Lecture 5

Question 1

What part of the adrenal gland is regulated by the HPA axis?

Answer 1

1. Adaptive response to stress
   a. Catecholamines-epinephrine, norepinephrine
   b. glucocorticoids-cortisol
2. Immune function
   a. anti-inflammatory-glucocorticoids

Question 2

What parts of the adrenal gland are not regulated by the HPA?

Answer 2

1. Maintenance of water, sodium, potassium balance and blood pressure
   a. mineralocorticoids-aldosterone
2. site of weak androgen production
   a. DHEA/DHEAS

Question 3

WHat is the HPA axis?

Answer 3

H=hypothalamus=CRH
P=pituitary=ACTH
A=adrenal=multiple hormones

Question 4

What does CRH stimulate?

Answer 4

anterior pituitary (POMC/ACTH)

Question 5

How is CRH released? How does this effect ACTH? WHat is CRH half life?

Answer 5

CRH is pulsatile
results in episodic release of ACTH
-half life= 5 min

Question 6

What g-protein coupled receptor deos CRH bind with highest affinity to?

Answer 6

CRH R1 in anterior pituitary

-but CRH can activate at least 5 different G proteins

Question 7

What pathway is important for ACTH release?

Answer 7

PKA pathway

-influx of intracellular calcium–>release of ACTH

Question 8

What type of effect is there when there is AVP and CRH?

Answer 8

synergistic effect

-ACTH release is amplified in the presence of AVP

Question 9

What is the precursor to ACTH?

Answer 9

POMC

Question 10

What does ACTH bind to?

Answer 10

1. binds with high affinity to melanocortin 2 receptor (MC2R) in adrenal gland
2. binds with low affinity to MC1R (skin)
   - high levels of ACTH lead to hyperpigmentation

Question 11

WHat does ACTH do?

Answer 11

steroid biosynthesis-stimulates conversion of cholesterol to progesterone

Question 12

What is the cortex derived from?

Answer 12

mesoderm

-glandular part

Question 13

What is the medulla derived from?

Answer 13

neural crest: modified sympathetic postganglionic neurons

-sympathetic innervation synapses on medullary cells

Question 14

What are the three zones the cortex is divided into what does each cortex make?

Answer 14

1. zona glomerulosa-Mineralocorticoids
2. zona fasciculata- glucocorticoids (cortisol)
3. zona reticularis- weak androgens (DHEAS

Question 15

What is the largest zone?

Answer 15

zona fasciculata-makes glucocorticoids

Question 16

What is made in the medulla?

Answer 16

catecholamines

Question 17

Why would you find big lipid droplets in the steroidogenic cell?

Answer 17

steroids need a lot of cholesterol

Question 18

Why are there two blood supplies the medulla?

Answer 18

• one brings in fresh blood

- one brings hormones and hormone precursors down from the cortex into the medulla

Question 19

What do suprarenal arteries in the cortex break into?

Answer 19

subcapsular plexus of capillaries (fenestrated)

-second plexus also at the zona reticularis before entering the medulla

Question 20

Where does all the blood from the medulla drain into?

Answer 20

central vein

Question 21

What is cortisol released in response to what does it bind to?

Answer 21

• acute/chronic stress (physical-starvation, illness, psychological)
• binds with equal and high affinity to both glucocorticoid receptor and mineralocorticoid receptor in cytoplasm

Question 22

What is cortisone converted to and by what?

Answer 22

cortisol by 11b-HSD1

Question 23

Is the cortisone bound in the blood?

Answer 23

yes by corticosteroid binding globulin (CBG)/ Transcortin

Question 24

How much of cortisone is bound to CBG?

Answer 24

90% and 7% bound to albumin 3% free

-30 fold higher affinity for cortisol than aldosterone

Question 25

What decreases CBG?

Answer 25

- estrogen decreases CBG | - shock/ severe infection decreases CGB

Question 26

How much of the cortical zone hormones does glucocorticoids make up?

Answer 26

80%

Question 27

When and how is glucocorticoids released?

Answer 27

circadian manner | peaks around 8 am

Question 28

How are glucocorticoids dissociated from CBG?

Answer 28

specific enzymes in specific tissues

Question 29

What role does cortisol play in metabolism?

Answer 29

- counter regulatory hormone to insulin - mobilizes energy stores and increases plasma glucose - increases gluconeogenesis - increases lipolysis - breaks down muscle proteins-proteolysis - redistributes fat-abdominal obesity, depletion of subcutaneous fat - inhibits intestinal calcium absorption

Question 30

What two enzymes does cortisol stimulate to increase gluconeogenesis and plasma glucose levels?

Answer 30

1. PEP carboxykinase 2. glucose 6-phosphatase 3. tyrosine aminotransferase

Question 31

How does cortisol affect muscle?

Answer 31

1. inhibits glut4 insertion into the membrane -decreases glucose uptake into cell Maintains plasma glucose

Question 32

What type of receptor is GR?

Answer 32

nuclear steroid receptor ubiquitously expressed in most tissue cortisol binding dissociates GR from chaperone proteins in cytoplasm cortisol gr complex translocates to the nucleus and acts as TF on gene promoters

Question 33

Cortisol increases transcription of the E3 ubiquitin ligase MuRF-1 what does this stimulate

Answer 33

proteolysis

Question 34

Cortisol also inhibits amino acid uptake and AKT phosphorylation resulting in what?

Answer 34

decreased protein synthesis

Question 35

What are cortisols actions in adipose tissue?

Answer 35

1.Increased lipolysis - increases transcription of Mgll - ->enzyme monoacylglycerol lipase (MAG) - increases transcription of Lipe - ->hormone sensitive lipase - increases transcription of Angpt14 - ->increases intracellular cAMP and activates hormone sensitive lipase 2. redistributes fat stores-results in abdominal obesity, depletion of subcutaneous fat

Question 36

What does cortisol do to the immune response?

Answer 36

Inhibits Immune function - stimulates anti-inflammatory cytokines - inhibits prostaglandins - suppresses antibody production - increases neutrophils, platelets and RBCs - anti-inflmmatory effects are primary reason for glucocorticoid therapy *GR increases IKB transcription-->prevents NF-KB nuclear translocation

Question 37

How does cortisol affect bone?

Answer 37

1. inhibits intestinal calcium absorption-active transport 2. inhibits bone formation-decreases IGF-I receptors 3. Increases bone resorption-activates osteoclasts

Question 38

How does cortisol affect the cardiovascular system?

Answer 38

- stimulates RBC production - maintains responsiveness to catecholamine pressor effects * Glucocorticoid excess results in hypertension - maintains vascular integrity and reactivity

Question 39

How does cortisol effect the CNS?

Answer 39

``` emotional response -depression -anxiety -nervousness -panic -rage/aggression perception Negative feedback on CRH and ACTH release ```

Question 40

What is cushing disease?

Answer 40

excessive cortisol secretion due to pituitary adenoma

Question 41

What is cushing syndrome?

Answer 41

excess cortisol production

Question 42

What are the symptoms of cushing? What can these symptoms also result from?

Answer 42

1. change in body fat distribution-moon face, buffalo hump, abdominal obesity, thin skin, bruising 2. inhibition of intestinal calcium absorption-osteoporosis 3. hypertension-excess glucocorticoids activate MR 4. glucose intolerant-antagonism of insulin action 5. purple striae-fragile thin skin stretches over increased abdominal fat, vessels, hemorrhage into striae ** Also occur with long term glucocorticoid therapy

Question 43

How does HPA axis respond to chronic glucocorticoid therapy or primary adrenal excessive cortisol production?

Answer 43

1. high levels of cortisol exert negative feedback on CRH and ATCH 2. prolonged shutdown of HPA axis leads to atrophy of zona fasciculata and inability to synthesize endogenous glucocorticoids

Question 44

What medical emergencies is cortisol used to treat?

Answer 44

septic shock, severe asthma, sever autoimmune disease flare | -usually no long term side effects

Question 45

What chronic medical conditions is cortisol used to treat?

Answer 45

anti-inflammatory immunosuppressive adrenal insufficiency pre-term infants-improved lung function

Question 46

What is adrenal insufficiency?

Answer 46

Failure of adrenal to secrete glucocorticoids, mineralocorticoids or both

Question 47

What is primary adrenal insufficiency?

Answer 47

Failure at adrenal | Addison's disease=autoimmune destruction of adrenals 70% of primary AI cases

Question 48

What is secondary AI?

Answer 48

failure to secrete CRH or ACTH | -most common cause=sudden cessation of glucocorticoid therapy