Endocrinology 6 Flashcards
Describe the actions of aldosterone and its regulation by the renin-angiotensin II system.
What are mineralocorticoids?
What is the primary endogenous mineralocorticoid? What is its precursor?
Hormones that promote sodium retention by the kidney.
- Secondary result is water retention
Zona Glomerulosa (outermost layer of adrenal cortex)
- Produces aldosterone (mineralocorticoid).
- Primary cells in body that have aldosterone synthase. Steroid hormones that regulate sodium/water balance
Aldosterone – primary endogenous mineralocorticoid; other steroid hormones can have mineralocorticoid actions
Example: 11-Deoxycorticosterone (precursor of
aldosterone) has mineralocorticoid action
What are the sites of action for aldosterone?
MR expression high in these tissues
Distal tubule in kidney
Colon
Salivary ducts
Sweat ducts
Describe aldosterone’s action in the kidney.
Aldosterone stimulates sodium and water reabsorption in the kidney; increases potassium secretion
Aldosterone increases transepithelial Na+ transport in the distal tubule and collecting duct of the nephron.
Aldosterone also promotes potassium excretion in
the collecting duct cells. Increases in extracellular fluid K+ concentration simulate aldosterone release.
Summarize the Renin-Angiotensin-Aldosterone System.
Decreased blood pressure stimulates renin release from kidney (juxtaglomerular apparatus).
Renin cleaves angiotensinogen (from liver) to angiotensin I.
Angiotensin converting enzyme (ACE) converts to angiotensin II.
Angiotensin II is a vasoconstrictor and stimulates aldosterone.
Compare and contrast the effects of AVP and aldosterone on osmoregulation.
Aldosterone – primary regulator of extracellular volume
- Stimulates sodium and water reabsorption in kidney
- Stimulates potassium excretion
- Net Result = increased extracellular fluid volume and blood pressure (sodium in extracellular space retains water)
AVP/ADH – primary regulator of free water balance
- Stimulates distal nephron water permeability – -increased water retention
- Decreases plasma osmolality which secondarily affects sodium concentration in the blood
Describe the signaling pathways and tissue specificity of GR and MR, and how receptor specificity is regulated for glucocorticoids and mineralocorticoids.
Slide 14
Primary high-affinity receptor — MR (mineralocorticoid receptor
MR is a member of the nuclear receptor superfamily
- MR binds with high affinity to both glucocorticoids and mineralocorticoids.
- Glucocorticoids are 100 – 1000 fold higher than mineralocorticoids – but 95% is bound to
CBG.
- Aldosterone does not have a specific binding protein.
- Conversion of cortisol to cortisone by 11B-HSD Type 2 inactivates glucocorticoids.
How is cortisol converted to cortisone?
What effect will the drug carbenoxolone have?
What effect will licorice have?
Describe the role of 11B-HSD1 as a potential drug for DM T2.
Kidney: Cortisol is normally converted to the inactive *cortisone by 11B-HSD2.
Certain drugs (carbenoxolone) will inhibit 11B-HSD2 resulting in excess MR activation. (Carbenoxolone used to treat esophogeal inflammation – increases local cortisol)
Licorice (glycyrrhetinic acid) also inhibits 11B-HSD2 – excessive consumption can lead to increased sodium and water retention.
Local production of Cortisol by 11B-HSD1 potential pathogenic role in DM T2 – novel drug target
Between 11B-HSD1 and 2 which is a reductase, which is a dehydrogenase?
Where are each expressed?
11BHSD1 is NADPH-dependent reductase that converts inactive cortisone to active cortisol. Functions mostly as reductase in intact cells and organs.
11BHSD2 is dehydrogenase that converts cortisol to cortisone. Expressed in liver, adipose, gonadal, and CNS tissues. NAD-dependent. Highly expressed in kidney and colon.
Slide 15
Describe the main function of the zona reticularis and the importance of adrenal androgens.
What is it a precursor for? Where converted?
How does it change with age?
Why called “weak androgens”?
How does it affect women? Postmenopausal women?
DHEA/S; metabolite = androstendione
Precursor for the more potent androgen testosterone, and for estrogens – converted in reproductive tissues.
50% of total androgen precursors in adult male prostate comes from adrenal
Declines with age – peaks between 20 – 30.
“weak androgen” due to its low binding affinity for androgen receptors (AR).
Increases libido in women; primary source of androgen and estrogen in postmenopausal women
List the major steroid biosynthetic enzymes required for adrenal cortical hormones and explain the physiological consequences for these enzyme deficiencies.
What is first step in steroid hormone biosynthesis?
How is cholesterol imported into the cell?
What happens to free cholesterol? What enzyme carries this out and what stimulates this enzyme?
What enzyme transfers cholesterol from outer mitochondria membrane to inner?
What is RLS in steroid hormone biosynthesis? What regulates it?
Slide 20
Slide 21
Conversion of cholesterol to pregnenolone. This is the first step in steroid hormone biosynthesis.
Cholesterol is imported into the cell as LDL or HDL particles.
Free cholesterol is esterified by the enzyme cholesterol ester hydrolyase. This enzyme is
stimulated by ACTH.
Steroidogenic regulatory protein (StAR) transfers cholesterol from
the outer mitochondria to the inner mitochondria.
This is a rate-limiting step in steroid hormone biosynthesis and is regulated by ACTH.
List the major steroid biosynthetic enzymes required for zona fasiculata.
Primary product?
What are clinically relevant enzymes?
Draw pathway.
Slide 21
Slide 22
What will a 21alpha hydroxylase deficiency cause?
Describe the clinical indications and the disease.
21alpha hydroxylase deficiency - results in excess DHEA, no mineralocorticoids or glucocorticoids
Most common cause of CAH
Clinical indications: virilization (masculinization) ambiguous genitalia at birth, sodium loss
No cortisol
No aldosterone/MR activity
Increased androgens
Clinical presentation: Hypotension Hyperkalemia High plasma renin Masculinization High ACTH
Slide 23, 24 (see in zona glomerulosa and fasciculata)
List the major steroid biosynthetic enzymes required for zona glomerulosa.
Primary product?
What are clinically relevant enzymes?
Draw pathway.
Primary Product: Aldosterone
Slide 25
Describe the effects of a CYP11B1: 11-hydroxylase deficiency.
Describe clinical presentation.
No cortisol
Low aldosterone, but high MR activity
Increased androgens
Clinical presentation: Hypertension* due to excess 11-deoxycorticosterone Hypokalemia Masculinization High ACTH
Slide 26
(zona fasiculata… no cortisol…)
List the major steroid biosynthetic enzymes required for zona reticularis.
Primary product?
What are clinically relevant enzymes?
Draw pathway.
Primary Product: DHEA/S
Slide 27
