Adrenal Steroids 2 Flashcards
(40 cards)
What are the 3 steps from cholesterol in lipid droplets to the first step of steroid synthesis and where in the cell do they occur?
1) Cholesterol in lipid droplet (cytosol) cleaved by cAMP-dependent Esterase
2) Cholesterol brought by StAR protein into mitochondria (cAMP-dependent)
3) P450 cleaves side chain to make pregnenolone (cAMP-dependent)
What are the 3 regions of the adrenal cortex and which hormones do they make?
1) Zona glomerulosa: mineralocorticoids
2) Zona fasciculata: glucocorticoids
3) Zona reticularis: weak androgens
What is the control mechanism for each zona of the adrenal cortex? Which class of hormone is affected?
1) Z. glomerulosa: renin-angiotensin (aldosterone - mineralocorticoid) 2) Z. fasciculata: ACTH (Cortisol - glucocorticoid) 3) Z. reticularis: ACTH (DHEA - weak androgen)
What are the 5 intermediates of mineralocorticoid synthesis?
1) Cholesterol
2) Pregnenolone
3) Progesterone
4) 11-deoxycorticosterone (DOC - active)
5) Corticosterone
6) Aldosterone
What are the 3 steroid conversion steps that occur in the Z. fasciculata?
1) Pregnenolone –> 17OH Pregnenolone
2) Progesterone –> 17OH Progesterone
3) Corticosterone –> Cortisol
Which 2 steroid conversions occur in the Zona reticularis?
17OH Pregnenolone & 17-OH Progesterone are converted to androgens.
What is the order of enzymatic reactions in mineralocorticoid synthesis?
1) P450 SCC
2) 3b-hydroxysteroid DH & d5-4 isomerase (SER)
3) 21-hydroxylase (SER)
4) 11b-hydroxylase (mito)
5) 18-hydroxylase, then 18-hydroxydehydrogenase (mito)
What are the 2 equilibrium forms of aldosterone? What is the significance of the 2 forms?
Aldehyde & Hemiacetal
The hemiacetal protects aldosterone from degradation by enzymes targeting glucocorticoids.
Which important enzyme is missing from the glomerulosa, creating specificity of this tissue for mineralocorticoid synthesis?
Glomerulosa lacks 17a-hydroxylase, so it does not produce hormones of cortisol, androgen, or estrogen pathways
What factor regulates mineralocorticoid synthesis?
Angiotensin II
What is the specificity of mineralocorticoid receptors for mineralocorticoids vs glucocorticoids? How is selectivity regulated?
Glucocorticoids bind tightly to MC receptors. Tissues with MC receptors protect from GC by enzymatically inactivating them.
- 11b-HSD removes H from 11-OH on GCs –> inactive ketone
- Aldosterone’s 11-OH protected by hemiacetal
How is aldosterone transported and excreted?
Binds weakly to albumin & cortisol binding globulin for transport
Half-life around 15 min, rapidly metabolized by liver
Excreted in urine as tetrahydro form
What are the 2 mechanisms that affect aldosterone synthesis?
1) Renin-Angiotensin system
2) Potassium levels
NOT usually regulated by ACTH or sodium levels
What is the controlling step of the renin-angiotensin cascade? Where does it occur?
Renin production in juxtoglomerular cells of renal afferent arteriole
What factors stimulate & inhibit renin production?
Stimulated by:
- Decreased BP
- Salt depletion
Inhibited by:
- Increased BP
- Salt loading
- Negative feedback from angiotensin II
What is the function of renin?
Cleaves angiotensinogen into angiotensin I, which rapidly converts to angiotensin II via angiotensin-converting enzyme
What is the function of angiotensin II? What is another factor that has similar function?
- Acts on adrenal glomerulosa cells
- Activates aldosterone synthesis at 2 steps:
1) cholesterol to pregnenolone
2) corticosterone to aldosterone
Potassium regulates same steps
What is the role of atrial natriuretic hormone? Where is it produced?
- ANH, aka ANF, is a vasodilator
- Decreases aldosterone synthesis by decreasing renin production as well as aldosterone itself
- Produced in right atrium in response to stretch
What is the function of 17a-hydroxylase and where does it work?
Converts pregnenolone (sometimes progesterone) to 17-hydroxy derivative
In the zona fasciculata, is 17a-hydroxylase activity obligatory? Why?
17a-hydroxylation is not obligatory; cortisol & DOC pathways can both occur, but fasciculata lacks 18-hydroxylase so aldosterone can’t be produced. (18-hydroxylase present only in glomerulosa)
How does the predominant glucocorticoid differ between humans and rodents? Why?
Corticosterone is main GC in rodents, Cortisol in humans, because humans have more 17a-hydroxylase activity
Which hormone stimulates steroid synthesis? How is this hormone regulated?
Adrenocorticotropic hormone (ACTH) release from anterior pituitary stimulates steroid synthesis. Glucocorticoids are the only steroid that feeds back to inhibit ACTH & CRH
Which carrier proteins does cortisol bind? How much is unbound? What is its half life?
Cortisol binds CBG, some albumin
8% free
1.5-2hr half life
Which carrier proteins does corticosterone bind? How much is unbound? What is its half life?
Binds CBG weakly
half life <1hr
