HPA Axis and Adrenal Gland Flashcards
(138 cards)
1
Q
What is regulated by the HPA axis?
A
Adaptive response to stress: catecholamines (epi, norepi) and glucocorticoids (cortisol)
Immune function: anti-inflammatory (glucocorticoids)
2
Q
What is not regulated by the HPA axis?
A
maintenance of water, sodium, potassium balance, and blood pressure: mineralocorticoids (aldosterone)
Is a site of weak androgen production: DHEA/DHES
3
Q
What is included in the HPA axis, and what do they secrete?
A
H = hypothalamus: CRH/CRF P = pituitary: ACTH A = Adrenals: multiple
4
Q
What is the feedback of the HPA axis?
A
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
5
Q
What is CRH?
A
corticotropin-releasing hormone, 41 AA, central regulator of HPA axis
6
Q
What produces CRH and what does it stimulate
A
produced in parvocellular neurons of PVN
stimulates anterior pituitary
7
Q
In what manner is CRH released, and what is its half life?
A
pulsatile release, resulting in episodic release of ACTH
half life is 5 min
8
Q
What are the two receptors for CRH, where are they located, and what are the binding affinities?
A
CRH R1: in anterior pituitary, binds CRH with highest affinity
CRH R2: binds with higher affinity to urocortin
9
Q
What is the relationship between AVP and CRH?
A
There is a synergistic effect of AVP and CRH - ACTH release is enhanced in the presence of AVP
10
Q
How is AVP involved in HPA axis feedback?
A
Cortisol inhibits the synthesis of AVP in the CNS
11
Q
Where is ACTH synthesized, and from what?
A
produced in the anterior pituitary (corticotroph)
precursor is pro-opiomelanocortin (POMC)
12
Q
What regulates ACTH?
A
regulated by CRH and AVP from hypothalamus
13
Q
What receptors does ACTH bind, and what does high levels of ACTH lead to?
A
binds with high affinity to melanocortin 2 receptor (MC2R) and with low affinity to MC1R(skin)
high levels of ACTH can lead to hyperpigmentation
14
Q
What intracellular signal is increased upon ACTH binding MC2R?
A
cAMP
15
Q
What are the immediate effects of ACTH binding MC2R?
A
increased cholesterol esterase decreased cholesterol ester synthetase increased cholesterol transport into the mito increased cholesterol binding to P450 increased pregnenolone production increased StAR production
16
Q
What are the subsequent effects of ACTH binding MC2R?
A
increased transcription of P450s
increased adrenoxin, LDL and HDL receptors
17
Q
What are the long term effects of ACTH binding MC2R?
A
increased size and functional complexity of organelles
increased size and number of cells
18
Q
What is functionally unique about the adrenal gland?
A
it is functionally two glands
19
Q
What s the cortex derived from and what does it produce?
A
derived from mesoderm, produces steroids
20
Q
What is the medulla derived from and what does it produce?
A
derived from neural crest cells, produces catecholamines
21
Q
What does sympathetic innervation synapse on in the adrenal gland?
A
medullary cells - epi/norepi
22
Q
What layers is the cortex divided into, and what does each produce?
A
outer zona glomerulosa: mineralocorticoids
middle zona fasciculata: glucocorticoids (cortisol)
inner zona reticularis: weak androgens (DHEAS)
23
Q
Describe the blood supply of the adrenal cortex
A
suprarenal arteries break into subcapsular plexus of fenestrated capillaries
second plexus at the zona reticularis before entering the medulla
24
Q
describe the blood supply of the adrenal medulla
A
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
25
What is cortisol released in response to?
acute/chronic stress either physical, such as starvation or illness, or psychological
26
What does cortisol bind to, and where?
high affinity to glucocorticoid receptors (GR) and mineralocorticoid receptors (MR) in cytoplasm
27
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
28
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
29
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
30
Where are glucocorticoids made?
zona fasciculata
31
What is the active glucocorticoid in humans?
cortisol
32
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)
33
How does cortisol affect muscle?
maintain muscle function, decrease muscle mass
34
How does cortisol affect bone?
decrease bone formation, increase bone resorption
35
How does cortisol affect the brain?
modulates emotional tone and wakefulness
36
How does cortisol affect the kidneys?
increase glomerular filtration and free water clearance
37
How does cortisol affect connective tissue?
decreases connective tissue
38
How does cortisol affect the immune system?
inhibits inflammatory and immune responses
39
How does cortisol affect the fetus?
facilitates maturation
40
How does cortisol affect the heart?
maintains cardiac output, increases arteriolar tone, decreases endothelial permeability
41
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
42
How does cortisol stimulate gluconeogenesis?
stimulates G6Pase, PEP CKase, and tyrosine aminotransferase
43
How does cortisol regulate muscle to maintain blood glucose levels?
cortisol inhibits GLUT4 insertion in the membrane which decreases glucose uptake in muscle cells
44
How does cortisol stimulate proteolysis?
increases MuRF1, which activates protein degradation
45
How does cortisol stimulate lipolysis?
increase Mgll (monoacylglycerol lipase) and Lipe (hormone sensitive lipase) which increases breakdown of fat
46
how are local inflammatory responses decreased?
GR action of NF-kappa-B
47
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)
48
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
49
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
50
What are cortisol actions on the cardiovascular system?
increase in RBC production
maintains responsiveness to catecholamine pressor functions
maintains vascular integrity and reactivity
51
What are the pressor functions that cortisol maintains?
constricts peripheral blood vessels via alpha-adrenergic receptors
dilate coronary arteries via beta-adrenergic receptors
52
What affect does glucocorticoid excess have on the cardiovascular system?
hypertension
53
What are the actions of cortisol on the CNS?
modulates emotional response, depression, anxiety, nervousness, panic, aggression, perception
54
What is the negative feedback action of cortisol on the CNS?
negative feedback on CRH/ACTH release
55
What is Cushing disease/syndrome
Cushing disease: excess cortisol secretion due to pituitary adenoma
Cushing syndrome: excess cortisol due to all others
56
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
57
What are some medical emergencies that would warrant glucocorticoid use?
high acute dose to treat septic shock, sever asthma, severe autoimmune disease flare
58
What chronic conditions would you use glucocorticoids for?
anti-inflammatory, immunosuppressive, adrenal insufficiency, pre-term infants (improves lung function)
59
What is adrenal insufficiency (AI)?
failure of adrenals to secrete glucocorticoids, mineralocorticoids, or both
60
What is primary AI?
failure at the adrenal gland
Addison's disease: autoimmune destruction of adrenals
70% of adrenal cases are primary
61
What is secondary AI?
Failure to secrete CRH or ACTH
62
What is the most common cause of secondary AI?
sudden cessation of glucocorticoid therapy
63
What are some synthetic glucocorticoid analogs?
Cortisol, prednisone, methylprednisone, dexamethasone, fludrocortisone
64
What kind of cells are in the adrenal medulla, and what do the secrete?
Chromaffin cells, secrete NE and Epi (catecholamines)
65
What are mineralocorticoids?
Steroid hormones that regulate water and sodium balance
66
What is the main endogenous mineralocorticoid?
aldosterone, but other steroid hormones can have mineralocorticoid action (such as the precursor to aldosterone, 11-deoxycortiosterone)
67
Where does mineralocorticoids act? (Where are MR high?)
distal tubule in the kidney
colon
salivary ducts
sweat ducts
68
What does aldosterone do in the kidney?
stimulates water and sodium reabsorption, potassium secretion
69
When is the renin-angiotensis-aldosterone system invoked?
drop in blood pressure
70
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
71
What does aldosterone primarily regulate?
extracellular volume
72
What does aldosterone stimulate?
increased sodium and water reabsorption
| increased potassium excretion
73
What is the net result of aldosterone stimulation?
increased fluid volume and blood pressure
74
What does AVP/ADH primarily regulate?
free water balance
75
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
76
What is cortisol normally converted into in the kidney, and by what?
cortisone, by 11beta-HSD2
77
What are some examples of 11beta-HSD2 inhibitors?
the drug carbenoxolone and licorice, resulting in increased MR activation and increased sodium and water retention
78
What is a potential role of 11beta-HSD1 in DMT2?
local production of cortisol
79
What is produced in the zona reticularis?
DHEA/S
80
What is the metabolite of DHEA/S?
androstenedione
81
What is the role of DHEA/S?
precursor for T and E
50% of androgen precursors in prostate comes from adrenal
82
When does DHEAS peak?
20-30, declines with age
83
Does DHEAS bind androgen receptors?
considered a weak androgen as it binds ARs with low affinity
84
What does DHEAS do in postmenopausal women?
primary source of androgen/estrogen
85
What is congenital adrenal hyperplasia (CAH)?
21-alpha hydroxylase deficiency (most common cause of CAH) results in excess DHEA and no mineralocorticoids or glucocorticoids
86
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
87
What is the hormonal affect of CYP11B1: 11-hydroxylase deficiency?
No cortisol
low aldosterone, but high AR activity
increased androgens
88
What is the clinical presentation of CYP11B1: 11-hydroxylase deficiency?
hypertension due to increased 11-deoxycorticosterone
hypokalemia
virilization
High ACTH
89
What is the hormonal presentation of CYP17: 17alpha-hydroxylase deficiency
no cortisol
low aldosterone, high MR activity
decreased androgens
90
What is the clinical presentation of CYP17: 17alpha-hydroxylase deficiency?
hypertension
hypokalemia
feminization/pseudohermaphroditism
high ACTH
91
What does 11-hydroxylase deficiency syndrome refer to?
defect in CYP11B1 (in the z. fasciculata)
92
What is CYP11B2 and where is it located?
11-hydroxylase or aldosterone synthase, located in the zona glomerulosa
93
What is CYP11B2 stimulated by?
angiotensin II
94
What does CYP11A1 do, and where is it located?
Cholesterol side chain cleavage, in all zones of the adrenal cortex
95
What does CYP21A2 code for, and where is it located?
21alpha-hydroxylase, located in the fasciculata and the glomerulosa
96
What does CYP11B1/CYP11B2 code for, and where is it located?
11-hydroxylase, fasciculata/glomerulosa
97
What does CYP17 code for, and where is it located?
17alpha-hydroxylase, fasciculata/reticularis
98
What does CYP11B2 code for, and where is it located?
Aldosterone synthase, glomerulosa
99
What does CYP21A2 do?
formation of deoxycortisol from 17(OH)progesterone (fasciculata)
formation of deoxycorticosterone from progesterone (glomerulosa)
100
What does CYP17 do?
conversion of progesterone to 17(OH)progesterone (fasciculata)
conversion of pregnenolone to 17(OH) pregnenolone (reticularis)
101
What does CYP11B1 do?
formation of cortisol from deoxycortisol (fasciculata)
102
What does CYP11B2 do?
formation of aldosterone from 8(OH)corticosterone (glomerulosa)
103
What does ACTH do in the adrenal?
stimulates conversion of cholesterol to pregnenolone
104
How does ACTH stimulate conversion of cholesterol to pregnenolone?
activation of StAR activity
105
What does StAR do?
transport of cholesterol from outer mito membrane to inner mito membrane
106
What is the first step in steroid biosynthesis?
cleavage of the cholesterol side chain by CYP11A1
107
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)
108
What are the affects of ACTH on the adrenal medulla?
conversion of dopamine to norepinephrine
109
What is the adrenal medulla derived from?
originates from the same neural crest area that forms the sympathetic ganglia
110
What are medullary cells innervated by?
sympathetic preganglionic fibers
111
What kind of neurons are the adrenal medulla cells considered to be?
modified post-ganglionic sympathetic neurons (no dendrites or axons)
112
What kind of cells is the adrenal medulla made up of?
cords of polyhedral shaped epithelial cells
113
What do most medullary cells release, and how are they stored?
epinephrine, stored in granules
114
What control is the release of epi granules under?
rapid release under sympathetic NS control
115
What are the catecholamines?
dopamine, NE, Epi
116
What is the rate limiting step in catecholamine synthesis?
tyrosine hydroxylase
117
Where does the pathway stop in dopaminergic cells in the brain?
dopamine...
118
What conversion to peripheral nerves do?
dopamine to norepinephrine
119
What stimulates the conversion of NE to Epi, and where does it occur?
Cortisol, only in the adrenal medulla
120
What is Epi released in response to?
cold, pain, perceived danger
121
What are the three main targets of epinephrine?
muscle, liver, fat
122
What affect does epi have in the muscle?
Glycogenolysis: ATP for local energy
123
What receptors does Epi act through?
both alpha and beta adrenergic
124
What is the affect of Epi on alpha adrenergic receptors?
vasoconstriction in periphery
125
What is the affect of Epi on beta1 adrenergic receptors?
increased CO, heart rate
126
What is the affect of Epi on beta2 adrenergic receptors?
targets liver, muscle, GI, and bronchioles
127
What are the metabolic functions of Epi?
glucose release, increased metabolic rate
128
does NE or Epi bind better to alpha adrenergic receptors?
NE
129
Does NE or Epi bind better to beta?
both equally
130
What does acute stress activate?
the sympathetic NS and the release of NE
131
What is the response to chronic stress?
NE stimulates CRH to initiate HPA response
132
What is the end product in the metabolism of catecholamines?
VMA (vanillylmandelic acid)
133
What can VMA be used for clinically?
detect tumors producing excess catecholamines
134
What breaks down NE and Epi?
MAO and COMT
135
What are pheochromocytomas?
tumors originating from chromaffin cells
136
What is the result of a pheochromocytoma?
catecholamine overproduction
137
What are the symptoms of a pheochromocytoma?
hypertension (no response to medication), headaches, tachycardia
138
What are pheos known as?
the 10% tumor
