HPA Axis and Adrenal Gland Flashcards
What is regulated by the HPA axis?
Adaptive response to stress: catecholamines (epi, norepi) and glucocorticoids (cortisol)
Immune function: anti-inflammatory (glucocorticoids)
What is not regulated by the HPA axis?
maintenance of water, sodium, potassium balance, and blood pressure: mineralocorticoids (aldosterone)
Is a site of weak androgen production: DHEA/DHES
What is included in the HPA axis, and what do they secrete?
H = hypothalamus: CRH/CRF P = pituitary: ACTH A = Adrenals: multiple
What is the feedback of the HPA axis?
short feedback loop: ACTH directly inhibits release of CRH in hypothalamus
long feedback loop: cortisol inhibits release of ACTH in pituitary and inhibits factors affecting CRH release in the hypothalamus
What is CRH?
corticotropin-releasing hormone, 41 AA, central regulator of HPA axis
What produces CRH and what does it stimulate
produced in parvocellular neurons of PVN
stimulates anterior pituitary
In what manner is CRH released, and what is its half life?
pulsatile release, resulting in episodic release of ACTH
half life is 5 min
What are the two receptors for CRH, where are they located, and what are the binding affinities?
CRH R1: in anterior pituitary, binds CRH with highest affinity
CRH R2: binds with higher affinity to urocortin
What is the relationship between AVP and CRH?
There is a synergistic effect of AVP and CRH - ACTH release is enhanced in the presence of AVP
How is AVP involved in HPA axis feedback?
Cortisol inhibits the synthesis of AVP in the CNS
Where is ACTH synthesized, and from what?
produced in the anterior pituitary (corticotroph)
precursor is pro-opiomelanocortin (POMC)
What regulates ACTH?
regulated by CRH and AVP from hypothalamus
What receptors does ACTH bind, and what does high levels of ACTH lead to?
binds with high affinity to melanocortin 2 receptor (MC2R) and with low affinity to MC1R(skin)
high levels of ACTH can lead to hyperpigmentation
What intracellular signal is increased upon ACTH binding MC2R?
cAMP
What are the immediate effects of ACTH binding MC2R?
increased cholesterol esterase decreased cholesterol ester synthetase increased cholesterol transport into the mito increased cholesterol binding to P450 increased pregnenolone production increased StAR production
What are the subsequent effects of ACTH binding MC2R?
increased transcription of P450s
increased adrenoxin, LDL and HDL receptors
What are the long term effects of ACTH binding MC2R?
increased size and functional complexity of organelles
increased size and number of cells
What is functionally unique about the adrenal gland?
it is functionally two glands
What s the cortex derived from and what does it produce?
derived from mesoderm, produces steroids
What is the medulla derived from and what does it produce?
derived from neural crest cells, produces catecholamines
What does sympathetic innervation synapse on in the adrenal gland?
medullary cells - epi/norepi
What layers is the cortex divided into, and what does each produce?
outer zona glomerulosa: mineralocorticoids
middle zona fasciculata: glucocorticoids (cortisol)
inner zona reticularis: weak androgens (DHEAS)
Describe the blood supply of the adrenal cortex
suprarenal arteries break into subcapsular plexus of fenestrated capillaries
second plexus at the zona reticularis before entering the medulla
describe the blood supply of the adrenal medulla
dual blood supply that bathes medullary cells in blood carrying corticosteroids from the cortex - important for conversion of NE to E
arterioles break into fenestrated, diaphragmated capillaries
all blood drains to the central vein
What is cortisol released in response to?
acute/chronic stress either physical, such as starvation or illness, or psychological
What does cortisol bind to, and where?
high affinity to glucocorticoid receptors (GR) and mineralocorticoid receptors (MR) in cytoplasm
What is the inactive form of cortisol, and how is it processed?
cortisone. It cannot bind MR, but if it is taken up by a cell via GR, it can be converted to cortisol via 1-beta-HSD1 and released after which it can bind MR
What is cortisol binding globulin, and what percent of cortisol is bound in the plasma?
CBG, aka transcortin is in the serine protease inhibitor family, but is not a protease inhibitor
90% cortisol bound to CBG in the blood, 7% bound to albumin, 3-4% free
30-fold Higher affinity for cortisol than aldosterone
What will decrease CBG, and what is the result?
estrogen or shock/severe infection can decrease CBG, resulting in a higher amount of free cortisol
Where are glucocorticoids made?
zona fasciculata
What is the active glucocorticoid in humans?
cortisol
discuss some general features of glucocorticoids
accounts for 80% of cortical hormones
released in circadian manner, peaking around 8am
must dissociate from CBG in order to be active (~5% free)
How does cortisol affect muscle?
maintain muscle function, decrease muscle mass
How does cortisol affect bone?
decrease bone formation, increase bone resorption
How does cortisol affect the brain?
modulates emotional tone and wakefulness
How does cortisol affect the kidneys?
increase glomerular filtration and free water clearance
How does cortisol affect connective tissue?
decreases connective tissue
How does cortisol affect the immune system?
inhibits inflammatory and immune responses
How does cortisol affect the fetus?
facilitates maturation
How does cortisol affect the heart?
maintains cardiac output, increases arteriolar tone, decreases endothelial permeability
What are the metabolic functions of cortisol?
potent counter-regulatory hormone to insulin
mobilizes energy stores - increased gluconeogenesis, lipolysis, and proteolysis, increasing plasma glucose (“glucocorticoid”)
redistributes fat - results in abdominal obesity, depletion of subcutaneous fat (protecting organs)
inhibits intestinal Ca absorption
How does cortisol stimulate gluconeogenesis?
stimulates G6Pase, PEP CKase, and tyrosine aminotransferase
How does cortisol regulate muscle to maintain blood glucose levels?
cortisol inhibits GLUT4 insertion in the membrane which decreases glucose uptake in muscle cells
How does cortisol stimulate proteolysis?
increases MuRF1, which activates protein degradation
How does cortisol stimulate lipolysis?
increase Mgll (monoacylglycerol lipase) and Lipe (hormone sensitive lipase) which increases breakdown of fat
how are local inflammatory responses decreased?
GR action of NF-kappa-B
How do you inhibit NF-kB activity?
GR increases IkB which inhibits NFkB
Cortisol/GR binds NFkB, keeping it in the cytosol (prevents nuclear translocation)
What effects does cortisol have on the immune system?
decreased inflammation (reason for glucocorticoid therapy)
stimulates anti-inflammatory cytokines
inhibits prostaglandins
suppresses Ab formation
increases neutrophils, platelets, and RBC
How does cortisol affect bone?
inhibits intstinal Ca absorption (paracellular pathway)
inhibits bone formation via decreasing IGF-1 receptors
increases bone resorption by increasing activity of osteoclasts
What are cortisol actions on the cardiovascular system?
increase in RBC production
maintains responsiveness to catecholamine pressor functions
maintains vascular integrity and reactivity
What are the pressor functions that cortisol maintains?
constricts peripheral blood vessels via alpha-adrenergic receptors
dilate coronary arteries via beta-adrenergic receptors
What affect does glucocorticoid excess have on the cardiovascular system?
hypertension
What are the actions of cortisol on the CNS?
modulates emotional response, depression, anxiety, nervousness, panic, aggression, perception
What is the negative feedback action of cortisol on the CNS?
negative feedback on CRH/ACTH release
What is Cushing disease/syndrome
Cushing disease: excess cortisol secretion due to pituitary adenoma
Cushing syndrome: excess cortisol due to all others
What are the symptoms of Cushing?
change in body fat/composition: buffalo hump, abdominal obesity, moon face, thin skin, easy bruising
osteoporosis
hypertension
glucose intolerant
purple striae: stretching of fragile skin over abdominal fat leads to hemorrhaging into striae
emotional disturbances
What are some medical emergencies that would warrant glucocorticoid use?
high acute dose to treat septic shock, sever asthma, severe autoimmune disease flare
What chronic conditions would you use glucocorticoids for?
anti-inflammatory, immunosuppressive, adrenal insufficiency, pre-term infants (improves lung function)
What is adrenal insufficiency (AI)?
failure of adrenals to secrete glucocorticoids, mineralocorticoids, or both
What is primary AI?
failure at the adrenal gland
Addison’s disease: autoimmune destruction of adrenals
70% of adrenal cases are primary
What is secondary AI?
Failure to secrete CRH or ACTH
What is the most common cause of secondary AI?
sudden cessation of glucocorticoid therapy
What are some synthetic glucocorticoid analogs?
Cortisol, prednisone, methylprednisone, dexamethasone, fludrocortisone
What kind of cells are in the adrenal medulla, and what do the secrete?
Chromaffin cells, secrete NE and Epi (catecholamines)
What are mineralocorticoids?
Steroid hormones that regulate water and sodium balance
What is the main endogenous mineralocorticoid?
aldosterone, but other steroid hormones can have mineralocorticoid action (such as the precursor to aldosterone, 11-deoxycortiosterone)
Where does mineralocorticoids act? (Where are MR high?)
distal tubule in the kidney
colon
salivary ducts
sweat ducts
What does aldosterone do in the kidney?
stimulates water and sodium reabsorption, potassium secretion
When is the renin-angiotensis-aldosterone system invoked?
drop in blood pressure
describe the renin-angiotensin-aldosterone system
decreased blood pressure stimulates renin release from the kidney (from the juxtaglomerular apparatus)
Renin cleaves angiotensinogen (from the liver) to angiotensin I
ACE converts angiotensin I to angiotensin II
Angiotensin II is a vasoconstrictor and stimulates aldosterone release
What does aldosterone primarily regulate?
extracellular volume
What does aldosterone stimulate?
increased sodium and water reabsorption
increased potassium excretion
What is the net result of aldosterone stimulation?
increased fluid volume and blood pressure
What does AVP/ADH primarily regulate?
free water balance
How does AVP/ADH regulate the free water balance?
stimulates distal nephron water permeability- increased water retention
decreases plasma osmolality, which secondarily affects sodium concentration in the blood
What is cortisol normally converted into in the kidney, and by what?
cortisone, by 11beta-HSD2
What are some examples of 11beta-HSD2 inhibitors?
the drug carbenoxolone and licorice, resulting in increased MR activation and increased sodium and water retention
What is a potential role of 11beta-HSD1 in DMT2?
local production of cortisol
What is produced in the zona reticularis?
DHEA/S
What is the metabolite of DHEA/S?
androstenedione
What is the role of DHEA/S?
precursor for T and E
50% of androgen precursors in prostate comes from adrenal
When does DHEAS peak?
20-30, declines with age
Does DHEAS bind androgen receptors?
considered a weak androgen as it binds ARs with low affinity
What does DHEAS do in postmenopausal women?
primary source of androgen/estrogen
What is congenital adrenal hyperplasia (CAH)?
21-alpha hydroxylase deficiency (most common cause of CAH) results in excess DHEA and no mineralocorticoids or glucocorticoids
What are the clinical indications of CYP21A2: 21-alpha hydroxylase deficiency?
virilization, ambiguous genitalia at birth, sodium loss, high plasma renin, hypotension, hyperkalemia, high ACTH
What is the hormonal affect of CYP11B1: 11-hydroxylase deficiency?
No cortisol
low aldosterone, but high AR activity
increased androgens
What is the clinical presentation of CYP11B1: 11-hydroxylase deficiency?
hypertension due to increased 11-deoxycorticosterone
hypokalemia
virilization
High ACTH
What is the hormonal presentation of CYP17: 17alpha-hydroxylase deficiency
no cortisol
low aldosterone, high MR activity
decreased androgens
What is the clinical presentation of CYP17: 17alpha-hydroxylase deficiency?
hypertension
hypokalemia
feminization/pseudohermaphroditism
high ACTH
What does 11-hydroxylase deficiency syndrome refer to?
defect in CYP11B1 (in the z. fasciculata)
What is CYP11B2 and where is it located?
11-hydroxylase or aldosterone synthase, located in the zona glomerulosa
What is CYP11B2 stimulated by?
angiotensin II
What does CYP11A1 do, and where is it located?
Cholesterol side chain cleavage, in all zones of the adrenal cortex
What does CYP21A2 code for, and where is it located?
21alpha-hydroxylase, located in the fasciculata and the glomerulosa
What does CYP11B1/CYP11B2 code for, and where is it located?
11-hydroxylase, fasciculata/glomerulosa
What does CYP17 code for, and where is it located?
17alpha-hydroxylase, fasciculata/reticularis
What does CYP11B2 code for, and where is it located?
Aldosterone synthase, glomerulosa
What does CYP21A2 do?
formation of deoxycortisol from 17(OH)progesterone (fasciculata)
formation of deoxycorticosterone from progesterone (glomerulosa)
What does CYP17 do?
conversion of progesterone to 17(OH)progesterone (fasciculata)
conversion of pregnenolone to 17(OH) pregnenolone (reticularis)
What does CYP11B1 do?
formation of cortisol from deoxycortisol (fasciculata)
What does CYP11B2 do?
formation of aldosterone from 8(OH)corticosterone (glomerulosa)
What does ACTH do in the adrenal?
stimulates conversion of cholesterol to pregnenolone
How does ACTH stimulate conversion of cholesterol to pregnenolone?
activation of StAR activity
What does StAR do?
transport of cholesterol from outer mito membrane to inner mito membrane
What is the first step in steroid biosynthesis?
cleavage of the cholesterol side chain by CYP11A1
What are the affects of ACTH on the adrenal cortex?
stimulates cellular hypertrophy
stimulates biosynthesis of cortisol
stimulates biosynthesis of DHEA (CYP17)
stimulates 11beta-hydroxylase (CYP11B1)
What are the affects of ACTH on the adrenal medulla?
conversion of dopamine to norepinephrine
What is the adrenal medulla derived from?
originates from the same neural crest area that forms the sympathetic ganglia
What are medullary cells innervated by?
sympathetic preganglionic fibers
What kind of neurons are the adrenal medulla cells considered to be?
modified post-ganglionic sympathetic neurons (no dendrites or axons)
What kind of cells is the adrenal medulla made up of?
cords of polyhedral shaped epithelial cells
What do most medullary cells release, and how are they stored?
epinephrine, stored in granules
What control is the release of epi granules under?
rapid release under sympathetic NS control
What are the catecholamines?
dopamine, NE, Epi
What is the rate limiting step in catecholamine synthesis?
tyrosine hydroxylase
Where does the pathway stop in dopaminergic cells in the brain?
dopamine…
What conversion to peripheral nerves do?
dopamine to norepinephrine
What stimulates the conversion of NE to Epi, and where does it occur?
Cortisol, only in the adrenal medulla
What is Epi released in response to?
cold, pain, perceived danger
What are the three main targets of epinephrine?
muscle, liver, fat
What affect does epi have in the muscle?
Glycogenolysis: ATP for local energy
What receptors does Epi act through?
both alpha and beta adrenergic
What is the affect of Epi on alpha adrenergic receptors?
vasoconstriction in periphery
What is the affect of Epi on beta1 adrenergic receptors?
increased CO, heart rate
What is the affect of Epi on beta2 adrenergic receptors?
targets liver, muscle, GI, and bronchioles
What are the metabolic functions of Epi?
glucose release, increased metabolic rate
does NE or Epi bind better to alpha adrenergic receptors?
NE
Does NE or Epi bind better to beta?
both equally
What does acute stress activate?
the sympathetic NS and the release of NE
What is the response to chronic stress?
NE stimulates CRH to initiate HPA response
What is the end product in the metabolism of catecholamines?
VMA (vanillylmandelic acid)
What can VMA be used for clinically?
detect tumors producing excess catecholamines
What breaks down NE and Epi?
MAO and COMT
What are pheochromocytomas?
tumors originating from chromaffin cells
What is the result of a pheochromocytoma?
catecholamine overproduction
What are the symptoms of a pheochromocytoma?
hypertension (no response to medication), headaches, tachycardia
What are pheos known as?
the 10% tumor
