Endocrine 6: adrenal glands continued Flashcards
Define mineralocorticoids.
- steroid hormones that affect water and sodium balance
- primarily aldosterone
- other steroids can have the same effect (ex: 11-deoxycorticosterone (DOC), which is an aldosterone precursor)
Where are the aldosterone sites of action?
- kidney DT
- colon
- salivary duct
- sweat ducts
Describe aldosterone’s mechanism of action at its main target site, the kidney.
Overall: increased K excretion, increased Na and water reabsorption
- increased extracellular K stimulates aldosterone
- aldosterone stimulates Na/K ATPase to kick K out and bring Na back in
How does the Renin-Angiotensin system regulate Aldosterone (RATA)?
- decreased blood volume and blood pressure signals renin release from JGA of the kidney
- angiotensinogen is released from the liver
- renin cleaves angiotensinogen to angiotensin I
- ACE converts that to angiotensin II
- angiotensin II acts as a vasoconstrictor AND stimulates aldosterone release from the adrenal cortex ZG
Compare and contrast the mechanisms of action of Aldosterone and AVP on osmoregulation.
ALDOSTERONE
- regulates extracellular volume
- stimulates Na and water reabsorption at the kidney
- stimulates K excretion
- increases blood volume and pressure
AVP
- regulates free water balance
- increases water permeability of distal tubule to stimulate water retention
- decreases osmolarity, which affects sodium balance
Describe aldosterone action inside the cell.
- target cell = mineralocorticoid target cell
- binds to MR-chaperone
- chaperone protein dissociates
- MR-aldosterone translocated to nucleus
- acts as TF
- –> signals inactivation of cortisol by converting it to cortisone via 11B-HSD2
Describe inactivation and reactivation of cortisol.
- in MR cells, cortisol => cortisone via 11B-HSD2 (dehydrogenase)
- in GR cells, cortisone => cortisol via 11B-HSD1 (reductase)
- process is dependent on NADPH
What is carbenoxolone?
drug that inhibits 11B-HSD2
=> unable to inactivate cortisol
=> excess binding to MR
=> excess aldosterone functions
What drugs block 11B-HSD2?
- carbenoxolone
- licorice
Describe the relationship between cortisol, 11B-HSD1, and T2DM.
- local production of 11B-HSD1 leads to increased cortisol
- increased cortisol => excess MR binding
- leads to increased local water retention
- can lead to obesity
What is the main function of the zona reticularis?
makes weak androgens (DHEA)
Characterize the weak androgens/DHEA.
- low affinity for androgen receptors
- serve as precursors for higher affinity androgens (testosterone and estrogen)
- metabolite = androstenedione
- decline with age (after 30)
- increases libido in women (primary source of androgen and estrogen in postmenopausal women)
- responsible for adrenarche (axillary and pubic hair)
Overview the cholesterol precursor biosynthetic pathway.
- cholesterol is synthesized in the cytosol or taken in by HDL/LDL
- cholesterol enters the mitochondria via StAR protein and enzyme P450scc/desmolase/gene CYP11A1 (activated by ACTH)
- inside the mitochondria, it becomes pregnenolone, which is needed for all subsequent pathways
What is the significance of the enzyme 3B-HSD?
- in the ZG and ZF, this enzyme is required to change pregnenolone to progesterone
- converts delta 5 to delta 4 double bonds
- hence, these zones are called delta 4 pathways, while ZR is a delta 5 pathway
What is the mechanism of hormone production in the Zona Fasciculata?
- cholesterol => pregnenolone (P450scc/desmolase/CYP11A1)
- pregnenolone => progesterone (3B-HSD
- progesterone => 17-OH-progesterone (17-hydroxylase/CYP17)
- 17-OH-progesterone => 11-deoxycortisol (21-hydroxylase/CYP21A2)
- 11-deoxycortisol => cortisol (11-hydroxylase/CYP11B1)
List the important enzymes of cortisol production.
ZF
- P450scc/desmolase/CYP11A1
- 3B-HSD
- 17-hydroxylase/CYP17
- 21-hydroxylase/CYP21A2
- 11-hydroxylase/CYP11B1
Where is 17-hydroxylase made?
only in ZF and ZR
Where is CYP11B2 made?
only in ZG
Describe what a 21-hydroxylase deficiency can lead to.
- most common cause of Congenital Adrenal Hyperplasia
- cannot make cortisol => no negative feedback => excess ACTH => constant stimulation of adrenals => proliferation and hyperplasia => excess DHEA, no glucocorticoids, no mineralocorticoids
- Sx: masculinization (virilization), ambiguous genitalia, sodium loss/hypotension, hyperkalemia, high plasma renin (no aldosterone), high ACTH
Explain the symptoms of 21-hydroxylase deficiency.
- excess ACTH b/c loss of negative feedback mediated by cortisol
- excess DHEA b/c constant stimulation of HPA
- no aldosterone/MR activity => can’t control osmolarity => excess renin => loss of sodium and water => hypotension
- masculinization and ambiguous genitalia due to excess DHEA/androgens
What is the mechanism of hormone production in the Zona Glomerulosa?
- cholesterol => pregnenolone (P450scc/desmolase/CYP11A1)
- prenenolone => progesterone (3B-HSD)
- progesterone => 11-deoxycorticosterone (11-DOC) (21-hydroxylase/CYP21A2)
- 11-DOC => corticosterone (11-hydroxylase/CYP11B2)
- corticosterone => 18-OH-corticosterone (18-hydroxylase/CYP11B2)
- 18-OH-corticosterone => aldosterone (18-oxidase/CYP11B2)
List the important enzymes in the zona glomerulosa.
- P450scc/desmolase/CYP11A1
- 3B-HSD
- 21-hydroxylase/CYP21A2
- CYP11B2 - 11-hydroxylase
- CYP11B2 - 18-hydroxylase
- CYP11B2 - 18-oxidase
Contrast CYP11B1 to CYP11B2.
CYP11B1 - found in ZF
- 11-hydroxylase
- converts 11-deoxycortisol to cortisol in the ZF
- stimulated by ACTH
CYP11B2 - found in ZG
- 11-hydroxylase (11-DOC => corticosterone)
- 18-hydroxylase (corticosterone => 18-OH-corticosterone)
- 18-oxidase (18-OH-corticosterone => aldosterone)
- stimulated by RATA
What is the CYP11B2 complex called?
aldosterone synthase
Describe what an 11-hydroxylase/CYP11B1 deficiency can lead to.
- 2nd main cause of CAH
- cannot produce cortisol in ZF => excess ACTH due to loss of negative feedback
- increased DHEA/androgens due to constant stimulation of adrenals
- low aldosterone
- high MR activity
- Sx: hypertension, hypokalemia, masculinization
Explain the symptoms of CYP11B1/11-hydroxylase activity.
- excess ACTH due to loss of negative feedback mediated by cortisol
- excess ACTH stimulation of adrenals leads to excess DHEA/androgens => masculinization, CAH
- buildup of progesterone in ZF will cause 21-hydroxylase/CYP21A2 to push it into a parallel pathway that produces 11-DOC => acts as MR => stimulates sodium and water retention => hypertension and hypokalemia
- b/c the excess MR activity by 11-DOC is keeping blood pressure high, renin will not stimulate aldosterone production => low levels of aldosterone
Describe the mechanism of hormone production in the Zona Reticularis.
ZR (delta 5 pathway)
- cholesterol => pregnenolone (P450scc/desmolase/CYP11A1)
- pregnenolone => 17-OH-pregnenolone (17-hydroxylase/CYP17)
- 17-OH-pregnenolone => DHEA (CYP17)
- DHEA => DHEAS
- DHEA => androstenedione (minor product)
List the important enzymes of the Zona Reticularis.
- P450scc/desmolase/CYP11A1
- 17-hydroxylase/CYP17
- CYP17
Describe what a 17-hydroxylase/CYP17 deficiency can lead to.
- rare cause of CAH
- no cortisol, no DHEA => high ACTH
- excess 11-DOC => low aldosterone, high MR activity
- Sx: hypertension, hypokalemia, feminization, pseudohermaphaditism,
Compare the symptoms of 21-hydroxylase/CYP21A2, 11-hydroxylase/CYP11B1, and 17-hydroxylase/CYP17.
21-hydroxylase = cannot make cortisol or aldosterone
- excess ACTH => excess DHEA => CAH, masculinization, ambiguous genitalia
- no aldosterone/MR (can’t make 11-DOC) => renin is stimulating the ZG but no aldosterone released in response to low BP => continued loss of sodium and water => hypotension, hyperkalemia => high plasma renin
OVERALL: no cortisol, no aldosterone, excess DHEA (masculinization, hypotension)
11-Hydroxylase/CYP11B1 = cannot make cortisol
- excess ACTH => excess DHEA => CAH, masculinization, ambiguous genitalia
- excess 11-DOC => excess MR activity => sodium and water reabsorption => hypertension, hypokalemia
- high blood volume and blood pressure => no renin stimulation => low aldosterone
OVERALL: no cortisol, excess 11-DOC/MR, excess DHEA (maculinization, hypertension)
17-hydroxylase/CYP17 = cannot make cortisol or DHEA
- excess ACTH
- feminization (pseudohermaphaditism) due to low DHEA
- excess 11-DOC => hypertension, hypokalemia
- low aldosterone
OVERALL: no cortisol, no DHEA (feminization, hypertension)
List the ACTH targets and their effects in the adrenal.
- activates StAR => steroid biosynthesis
- stimulates cellular hypertrophy, cortisol synthesis, DHEA (CYP17), 11-hydroxylase (CYP11B1)
- dopamine to norepinephrine in the medulla
Define chromaffin cells.
- adrenal medulla cells
- mostly release epinephrine
- under sympathetic control
- require cortisol to convert norepi to epi in the medulla
What are the physiological effects of epinephrine?
- arousal: pupil dilation, sweating, bronchial relaxation
- metabolic: gluconeogenesis in the liver, breakdown of fat and glycogen to release glucose
- cardiovascular: vasoconstriction of blood, increased HR
What stimulates epinephrine release?
- acute stress
- cortisol
- sympathetic stimulation
=> characterized by rapid release and rapid return
Compare the acute and long-term stress responses.
Acute = catecholamines
- stimulated by sympathetics
- norepinephrine stimulates CRH
- norepinephrine has short term responses (arousal)
Long-Term = cortisol
- stimulated by CRH and HPA axis
- negative feedback loop
- inhibits rest and digest, immune, inflammation
- creates epinephrine
Recall the metabolism and excretion of catecholamines.
- facilitated by MAO and COMT
- creates metanephrine/noremetanephrine metabolites
- MAO+AD and COMT lead to VMA
- VMA in urine used diagnostically to test for catecholamine releasing tumors
Define pheochromocytomas.
- chromaffin cell tumor leads to catecholamine overproduction
- Sx: unresponsive HTN, migraines, tachycardia
- DDx: urinary VMA
- Tx: surgery, alpha/beta-blockers
Why are pheochromocytomas the 10% tumor?
- 10% malignant
- 10% lead to stroke
- 10% recurrence after surgery
- 10% bilateral
- 10% children
- 10% familial
- 10% extra-adrenal
- 10% present with MEN
