76 - Adrenal gland continued Flashcards
What are mineralocorticoids and what do they do?
Hormones that promote Na+ retention by the kidney (secondary result is water retention)
What is the primary endogenous mineralocorticoid?
Aldosterone
What part of the adrenal gland does mineralocorticoid synthesis occur?
Zona glomerulosa (primary cells in body that have aldosterone synthase)
What are the 4 big sites of action for aldosterone?
What receptor would you expect to find there in high abundance?
- Distal tubule in kidney; colon; salivary ducts, sweat ducts
- MR
Increased extracellular K+ will (stimulate/inhibit) aldosterone?
Stimulate (Basolateral NKP- Na reabsorbed, K excreted)
RAA system:
Decreased blood pressure stimulates _______ release from kidney (juxtaglomerular apparatus).
Renin
RAA system:
Renin cleaves _________ (from what organ?) to __________.
Angiotensinogen (liver) to angiotensin I
RAA system:
______________ converts ANG I to ______________.
- ACE (angiotensin converting enzyme)
- Angiotensin II
RAA system:
- Angiotensin II stimulates ___________. It also acts to ___________.
- Aldosterone
- Vasoconstrict
What are the effects of aldosterone?
What is the net result?
Increase Na+ reabsorption and K+ secretion at cortical collecting ducts
- Net Result = increased extracellular fluid volume and BP (sodium in extracellular space retains water)
How would you differentiate aldosterone vs. ADH/AVP?
Aldosterone: The Na hormone
- primary regulator of extracellular volume
ADH/AVP: The water hormone
- primary regulator of free water balance
What is the primary effect of ADH?
What is the secondary effect?
Decreases plasma osmolality which secondarily affects sodium concentration in the blood
Recall: aldosterone primarily binds ____, while cortisol primarily binds ____.
MR, GR
What is the name of the hormone that converts cortisol to cortisone and vice versa?
- Cortisol to cortisone: 11beta-HSD2
- Cortisone to cortisol: 11beta-HSD1
Why is cortisol converted to cortisone by 11beta-HSD2?
Inactivates it (so aldosterone can bind to the MR)
Which is higher concentration in the blood, glucocorticoids or mineralocorticoids?
Glucocorticoids (100-1000x)
What are the binding proteins for cortisol and for aldosterone?
- Cortisol: CBG (95% bound)
- Aldosterone: doesn’t have a binding protein
What would be the effect of inhibiting 11beta-HSD2?
Increased levels of cortisol, excessive MR activation! (competes w/aldosterone and has much higher blood conc.)
What would be the effect of excessive licorice consumption?
Licorice (glycyrrhetinic acid) inhibits 11β-HSD2. - - Excessive consumption can lead to increased Na+ (due to cortisol binding MRs) and subsequent H2O retention
(extra) What’s a drug that was mentioned that inhibits 11beta-HSD2?
What is it used to treat?
Carbenoxolone
- Treats esophageal inflammation by increasing cortisol (anti-inflammatory)
What is DHEA/S and where is it produced?
Weak androgen
- Produced in zona reticularis
What is DHEA/S a precursor for?
Precursor for more potent androgen testosterone, and for estrogens (converted in reproductive tissues)
How does DHEA/S change w/age?
When does it peak?
Declines with age
- Peaks between 20 – 30.
How does DHEA/S affect women
Increases libido; primary source of androgen and estrogen in postmenopausal women
What is the first step in steroid hormone biosynthesis? What 2 enzymes are required?
Convert cholesterol to pregnenolone
- Requires CE hydrolase- stimulated by ACTH
- Requires StAR, which xfers chol from OMM to IMM
What is the primary product of steroid hormone synthesis in the zona fasciculata?
Cortisol
What genes and intermediates are clinically relevant in cortisol formation in the ZF?
- Chol -> pregnenolone (CYP11A1)
- Pregnenolone -> progesterone
- Progesterone -> 17(OH)-progesterone (CYP17)
- 17(OH)-progesterone -> 11-deoxycortisol (CYP21A2)
- 11-deoxycortisol -> cortisol (CYP11B1)
What are the enzyme names for CYP11A1?
chol -> prenenolone
Desmolase/P450scc (chol. small chain cleavage)
What are the enzyme names for CYP21A2?
(Progesterone -> 11-DOC in ZG)
(17-OH-progesterone -> 11-deoxycortisol in ZF)
21alpha-hydroxylase/p450c21
What are the enzyme names for CYP11B1?
11-deoxycortisol -> cortisol in ZF
11-hydroxylase/P450c11
What are the enzyme names for CYP11B2?
last 3 rxns in ZG
Aldosterone synthase/P450aldo
What are the enzyme names for CYP17?
(Progesterone -> 17(OH)progesterone in ZF)
(Pregnenolone -> 17(OH)pregnenolone in ZR)
17alpha-hydroxylase/P450C17
What enzyme/gene is deficient in Congenital Adrenal Hyperplasia (CAH)?
What adrenal pw’s are affected?
What steps are interrupted?
What accumulates?
21α hydroxylase deficiency (P450c21 or CYP21A2)
- ZG and ZF blocked, ZR builds up
- No mineralocorticoids cuz it interrupts progesterone -> 11-DOC in ZG
- No cortisol cuz it interrupts 17(OH)progesterone -> 11-deoxycortisol in ZF
- Excess DHEA/S (ACTH has no negative feedback cuz no cortisol, so everything shunts to ZR pw)
*What are the clinical indications of CAH? (explain how the sx are caused)
- Virilization (masculinization due to shunt to ZR pw of DHEA/S)
- Ambiguous genitalia at birth (^ ZR)
- Na+ loss (no mineralocorticoids)
- Hypotension (no mineralocorticoids or glucocorticoids to stimulate MR’s)
- Hyperkalemia (no aldosterone so no K+ secretion)
- High plasma renin (response to low BP from low aldosterone)
- High ACTH (lack of negative feedback from the absent cortisol/aldosterone production)
What is the primary product of steroid hormone synthesis in the zona glomerulosa?
Aldosterone
What genes and intermediates are clinically relevant in aldosterone formation in the ZG?
- Chol -> pregnenolone (CYP11A1)
- Pregnenolone -> progesterone
- Progesterone -> 11-DOC (CYP21A2)
- 11-DOC -> corticosterone (CYP11B2)
- Corticosterone -> 18(OH)corticosterone (CYP11B2)
- 18(OH)corticosterone -> aldosterone (CYP11B2)
What would be the effects of a CYP11B1 (11-hydroxylase) deficiency?
(explain each effect)
- No cortisol (interrupts 11-deoxycortisol -> cortisol in ZF)
- High ACTH (no neg feedback from cortisol)
- High MR activity (11-DOC is active, still can activate MR receptors)
- Low aldosterone (due to HTN, Ang II not present to stimulate aldosterone synthase)
- Increased androgens (ZR shunt)
Which pw’s would be affected in CYP11B1/11-hydroxylase deficiency? (NOT CYP11B2)
What would be the clinical presentation of CYP11B1 (11-hydroxylase) deficiency? (explain why)
ZF blocked, would stimulate ZG and ZR.
- Hypertension* due to excess 11-DOC (aldosterone levels low because its synthase is regulated by Ang II, not HPA axis)
- Hypokalemia due to MR stimulation by 11-DOC
- Masculinization (increased ZR androgens)
- High ACTH (no negative feedback)
What is the primary product of steroid hormone synthesis in the zona reticularis?
DHEA/S
What genes and intermediates are clinically relevant in DHEA/S formation in the ZR?
- Chol -> pregnenolone (CYP11A1)
- Pregnenolone -> 17(OH)pregnenolone (CYP17)
- 17(OH)pregnenolone -> DHEA
4a. DHEA -> DHEAS
4b. DHEA -> Androstenedione (minor product)
Which pw’s would be affected in CYP17 (17α-hydroxylase) deficiency?
What would be the effects of a CYP17 (17α-hydroxylase) deficiency? (explain why)
ZF and ZR blocked, would stimulate ZG
- No cortisol (interrupts progesterone -> 17(OH)progesterone in ZF)
- Low aldosterone, high MR activity (11-DOC builds up and binds MRs, aldosterone inhibited because requires Ang II, but BP is high)
- Decreased androgens (interrupts pregnenolone -> 17(OH)pregnenolone, low DHEA/S)
What would be the clinical presentation of CYP17 (17α-hydroxylase) deficiency? (explain why)
- Hypertension (increased 11-DOC which binds MRs, but low aldosterone because it’s regulated by Ang II, which would be low)
- Hypokalemia (low aldosterone)
- Feminization/pseudohermaphroditism (ZR blocked, decreased weak androgens)
- High ACTH (no cortisol negative feedback)
Which of the steroidogenic genes are stimulated by ANG II (not ACTH)?
CYP11B2 (makes aldosterone)
- AKA aldosterone synthase, p450aldo
- Only in ZG
What are the major targets/effects of ACTH in adrenals?
- Stimulates conversion of cholesterol to pregnenolone by activating StAR activity
- Stimulates cellular hypertrophy
- Stimulates biosynthesis of cortisol
- *Stimulates biosynthesis of DHEA (CYP17)
- Stimulates 11β-hydroxylase (CYP11B1)
- Stimulates conversion of dopamine to NE (medulla)
Adrenal medullary cells are innervated by:
Sympathetic preganglionic fibers
(Originates from same neural crest area that forms sympathetic ganglia)
- Considered to be modified post-ganglionic sympathetic neurons (no dendrites or axons).
Most cells of the adrenal medulla release ____________. (stored in granules)
Epinephrine
What system controls the release of epinephrine from the adrenal medulla?
Sympathetic NS
What does the cellular architecture of the adrenal medulla look like?
Cords of polyhedral shaped epithelial cells
What stimulates the conversion of NE to E in the adrenal medulla?
Cortisol
What generally causes the release of epinephrine?
How long does it take for release to occur?
Response to acute stress: (pain, cold, perceived danger)
- Rapid activation/return
Epinephrine release is mediated by the symp NS, but what nerve in particular innervates its release from the medulla?
Splanchnic nerve
What types of receptors do epi/NE bind?
Alpha and beta adrenergic receptors
What is the overall goal of releasing adrenaline during the “fight or flight” sympathetic response, in terms of the brain and muscle?
What are the 3 main targets?
- Increase nutrient supply to muscle, and adequate supply of O2/Glucose for brain
- Muscle, liver, adipose tissue
What are the physiological effects of epi (and NE) through beta2 receptors? (think it out)
Dilation + other effects
- SkM: arteriolar vasodilation, ^ glycogenolysis, v Glucose uptake
- Bronchiolar dilation
- Decreased GI motility
- Adipose: ^ Lipolysis, v Glucose uptake (beta3 as well)
- Liver: ^ Glycogenolysis, ^ GNG, ^ ketogenesis
- Pancreatic alpha cells: ^ Glucagon
What are the physiological effects of epi (and NE) through alpha receptors? (think it out)
Constriction + other effect
- Vein and lymphatic constriction
- Splanchnic arteriolar vasoconstriction
- Pancreatic beta cells: v Insilin
- Iris dilation
What are the physiological effects of epi (and NE) through beta1 receptors?
HEART:
- ^ Inotropy (myocardial contraction strength)
- ^ Chronotropy (rate of SA node)
- ^ Lusitropic (myocardial relaxation)
During acute stress, what catecholamine is actually released?
NE
What catecholamine stimulates the release of CRH, which will eventually release cortisol?
NE
What is the longer-term response to stress, and what is the shorter term response?
- Short-term: directly release NE (symp NS)
- Long-term: release CRH, leads to cortisol and epi
What is released at the site of tissue injury that can stimulate the stress response?
Cytokines
In the metabolism of catecholamines, what does MAO break down epi and NE into in the adrenal medulla, liver, and kidney? (1 thing)
DHPG
What can act on DHPG in the liver and kidney to make VMA (vanillylmandelic acid)?
COMT/AD
In the metabolism of catecholamines, what does COMT break down epi and NE into in the adrenal medulla, liver, and kidney? (2 things)
Metanephrine, normetanephrine
What can act on metanephrine and ormetanephrine in the liver and kidney to make VMA (vanillylmandelic acid)?
MAO
How can VMA be used clinically?
VMA levels can be used to detect tumors producing excess EPI or NE (indicating their breakdown)
What is a pheochromocytoma?
Tumors originating from chromaffin cells: catecholamine overproduction
Sx of pheochromocytomas?
HTN (no response to medication), headaches, tachycardia
How do you dx pheochromocytomas?
Measurements of urinary metanephrines
Tx for pheochromocytomas?
Surgery. Pre-surgery, give alpha/beta blockers
Why is a pheochromocytoma known as the 10% tumor?
- 10% malignant
- 10% bilateral
- 10% in children
- 10% familial (have family member w/same tumor)
- 10% recur (5 - 10 years)
- 10% associated with MEN* syndromes (rare syndromes of endocrine tumors)
- 10% present w/CVA
- 10% extra-adrenal (found within nervous tissue outside adrenal glands)
What gene/enzyme converts pregnenolone to progesterone?
What zones is this in?
What other rxn does it catalyze?
3beta-HSD
- All 3 zones
- Also converts DHEA to androstenedione (minor product)
Where are 11beta-HSD 1 and 2 found?
Kidney (type 2- not sure what this means)
- Not p450 family
What adrenal cortex zones contain CYP11A1/desmolase/p450scc?
All 3
What adrenal cortex zones contain CYP21A2/21alpha-hydroxylase/p450c21?
ZG and ZF
What adrenal cortex zones contain CYP11B2/aldosterone synthase/p450aldo?
ZG only
What adrenal cortex zones contain CYP11B1/11-hydroxylase/p450c11?
ZF only, I believe
What adrenal cortex zones contain CYP17/17alpha-hydroxylase/P450c17?
ZF and ZR
