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












