L72: HPA Axis and Adrenal Gland Flashcards
What does the HPA Axis regulate in the adrenal gland?
Response to stress: Catecholeamines (Epi/NE), Glucocorticoids (Cortisol)
Immune Function: Anti-inflammatory (glucocorticoids)
What functions of the adrenal gland are NOT regulated by the HPA Axis?
Maintenance of water, sodium, potassium balance and blood pressure by Mineralocorticoids (Aldosterone)
Weak Androgen production (DHEA)
What is the HPA Axis
Hypothalamic-Pituitary-Adrenal Axis
CRH made in PVN of hypothalamus -> released at median eminence-> stimulate POMC gene expression -> ACTH release from corticotropes in anterior pituitary-> ACTH stimulates Adrenal Cortex-> produce cortisol
Classic Negative Feedback Pathways: ACTH (short neg to hypothalamus CRH), Cortisol (long neg to pituitary and hypothalamus)
Where is CRH produced?
Parvocellular Neurons of the PVN
What does CRH do?
Stimulates anterior pituitary to express POMC gene -> ACTH production
How is CRH secreted?
pulsatile -> leads to episodic release of ACTH
What are CRH receptors? Which binds CRH with highest affinity?
CRH R1 and CRH R2: GPCRs
Highest affinity to CRH R1 in anterior pituitary
How do AVP and CRH work in conjunction?
Synergistic actions to increase amplitude of ACTH release from anterior pituitary
What does the release of cortisol lead to for AVP and CRH?
NEgatively inhibits the synthesis and release of CRH and AVP by binding to the nuclear steroid glucocorticoid receptor in pituitary and hypothalamus
How is ACTH regulated?
REgualted by CRH and AVP from hypothalamus
What is the precursor for ACTH?
POMC (preprohormone)
What does ACTH do in the adrenal gland?
Steroid biosynthesis: stimulate conversion of cholesterol to pregnenolone
Z.Fasciculata and Z.Reticularis: syntehsis of cortisol and DHEA
Adrenal Medulla: Convert dopamine to NE
Does ATCH regulate Aldosteron in the Z.Glomerulosa?
NO. But it does regulate the synthesis of aldosterone precursors
What are the receptors for ACTH?
MC2R(adrenal cortex):Binds with high affinity to MC2R
MC1R(skin): binds with low affinity;High levels of ACTH can lead to hyperpigmentation
What are hte laeyrs of the adrenal gland from inner to outer?
Adrenal Medulla -> ZReticularies->Z.Fasciculata->Z.Glomerulosa
Which artery perfuses the cortex and adrenal medulla?
Capsular Artery
How does blood flow from the capsular artery?
From outer cortex to adrenal core via capillary beds -> controls access of steroid hormones to general circulation
Where are glucocorticoids made?
Z.Fasciculata
What are the glucocorticoids?
Cortisol
Corticosterone
How are glucocorticoids transported in blood?
Bound to transport proteins CBG (must dissociate to be active)
How much of glucocorticoids are free in circulation?
~5%
How are glucocorticoids released?
in circadian manner, peaks at around 8am
Where are Corticosteroid binding globulins (CBG) made?
Liver
How much of cortisol in circulation are bound to CBG? Albumin?
CBG: 90%
Albumin: 7%
Free Cortisol: 3-4%
Which hormone does CBG bind with higher affinity with cortisol or aldosterone?
Cortisol (30x higher)
How does estrogen impact CBG?
Decreases CBG -> increased free cortisol
How does shock/infection affect CBG?
Decreases CBG levels
What kind of receptors do glucocorticoids bind?
Nuclear steroid receptor
Where are glucocorticoid receptors found?
Most tissues
What is the sequence of cortisol going to target tissue?
Cortisone (blood) -> Cross into target cell -> Dissociates chaperone from GR (glucocorticoid receptor) -> GR/Cortisol complex -> goes to nucleus -> act as transcription factor for gene transcription
What converts Cortisone in the cell to Cortisol?
11B-HSD1
How does cortisol affect muscle?
Decrease muscle mass-
Increase transcription of E3 ubiquitin ligase (MuRF-1) => Inc proteolysis
Inhibit amino acid uptake and AKT phosphorylation => decreased protein synthesis
How does cortisol affect bone?
Inhibit intestinal calcium absorption
Inhibit bone formation (decrease IGF-1 receptors)
Increase bone resorption by activating osteoclasts
How does cortisol affect immune response?
Inhibit inflammation and immune responses:
Binds to activated NF-kB and prevent its nuclear binding
Increases transcription of IkB (binds NF-kB in cytosol)
How does cortisol affect the kidneys?
Increase GFR and increase free water clearance
How does cortisol affect the cardiovascular system?
Maintain cardiac output
Increase arteriolar tone
Decrease endothelial permeability
Stimulates RBC production
What is cortisol’s actions on metabolism?
Counter-regulatory to insulin: mobilize energy stores and increases plasma glucose:
Increase gluconeogenesis
Antagonize insulin action
Inhibit intestinal calcium absorption
How does cortisol increase plasma glucose?
Increases tyrosine aminotransferase, PEP Carboxykinase, G6Phosphatase
Decrease GLUT4 insertion in muscle cells
How does cortisol act on adipose tissue?
Increase lipolysis
Redistribute fat stores -> abdominal obesity and depletion of subcutaneous fat (thinning of limbs)
What are the results of cortisol’s inhibition of immune function?
Inc anti-inflammatory cytokines
Inhibit prostaglandins
Suppress antibody formaiton
Increase neutrophils, platelets, RBCs
What does glucocorticoid deficiency lead to in terms of cardiovascular funciton?
Hypotension
What are cortisol’s actions on the CNS
Emotional response, perception, negative feedback on CRH and ACTH
What is Cushing’s disease?
Excessive cortisol secretion due to pituitary adenoma -> get excessively high levels of ACTH
What is cushing syndrome?
All others due to excess cortisol production (ex: exogenous cortisol intake) usually leads to low ACTH levels due to neg feedback.
What happens with Cushing’s Disease?
Change in body fat Distribution: moon face, abdominal obesity, thin skin, bruising, buffalo hump
Osteoporosis: inhib calcium absorption in intestine
HTN: excess glucocorticoids-> activate MR(cortisol binds GR and MR equally)
Glucose intolerant: antagonzie insulin action
Purple Striae: fragile thin skin stretching over abdominal fat -> hemmorhage into striae
What can also present similar to Cushing’s disease?
Long term glucocorticoid therapy treatment
What is a consequence of prolonged glucocorticoid therapy?
Shutdown of HPA axis due to negative feedback on CRH and ACTH -> atrophy of Z.Fasciculata -> can’t synthesize endogenous glucocorticoids
What is the sequence of the normal HPA Axis?
Hypothalamus ->CRH ->Pituitary ->ACTH -> Z.FAsciculata -> Cortisol
What is Adrenal Insufficiency?
Failure of adrenal to secrete glucocorticoids, mineralocorticoids, or both
Primary: Failure at adrenal
Secondary: Failure to secrete CRH or ACTH
What is Addison’s Disease?
Primary Adrenal Insufficiency due to autoimmune destruction of adrenals
What is the most common cause of secondary Adrenal Insufficiency?
Sudden cessation of glucocorticoid therapy
