ald enters the cell and once it enters the cell, it will form complex with Mineralocorticoid Receptor (MR)
-Once you have the Ald-MR complex, it will enter your nucleus then bind to specific region in your DNA which it can now start transcription process and at the end of that you produce your proteins
-Proteins produced/enhanced/stimulated by aldosterone
>Na/K pump on basolateral membrane
>ENaC (epithelial Na channel) on the apical membrane
-Overall effect of ald is it inc blood lvls of you Na through reabs from kidneys and absorption from colon. And opposite to that, you secrete K, so you would lower down blood K+ lvl.

Question 25

What is Amiloride? Mechanism?

Answer 25

Amiloride:
>Diuretics: drugs that induces urination or secretion of your electrolytes. Most of these act on channels on your tubules. Once of which would be your Amiloride (example of K sparing diuretics) so when you give this drug, K+ will not be excreted because it blocks your ENaC

Question 26

What happens if your cortisol for some unknown reason goes to your principal cells?

Answer 26

> Note: MR has similar affinity for both cortisol and aldosterone
E.g. Cortisol for some unknown reason napunta kay principal cells, it can activate your MR so pwede maproduce yung Na/K ATPase and ENaC so you can have Na reabsorption as well
But in reality that does not happen bc of this enzyme:
For e.g. this is your MC target cell sa CD, when your cortisol enters that cell, there is a specific enzyme that will inactivate your cortisol: 11beta-hydroxysteroid dehydrogenase type 2 (it will convert cortisol to cortisone which can’t activate MR. What’ll happen? Lalabas lang siya/aalis lang siya. Once cortisone travels the blood and enters its target cell (e.g. liver cells/hepatocytes), there is another specific enzyme: But in reality that does not happen bc of this enzyme:
For e.g. this is your MC target cell sa CD, when your cortisol enters that cell there is a specific enzyme that inactivates your cortisol DH type 1 which converts cortisone back to cortisol so cortisol now can activate MR
So this enzyme is a protective mech of your renal cells against cortisol

Question 27

1. Hormones from adrenal medulla? Main?
2. Derived from?
3. Modulated by?

Answer 27

1. Cathecolamines:
   >Epinephrine: Main, 80%
   >NorE: 20%
2. Derived from tyrosine, a non-essential amino acid
3. Modulated by HPA axis
   >This is parang sympathetics: fight or flight
   >Higher centers will cause the activation of your ANS. Your Ach will target your medulla which causes the conversion and release of your epinephrine so epineph can now act on distant cells

Question 28

Synthesis of catecholamines?

Answer 28

Tyr is synthesized from phenylalanine in the liver -> Tyr will be hydroxylated forming your dihydroxyphenylalanine (DOPA) -> DOPA will be decarboxylated to dopamine ->dopamine will be hydroxylated to form NorE -> NorE will have a methyl grp (from SAM) attached to it by PNMT forming your Epinephrine

Question 29

Metabolism of cathecolamines?

Answer 29

Catecholamines are broken down by 2 sets of enzymes:

1. COMT (Cathecol-O-methytransferase)
2. MAO (Monoamine oxidase)

After the action of these 2 enzymes, your produce VMA (Vanillylmandelicacid) which is excreted in the urine.

Question 30

Physiologic effects of Epinephrine and NorE

Answer 30

Type -> G protein -> Location & Function

Alpha1 -> Gq -> Smooth ms vasoconstriction, pupils mydriasis (dilation), bladder constriction

Alpha2 -> Gi -> Pancreas insulin secretion inhibition, Presynaptic neuron (Inhibit ACh and NE release)

Beta1 -> Gs -> Inc HR and contractility, inc renin release

Beta2 -> Gs -> Bronchial smooth ms dilation, uterus/bladder relaxation, GI motility

Beta3 -> Gs -> Adipose tissue (promotes thermogenesis)

Question 31

Cushing’s syndrome

Answer 31

> GC xs

>Can be due to exogenous anti-inflammatory steroids, tumors

Question 32

Addison’s disease

Answer 32

> 1’ adrenal insufficiency
Deficiency in both ald and cortisol
Hyperpigmentation

Question 33

Chronic steroid intake/Adrenal crisis

Answer 33

Chronic steroid intake (Question earlier)
Remember normal HPA Axis
However if you have a px taking exogenous steroids/drugs mimicking cortisol fx for long periods of time, this exogenous steroid will exert a negative effect on your hypothalamus and pituitary so your CRH and ACTH will be decreased. Diba as mentioned earlier, long term effect of ACTH is it inc size of adrenal cortex and vv long term low lvls of ACTH will cause shrinking of adrenal cortex particularly your fasciculata so this is what you expect. What’ll happen is if you immediately stop this exogenous steroid, there will be no negative feedback exerted on your hypothalamus and pit so your body will think that it needs to prod cortisol so your CRH and ACTH will be v high but if you look at your fasciculata, it is atrophied so even if you have v high lvls of ACTH, your cortisol release initially would be absent or decreased so that would be a problem bc remember cortisol and aldosterone are stress hormones so they are in order to cope up for stressors you encounter (e.g. inflammation, dehydration) so failure to prod your cortisol bc of immediate withdrawal of exogenous corticosteroid, this can precipiate a condition known as your adrenal crisis (so they are not able to cope up to a stressful event) these px could die. So impt thing to take note of, you advise px if he want to stop taking the drug, slowly taper dose so you give enough time for adrenal gl to go back to its original size

Question 34

Hyperaldosteronism

Answer 34

Hyperaldosteronism
>Symptoms:
>So K lvls is high (so you can have hypernatremia and hyperosmotic plasma)
Consequences: BP would increase if sobrang taas but what would initially happen if you have a hyperosmotic plasma? Inc ADH/secrete. Now if your Na is v high, it will cause a concomitant inc in ADH so you reabs Na and water w/c results to an inc in your ECvolume. Kung masyadong madami pwedeng magoverload.

> Inc ANP release
Kung masyado madami si vol -> it could cause ANP release
So not much of symptoms assoc w/ hyperaldosteronism

Question 35

Congenital Adrenal Hyperplasia

Answer 35

CAH
-Char by an absence of any enzyme on SH synth but most common: 21beta-hydoxylase
>One of the diseases that can be screened using NBS
>24 hrs after birth, you get blood from baby, then analyze blood
>If the newborn has CAH, can be detected
>If 21beta-OHase is absent, your body will not be able to produce aldosterone and cortisol so wala
>So your zona glomerulosa and fasciculata will not be able to prod aldosterone and cortisole BUT no effect on Z. Reticularis bc wala namang deficient eh so its fxn remains intact.
>The hyperplasia here is bc of an inc in ACTH since the newborn’s body is not producing enough cortisol, no feedback is exerted on pituitary so body would secrete more ACTH and bc of this inc ACTH, your z. Reticularis will be stimulated to prod more and more of your androgens.

Problem is that if the newborn is a female genotypically (XX), they could have masculinizing symptoms
More prominent: Enlargement of clitoris (“Ambiguous genitalia”: if clitoris or penis)
Management for px w/ CAH: so give ald and cortisol bc same as Addison’s na walang prod of cortisol and aldosterone

Question 36

Pheochromocytoma

Answer 36

Pheochromocytoma
>Char by a tumor on adrenal medulla (particularly the chromaffin cells)
>As a result, bc of tumor on adrenal medulla you are producing lots of NE and epineph -> so there will be excessive activation of sympathetic NS so you can have these symptoms:hypertension, headaches, sweating, palpitations, chest pain