Lecture 6: HPA Axis and Adrenal Gland - Part 2 Flashcards
What are mineralocorticoids?
steroid hormones that regulate sodium/water balance
What is the primary endogenous mineralocorticoid?
aldosterone
What is the precursor to aldosterone?
11-deoxycorticosterone
What 4 sites has high mineralocorticoid action?
1) distal tubule in kidney
2) colon
3) salivary ducts
4) sweat ducts
MR IS ONLY FOUND IN THESE 4 PLACES
What is the main target of MR action?
kidney (stimulates sodium and water reabsorption; also increases potassium secretion)
What is the main stimulator of aldosterone?
potassium levels
What stimulates renin release from the JGA of the kidney?
decreased blood pressure
What does renin do?
cleave angiotensinogen (from the liver) to angiotensin I
What converts AT1 to ATII?
Angtiontensin converting enzyme (ACE)
What does ATII do?
VASOCONSTRICTS and stimulates aldosterone
How does cortisol influence the renin-angiotensin system?
increases substrate of angiotensinogen
_________ is the primary regulator of ECV while ________ is the primary regulator of free water balance
aldosterone; ADH
What 2 things does aldosterone do?
1) stimulates Na+ and water reabsorption in the kidney
2) stimulates K+ excretion
NET RESULT: increases ECV and BP (sodium in extracellular space pulls water)
What does ADH do?
1) stimulates distal nephron water permeability (increases water retention)
2) decreases plasma osmolality which secondarily affects sodium conc in the blood
What happens when cortisol enters a mineralocorticoid cell?
it is deactivated to cortisone (inactive) and then flows back to the blood where it encounters another cell that converts it back to cortisol
What is the main hormonal actor on mineralocorticoid cells?
aldosterone (mineralocorticoid)
What form of glucocorticoid enters GC target cells?
cortisone (converts to cortisol by 11b-HSD1) then binds to GR
Which 11b-HSD is in the GC cells? Mineralocorticoid cells?
GC cells: 1
MC cells: 2
What inhibits 11B-HSD2 and what effects does that inhibition have on homeostasis?
carbenoxolone and licorice
block 11B-HSD2, cortisol cannot be converted to inactive cortisone so leads to increased sodium and water retention
What zone is right up against the medulla?
zona reticularis (makes weak androgens)
Why are androgens produced in the reticularis considered “weak?”
low binding affinity for androgen receptors
When is the adrenal gland the primary source of androgen and estrogen for women?
post menopausal
What fraction of total androgen precursors in adult male prostate come from adrenal?
50%
What is the precursor for all steroid hormones?
pregnenolone
The first step towards steroid hormone production is regulated by what?
ACTH
What is CYP11A1 and what does it do?
converts FC to pregnenolone
it is a desmolase - cleaves cholesterol side chain
Match aldosterone, cortisol, androstenedione with glomerulosa, fasciculata, reticulata
aldosterone —-> glomerulosa
cortisol —–> fasciculata
androstenedione —-> reticularis
What is the flow from cholesterol to becoming cortisol?
cholesterol –> pregnenolone –> progesterone –> 17(OH) progesterone –> 11-deoxycortisol –> cortisol
What happens in a 21a hydroxylase deficiency?
excess DHEA, no mineralocorticoids/GCs
most common cause of congenital adrenal hyperplasia
signs: virilization, ambiguous genitalia
Why do androgens increase when mineralocorticoids decrease (as in a CYP21A2 deficiency?)?
blood flow trickles down through zones so all precursors are high (ACTH stimulates upstream pathways and enzymes that are part of pathway leading to excessive androgen production)
What is the gene for 11 hydroxylase?
CYP11B1
What happens in a 11 hydroxylase deficiency?
no cortisol; low aldosterone; high MR activity; increased androgens
signs: masculinzation, hypertension
17a hydroxylase is only found where?
fasciculata and reticularis (NOT glomerulosa)
What happens in a 17a hydroxylase deficiency?
no cortisol; high aldosterone; decreased androgens
What is the only important enzyme found in the zona reticularis?
17a hydroxylase (also in fasciculata)
Which enzyme is only found in the glomerulosa?
aldosterone synthase (CYP11B2)
aka 11 hydroxylase
An 11 hydroxylase deficiency is referring to a defect where?
CYP11B1 in z. fasciculata
What is the ACTH receptor?
MC2R
What are the ACTH targets in the adrenal gland?
1) stimulates conversion of cholesterol to pregnenolone by activating StAR
2) stimulates cellular hypertrophy
3) stimulates biosynthesis of cortisol, DHEA, 11b-hydroxylase
4) stimulates conversion of dopamine to norep (medulla)
What is the predominant catecholamine secreted from the adrenal medulla?
epinephrine (not norep)
the adrenal medulla originates from ______________
neural crest (same type that forms sympathetic ganglia)
Describe the morphology of the adrenal medulla cells
cords of polyhedral shaped epithelial cells
What are the 3 catecholamines?
1) dopamine
2) norepinephrine
3) epinephrine
What is the pathway of catecholamine synthesis?
tyrosine —-> XDOPA —–> Dopamine —–> Norepinephrine —–> epinephrine
What is the rate limiting step in catecholamine synthesis?
tyrosine hydroxylase (converts tyrosine to XDOPA)
Where in the body does the pathway stop at dopamine?
brain (dopaminergic neurons)
Where in the body does the pathway convert dopamine to norep?
peripheral nerves
What stimulates conversion of norep to ep? And where?
Cortisol in the adrenal medulla
Which intermediate of the tyrsoine —> catecholamine pathway is found in greatest abundance?
epinephrine
What happens to the tyrosine —-> catecholamine pathway in the absence of cortisol?
build up of norep
What are the 3 main targets of epineprine?
1) muscle
2) liver
3) fat
What does epinephrine do in the skeletal muscle?
promotes glycogenolysis (releases ATP for local energy —> cannot provide energy for the whole body because glucose 6-phosphatase is not expressed in skeletal muscle)
What does epinephrine do on liver?
releases glucose into the blood
antagonize what insulin is doing
What does epinephrine do in fat?
promote lipolysis
What is the main goal of epinephrine?
to get energy to muscle and adequate oxygen and glucose to brain (vasoconstricts everything but coronaries)
leads to GI and bronchial muscle relaxation
increases metabolic rate
In times of stress, cortisol increases and epinephrine __________
INCREASES (cortisol converts norep to ep)
Acute stress activates the symp and stimulates the release of _____
NE
What does NE do?
stimulates CRH to initiate HPA response to long-term stress
What is produced when you have an excess of catecholamines produced?
VMA (used to clinically detect tumors producing excess EPI or NE)
What are pheochromocytomas?
tumors originating from the chromaffin cells
What are symptoms of too much catecholamine production?
hypertension, headaches, tachy
Why are pheochromocytomas called the 10% tumor?
10% of them are malignant, bilateral, in children, familian, recur, MEN syndrome, stroke, extra-adrenal
