Endocrinology 7- HPA Axis pt 1 Flashcards
5 cell types of anterior pituitary
somatotrope gonadotrope corticotrope thyrotrope lactotrope
What is the hypothalamic hormone that is released to start the HPA axis
CRH/CRF
Pituitary hormone released in HPA axis
ACTH
Adrenal hormones released as part of the HPA axis
Cortisol, aldosterone, androgens, catecholamines
Where is CRH released from in hypothalamus?
Parvocellular neurons of PVN
What gene is ACTH on?
POMC gene
In what manner is CRH released?
pulsatile
half life of CRH
5min
Receptor for CRH
Highest affinity binding is to CRH R1 in anterior pituitary, CRh R2 binds higher affinity to other things. But CRH can activate at least 5 different G proteins
How is ACTH synergized with AVP?
AVP synergizes with corticotropes to make sure there is a proper stress response - osmoregulatory and stress is appropriately responded to
ACTH- what two hypothalamic hormones regulate its generation?
CRH and AVP
What is the precursor to ACTH
POMC (pro opiomelanocortin
When this is broken down there are beta endorphans, alpha msh, acth, and more
What receptor does ACTH bind with highest affinity to?
Melanocortin 2 receptor
What receptor does ACTH bind with lower affinity to – what is the consequence of this
MC1R – high ACTH levels can lead to hyperpigmentation
How can cortisol impact ACTh release
negative feedback on anterior pituitary corticotrophs and CRH
hypothalamic neurons
Does ACTH affect immediate, long term, or itnermediate term outcomes?
All 3 – in long term, it affects size and complexity of organelles and number of cells, other effects are intermediate or short term
middle of adrenal gland is called what
medulla
What kind of tissue is the middle of the adrenal gland derived from
neural tissue - you get direct sns innevation here
what kinds of hormones are made in the medulla of the adrenal gland
catecholamines
3 regions of adrenal cortex
zona glomerulosa, zona fasiculata, zona reticularis
hormone type made in zona glomerulosa
mineralocorticoids
hormone type made in zona fasiculata
glucocorticoids
hormone type made in zona reticularis
weak androgens
as opposed to the medulla, which makes catecolamines, what kind of hormone does the adrenal cortex make?
steroid hormones
What is the trickle down effect of the adrenal gland?
The blood supply of the medulla travels down from cortex - this is important for the conversion of norepinephrine to epinephrine
What hormone is required to get epinephrine from norepinephrine
cortisol
zona fasiculata makes what hormone
cortisol (or corticosterone in rodents)
What kind of expression pattern does cortisol show
circadian rhythm - peak is around 8AM, but as you get older you can shift rhythm based on environment
How is cortisol usually transported in blood
bound to transport proteins (CBG) and must dissociate to be active - around 5% of cortisol is free
how much cortisol is free in blood
5%
Can the cortisol binding globulin also bind to other things
yes, aldosterone but it is much less higher affinity for it
how does estrogen impact free cortisol
it increases CBG, so there is less free cortisol
where is the glucocorticoid receptor
inside the cell
How does glucocorticoid receptor work?
cortisol binds, chaperones dissociae from glucocorticoid receptors, and GR-Cortisol complex impacts gene transcription
in absence of cortisol, how does the Glucocorticoid receptor (GR) exist
bound to chaperones in cytoplasm
what enzyme is importnant for increasing local cortisol concentrations
11B HSD 1
7 key functions of cortisol
Metabolism - glucose mobilizing Muscle - proteolysis Adipsoe tissue - lipolysis Immune/inflammation - suppression bone - resorption cardiovascular - maintain CO, increase arteriolar tone, decrease endothelial permeability CNS Maturation of fetus -- important in lung dvelopment and surfactants
Metabolic actions of cortisol
potent counter- regulatory hormone to insulin
mobilizes energy stores, increase plasma glucose (glucocorticoid)
What does cortisol do to glucose balance
increase gluconeogenesis and plasma glucose levels
how does cortisol impact fat
lipolysis
redistribution of fat (abdominal obesity but depletion of subcutaneous fat)
how dos cortisol impact protein
proteolysis
Insulin is an anabolic hormone, how does cortisol compare?
it is oppository - it is catabolic
How does cortisol impact how glucose can be taken up into cells
decreases GLUT4 insertion into membrane
What key enzymes are impacted by cortisol for gluconeogenesis
PEPCK
Tyrosine aminotransferase
glucose 6 phosphatase
How does cortisol impact amino acid uptake into muscle cells
inhibits it
how does cortisol impact muscle breakdwn? What is it doing?
increases transcription of an E3 ligase
What would be the impact of chronic high glucocrticoids on muscle?
will eventually cause muscle weakness due to wasting as result of actions of cortisol on muscle
Cortisol increases expression of what three key genes with regard to lipolysis
MgII, Lipe, and Angpt14 – these are lipases that will all activate hormone sensitive lipase (you’re going to be mobilizing fat)
Glucocorticoid receptor does what to NFkB
inhibits it - this is through increasing the IkB transcription - this then prevents NFkB nuclear translocation – thus decreasing local inflammatory responses
How does cortisol impact the immune system
Stimulate anti-inflammatory cytokines, inhibit pro inflammatory cytokines, inhibit PLA and decrease PG’s , leukotrines, and thrombocytes. You also get vasodilation, and neutrophil number is increased but nonfunctional - therefore, you could suppress inflammation when using glucocorticoids, but risk reducing ab production as well
how does cortisol impact bone
IGF-I receptors are going to be inhabited as well as intestinal calcium absrption going up so cortisol impacts calcium in many ways -
Inhibits intestinal calcium absorption therefore - transcellular transport
Inhibits bone formation and decreases IGF-I receptors
Increases bone resorption, activation of osteoclasts
How does cortisol impact cardiovascular health
during physical stress we want blood to flow to heart and brain, away fro periphery. Therefore it stimulates RBC production and maintains responsiveness to catecholamine pressor effects – constrict peripheral vessels via a-adrenergic receptors, dilate coronary arteries in heart via beta adrenergic receptors is what we want. Because of the stimulation of these receptor types, glucocorticoid excess = increased blood pressure, hypertension. However, cortisol is requried to maintain vascular integrity and reactivity
Cortisol impact on CNS
Emotional response - anxiety, depression, nervousness, panic, feeding behavior, rage and aggression
perception
Negative feedback on CRH and ACTH release
Cushing disease vs cushing syndrome
cushing disease = excessive cortisol secretion due to ACTH secreting pituitary adenoma
cushing syndrome - symptoms of cushing ddisease due to other cuases than pituitary adenoma
some causes of cushing syndrome
exogenous glucocorticoid therapy
small lung cell carcinoma that secretes acth
adrenal tumor
Changes to body that occur in cushing syndrome and cushing disease
Changes in body fat distribution (moon fase, buffalo hump, abdominal obesity, thin skin, bruising), inhibition of intestinal calcium absorption leading to osteoporosis, hypertension possibly due to excess glucocorticoids activating MR, glucose intolerance due to antagonism of insulin action, and purple striae from fragile skin stretching over increased abdominal fat, and vessels hemorrahging into striae
When is glucocorticoid therapy given
medical emergencies to treat sepsis, asthma, autimmune diseases
Chronic usage for anti-inflammatoyr, immunosuppressive, adrenal insufficiency, pre=term infants to help with lungs
You MUSt wean off if you are giving chronically
Adrenal insufficiency
Failure of adrenal gland, can be primary adrenal failure or secondary failure (addison’s disease, or secondary)
Addison’s disease
autoimmune disease (primary disease) where adrenal cortex is attacked, first symptoms are related to ones of adrenal cortex
Secondary adrenal insufficiency
failure to secrete CRH or ACTH - usually ACTH – most common cause is sudden cessation of glucocorticoid therapy
