Endocrine 5: adrenal gland, HPA Flashcards
What are the components of the HPA axis?
H - PVN - makes CRH
P - ACTH
A - many hormones
What is the main stimulus for HPA?
stress
What is the negative feedback component of HPA?
cortisol
What adrenal functions are regulated by the HPA axis?
- stress response via catecholamines and cortisol
- anti-inflammatory and decreased immune function via glucocorticoids
What adrenal functions are not regulated by the HPA axis?
- maintenance of water, sodium, potassium balance
- BP
^^ via mineralcorticoids (aldosterone) - weak androgen synthesis (DHEAs)
Describe negative feedback of the HPA.
- short loop via ACTH on CRH
- long loop via cortisol on ACTH and CRH
Describe structure and synthesis of CRH.
- 41 AA
- produced by PVN
- stimulates transcription of POMC gene and ACTH release in anterior pituitary (corticotrophs)
Describe the mechanism of action of CRH.
- binds with high affinity to CRH R1 receptor in the anterior pituitary
- stimulates one of 5 GPCRs depending on the tissue it activates
- main = adenylyl cyclase => PKA => ACTH release
Define CRH R2 receptor.
- in the brain
- lower affinity for CRH
- higher affinity for urocortin
What determines the action of CRH?
- tissue
- GPCR pathway
Describe the synergistic effects of AVP and CRH.
- responds to same stimuli
- amplifies ACTH synthesis and release from the pituitary
- increased release of cortisol
- cortisol negatively feeds back on CRH and AVP and ACTH
Describe structure and production of ACTH.
- part of POMC gene (makes other hormones too)
- produced by anterior pituitary corticotrophs
- regulated by CRH and AVP (hypothalamus), cortisol
Describe the mechanism of action of ACTH.
- binds with high affinity to melanocortin 2 receptor (MC2R) on the adrenal cortex
- production of cortisol
- binds with lower affinity to MC1R on skin
What can excess ACTH lead to?
hyperpigmentation
- excess levels causes binding to lower affinity MC1R on the skin
congenital adrenal hyperplasia
What are the immediate effects of ACTH binding to MC2R?
- increased cholesterol synthesis enzymes
- decreased cholesterol degradation enzymes
- increased cholesterol transport into inner mitochondria
- increased expression of StAR protein
- increased expression of P450scc enzyme
- increased pregnenolone production
- increased synthesis of adrenoxin cofactor for cholesterol enzymes
- increased LDL/HDL receptors
- increased cholesterol uptake
What are the long term effects of ACTH binding to MC2R?
- increased size of adrenal glands
- increased proliferation of adrenal cells
Describe embryological derivation of adrenal gland.
cortex = mesoderm = glandular medulla = neural = modified postganglionic sympathetic neuron
How do the cortex and medulla differ?
Cortex
- glandular
- steroid synthesis
Medulla
- neural
- catecholamine synthesis
List the zones and their functions of the adrenal cortex.
- zona glomerulosa makes mineralcorticoids, aldosterone
- zona fasciculata makes glucocorticoids, cortisol; biggest
- zona reticularis makes weak androgens, DHEA
Describe adrenal blood supply.
There is a dual blood supply by the capsular artery 1. Cortex - subscapular plexus in ZG 2. Medulla - medullary plexus drains out medullary vein
What is unique about adrenal cortex blood flow? Give an example.
hormones made in upper layers are carried down to the lower layers
- mineralcorticoids made in ZG go to ZF, add glucocorticoids, go to ZR, add androgens, go to medulla
For example, cortisol must be present for norepinephrine to be converted to epinephrine (which occurs in medulla)
Describe mechanism of action of cortisol in target cells.
- enters glucocorticoid target cell
- binds to glucocorticoid intracellular receptor (apo; bound to chaperone proteins)
- chaperone protein dissociates
- GR-cortisol enters nucleus
- acts as transcription factor
What is unique about cortisol affinity for GR and MR?
has equal affinity for MR => must be inactivated in cells where MR must be stimulated (aldosterone active cells)
- cortisol is converted to cortisone via 11B-HSD2
- to reactivate cortisol, cortisone is converted back to cortisol by 11B-HSD1
Describe the properties of CBG.
CBG = cortisol binding globulin = transcortin
- made in liver (affected by liver disease)
- high affinity for cortisol (surrounds the molecule completely)
- 90% of cortisol is bound to CBG
- tight binding keeps it out of aldosterone tissue
- stress, shock, liver disease lead to decrease in CBG => free cortisol is more readily available.
What are glucocorticoids?
- made in ZF
- 80% of cortical hormones
- peaks in the morning
- bound to CBG
Define pleiotropic.
- has effects on a variety of tissues
- action and function depends on G protein pathway and tissue
List actions of cortisol.
- increased bone resorption => decreased bone formation
- decreased collagen formation
- inhibition of inflammation
- inhibition of immune response
- maintains cardiac output and blood pressure during stress
- maintains free water clearance
- modulates emotion, wakefulness
- promotes proteolysis, lipolysis, gluconeogenesis
- counterregulation of insulin
List metabolic actions of cortisol
- counterregulation of insulin
- mobilization of glucose
- liver gluconeogenesis
- adipose lipolysis
- muscle proteolysis
- fat redistribution from skin to visceral organs and abdomen
- inhibits calcium absorption
List 3 main liver enzymes of gluconeogenesis that are activated by cortisol.
- glucose 6 phosphatase
- PEPCK
- tyrosine transaminase
What action does cortisol have on the muscle?
inhibits translocation of GLUT4 to apical membrane
- inhibits glucose uptake into the cell
- maintains glucose level in the blood so that glucose gets to the brain and heart
Describe how cortisol activates proteolysis.
- blocks AKT phosphorylation
- FOX-O remains active
- FOX-O goes to the nucleus
- increases expression of MuRF1, an E3 ubiquitin ligase
- promotes degradation
What enzymes are involved in cortisol-mediated lipolysis?
- monoacylglycerol (MAG) lipase, gene = MGL1
- hormone sensitive lipase, gene = Lipe
- Angpt14 gene activates hormone sensitive lipase
Explain how glucocorticoids are involved in anti-inflammatory action.
- cortisol binds to GR
- GR-cortisol goes to nucleus and activates gene transcription of I-Kb
- I-Kb binds to NF-Kb in cytosol and inactivates it (prevents translocation to nucleus)
- GR-cortisol also binds to NF-Kb in cytosol and prevents translocation
- NF-Kb cannot get to the nucleus, no transcription of inflammatory cytokines
List actions of cortisol inhibition of immune response.
- decrease inflammation
- stimulate anti-inflammatory cytokines
- inhibit prostaglandins
- suppress antibody production (inhibit helper T cells)
- increase neutrophils, platelets, RBCs
Describe the effect of cortisol on the bone.
- cortisol inhibits transcriptions of protein transporters for intestinal calcium absorption ====> decreased dietary calcium
- increased PTH => increased bone resorption
- decreased IGF1 receptors in bone
===> inhibit bone formation, activate osteoclast bone resorption
Describe cardiovascular effects of cortisol.
permissiveness - maintains cardiac output and BP to ensure enough oxygen and blood to brain and heart
- stimulates RBCs (increased oxygen delivery)
- upregulation of alpha adrenergic receptors in the vasculature => vasoconstriction => shunting
- upregulation of beta adrenergic receptors in the heart => vasodilation => bring more blood in
Define Cushing’s Disease.
- excess glucocorticoids due to pituitary corticotrophic adenoma
Define Cushing’s Syndrome.
- excess glucocorticoids for reasons other than a tumor
Describe Cushing’s Syndrome/Disease.
Symptoms
- fat redistribution to abdomen, back, face
- osteoporosis due to bone resorption
- hypertension due to binding to mineralcorticoid receptors and activation of aldosterone
- glucose intolerance due to insulin antagonism
- purple striae due to thin skin prone to bruising and hemorrhage
Cause - most common is glucocorticoid long-term therapy
What are reasons for glucocorticoid therapy?
Immediate
- acute shock
- acute intense inflammation
- severe asthma
- severe autoimmune disease flare-up
Long-term
- anti-inflammatory
- immunosuppression
- adrenal insufficiency
- premature babies (increase lung function)
What does long-term glucocorticoid therapy due to the adrenal gland?
- atrophy of ZF b/c chronic negative feedback stops ACTH production => no ZF stimulation
- Cushing’s
- must be weaned off (if sudden => lethal)
Describe some glucocorticoid analogs.
- prednisone has high GR affinity and low MR affinity
- dexamethasoen has zero MR affinity (used for diagnosing)
Describe primary adrenal insufficiency.
Addison’s Disease
- autoimmune destruction of adrenal gland
Describe secondary adrenal insufficiency.
- can’t secrete CRH or ACTH
- due to sudden cessation of glucocorticoid therapy
