Lecture 5: HPA Axis and Adrenal Gland Part 1 Flashcards
What two major functions are regulated by the HPA axis?
1) Adaptive response to stress
2) Immune function
What are the 2 legs of the adaptive response to stress?
1) Catecholamines (epi and NE)
2) Glucocorticoids (cortisol)
What is NOT regulated by the HPA axis?
maintenance of water, sodium, potassium balance and blood pressure
What is the HPA axis?
H - hypothalamus (CRH/CRF}
P - pituitary (ACTH)
A - adrenal
What promotes CRH release?
STRESS
hypoglycemia, emotional, physical, etc
What is the central regulator of the HPA axis and where is it produced?
CRH (made in PVN)
responsible for stimulating POMC/ACTH
True or false: CRH is released in a pulsatile fashion
TRUE (5 min half life)
What kind of receptor does CRH bind to?
GPCR
highest affinity to CRH R1
How does the presence of AVP affect ACTH release?
Amplifies it
What cell type in the anterior pituitary produces ACTH?
corticotrophs
What is the precursor to ACTH?
POMC (pre-opiomelanocortin)
What receptor does ACTH bind to with the highest affinity? lowest?
Highest: MC2R
lowest: MC1R (skin)
What do high levels of ACTA lead to?
hyperpigmentation
What are the immediate effects of ACTH binding to MC2R?
1) increased cholesterol esterase activity
2) decrease cholesterol ester synthetase
3) increase cholesterol transport into mitochondria
4) increase pregnenolone production
5) increase StAR protein (bring cholesterol from outer to inner mito)
What are the long term effects of ACTH action?
increased size and functional complexity of organelles
What secondary messenger does ACTH/MC2R work through?
cAMP
The adrenal cortex derives from __________ while the medulla derives from ____________
mesoderm; neural crest (modified sympathetic postganglionic neurons)
What hormones are produced in the cortex?
steroid hormones (aldosterone and androgens)
What are produced by the medulla?
catecholamines (epi and norepi)
What are the 3 parts of the adrenal cortex?
1) zona glomerulosa
2) zona fasciculata
3) zone reticularis
What is produced in the zona glomerulosa of the adrenal cortex?
mineralocorticoids
What is produced in the zona fasciculata of the adrenal cortex?
glucocorticoids (cortisol)
What is produced in the zona reticularis?
weak androgens (DHEAS)
True or false: there is a high density of lipid droplets in the adrenal cortex
True - site of steroid synthesis (needs cholesterol as building block)
Describe the blood supply to the adrenal cortex?
suprarenal arteries break into subcapsular plexus of capillaries (fenestrated)
second plexus forms at the zona reticularis before entering the medulla
Describe the blood supply to the adrenal medulla
DUAL BLOOD SUPPLY
bathed in blood carrying corticosteroids from cortex (which is important for conversion of NE to E)
arterioles break into fenestrated capillaries
Why is it important for the medulla to get the blood from the cortex?
it is laden with corticosteroids which are important in converting NE to E in the medulla
When is cortisol released?
in response to acute or chronic stress
starvation, illness, psychological
What receptor does cortisol bind to?
glucocorticoid receptor GR (high affinity) and mineralocorticoid receptor (MR) in the CYTOPLASM
What converts cortisone to cortisol?
11b-HSD1
What form of the ACTH end product is in the blood?
cortisone (becomes cortisol inside the cell after 11b-HSD1 acts on it)
Is circulating cortisol bound or unbound?
BOUND (90% to CBG; 7% to albumin; 3% free)
What is CBG?
Corticosteroid Binding Globulin (CBG) aka Transcortin
binding protein for cortisol in the blood
Does CBG have higher affinity for cortisol or aldosterone?
cortisol (30x)
What effect does estrogen have on CBG?
decreases it resulting in increased free cortisol
How does shock/severe infection alter CBG?
decreases it
Where are glucocorticoids made?
zona fasciculata (F makes G)
When does cortisol peak in humans?
8am
When is cortisol active?
when it dissociates from CBG and is free cortisol
What effect does cortisol have on bone?
decrease bone formation and increase bone resorption
What effect does cortisol have on connective tissue?
decreases it
What effect does cortisol have on the brain?
modulates emotional tone, wakefulness
What effect does cortisol have on the kidney?
increases glomerular filtration and free water clearance
What effect does cortisol have on the fetus?
facilitates maturation
What effect does cortisol have on the heart?
maintains cardiac output, increases arteriolar tone, decreases entothelial permeability
What effect does cortisol have on inflammatory and immune response?
INHIBITS it
immunosuppressive drug
How do glucocorticoids influence plasma glucose levels?
counter regulates insulin - mobilizes glucose to the plasma (why it is called glucocorticoid)
- increases gluconeogenesis and plasma glucose levels
- increases lipolysis
- increases proteolysis
- redistributes fat (abdominal obesity)
- antagonizes insulin
- inhibits intestinal calcium absorption
How does cortisol increase gluconeogenesis?
stimulates these enzymes:
1) glucose 6-phosphatase
2) phosphoenolpyruvate carboxykinase
3) tyrosine aminotransferase
How does cortisol decrease glucose uptake in muscle cells?
inhibits GLUT4 insertion in membrane
does this to maintain plasma glucose
How does cortisol contribute to proteolysis?
increases MuRF1 (E3 ubiquitin ligase) to promote protein degradation
How do glucocorticoids promote lipolysis in adipocytes?
activates the transcription of Lipe, MgII, and Angptl4.
Lipe and MgII are enzymes in the lipolytic pathway
Angptl4 is a secreted protein that binds to a receptor to increase cAMP levels in adipocytes which phosphorylates Lipe via PKA
Cortisol binds to the GR inside the cell, kicking HSP off and moving the coritosl-GR complex into the nucleus. How does this complex act as a transcription factor?
decreases transcription of IL1B and TNF genes
increases IKB gene expression (which sequesters NFKB, preventing it from having its inflammatory response)
How does cortisol have an anti-inflammatory response?
sops up NFkB by increasing expression of IKB
What are the 5 mechanisms for cortisol action on the immune system?
1) decrease inflammation
2) stimulates anti-inflammatory cytokines
3) inhibits prostaglandins
4) suppresses antibody production
5) increases neutrophils, platelets, RBCs
How does cortisol inhibit bone formation? increase bone resorption?
- decreases IGF-1 receptors
- activates osteoclasts
What effects does cortisol have on cardiovascular health?
stimulates RBC production
maintains responsiveness to catecholamine pressor effects (constricts peripheral vessels via alpha adrenergic receptors; dilates coronaries via beta adrenergic)
Glucocorticoid excess leads to hypo or hypertension?
HYPER (increased bp)
What is Cushing Disease? How does it differ from Cushing syndrome?
excessive cortisol secretion due to pituitary adenoma
syndrome = all other reasons for excess cortisol
What are some of the symptoms of Cushing Disease?
- change in body fat distribution
- hypertension
- glucose intolerant
- purple striae
When are glucocorticoids needed?
- septic shock, severe asthma, severe autoimmune disease
- anti-inflammatory, immunosuppressive, adrenal insufficiency, pre-term infants
Why is it so important for patients to be weaned from glucocorticoid therapy?
glucocorticoids inhibit CRH which inhibits ACTH which feeds zona fasciculata so that zone starts to atrophy
Describe primary adrenal insufficiency
failure at adrenal end (cannot secrete glucocorticoids, mineralocorticoids, or both)
What is an example of primary adrenal insufficiency?
Addison’s Disease (autoimmune destruction of adrenals)
Describe secondary adrenal insufficiency
failure to secrete CRH or ACTH
most common cause = sudden cessation of glucocorticoid therapy
When is too long to be on glucocorticoids?
3 weeks (zona fasciculata starts to atrophy at 3 weeks and stops making endogenous cortisol)
