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FHB IV- Endocrinology > Endocrinology 5 > Flashcards

Endocrinology 5 Flashcards

1
Q

List the main components of the neuroendocrine HPA axis and describe how internal/external factors influence that axis.

Are glucocorticoids and mineralocorticoids regulated by HPA axis? DHEA/DHEAS?

Describe what is regulated by HPA axis and what is not regulated.

A

REGULATED BY HPA AXIS:
Adaptive response to stress
Catecholamines – epinephrine, norepinephrine
Glucocorticoids – cortisol

Immune function
Anti-inflammatory – glucocorticoids

NOT REGULATED BY HPA AXIS:
Maintenance of water, sodium, potassium balance and blood pressure
Mineralocorticoids – aldosterone

Site of “weak” androgen production
DHEA/DHEAS

Slide 6/7

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2
Q

Discuss the structure and function for CRH.

Where is CRH produced?
How many aa?
What does it stimulate?

Describe the half life

A

Central regulator of HPA axis - 41 amino acids

Produced in parvocellular neurons of PVN

Stimulates anterior pituitary (POMC/ACTH)

CRH is pulsatile – results in episodic release of ACTH. Half-life ~5 min

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3
Q

Describe the receptors and intracellular signaling pathways for CRH.

A

G protein-coupled receptors – CRH R1 and CRH R2. Binds with highest affinity to CRH R1 in anterior pituitary. CRH R2 binds with higher affinity to Urocortin.
Evidence for multiple intracellular signaling pathways – CRH can activate at least 5 different G proteins

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4
Q

Compare and contrast the role of AVP in mediating the physiological response to stress to its role in osmoregulation.

A

ACTH release is amplified in the presence of AVP

Slide 13, 14

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5
Q

Describe the structure, function, receptors, and target sites for ACTH.

What is it produced?
What regulates it?
What is its precursor?

What does it bind to with high affinity? Low affinity?

A

Produced in the anterior pituitary (corticotroph)
Regulated by CRH and AVP from hypothalamus
Precursor = POMC (pro-opiomelanocortin)

Binds with high affinity to melanocortin 2 receptor (MC2R)

Binds with low affinity to MC1R (skin)

Slide 17

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6
Q

What will high levels of ACTH lead to?

A

High levels of ACTH lead to hyperpigmentation

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7
Q

When ACTH binds to MC2R receptor, what are the downstream effects? (immediate, subsequent, and long term)

A

Slide 18

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8
Q

Describe the anatomical organization and histology of the adrenal gland, functional cortical zones and their associated hormones, and the medullary compartment.

A

Slide 20-22

zona glomerulosa Mineralocorticoids

zona fasciculata Glucocorticoids (cortisol)

zona reticularis weak androgens (DHEAS)

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9
Q

Describe the embryology of the cortex and medulla.

What do they develop from?

What do sympathetic innervation synapse on?

A

Embryology- Slide 20

Cortex derives from mesoderm
Medulla derives from neural crest: modified “sympathetic postganglionic neurons”.
Sympathetic innervation synapses on medullary cells.

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10
Q

Describe: ADRENAL: BLOOD SUPPLY (cortex and medulla)

A

Cortex: Suprarenal arteries break into subcapsular plexus of capillaries (fenestrated).

Second plexus also at the Z. reticularis before entering medulla.

Medulla: Dual blood supply

  • Bathes the medullary cells with blood carrying corticosteriods from the cortex – important for conversion of NE to E.
  • Arterioles break into fenestrated (with diaphragm) capillaries.
  • All blood drains into central vein
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11
Q

Describe the receptors, intracellular signaling pathways, and hormone transport regulating glucocorticoid actions.

When are they released?
To what do they bind in the cytoplasm?

How is cortisone converted to cortisol?

A

Slide 26

Released in response to acute/chronic stress (physical – starvation, illness; psychological)

Binds with high affinity to glucocorticoid receptor (GR) and mineralocorticoid receptor (MR) in cytoplasm

Cortisone converted to Cortisol by 11beta-HSD1

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12
Q

Describe Corticosteroid Binding Globulin (CBG)/Transcortin

(structure)
Where made?
How travels in plasma?
Affinity for cortisol vs aldosterone?
How does Estrogen affect CBG? 
How does shock/severe infection affect CBG?
A

-383 AA glycoprotein made in the liver
-90% circulating cortisol bound to CBG; 7% bound to albumin
-3 - 4% “free” cortisol
30-fold higher affinity for cortisol than aldosterone
-Estrogen decreases CBG – results in increased free cortisol
-Shock/severe infection decreases CBG

Serpin family:
Serine protease inhibitor

NOT a protease inhibitor

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13
Q

Where are glucocorticoids made?

How are they released?

How do they travel in blood?

A

Made in the Zona Fasciculata Cortisol (active in humans/fish) Corticosterone (active in rodents)

Accounts for more than 80% of cortical hormones

Released in circadian manner – peaks around 8:00 AM

Bound to transport proteins in blood (CBG) – must dissociate in order to be active (~ 5% free)

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14
Q

Explain what it means for glucocorticoids to be “pleiotropic” and discuss the effects of cortisol on immune function, metabolism, cardiovascular system, CNS, and bone

A
  • maintain muscle function; decrease muscle mass
  • decrease bone formation, increase bone resorption
  • decrease connective tissue
  • inhibit inflammatory and immune responses
  • maintain cardiac output; increase arteriolar tone; decrease endothelial permeability
  • facilitate maturation of the fetus
  • increase glomerular filtration and free water clearance
  • modulate emotional tone, wakefulness

Slide 30

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15
Q

What are cortisol actions (metabolism)?

How will it affect...
gluconeogenesis?
lipolysis?
proteolysis? protein synthesis?
Ca absorption?
A

Metabolic Actions – potent counter-regulatory hormone to insulin. Mobilizes energy stores – increase plasma glucose = “glucocorticoid”.

Increase gluconeogenesis and plasma glucose levels
Increase lipolysis
Breaks down muscle protein - proteolysis
Redistributes fat – abdominal obesity, depletion of subcutaneous fat
Antagonizes insulin action
Inhibits intestinal calcium absorption** (will discuss more in Ca2+ regulation lecture)

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16
Q

Show how cortisol works to increase gluconeogenesis and plasma glucose levels (through pathway).

A

It Stimulates glucose-6-phosphatase

Stimulates phosphoenolpyruvate carboxykinase

Stimulates tyrosine aminotransferase

Slide 32

17
Q

Describe cortisol’s affect on muscle.

What receptor does it affect? What is the overall effect?

A

Inhibits GLUT4 insertion in membrane

Decreases glucose uptake in muscle cells

Maintains Plasma Glucose!

Slide 33

18
Q

Descrieb cortisol’s role in muscle proteolysis.

A

Cortisol stimulates this pathway/increases MuRF1 (E3 ubiquitin ligase)

Slide 34

19
Q

How do glucocorticoids affect activity in adipocytes?

A

they promote lipolysis

Slide 35

20
Q

Describe: GLUCOCORTICOID RECEPTOR (GR).

A

Local inflammatory responses decreased by GR action on NF-kB

GR increases IκB transcription

Glucocorticoids prevent NF-kB nuclear translocation

Slide 36

21
Q

How does cortisol affect the immune system?

A

Immune –
Decreases inflammation

stimulates anti-inflammatory cytokines

inhibits prostaglandins

Suppresses antibody production

Increases neutrophils, platelets, and RBCs

Anti-inflammatory effects are primary reason for glucocorticoid therapy.

22
Q

Describe cortisol actions in relation to the bone.

A

Bone
Inhibits intestinal calcium absorption – transcellular transport

Inhibits bone formation – decrease IGF-I receptors

Increases bone resorption – activation of osteoclasts

Slide 38

23
Q

Describe the cardiovascular effects of cortisol.

RBC?
How are peripheral vessels affected? Dilated or constricted?

How are coronary arteries affected?

What will glucocorticoid excess lead to in terms of bp?

A

Cardiovascular – during “physical stress” want blood to flow to brain/heart – away from periphery

Stimulates red blood cell production

Maintains responsiveness to catecholamine pressor effects
constrict peripheral vessels via alpha-adrenergic receptors

Dilate coronary arteries in heart via beta-adrenergic receptors

Glucocorticoid excess = increased blood pressure/hypertension
Maintains vascular integrity and reactivity

24
Q

Describe the CNS actions of cortisol.

How are CRH and ACTH affected?

Emotional response?

A 
Central Nervous System – 
Emotional response 
	depression 
	anxiety 
	nervousness 
	panic 
	rage/aggression

Perception

Negative feedback on CRH and ACTH release

25
Q

Explain the consequences of over/under production of glucocorticoids and glucocorticoid therapy.

Describe Cushing disease. Excessive or under production of cortisol? What will be the effects? Ca/fat/bp/glucose?

A

“Cushing disease” – excessive cortisol secretion due to pituitary adenoma
“Cushing syndrome” – all others

Change in body fat distribution – moon face, buffalo hump, abdominal obesity, thin skin, bruising

Inhibition of intestinal calcium absorption – osteoporosis

Hypertension – excess glucocorticoids activate MR

Glucose intolerant – antagonism of insulin action

Purple Striae – Fragile thin skin stretches over increased abdominal fat, vessels hemorrhage into striae

**Also occurs with long-term glucocorticoid therapy

Slide 42

26
Q

Describe glucocorticoid therapy.

When is it used?

A

Medical Emergencies
High acute dose to treat septic shock, severe asthma, severe autoimmune disease flare

Usually no long-term side effects

Chronic
Anti-inflammatory 
Immunosuppressive
Adrenal insufficiency
Pre-term infants – improved lung function

Slide 43

27
Q

Describe/name the synthetic glucorticoid analogs.

A 
cortisol
prednisone
methylprednisone
dexamethasone
fludrocortisone

Slide 44

28
Q

Describe primary and secondary adrenal insufficiency. What are causes of each?

A

Failure of adrenal to secrete glucocorticoids, mineralocorticoids, or both.

Primary – failure at adrenal
Addison’s Disease = autoimmune destruction of adrenals
70% of primary AI cases

Secondary – failure to secrete CRH or ACTH
Most common cause = sudden cessation of glucocorticoid therapy

Anticipated if patient takes greater than 30 mg hydrocortisone, 7.5 mg prednisone, 0.75 mg dexamethasone for longer than 3 weeks

FHB IV- Endocrinology (17 decks)

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