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FHB Block 4 > HPA Axis and Adrenal Gland > Flashcards

HPA Axis and Adrenal Gland Flashcards

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)

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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

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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
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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

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5
Q

What is CRH?

A

corticotropin-releasing hormone, 41 AA, central regulator of HPA axis

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6
Q

What produces CRH and what does it stimulate

A

produced in parvocellular neurons of PVN

stimulates anterior pituitary

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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

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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

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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

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10
Q

How is AVP involved in HPA axis feedback?

A

Cortisol inhibits the synthesis of AVP in the CNS

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11
Q

Where is ACTH synthesized, and from what?

A

produced in the anterior pituitary (corticotroph)

precursor is pro-opiomelanocortin (POMC)

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12
Q

What regulates ACTH?

A

regulated by CRH and AVP from hypothalamus

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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

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14
Q

What intracellular signal is increased upon ACTH binding MC2R?

A

cAMP

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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
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16
Q

What are the subsequent effects of ACTH binding MC2R?

A

increased transcription of P450s

increased adrenoxin, LDL and HDL receptors

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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

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18
Q

What is functionally unique about the adrenal gland?

A

it is functionally two glands

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19
Q

What s the cortex derived from and what does it produce?

A

derived from mesoderm, produces steroids

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20
Q

What is the medulla derived from and what does it produce?

A

derived from neural crest cells, produces catecholamines

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21
Q

What does sympathetic innervation synapse on in the adrenal gland?

A

medullary cells - epi/norepi

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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)

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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

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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

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25
Q

What is cortisol released in response to?

A

acute/chronic stress either physical, such as starvation or illness, or psychological

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26
Q

What does cortisol bind to, and where?

A

high affinity to glucocorticoid receptors (GR) and mineralocorticoid receptors (MR) in cytoplasm

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27
Q

What is the inactive form of cortisol, and how is it processed?

A

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

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28
Q

What is cortisol binding globulin, and what percent of cortisol is bound in the plasma?

A

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

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29
Q

What will decrease CBG, and what is the result?

A

estrogen or shock/severe infection can decrease CBG, resulting in a higher amount of free cortisol

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30
Q

Where are glucocorticoids made?

A

zona fasciculata

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31
Q

What is the active glucocorticoid in humans?

A

cortisol

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32
Q

discuss some general features of glucocorticoids

A

accounts for 80% of cortical hormones

released in circadian manner, peaking around 8am

must dissociate from CBG in order to be active (~5% free)

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33
Q

How does cortisol affect muscle?

A

maintain muscle function, decrease muscle mass

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34
Q

How does cortisol affect bone?

A

decrease bone formation, increase bone resorption

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35
Q

How does cortisol affect the brain?

A

modulates emotional tone and wakefulness

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36
Q

How does cortisol affect the kidneys?

A

increase glomerular filtration and free water clearance

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37
Q

How does cortisol affect connective tissue?

A

decreases connective tissue

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38
Q

How does cortisol affect the immune system?

A

inhibits inflammatory and immune responses

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39
Q

How does cortisol affect the fetus?

A

facilitates maturation

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40
Q

How does cortisol affect the heart?

A

maintains cardiac output, increases arteriolar tone, decreases endothelial permeability

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41
Q

What are the metabolic functions of cortisol?

A

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

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42
Q

How does cortisol stimulate gluconeogenesis?

A

stimulates G6Pase, PEP CKase, and tyrosine aminotransferase

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43
Q

How does cortisol regulate muscle to maintain blood glucose levels?

A

cortisol inhibits GLUT4 insertion in the membrane which decreases glucose uptake in muscle cells

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44
Q

How does cortisol stimulate proteolysis?

A

increases MuRF1, which activates protein degradation

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45
Q

How does cortisol stimulate lipolysis?

A

increase Mgll (monoacylglycerol lipase) and Lipe (hormone sensitive lipase) which increases breakdown of fat

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46
Q

how are local inflammatory responses decreased?

A

GR action of NF-kappa-B

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47
Q

How do you inhibit NF-kB activity?

A

GR increases IkB which inhibits NFkB

Cortisol/GR binds NFkB, keeping it in the cytosol (prevents nuclear translocation)

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48
Q

What effects does cortisol have on the immune system?

A

decreased inflammation (reason for glucocorticoid therapy)

stimulates anti-inflammatory cytokines

inhibits prostaglandins

suppresses Ab formation

increases neutrophils, platelets, and RBC

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49
Q

How does cortisol affect bone?

A

inhibits intstinal Ca absorption (paracellular pathway)

inhibits bone formation via decreasing IGF-1 receptors

increases bone resorption by increasing activity of osteoclasts

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50
Q

What are cortisol actions on the cardiovascular system?

A

increase in RBC production

maintains responsiveness to catecholamine pressor functions

maintains vascular integrity and reactivity

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51
Q

What are the pressor functions that cortisol maintains?

A

constricts peripheral blood vessels via alpha-adrenergic receptors

dilate coronary arteries via beta-adrenergic receptors

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52
Q

What affect does glucocorticoid excess have on the cardiovascular system?

A

hypertension

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53
Q

What are the actions of cortisol on the CNS?

A

modulates emotional response, depression, anxiety, nervousness, panic, aggression, perception

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54
Q

What is the negative feedback action of cortisol on the CNS?

A

negative feedback on CRH/ACTH release

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55
Q

What is Cushing disease/syndrome

A

Cushing disease: excess cortisol secretion due to pituitary adenoma

Cushing syndrome: excess cortisol due to all others

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56
Q

What are the symptoms of Cushing?

A

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
Q

What are some medical emergencies that would warrant glucocorticoid use?

A

high acute dose to treat septic shock, sever asthma, severe autoimmune disease flare

58
Q

What chronic conditions would you use glucocorticoids for?

A

anti-inflammatory, immunosuppressive, adrenal insufficiency, pre-term infants (improves lung function)

59
Q

What is adrenal insufficiency (AI)?

A

failure of adrenals to secrete glucocorticoids, mineralocorticoids, or both

60
Q

What is primary AI?

A

failure at the adrenal gland

Addison’s disease: autoimmune destruction of adrenals

70% of adrenal cases are primary

61
Q

What is secondary AI?

A

Failure to secrete CRH or ACTH

62
Q

What is the most common cause of secondary AI?

A

sudden cessation of glucocorticoid therapy

63
Q

What are some synthetic glucocorticoid analogs?

A

Cortisol, prednisone, methylprednisone, dexamethasone, fludrocortisone

64
Q

What kind of cells are in the adrenal medulla, and what do the secrete?

A

Chromaffin cells, secrete NE and Epi (catecholamines)

65
Q

What are mineralocorticoids?

A

Steroid hormones that regulate water and sodium balance

66
Q

What is the main endogenous mineralocorticoid?

A

aldosterone, but other steroid hormones can have mineralocorticoid action (such as the precursor to aldosterone, 11-deoxycortiosterone)

67
Q

Where does mineralocorticoids act? (Where are MR high?)

A

distal tubule in the kidney

colon

salivary ducts

sweat ducts

68
Q

What does aldosterone do in the kidney?

A

stimulates water and sodium reabsorption, potassium secretion

69
Q

When is the renin-angiotensis-aldosterone system invoked?

A

drop in blood pressure

70
Q

describe the renin-angiotensin-aldosterone system

A

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
Q

What does aldosterone primarily regulate?

A

extracellular volume

72
Q

What does aldosterone stimulate?

A

increased sodium and water reabsorption

increased potassium excretion

73
Q

What is the net result of aldosterone stimulation?

A

increased fluid volume and blood pressure

74
Q

What does AVP/ADH primarily regulate?

A

free water balance

75
Q

How does AVP/ADH regulate the free water balance?

A

stimulates distal nephron water permeability- increased water retention

decreases plasma osmolality, which secondarily affects sodium concentration in the blood

76
Q

What is cortisol normally converted into in the kidney, and by what?

A

cortisone, by 11beta-HSD2

77
Q

What are some examples of 11beta-HSD2 inhibitors?

A

the drug carbenoxolone and licorice, resulting in increased MR activation and increased sodium and water retention

78
Q

What is a potential role of 11beta-HSD1 in DMT2?

A

local production of cortisol

79
Q

What is produced in the zona reticularis?

A

DHEA/S

80
Q

What is the metabolite of DHEA/S?

A

androstenedione

81
Q

What is the role of DHEA/S?

A

precursor for T and E

50% of androgen precursors in prostate comes from adrenal

82
Q

When does DHEAS peak?

A

20-30, declines with age

83
Q

Does DHEAS bind androgen receptors?

A

considered a weak androgen as it binds ARs with low affinity

84
Q

What does DHEAS do in postmenopausal women?

A

primary source of androgen/estrogen

85
Q

What is congenital adrenal hyperplasia (CAH)?

A

21-alpha hydroxylase deficiency (most common cause of CAH) results in excess DHEA and no mineralocorticoids or glucocorticoids

86
Q

What are the clinical indications of CYP21A2: 21-alpha hydroxylase deficiency?

A

virilization, ambiguous genitalia at birth, sodium loss, high plasma renin, hypotension, hyperkalemia, high ACTH

87
Q

What is the hormonal affect of CYP11B1: 11-hydroxylase deficiency?

A

No cortisol

low aldosterone, but high AR activity

increased androgens

88
Q

What is the clinical presentation of CYP11B1: 11-hydroxylase deficiency?

A

hypertension due to increased 11-deoxycorticosterone

hypokalemia

virilization

High ACTH

89
Q

What is the hormonal presentation of CYP17: 17alpha-hydroxylase deficiency

A

no cortisol

low aldosterone, high MR activity

decreased androgens

90
Q

What is the clinical presentation of CYP17: 17alpha-hydroxylase deficiency?

A

hypertension

hypokalemia

feminization/pseudohermaphroditism

high ACTH

91
Q

What does 11-hydroxylase deficiency syndrome refer to?

A

defect in CYP11B1 (in the z. fasciculata)

92
Q

What is CYP11B2 and where is it located?

A

11-hydroxylase or aldosterone synthase, located in the zona glomerulosa

93
Q

What is CYP11B2 stimulated by?

A

angiotensin II

94
Q

What does CYP11A1 do, and where is it located?

A

Cholesterol side chain cleavage, in all zones of the adrenal cortex

95
Q

What does CYP21A2 code for, and where is it located?

A

21alpha-hydroxylase, located in the fasciculata and the glomerulosa

96
Q

What does CYP11B1/CYP11B2 code for, and where is it located?

A

11-hydroxylase, fasciculata/glomerulosa

97
Q

What does CYP17 code for, and where is it located?

A

17alpha-hydroxylase, fasciculata/reticularis

98
Q

What does CYP11B2 code for, and where is it located?

A

Aldosterone synthase, glomerulosa

99
Q

What does CYP21A2 do?

A

formation of deoxycortisol from 17(OH)progesterone (fasciculata)

formation of deoxycorticosterone from progesterone (glomerulosa)

100
Q

What does CYP17 do?

A

conversion of progesterone to 17(OH)progesterone (fasciculata)

conversion of pregnenolone to 17(OH) pregnenolone (reticularis)

101
Q

What does CYP11B1 do?

A

formation of cortisol from deoxycortisol (fasciculata)

102
Q

What does CYP11B2 do?

A

formation of aldosterone from 8(OH)corticosterone (glomerulosa)

103
Q

What does ACTH do in the adrenal?

A

stimulates conversion of cholesterol to pregnenolone

104
Q

How does ACTH stimulate conversion of cholesterol to pregnenolone?

A

activation of StAR activity

105
Q

What does StAR do?

A

transport of cholesterol from outer mito membrane to inner mito membrane

106
Q

What is the first step in steroid biosynthesis?

A

cleavage of the cholesterol side chain by CYP11A1

107
Q

What are the affects of ACTH on the adrenal cortex?

A

stimulates cellular hypertrophy

stimulates biosynthesis of cortisol

stimulates biosynthesis of DHEA (CYP17)

stimulates 11beta-hydroxylase (CYP11B1)

108
Q

What are the affects of ACTH on the adrenal medulla?

A

conversion of dopamine to norepinephrine

109
Q

What is the adrenal medulla derived from?

A

originates from the same neural crest area that forms the sympathetic ganglia

110
Q

What are medullary cells innervated by?

A

sympathetic preganglionic fibers

111
Q

What kind of neurons are the adrenal medulla cells considered to be?

A

modified post-ganglionic sympathetic neurons (no dendrites or axons)

112
Q

What kind of cells is the adrenal medulla made up of?

A

cords of polyhedral shaped epithelial cells

113
Q

What do most medullary cells release, and how are they stored?

A

epinephrine, stored in granules

114
Q

What control is the release of epi granules under?

A

rapid release under sympathetic NS control

115
Q

What are the catecholamines?

A

dopamine, NE, Epi

116
Q

What is the rate limiting step in catecholamine synthesis?

A

tyrosine hydroxylase

117
Q

Where does the pathway stop in dopaminergic cells in the brain?

A

dopamine…

118
Q

What conversion to peripheral nerves do?

A

dopamine to norepinephrine

119
Q

What stimulates the conversion of NE to Epi, and where does it occur?

A

Cortisol, only in the adrenal medulla

120
Q

What is Epi released in response to?

A

cold, pain, perceived danger

121
Q

What are the three main targets of epinephrine?

A

muscle, liver, fat

122
Q

What affect does epi have in the muscle?

A

Glycogenolysis: ATP for local energy

123
Q

What receptors does Epi act through?

A

both alpha and beta adrenergic

124
Q

What is the affect of Epi on alpha adrenergic receptors?

A

vasoconstriction in periphery

125
Q

What is the affect of Epi on beta1 adrenergic receptors?

A

increased CO, heart rate

126
Q

What is the affect of Epi on beta2 adrenergic receptors?

A

targets liver, muscle, GI, and bronchioles

127
Q

What are the metabolic functions of Epi?

A

glucose release, increased metabolic rate

128
Q

does NE or Epi bind better to alpha adrenergic receptors?

A

NE

129
Q

Does NE or Epi bind better to beta?

A

both equally

130
Q

What does acute stress activate?

A

the sympathetic NS and the release of NE

131
Q

What is the response to chronic stress?

A

NE stimulates CRH to initiate HPA response

132
Q

What is the end product in the metabolism of catecholamines?

A

VMA (vanillylmandelic acid)

133
Q

What can VMA be used for clinically?

A

detect tumors producing excess catecholamines

134
Q

What breaks down NE and Epi?

A

MAO and COMT

135
Q

What are pheochromocytomas?

A

tumors originating from chromaffin cells

136
Q

What is the result of a pheochromocytoma?

A

catecholamine overproduction

137
Q

What are the symptoms of a pheochromocytoma?

A

hypertension (no response to medication), headaches, tachycardia

138
Q

What are pheos known as?

A

the 10% tumor

FHB Block 4 (13 decks)

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