Flashcards in Lecture 24: Adrenal Steroids Deck (100)
Describe the naming nomenclature of adrenal steroids.
Number of Cs:
- 21 Cs: pregn-
- 19 Cs: androst-
- 18 Cs: estr-
Ring double bonds:
- None: -ane
- One: -ene
- Two: -diene
What are the first 3 steps common to the synthesis of all adrenal steroids? What is the rate-limiting step? What are all 3 enzymes activated by?
1. Esterase: lipid droplets made of cholesterol ester => free cholesterol + FA
2. StAR protein: cytosol free cholesterol => mito cholesterol (rate-limiting step)
3. P450 side-chain cleavage (P450-SCC): cholesterol => pregnenolone (cut off 6Cs with carboxyl group left on C20) + isocaproaldehyde
All 3 activated by cAMP
How many Cs in pregnenolone?
How many Cs in isocaproaldehyde?
Describe the detailed cell composition of the adrenal cortex with the function of each layer.
1. Connective tissue capsule
2. Zona glomerulosa: where mineralcorticoids are synthesized (aldosterone mostly)
3. Zona fasciculata: where glucocorticoids are synthesized (cortisol mostly)
4. Zona reticularis: where androgens are synthesized
5. Medulla: where catecholamines are synthesized (DHEA mostly)
What is another name for 11-deoxycorticosterone?
Where is the enzyme 18-hydroxylase found?
Zona glomerulosa of the adrenal cortex
Explain how the RAA system works to stimulate aldosterone secretion. 6 steps
1. Drop in blood pressure/volume/sodium OR increase in potassium OR edema OR renal nerve activation
2. Juxtaglomerular apparatus (JGA) in kidney releases renin into circulation
3. Renin converts angiotensinogen secreted by the liver to angiotensin I
4. Angiotensin-converting enzyme (ACE) in vascular endothelium (secreted by the lungs) converts angiotensin I to angiontensin II and III
5. Angiotensin II/III bind to receptors on cells in the ZG of adrenal cortex to stimulate aldosterone production
6. Aldosterone acts on kidney tubules to stimulate sodium reabsorption to raise BP and potassium excretion to inhibit stimulation of aldosterone
What are the 2 regulators of aldosterone synthesis? Which is the main one?
1. RAA system (main one)
2. K+ levels
What 2 steps of aldosterone synthesis does angiotensin II stimulate?
1. Cholesterol to pregnenolone
2. Corticosterone to aldosterone
What 2 steps of aldosterone synthesis does K+ stimulate?
1. Cholesterol to pregnenolone
2. Corticosterone to aldosterone
What other effects does angiotensin II have other than stimulating aldosterone synthesis?
Increases blood pressure through vasoconstriction and increases ADH secretion
What are hypertensive patients prescribed? Example?
Eg: ramipril (altace)
Where do the juxtaglomerular cells sense BP?
The renal artery
What 2 forms does aldosterone exist in?
How is aldosterone prevented from working on glucocorticoid receptors? What else is this super important for?
Its hemiacetal form protects the C11 hydroxyl
This is very important because steroids that do not have a protected C11 hydroxyl group (aka glucocorticoids) are deactivated by conversion of the hydroxyl into a ketone
Can the zona glomerulosa make steroids of the cortisol, androgen, or estrogen pathways? Why/Why not?
NOPE because it lacks the enzyme 17-α-hydroxylase
What 2 carrier proteins bind aldosterone in blood? Describe the binding.
Both weakly bound to aldosterone
What is the half life of aldosterone?
What other molecule on the aldosterone pathway has mineralcorticoid activity?
What step of the RAA system is the controlling step?
How is angiotensinogen II (and III) inactivated?
What is the main glucocorticoid in rodents?
Describe the regulation of cortisol secretion.
- Hypo: CRH
- Ant. Pit: CRH: POMC => ACTH
- Adrenal cortex: ACTH: + cortisol + aldosterone
Cortisol exerts (-) feedback on both the hypo and ant. pit.
What 2 carrier proteins bind cortisol in blood? Describe the binding.
1. CBG: strong
2. Albumin: weak
What is the half-life of cortisol?
How much aldosterone is free in the blood? Why?
To be able to quickly respond to changes in BP
How much cortisol is free in the blood? Why?
So it has a longer half-life and can regulate blood glucose levels over a longer period of time (hours between meals)
What carrier protein binds corticosterone in the blood?
What is the half-life of corticosterone?
Less than 1 hour
What other molecule has glucocorticoid activity?
How much deoxycorticosterone is free in the blood?
How are cortisol and corticosterone prevented from working on mineralcorticoid receptors? What enzyme catalyzes this reaction? Other name? Why is this important?
The tissues enzymatically inactivate them by 11-β hydroxysteroid dehydrogenase (HSD11B2) using NAD+ making the C11 hydroxyl into an inactive ketone, which is then activated in target tissues using NADPH
This is important because we have more glucocorticoids than we have mineralcorticoids, so the mineralcorticoid effects would be muted if we didn't have this protection mechanism
Which are present in larger quantities: mineralcorticoids or glucocorticoids?
Do glucocorticoids bind to mineralcorticoid receptors or glucocorticoid receptors tighter?
What is another name for CBG?
What is the weak androgen?
What are the 2 strong androgens?
What is the main sources of androgens in men?
What is the main sources of androgens in women?
Which is the major androgen produced by the adrenal cortex?
What does DHEA stand for?
Why does DHEA have a very long half-life?
Because it's often sulfated at the 3' and DHEA-3 sulfate binds very tightly to sex hormone binding globulin
Are steroids stored in the adrenal cortex?
Where is C17-20 lyase found?
Zona reticularis and gonads
What causes Addison's disease? Treatment? 8 Symptoms?
Autoimmune attack on adrenal cortex, which cannot produce cortisol nor aldosterone
Treatment: glucocorticoid and aldosterone replacement therapy
1. High ACTH (can also be ectopic)
2. Low BP
3. Low blood glucose levels
4. Intolerance to stress
5. Potential vascular collapse
7. Extreme insulin sensitivity
8. Very tan skin (palms, feet soles, gums, nails)
Why do Addison patients have very tan skin?
1. Lack of cortisol causes ACTH levels to rise
2. Breakdown of proopiomelanocortin (POMC) (to create ACTH) also produces α-melanocyte-stimulating hormone (α-MSH)
3. α-MSH stimulates melanocytes in the skin to produce pigment in response to UV
Why is aldosterone important during the stress response?
To increase blood flow to organs who need glucose during the stress response
What is the prepropetide of ACTH?
Proopiomelanocortin = POMC
What causes Cushing's disease? 4 symptoms? 3 prolonged effects? Effect on water retention and 4 symptoms?
Caused by pituitary adenoma that releases excess ACTH: high cortisol levels
1. Purple striae on skin (similar to stretch marks) due to skin proteolysis of collagen
2. Lipolysis in hips, thighs, and butt (not uniform) causing a redistribution of fat
3. Decreased resistance to infection
4. Decreased inflammatory response
1. Insulin resistance and Type 2 diabetes because constant hyperglycemia and free FAs also trigger insulin and gluconeogenesis
2. Redeposition in fat store in belly and back of neck (buffalo hump)
3. Excess androgens due to excess ACTH can cause virilization
Water retention increase due to mineralcorticoid effects of cortisol:
4. Moon facies (puffy and round and red)
What causes Cushing's syndrome? Symptoms? Treatment?
Cause is NOT pituitary adenoma but problem with adrenal gland (usually adrenal tumor or pharmacological use of glucocorticoids)
Symptoms: same as Cushing's disease
Treatment: adrenal gland removal
How to diagnose Cushing's disease vs syndrome?
Cushing's disease: high ACTH (which can cause high androgen levels) and cortisol levels
Cushing's syndrome: low levels of ACTH and high cortisol levels
Secondary adrenal insufficiency: cause? symptoms?
Lack of ACTH
Same symptoms as Addison's disease except no increase in skin pigmentation
Conn's syndrome: cause? 3 symptoms? Effect on renin/angiotensin II levels?
Adenoma of glomerulosa cells causing excess aldosterone
Symptoms: hypertension, edema, alkalosis
Renin and angiontensin II levels are low
What is another name for Conn's syndrome?
What is alkalosis?
Lack of blood potassium
Secondary aldosteronism: cause? 3 symptoms? Effect on renin/angiotensin II levels?
Hyperplasia and hyperfunction of juxtaglomerula cells due to arterial stenosis
Symptoms: hypertension, edema, alkalosis
Renin and angiontensin II levels are high
What does ANH stand for? What is another name for it?Where/When is it produced?
Atrial natriuretic hormone (ANH) = Atrial natriuretic factor (ANF)
Produced by right atrium in response to stretch, which signals high blood volume
How does ANH work?
5 pathways of action:
1) Inhibits the production of renin in the kidney
2) Inhibit aldosterone secretion in the zona glomerulosa
3) Causes renal glomerular cells to increase their GFR (glomerular filtration rate) and excrete more Na+ resulting in a decrease in blood volume
4) Potent vasodilator for vascular smooth muscle
5) Inhibits ADH secretion by the hypothalamus/post pit
What 2 hormones stimulate angiotensinogen secretion by the liver?
How are steroids made more soluble? What organ does this? Example of third method?
1. Dihydro form: add Hs on C4/5 double bond
2. Tetrahydro form: make C3 C=O into C-OH
3. Add hydrophilic molecule(s) to C3 (-OH) group (eg: glucoronic acid where glucose is added or sulfate)
2 reasons why increasing a steroid's solubility is important?
1. So it can dissociate from its carrier protein
2. So it can be excreted from the kidney
Where does the cholesterol used for steroid synthesis come from: de novo synthesis or LDL release?
What enzyme is unique to the zona glomerulosa? What does this mean?
MITO: 18-hydroxylase/18-hydroxydehydrogenase: corticosterone => aldosterone (carboxyl group added on C18: aldehyde group)
Only zona that can make aldosterone
What enzyme is unique to the zonas fasciculata and reticularis? What does this mean?
17-α-hydroxylase: pregnenolone => 17-hydroxypregnenolone
OR progesterone => 17-hydroxy-progesterone (OH added at C17 for both)
Only zona that can make cortisol is zona fasciculata because it also has 11-β-hydroxylase, which the zona reticularis lacks
Where does DHEA get converted into sex hormones?
In the sex organs
What enzyme is unique to the zona reticularis? What does this mean?
C17-20 lyase: 17-hydroxypregnenolone => DHEA OR 17-hydroxyprogesterone => androstenedione (chain at C17 cut off with carbonyl left)
Only zona that can make androgens
What do the enzymes 3-β-hydroxysteroid dehydrogenase/Δ5-4 isomerase do? Mechanism, substrates, products?
- Mechanism: Switch the double from between C5/6 to between C4/5 AND make hydroxyl on C3 a ketone
- Subtrates: pregnenolone, 17α-hydroxypregnenolone, DHEA
- Products: progesterone, 17α-hydroxyprogesterone, androstenedione
What does the enzyme 21-α-hydroxylase do? Mechanism, substrates, products? Other name?
- Mechanism: OH added at C21
- Substrates: progesterone, 17α-hydroxyprogesterone
- Products: 11-deoxycorticosterone, 11-deoxycortisol
- Other name: P450 21A2
What does the enzyme 11-β-hydroxylase do? Mechanism, substrates, products? Other name?
- Mechanism: OH added at C11
- Substrates: 11-deoxycorticosterone, 11-deoxycortisol
- Products: corticosterone, cortisol
- Other name: P450 11B2
What do the enzymes 18-hydroxylase/18-hydroxydehydrogenase do? Mechanism, substrates, products? Other name?
- Mechanism: C=O added on C18 => aldehyde group
- Substrates: corticosterone
- Products: aldosterone
- Other name: P450 11B2
What part of the adrenal cortex cells are all of the steroid enzymes found? What are the 2 exceptions?
What does the enzyme C17-20 lyase do? Mechanism, substrates, products?
- Mechanism: chain at C17 cut off with carbonyl left
- Substrates: 17α-hydroxypregnenolone, 17α-hydroxyprogesterone
- Products: DHEA, androstenedione
What does stenosis in the renal artery cause? What causes the stenosis?
Constriction/pinching in the renal artery upstream of the JGA cells causing pressure buildup behind the constriction and lower pressure after it making the JGA cells think there is chronic low BP so they secrete more renin leading to high BP
What is the 4 ring steroid nucleus called?
What is P450-SCC stimulated/inhibited by?
- Stimulated by cAMP
- Inhibited by aminoglutethimide
Does the zona reticularis have the enzyme 21-α-hydroxylase?
What 2 molecules on the steroid synthesis pathway can be made in all 3 zonas?
How can you convert 11-deoxycorticosterone directly to aldosterone without going through corticosterone?
Enzyme P450 11B2
Why is it important for all of the steroid synthesis to happen in either the mito or SER?
Need to happen in membranes to have hydrophobic environment!
T or F: mineralcorticoids do not have specific binding to a carrier protein?
What is cortisone? With what enzyme is it formed?
Inactive form of cortisol via 11-β-hydroxysteroid dehydrogenase
Inactivation of cortisol: NAD+ or NADP?
Activation of cortisone: NADH or NADPH?
How is aldosterone excreted?
Converted in liver to tetraldosterone 3-glucuronide which is then excreted in urine
What is the renin secretion by the JGA cells inhibited by?
1. High BP
2. Low K+
3. Angiotensin II/III
What secretes angiotensinogen?
What secretes renin?
What secretes ACE?
What is CAH? Other name for it? Difference between 2 main ones?
Congenital Adrenal Hyperplasia = Congenital Adrenogenital Syndrome
Deficiency of steroidogenic enzymes (90% due to 21-alpha-hydroxylase and others mainly 11-beta) causing an overproduction of ACTH and adrenal androgens leading to body growth, virilization, and ambiguous external genitalia
11-beta: lack of GC only, because 11-deoxycorticosterone is in excess and is an MC
What does the enzyme 17-α-hydroxylase do? Mechanism, substrates, products? Other name?
- Mechanism: OH added at C17
- Substrates: pregnenolone, progesterone
- Products: 17-hydroxypregnenolone, 17-hydroxyprogesterone
- Other name: P450 17A1
How are glucocorticoids activated in glucocorticoid responsive tissues?
HSD11B1: cortisone + NADPH => cortisol + NADP+
Where is HSD11B2 found?
In mineralcorticoid responsive tissue
Where is HSD11B1 found?
In glucocorticoid responsive tissue
What 6 factors will stimulate renin secretion from kidney?
1. Drop in blood pressure
2. Drop in blood volume
3. Drop in blood sodium
4. Increase in blood potassium
6. Renal nerve activation
In what 2 ways does angiotensin II act on the brain?
1. Increase ADH
2. Increase thirst
Other than aldosterone, what other hormone can act on the kidney tubules to conserve sodium?
What does StAR stand for?
Steroid Acute Regulatory Protein
What converts 11-deoxycorticosterone directly to aldosterone?