Endocrinology 5 Flashcards
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.
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
Discuss the structure and function for CRH.
Where is CRH produced?
How many aa?
What does it stimulate?
Describe the half life
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
Describe the receptors and intracellular signaling pathways for CRH.
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
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
Slide 13, 14
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?
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
What will high levels of ACTH lead to?
High levels of ACTH lead to hyperpigmentation
When ACTH binds to MC2R receptor, what are the downstream effects? (immediate, subsequent, and long term)
Slide 18
Describe the anatomical organization and histology of the adrenal gland, functional cortical zones and their associated hormones, and the medullary compartment.
Slide 20-22
zona glomerulosa Mineralocorticoids
zona fasciculata Glucocorticoids (cortisol)
zona reticularis weak androgens (DHEAS)
Describe the embryology of the cortex and medulla.
What do they develop from?
What do sympathetic innervation synapse on?
Embryology- Slide 20
Cortex derives from mesoderm
Medulla derives from neural crest: modified “sympathetic postganglionic neurons”.
Sympathetic innervation synapses on medullary cells.
Describe: ADRENAL: BLOOD SUPPLY (cortex and medulla)
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
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?
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
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?
-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
Where are glucocorticoids made?
How are they released?
How do they travel in blood?
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)
Explain what it means for glucocorticoids to be “pleiotropic” and discuss the effects of cortisol on immune function, metabolism, cardiovascular system, CNS, and bone
- 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
What are cortisol actions (metabolism)?
How will it affect... gluconeogenesis? lipolysis? proteolysis? protein synthesis? Ca absorption?
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)
Show how cortisol works to increase gluconeogenesis and plasma glucose levels (through pathway).
It Stimulates glucose-6-phosphatase
Stimulates phosphoenolpyruvate carboxykinase
Stimulates tyrosine aminotransferase
Slide 32
Describe cortisol’s affect on muscle.
What receptor does it affect? What is the overall effect?
Inhibits GLUT4 insertion in membrane
Decreases glucose uptake in muscle cells
Maintains Plasma Glucose!
Slide 33
Descrieb cortisol’s role in muscle proteolysis.
Cortisol stimulates this pathway/increases MuRF1 (E3 ubiquitin ligase)
Slide 34
How do glucocorticoids affect activity in adipocytes?
they promote lipolysis
Slide 35
Describe: GLUCOCORTICOID RECEPTOR (GR).
Local inflammatory responses decreased by GR action on NF-kB
GR increases IκB transcription
Glucocorticoids prevent NF-kB nuclear translocation
Slide 36
How does cortisol affect the immune system?
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.
Describe cortisol actions in relation to the bone.
Bone
Inhibits intestinal calcium absorption – transcellular transport
Inhibits bone formation – decrease IGF-I receptors
Increases bone resorption – activation of osteoclasts
Slide 38
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?
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
Describe the CNS actions of cortisol.
How are CRH and ACTH affected?
Emotional response?
Central Nervous System – Emotional response depression anxiety nervousness panic rage/aggression
Perception
Negative feedback on CRH and ACTH release
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?
“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
Describe glucocorticoid therapy.
When is it used?
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
Describe/name the synthetic glucorticoid analogs.
cortisol prednisone methylprednisone dexamethasone fludrocortisone
Slide 44
Describe primary and secondary adrenal insufficiency. What are causes of each?
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