Adrenal Steroids 2 Flashcards
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
Which carrier proteins does aldosterone bind? How much is unbound? What is its half life?
Binds Albumin & CBG (both weak)
36% free
Half life <15 min
Which carrier proteins does DOC bind? How much is unbound? What is its half life?
Binds albumin, CBG
4% free
How does the role of the adrenal glands differ between males and females?
Males: testes most important source of androgens
Females: Adrenal glands most important source of androgens
How does 17a-hydroxylase enable synthesis of androgens & estrogens? How does this affect where they can be produced?
17-hydroxyl group is necessary to allow cleavage of C17 side chain.
-Since z glomerulosa lacks 17a-hydroxylase, androgens/estrogens can only be made in fasciculata & reticularis
What is the major androgen produced in the adrenal gland? What is the mechanism of production?
Dehydroepianrosterone (DHEA)
-Produced by cleavage of C17 side chain by C17-20 lyase (found in adrenals & gonads)
What is a common modification of DHEA and why is it significant?
1) DHEA is often sulfated at the 3 position
2) DHEA-3-sulfate binds tightly to SHBG
3) Very long half life
What hormone can be derived from DHEA? Where does this occur? Which enzymes are involved?
In peripheral tissue, DHEA is converted to androstenedione (more potent) via 3b-hydroxylase and d5-4 isomerase
Which hormones can be derived from androstenedione? Which enzymes are involved?
1) Androstenedione reduced at C17 to testosterone via 17b-hydroxysteroid DH
2) Testosterone to 17b-estradiol via aromatase
Describe Addison’s Disease.
Adrenal unable to produce sufficient glucocorticoids
- Intolerant to stress, extremely sensitive to insulin
- Increased pigmentation from increased ACTH and other POMC peptides
Describe secondary adrenal insufficiency.
Lack of ACTH. Intolerant to stress, extremely insulin-sensitive, no increased pigmentation
Describe Cushing’s syndrome:
- Cause
- 5 physical traits
- 3 systemic effects
- 3 vascular symptoms
Excess of glucocorticoids
- Due to excess ACTH production by pituitary or adrenal tumor. Pituitary = cushing’s disease
1) Truncal obesity, buffalo hump, striae, thin legs, virilization
2) high gluconeogenesis, decreased immune system, low inflammatory response
3) Mineralocorticoid function of cortison –> hypertension, edema, alkalosis
Describe Conn’s syndrome.
Mineralocorticoid excess:
- due to adenomas of glomerulosa cells
- hypertension, edema, alkalosis
- low renin & angiotensin levels
- aka primary aldosteronism
Describe secondary aldosteronism
Renal artery stenosis decreases perfusion pressure sensed via juxtaglomerular cells, results in elevated renin & angiotensin
-leads to hyperplasia and hyperfunction of juxtaglomerular cells
Describe congenital adrenal hyperplasia (CAH).
-AKA congenital adrenogenital syndrome
-Due to deficiency in steroidogenic enzymes
(90% due to lack of 21-hydroxylase, most others 11b-hydroxylase)
-Overproduce ACTH & adrenal androgens
-Increased body growth, virilization, ambiguous external genitalia
What are ACE inhibitors and how do they work?
Angiotensin-converting-enzyme inhibitors:
Downregulates conversion of angiotensin 1 to 2 & 3
Lowers BP!
What is the main estrogen in post-menopausal women? In pregnant women?
1) Estrone
2) Estriol (not main but made during pregnancy)
