Endocrine Lecture 3 Flashcards
The Adrenal Gland:
What two things are regulated by the HPA axis?
What is done by the adrenal gland but not regulated by the HPA axis?
Regulated by the HPA Axis:
- adaptive response to stress
- catecholamines: Epi and NE
- Glucocorticoids: cortisol
- immune function: glucocorticoids
NOT regulated by the HPA Axis:
- maintenece of water, Na, K balance and BP
- aldosterone
- site of “weak” androgen production
The HPA Axis:
There are various physical (pain, cold, heat), emotional, chemical (hypoglycemia), STRESSORS that activate the ____ neurons in the ____ nucleus within the hypothalamus.
These secrete CRH, which goes into the hypophysial portal system, and goes into the anterior pituitary to activate ______ cells to release ____. That then goes to the adrenal gland to release ____ from the _____
Explain the feedback loop
HPA Axis: (stress response axis):
There are various physical (pain, cold, heat), emotional, chemical (hypoglycemia), STRESSORS that activate CRH neurons in the PVN within the hypothalamus.
CRH travels down the hypophysial portal system, goes into the anterior pituitary and activates corticotrope cells to release ACTH. ACTH then goes to the adrenal gland to stimulate cortisol release from the zona fasiculata.
Feedback: Cortisol has a long feedback loop where it can inhibit CRH release in the PVN, and also ACTH release from the anterior pitutiary.
CRH:
CRH is the _____ regulator of the HPA axis : 41 AA’s
Produced in _______ neurons of the _____
Stimulates the anterior pituitary: ___ gene, ___ hormone
CRH:
CRH is the central regulator of the HPA axis - 41 aa’s
Produced in parvocellular neurons of the PVN
Stimulates anterior pituitary (POMC gene, ACTH is released)
CRH is ______ : it results in episodic release of ACTH
This is important to allow what?
CRH is pulsatile: it results in episodic release of ACTH
This is important to allow recycling of receptors back to cell membrane surface
CRH:
CRH binds with highest affinity to ______ in the anterior pituitary
Evidence for multiple intracellcular signaling pathways (increase in intracellular ___ causes hormone release)
CRH:
CRH binds with highest affinity to CRH R1 in the anterior pituitary
Evidence for multiple intracellular signaling pathways (increase in intracellular Ca2+ causes hormone release)
Compare and contrast the role of AVP in mediating the physiological response to stress to its role in osmoregulation
ACTH release is AMPLIFIED in the presence of AVP
CRH with the presence of AVP causes a maximal response (maximal ACTH release) in response to stress
Explain cortisol’s feedback on both AVP and CRH
Cortisol:
Negative feedback on pituitary AND hypothalamus to regulate BOTH AVP and CRH
- cortisol decreases synthesis of CRH and AVP in hypothalamus
- cortisol decreases ACTH release from anterior pituitary
ACTH:
ACTH is produced in the _____ of the _____
It is regulated by ____ and ____ from the hypothalamus
Precursor is what?
ACTH:
ACTH is produced in the anterior pituitary
It is regulated by CRH and AVP from hypothalamus
Precursor: POMC
ACTH:
Binds with high affinity to _____ receptor in the adrenal cortex
Binds with low affinity to _____ receptor (location?)
High levels of ACTH leads to ________
ACTH:
ACTH binds with high affinity to MC2R receptor in the adrenal cortex
Binds with low affinity to MC1R receptor in the skin
High levels of ACTH leads to hyperpigmentation of the skin
Under normal conditions, acth only binds to mc2r, but when ACTH release is really high, the skin will darken
Explain the immediate, and long term effects of ACTH binding the MC2R receptor in the adrenal cortex
ACTH binds to MC2R on adrenal cortex
ACTH is basically stimulating steroid hormone biosynthesis (and steroid hormones come from cholesterol)… so ACTH wants to free up cholesterol to transport it from outer to inner mitochondrial membrane
Immediate: Increase cholesterol esterase, increase cholesterol transport into mitochondria by STAR protein, increase cholesterol binding to P-450, decrease cholesterol ester synthetase
Subsequent: Increase gene tx of P-450’s
Long Term: increase size and complexity of cells in the adrenal gland
Adrenal Gland:
Cortex derived from the ______
Medulla derives from the _______
Sympathetic innervation synpases on ____ cells
Adrenal Gland:
Cortex derived from mesoderm (glandular)
Medulla derives from neural crest
Sympathetic innervation synpases on medullary cells
Label the various layers of the adrenal gland in the picture
Give its name and what kind of hormones it produces
Goes down this way: GFRM
Zona Glomerularis: mineralcorticoids (aldosterone)
Zona fasiculatus: cortisol
Zona reticularis: weak androgens
Medulla: catecholamines (Epi and NE)
Adrenal Blood Supply:
Explain the two adrenal gland blood supplies:
Cortical Blood Supply
Medulla Blood Supply
Adrenal Blood Supply:
- Cortical Blood Supply: suprarenal arteries break into capillaries
- Medulla blood supply:
- bathes medullar cells with blood carrying corticosteroids from the cortex: important for conversion of NE to Epi
- arterioles break into fenestrated capillaries
- all blood drains into central vein
Glucocorticoids:
Made in the zona _______
Accounts for more than 80% of hormones made in adrenal cortex
Released in a _____ manner (peaks at ___)
Bound to transport proteins in the bood called ___, must ____ to be active
Glucocorticoids:
Made in the zona fasicularis (cortisol)
Accounds for more than 80% of hormones made in adrenal cortex
Released in a circadian manner (peaks at 8 am)
Bound to transport proteins in the blood called CBG, must dissociate to be active
CBG:
CBG is the binding protein for cortisol:
___% of cortisol is bound to CBG
There is WAY higher affintity for cortisol than aldosterone
What decreases CBG levels, thereby making more “active” cortisol?
CBG:
CBG is the binding protein for cortisol
90% of cortisol is bound to CBG (there is a TON of circulating cortisol, but only 3-4% of it is free cortisol)
30-fold higher affinity for cortisol than aldosteron
Estrogen decreases CBG, and shock/infection decreases CBG, allowing more free cortisol
Glucocorticiod Receptor (GR) What kind of receptor is GR?
Where is it expressed?
Explain what ligand binding does to GR
Glucocorticoid Receptor:
GR is a nuclear steroid receptor: transcription factor
It is ubiquitously expressed in most tissues
Ligand bindind dissociates GR from HSP in cytoplasm
Ligand bound GR then binds to GRE on gene promoters to increase tx
Cortisol: pleotropic hormone (many actions):
Briefly explain the key function of cortisol on the listed systems
- Metabolism
- Muscle
- Adipose Tissue
- Immune/Inflammation
- Bone
- Cardiovascular
- CNS
Cortisol Actions:
- Metabolism: glucose mobilizing
- Muscle: breakdown protein
- Adipose tissue: breakdown fat
- Immune/Inflammation: inhibit inflammation and immune responses
- Bone: decrease bone formation
- Cardiovascular: maintain cardiac output, increase arterial tone
- CNS: modulate emotional tone, wakefulness
Cortisol Actions: Metabolism:
Metabolic Actions: potent counter regulatory hormone to _______, mobilizes _____
- ______ gluconeogenesis
- _______ lipolysis
- ________ muscle protein
- Redistributes _____
- ____insulin action
- ______ intestinal calcium absorption
Cortisol Actions: Metabolism:
Metabolic Actions: potent counter regulator hormone to insulin. Mobilizes energy stores - wants to increase plasma glucsose:
- increases gluconeogenesis and plasma glucose levels
- increase lipolysis
- breaks down muscle protein - proteolysis
- redistributes fat - abdominal obesity
- antagonises insulin action
- inhibits intestinal calcium absorption
Cortisol is going to INCREASE gluconeogenesis: trying to increase plasma glucose levels
Explain how cortisol works to increase gluconeogenesis:
- cortisol stimulates which three enzymes?
- cortisol ______ GLUT4 insertion in the membrane
Cortisol increases gluconeogenesis in order to increase plasma glucose levels
Within the gluconeogenesis pathway, cortisol stimulates three enzymes:
- PEPCK
- tyrosine aminotransferase
- glucose-6-phosphatase
Cortisol decreases GLUT 4 insertion in the membrane (GLUT 4 is the big one that controls glucose uptake into cells)
Cortisol will increase muscle proteolysis in order to mobilize energy stores:
Explain the two ways that cortisol stimulates muscle proteolysis:
- Cortisol ____ AA uptake and AKT phosphorylation - FoxO translocates to ____ and increases ____
- Cortisol increases transcription of ______
Is the muscle breakdown via cortisol short term or long term?
Cortisol will increase muscle proteolysis in order to mobilize energy stores:
The two ways that cortisol promotes muscle proteolysis:
- Cortisol inhibits AA uptake and AKT phosphorylation (which when AKT is no longer phosphorylated, it cannot inhibit FoxO from going into the nucleus), so FoxO will translocate to the nucleus and increase atrogenin-1
- Cortisol increases transcription of MuRF-1 (atrogene) which will increase degradation of muscles
Cortisol and Lipolysis:
Glucocorticoid comes in, binds GR (GR loses its heat shock protein), goes into the nucleus and increases the expression of what?
Cortisol increases the expression of ____, ____, and ____ genes
This increases lipid breakdown and frees up FA and glycerol
Cortisol and Lipolysis:
GC will come into the cell, bind to GR (GR dissocaites from heat shock protein, is now GR-ligand), goes into the nucleus and increases the expression of certain genes
Cortisol increases the expression of MgII, Lipe, and Angpt14 genes
These genes help with lipolysis
Glucocorticoid Receptor (GR): Inflammatory Response
____ is pro-inflammatory, cortisol-GR keeps it out of nucleus via two ways:
Cortisol will bind to the GR, enter the nucleus:
- increase the trascription of ____ (which binds to ___ and keeps it out of the nucleus)
- cortisol-GR can also bind up any excess ___ and keep it out of the nucleus
Cortisol is the MOST potent inhibitor of ____ that we know of
Glucocorticoids are going to DECREASE inflammatory response by two ways:
NF-kb is proinflammatory, cortisol-GR keeps it out of the nucleus via two ways:
Cortisol will bind to the GR, enter the nucleus:
- increase transcription of I<strong>KB</strong> which will bind to NF-kb and keep it out of the nucleus
- cortisol-GR can also bind up any excess NF-kb and keep it out of the nucleus itself
Note: cortisol is the MOST POTENT inhibitor of inflammation that we know of
Cortisol Actions: Immune System:
- What does cortisol do to inflammation?
- Cortisol _______ anti-inflammatory cytokines, and _____ pro-inflammatory
- Cortisol _____ phospholipase A (thereby decreasing prostaglandins, thromboxane)
- Cortisol ____ antibody production
- Cortisol ____ blood cell types: neutrophils, platelets, and RBCs
- Cortisol _____ T-cell proliferation and migration
Anti-inflammatory effects are the primary reason for _____ therapy
Cortisol Actions: Immune System:
- decreases inflammation
- stimulates anti-inflammatory and inhibits pro-inflammatory
- inhibits phospholipase A (thereby reducing prostaglandins, thromboxane)
- suppresses antibody production
- INCREASES all blood cell types: neutrophils, RBCs, platelets (even through the WBC count increases, the neutrophils don’t work)
- decreases T-cell proliferation
Anti-inflammatory effects are primary reason for glucocorticoid therapy
Cortisol Actions: BONE
Bone:
- ______ intestinal calcium absorption
- ______ bone formation - decreases IGF-1 receptors
- _____ bone resorption - activating osteoclast
Cortisol Action: BONE
Bone:
- inhibits intestinal calcium absorption
- inhibits bone formation - decreases IGF-1 receptors
- increases bone resorption - activation of osteoclasts
Cortisol Actions: Cardiovascular:
Cardiovascular: during physical stress, wants blood to flow to brain and heart, away from periphery
Cortisol will _____ RBC production
Cortisol will maintain responsiveness to catecholamine pressor effects:
- _______ peripheral vessels via alpha 1 adrenergic receptors
- _____ coronary arteries in heart via beta adrenergic receptors
- glucocorticoid excess = ___ BP
Cortisol Actions: Cardiovascular:
Cardiovascular: during physical stress, wants blood to flow to brain and heart, away from periphery
Cortisol will stimulate RBC production (to carry more O2 to brain and heart)
Cortisol will maintain responsiveness to catecholamine pressor effects:
- constrict peripheral vessels via alpha 1 adrenergic receptors
- dilate coronary arteries in heart via beta-adrenergic receptors
- glucocorticoid excess = increased BP/hypertension
Maintains vascular integrity and reactivity
Cortisol Actions on the CNS:
What does cortisol do to the CNS?
Cortisol ____ the emotional response
(the mechanism is unknown but we do know the outcomes)
Cortisol Actions on the CNS:
Emotional response INCREASES:
depression, anxiety, nervousness, panic, feeding behavior, rage/aggresion
Perception is altered (due to NE)
negative feedback on CRH and ACTH release
Explain ADRENAL Insufficiency (AI)
Adrenal insufficiency is the failure of adrenal to secrete ____, _____ or both
Explain primary vs secondary AI
Adrenal Insufficiency (AI)
Adrenal Insufficiency is the failure of the adrenal gland to secrete glucocorticoids, mineralcorticoids, or both
Primary AI: failure at adrenal gland, Addison’s disease is a autoimmue destruction of the adrenal gland zona fasiculata cells (most of primary AI cases)
Secondary AI: failure to secrete CRH or ACTH
- most common cause = sudden cessation of glucocorticoid therapy
Reminder Slide:
The adrenal gland: what does the progression of the cortex zones look like?
What kind of hormone does each zone produce
Adrenal Gland: top to bottom is G–>F—>R
Zona glomerulosa: mineralcorticoids (aldosterone)
Zona Fasiculata: glucocorticoids (cortisol)
Zona Reticularus: weak androgens
GFR is all in the cortex
The adrenal medulla itself makes catecholamines
Mineralcorticoids:
Steroid hormones that regulate _____
_____ is the primary endogenous mineralcorticoid
Made in the zona ____ layer of the adrenal cortex
What does 11-deoxycorticosteroid do?
Aldosterone: Sites of Action:
MR expression is high in what tissues:
Unlike GR which is widely expressed, MR has very restricted tissue distribution
Aldosterone: Sites of Action:
MR expression is high in these tissues:
- distal tubule of kidney
- colon
- salivary duct
- sweat ducts
Unline GR which is widely expressed, MR has very restricted tissue distribution
Aldosterone’s Main target is where?
What does it do to sodium, water, and potassium?
Aldosterone Main Target: KIDNEY
Aldosterone stimulates sodium (and water) reabsorption in the kidney
Increases postassium secretion
(uptake Na back into cells, excrete K into urine)
Actions: aldosterone senses extracellular K, stimulates Ang II to make aldosterone, acts on kidney to stimulate Na/K pump
Low potassium will inhibit aldosterone
RAAS System:
________ stimulates renin release from the kidney (juxtaglomerular apparatus)
Renin then cleaves ____ to form _____
ACE then converts it to ____
_____ is a vasoconstrictor and stimulates aldosterone
RAAS:
Decreased BP stimulates renin release from the kidney
Renin then cleaves Angiotensinogen (from liver) to Ang I
ACE then converts Ang I to Ang II
Ang II is a vasoconstrictor and stimulates aldosterone
Aldosterone vs AVP/ADH:
Aldosterone: primary regulator of _____
- stimulates ____ & ____ reabsorption in kidney
- stimulates _____ excretion
- net result = increase in ___ and ____
AVP/ADH: primary regulator of _____
- stimulates distal nephron water permeability: _____ water retention
- ____ plasma osmolality, which secondarily affects ____ concentraion in blood
Aldosterone vs AVP/ADH:
Aldosterone: primary regulator of extracellular volume
- stimulates sodium and water reabsorption by the kidney
- stimulates potassium excretion
- Net Result = increased extracellular fluid volume and blood pressure (water follows sodium)
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
Cortisol binds with equally high affinity to MR and GR and is 100-1000 fold higher in concentration:
Explain the protective mechanisms to ensure that cortisol isn’t binding MR all the time and overflowing the system (there are two protective mechanisms)
Cortisol binds with equally high affinity to MR and GR and is 100-1000 fold higher in concentration
Protective Mechanisms:
- most of cortisol is not and bioactive and actuall bound to CBG, where as aldosterone is bound to albumin
- Tissue specific enzymes:
- 11B-HSD2 is a critical enzyme to ensure MR is not overstimulated by cortisol
- 11B-HSD2 deactivates cortisol by turning it into cortisone
SO minteralcorticoid target cells have a specific enzyme that deactivates cortisol and puts it back into bloodstream as cortisone
Kidney: cortisol is normally converted to the inactive ___ by enzyme ______
Certain drugs (like ________) will inhibit enzyme _____ to result in excess MR activation
- ________ is used to treat esophageal inflammation by causing increased local cortisol levels
Licorice also inhibits _______, excessive consumption of licorice can cause what?
Kidney: cortisol is normally converted to inactive cortisone by 11B-HSD2
Certain drugs (like carbenoxolone) will inhibit 11B-HSD2 resulting in excess MR activation
- carbenoxolone is used to treat esophageal inflammation by increasing local cortisol levels
Licorice: also inhibits 11BHSD2 - excessive consumption of licorice will lead to increased sodium and water retention (too much activation of MR by cortisol)
Where in the adrenal cortex are weak androgens made?
_______ is a precursor for testosterone and for estrogens (gets converted in reproductive tissues)
50% of total androgen precuros in males comes from ____ gland
Declines with age
“weak androgen” due to its low binding affinity to AR
Increases libido in women: primary source of androgen and estrogen in postmenopausal women
Zona reticularis makes weak androgens
DHEA/S is a precursor for testosterone and estrogen
50% of total andreogen precurors come from adrenal gland
Declines with age
weak androgen because weak affinity for AR
increases libido in women
What is the rate limiting step of adrenal steroid hormone biosynthesis?
A defect in what enzyme will result in NO steroid hormone production and also be embryonically lethal
Rate limiting step: STAR transferring FC from outer to inner mitochondria, regulated by ACTH
Enzyme defect in desmolase/P450scc/CYP11A1 will result in no steroid hormone production and also be lethal
What is the most common cause of congenital adrenal hyperplesia?
Explain the symptoms associated with it
___ cortisol
____ aldosterone
_____ androgens
Clinical presentation: _____tension, _____kelemiam _____ renun, high ACTH
Most common cause of congenital hyperplasia (CAH) is a defect in 21 alpha hydroxylase:
This causes NO cortisol, NO aldosterone, INCREASED androgens (masculinization)
Clinical presentation: hypotension, hyperkelemia, high renin (due to the hypotension), Masculinization, high ACTH
Explain what you will see with a defect in the enzyme 11-hydroxylase
___ cortisol
____ aldosterone
____ MR activity
____ androgens
Clinical presentation?
Defecient 11-hydroxylase:
no cortisol
no aldolsterone, but HIGH MR ACTIVITY (due to an increase in 11 DOC)
Increased androgens/masculinzation
Clinical signs: hypokelemia (high mr activity), hypertension, high acth, low renin
Explain a defect in 17 alpha hydroxylase:
___ cortisol
___ aldosterone, but ___ MR activity
____ androgens
Clinical presentation:
Defecient 17-alpha hydroxylase:
no cortisol
no aldosterone, but high MR activity
decreased androgens (femininity)
Clinical presentation: hypokelemia, hypertension, feminization, high ACTH
In all of the defeciencies why do you get a high ACTH?
In all the defeciency (21, 11, and 17)
there is no cortisol being made, no negative feedback… end up with high ACTH
Cortisol stimulates the conversion of ___ to ____
Acute stress activates SNS and stimulates NE release
NE stimulates ____ to initiate which axis?
Cortisol is needed in conversion of NE—> Epi
So acute stress activates SNS and stimulates NE release
NE stimulates CRH to then kick off HPA axis to increase cortisol
COMT Methylation:
converts DHPG to MHPG (precursor of VMA)
____ and ____ are excreted in urine and can be diagnostic for _______ (tumor)
Explain what that tumor is
COMT Methylation:
Converts DHPG to MHPG
Metanephrines and VMA are measured in urine to diagnose pheochromocytomas (tumor in chromaffin cells releasing high amounts of NE)
end up with HTN not responsive to medication, headaches and tachycardia
pheochromocytomas are also 10% tumor
