Lecture 6 (73): Adrenal Gland Part 2 Flashcards
What are the 3 layers of the adrenal medulla and which hormone is associated with it?
- zona glomerulosa = Mineralocorticoids
- zona fasciculata = Glucocorticoids (cortisol)
- zona reticularis weak androgens (DHEAS)
What are mineralcorticoids?
What is the primary endogenous mineralcorticoid?
What is its precursor?
- 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
Where is aldosterone (MR) expressed highly? 5
- distal tubule in kidney
- Colon
- Salivary ducts
- Sweat ducts
What is aldosterone’s main target?
Kidney
- promotes sodium and water reabsorption in the kidney
- increases potassium secretion
Describe the Renin-Angiotensin-Aldosterone System.
- What stimulates Renin release from the kidney?
- What forms?
- What converts AI to AII?
- What is the function of A II?
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.
State which performs the following functions (Aldosterone or AVP/ADH)
- 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)
- ALDOSTERONE
State which performs the following functions (Aldosterone or 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
AVP/ADH
Kidney: Cortisol is normally converted to the inactive *CORTISONE by what?
What happens if this enzyme is defective?
Licorice (glycyrrhetinic acid) does what?
- 11β-HSD2
- Certain drugs (carbenoxolone) will inhibit 11β-HSD2 resulting in excess MR activation.
- also inhibits 11β-HSD2 – excessive consumption can lead to increased sodium and water retention.
What enzyme converts Cortisone to the active CORTISOL?
Local production of Cortisol by 11β-HSD1 potential pathogenic role in DM T2 – novel drug target
What is the major compound in the Zona Reticularis?
DHEA/S; metabolite = androstendione
DHEA:
- Is the precursor for what androgen? Where is it converted
- Declines with what?
- Weak or strong androgen? Why?
- Increases what in women? Primary source of _____ and _____ in post-menopausal women.
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
What is the primary product of the zone fasciculata?
Important enzymes?
Where is 17 alpha - hydroxyls made?
Cortisol
enzymes:
cholesterol side chain cleavage
21alpha - hydroxylase
11-alpha-hydroxylase
17alpha - hydroxylase
MADE ONLY IN Z.fasciculata and z. reticularis
Congenital Adrenal Hyperplasia is a deficiency in which enzyme?
What is in excess amount?
What are the clinical implications?
21α 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
CYP21A2: 21α-hydroxylase deficiency
State 3 major things affected.
Clinical implications?
- No cortisol
- No aldosterone/MR activity
- Increased androgens
Clinical presentation: Hypotension Hyperkalemia High plasma renin Masculinization High ACTH
What is the primary product of the zone glomerulosa?
What are the clinically relevant enzymes?
Primary Product: Aldosterone
- Cholesterol side chain cleavage
- 21alpha-hydroxylase
- 11-alpha-hydroxylase
- 17-alpha-hydroxylase (only made in z.fascuculata and z. reticularis)
CYP11B1, is a deficiency in what?
what are the levels of the following:
- Cortisol
- Aldosterone
- androgen
What are the clinical implications?
11-hydroxylase deficiency
No cortisol
Low aldosterone, but high MR activity
Increased androgens
Clinical presentation: Hypertension* due to excess 11-deoxycorticosterone Hypokalemia Masculinization High ACTH
What is the primary product of Zona Reticularis?
DHEA/S
What is deficient in CYP17?
17α-hydroxylase deficiency
CYP21A2: 21α-hydroxylase deficiency
what are the levels of the following:
- Cortisol
- Aldosterone
- androgen
Clinical implications?
- No cortisol
- No aldosterone/MR activity
- Increased androgens
Clinical presentation: Hypotension Hyperkalemia High plasma renin Masculinization High ACTH
CYP11B1, is a deficiency in what?
what are the levels of the following:
- Cortisol
- Aldosterone
- androgen
What are the clinical implications?
11-hydroxylase deficiency
No cortisol
Low aldosterone, but high MR activity
Increased androgens
Clinical presentation: Hypertension* due to excess 11-deoxycorticosterone Hypokalemia Masculinization High ACTH
What is deficient in CYP17?
what are the levels of the following:
- Cortisol
- Aldosterone
- androgen
Clinical presentation?
17α-hydroxylase deficiency
Clinical presentation: Hypertension Hypokalemia Feminization/ pseudohermaphroditism High ACTH
What 2 important enzymes are found in
fasciculata and glomerulosa?
What enzyme is found only in fasciculate and RETICULARIS?
What enzyme is ONLY in GLOMERULOSA
21α-hydroxylase
11-hydroxylase
- 17α-hydroxylase
Aldosterone Synthase
Where is 11β-HSD1 and 2
?
What are the functions of both?
Kidney (type 2)
1 = convert cortisone to CORTISOL
2= opposite
What gene is defective and affects the following enzymes:
- Cholesterol Side Chain cleavage
- 21α-hydroxylase
- 11-hydroxylase
- 17α-hydroxylase
- Aldosterone synthase
- 11β-HSD1 and 2
- CYP11A1
- CYP21A2
- CYP11B1/CYP11B2
- CYP17
- CYP11B2
- not P450 family
_____ in z. glomerulosa can be called 11-hydroxylase or aldosterone synthase
11-hydroxylase deficiency syndrome refers to defect in _____ (z. fasciculata)
CYPB2
CYP11B1
Minerlcorticoid2 Receptor (MC2R) is what type of receptor?
ACTH
ACTH TARGETS IN ADRENAL:
- Stimulates the conversion of?
Where do the following occur?
- Cellular ____
- Biosynthesis of _____ & _____
- Enzyme?
WHERE
1. Stimulates conversation of dopamine to _____ where?
Steroid Biosynthesis:
1. 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 11β-hydroxylase (CYP11B1)
Adrenal Medulla:
1.Stimulates conversion of dopamine to norepinephrine in Adrenal Medulla
Adrenal medulla:
Originates from same _________ that forms sympathetic ganglia.
Medullary cells are innervated by ______
Considered to be modified _______
- neural crest area
- sympathetic preganglionic fibers.
- post-ganglionic sympathetic neurons (no dendrites or axons).
Adrenal Medulla:
- Cords of _____ shaped epithelial cells.
- Most cells release _______ – stored in granules.
- Rapid release under _______ NS control
- Polyhedral
- epinephrine
- sympathetic
How are chromaffin cells made?
Where are they found?
- “Chromaffin” cells: Catecholamines bind to chrome salts. Reaction oxidizes to brown color.
- Adrenal medulla
Catecholamines like dopamine, norepinephrine, and epinephrine.
What is the rate limiting enzyme in their production?
- Tyrosine Hydroxylase
2.
What does tyrosine hydroxylase convert?
Converts tyrosine to XDOPA (precursor of dopamine)
Catecholamines like dopamine, norepinephrine, and epinephrine.
What is the rate limiting enzyme in their production?
Where does the pathway stop?
What converts dopamine to NE?
______ stimulates conversion of norepinephrine to epinephrine – only where??
- Tyrosine Hydroxylase
- Pathway stops at dopamine in the dopaminergic neurons in brain.
- Peripheral nerves convert dopamine to norepinephrine (ACTH sympathetic stimulation)
NE to E = cortisol
- Cortisol, adrenal medulla.
What hormone does the following describe?
Response to acute stress: (pain, cold, perceived danger)
Rapid activation/rapid return
Mediated by the sympathetic nervous system – innervated by splanchnic nerve
Epinephrine
What are the 3 main targets of epinephrine?
What functions does it affect in these tissues?
- Muscle, liver, fat
- Glycogenolysis: ATP release for local energy (no glucose-6-phosphotase in skeletal muscle)
- Release glucose into blood in the liver (via glycogenolysis)
- Increase glucagon release from Alpha cells of the pancreatic islets
- increase TAG degradation in adipose tissue
What receptors does epinephrine act through?
How does it affect the following:
- Pupil
- Sweat
- GI and bronchial muscle?
BOTH alpha and beta adrenergic
Arousal
- pupil dilation, 2. sweating,
- GI and bronchial muscle relaxation
How does epinephrine affect the following:
- Metabolism
- Cardiovascular
- Glucose release,
increase metabolic rate - Vasoconstriction, increased heart rate (tachycardia)
Which is higher in the following scenario (NE or Isoproterenol:
- alpha adrenergic mediated
- Beta - adrenergic
- alpha adrenergic mediated - NE
- Beta - adrenergic
- Isoproterenol
What are 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
Where does the break down of EPI and NE to COMT and MAO occur?
- Adrenal Medulla
- Liver
- Kidney
Where does conversion of the followng occur:
- Metenephrine to MAO
- DHPG to COMT and AD
- Normetanephrine to MAO
and all of these finally to VMA
LIVER and Kidney
What is the breakdown product of NE and E
either:
Metenephrine or Normetanephrine
- Epinephrine Metenephrine
2. NE and Normetanephrine
What are pheochhromocytomas?
What are the symptoms?
DIagnosis?
Treatment?
- tumors originating from chromaffin cells.
- Diagnosis: measurements of urinary metanephrines
- surgery, pre-surgery: alpha/beta blockers
Why are pheochromocytoma the 10% tumor?
Because ~10 percent of pheochromocytomas are:
Malignant (90% benign)
Bilateral (found in both adrenal glands: 90% arise in just one of the two adrenal glands) In Children (90% in adults)
Familial (10% will have a family member with the same type of tumor)
Recur (10% will come back in 5 - 10 years)
Associated with MEN* syndromes (patients with rare syndromes of endocrine tumors)
Present with a stroke (10% of these tumors are found after the patient has a stroke)
Extra-Adrenal (found within nervous tissue outside of adrenal glands)
What are the extra-adrenal sites of pheochromocytomas?
Extra-adrenal sites of pheochromocytomas:
Sympathetic nerve chain along the spinal cord
Overlying the distal aorta (main artery from the heart)
Within the ureter (collecting system from the kidney)
Within the urinary bladder (And 90% in the adrenal glands)
