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
Describe the effects of a CYP17: 17alpha-hydroxylase deficiency.
Describe clinical presentation.
no cortisol
low aldosterone, high MR activity
Decreased androgens
Clinical presentation: Hypertension Hypokalemia Feminization/ pseudohermaphroditism High ACTH
Note: CYPB2 in z. glomerulosa can be called 11-hydroxylase or aldosterone synthase.
CYP11B2 stimulated by angiotensin II
11-hydroxylase deficiency syndrome refers to defect in CYP11B1 (z. fasciculata)
(fasciculata and reticularis)
For the following enzyme, provide the synonym, gene and zone:
Cholesterol side chain cleavage
Synonym: desmolase; P450scc
Gene: CYP11A1
Zone: all
For the following enzyme, provide the synonym, gene and zone:
21alpha-hydroxylase
Synonym: P450c21
Gene: CYP21A2
Zone: fasciculata and glomerulosa
For the following enzyme, provide the synonym, gene and zone:
11-hydroxylase
Synonym: p450c11
Gene: CYP11B1/CYP11B2
Zone: fasciculata/glomerulosa
For the following enzyme, provide the synonym, gene and zone:
17 alpha-hydroxylase
Synonym: P450c17
Gene: CYP17
Zone: fasciculata and reticularis
For the following enzyme, provide the synonym, gene and zone:
aldosterone synthase
Synonym: P450aldo
Gene: CYP11B2
Zone: glomerulosa
For the following enzyme, provide the synonym, gene and zone:
11B-HSD1 and 2
Synonym:
Gene: not P450 family
Zone: kidney (type 2)
Describe the immediate, subsequent and long term effects of ACTH’s activation of its MC2R receptor.
Slide 33
Describe ACTH targets in adrenals…
Adrenal cortex and medulla.
(steroid biosynthesis) Stimulates conversion of cholesterol to pregnenolone by activating StAR activity
Adrenal cortex-
- Stimulates cellular hypertrophy
- Stimulates biosynthesis of cortisol
- Stimulates biosynthesis of DHEA (CYP17)
- Stimulates 11beta-hydroxylase (CYP11B1)
Adrenal medulla- Stimulates conversion of dopamine to norepinephrine
Compare and contrast the metabolic response to stress mediated by catecholamines and glucocorticoids.
s
What does the adrenal medulla originate from?
What innervates medullary cells?
ADRENAL MEDULLA
Originates from same neural crest area that forms sympathetic ganglia.
Medullary cells are innervated by sympathetic preganglionic fibers.
Considered to be modified post-ganglionic sympathetic neurons (no dendrites or axons).
Describe the histology of the adrenal medulla. What kind of cells? What do the cells released? What is stored in cells?
When does rapid release occur?
What is major cell type? Analogous to what? 2 cell types, which more numerous? Innervated by waht? What causes release?
Cords of polyhedral shaped epithelial cells
Most cells release epinephrine – stored in granules.
Rapid release under sympathetic NS control.
Slide 37
“Chromaffin” cells: Catecholamines bind to chrome salts. Reaction oxidizes to brown color.
- Major cell type = chromaffin cells (pheochromocytes)
- Analogous to postganglionic sympathetic neurons
- 2 cell types: EPI (most numerous) and NE
- Sympathetic nerve stimulation (Ach) causes EPI and NE release from medulla.
- Innervated by splanchnic nerve
- Only site of epinephrine synthesis in the body
Inside chromaffin cells, what do catecholamines bind to?
“Chromaffin” cells: Catecholamines bind to chrome salts. Reaction oxidizes to brown color.
What are the catecholamines?
What is RLS?
Where does pathway stop in the brain?
Catecholamines: dopamine, norephinephrine, epinephrine (aka – adreneline)
Tyrosine hydroxylase is rate limiting step.
Pathway stops at dopamine in the dopaminergic neurons in brain.
Slide 38
What converts dopamine to NE?
What stimulates conversion of NE to E?
Peripheral nerves convert dopamine to norepinephrine
Cortisol stimulates conversion of norepinephrine to epinephrine – only in adrenal medulla.
Slide 38
Describe epinephrine.
What is it a response to?
How mediated?
Response to acute stress: (pain, cold, perceived danger)
Rapid activation/rapid return
Mediated by the sympathetic nervous system – innervated by splanchnic nerve
See flow chart on p 39
Describe the metabolic actions of epinephrine.
What are the 3 main targets?
3 main targets: muscle, liver, fat
in muscle will promote glycogenolysis: ATP for local energy (remember no G6Phosphatase in skeletal muscle)
In liver will release glucose into the blood
In adipose tissue will break TAG to FFA for production of ketoacids in liver
See slide 40
Describe epinephrine’s actions. What receptors does it stimulate?
What are the physical manifestations of arousal?
What are the metabolic effects?
Cardiovascular effects?
Acts through adrenergic receptors (both alpha and beta)
Arousal – pupil dilation, sweating, GI and bronchial muscle relaxation
Metabolic – glucose release, increased metabolic rate
Cardiovascular – vasoconstriction, increased heart rate (tachycardia)
How will alpha/beta adrenergic mediated receptors affect the following…
vasoconstriction/vasodilation
intestinal and bladder sphincter relaxation/contraction
bronchoconstriction/bronchodilation
uterine smooth muscle relaxation/contraction
decreased insulin release
increased glucagon release
increased renin release
glycogenolysis
alpha adernergic (NE greater or equal to E) - vasoconstriction, intestinal and bladder contraction, bronchoconstriction, uterine smooth muscle contraction, decreased insulin release
B-
vasodilation, intestinal and bladder wall relaxation, bronchodilation, uterus relaxation, glycogenolysis, increased glucagon release, increased renin release,
glycogenolysis
Describe the coordinated efforts of cortisol and EPI in stress response.
Acute stress activates the sympathetic NS and stimulates the release of NE.
NE stimulates CRH to initiate HPA response to long-term stress
Feedback loops occur at multiple levels
Describe the metabolic fate of catecholamines and consequences of overproduction.
How do you diagnose?
Treat?
Slide 46, 47
Clinical Issues – catecholamine overproduction
Pheochromocytomas – tumors originating from chromaffin cells.
Symptoms: hypertension (no response to medication), headaches, tachycardia,
Diagnosis: measurements of urinary metanephrines
Treatment: surgery, pre-surgery: alpha/beta blockers.
Describe Pheochromocytomas: the 10% tumor.
Slide 49
Summarize the 3 causes of Congenital Adrenal Hyperplasia (CAH).
Most common cause:
21alpha hydroxylase deficiency - excess DHEA, no mineralocorticoids or glucocorticoids
- virilization (masculinization) , ambiguous genitalia at birth, sodium loss
11beta hydroxylase deficiency (CYP11B1 gene) – excess DHEA, no cortisol
- Second most common abnormality in adrenal hormone synthesis
- Salt and water retention due to excess mineralocorticoid receptor activity
- Low aldosterone due to low renin, high ANP
17-hydroxylase deficiency –
- Salt and water retention due to excess mineralocorticoid receptor activity
- Feminization – no adrenal androgens
Note: all 3 enzyme deficiencies will result in excess ACTH stimulation of cortex due to lack
of negative feedback (i.e. no cortisol).
Note: CYP11B2 is stimulated by angiotensin II, not ACTH
