HPA Axis and Adrenal Gland Flashcards Preview

FHB Block 4 > HPA Axis and Adrenal Gland > Flashcards

Flashcards in HPA Axis and Adrenal Gland Deck (138):
1

What is regulated by the HPA axis?

Adaptive response to stress: catecholamines (epi, norepi) and glucocorticoids (cortisol)

Immune function: anti-inflammatory (glucocorticoids)

2

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

3

What is included in the HPA axis, and what do they secrete?

H = hypothalamus: CRH/CRF
P = pituitary: ACTH
A = Adrenals: multiple

4

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

5

What is CRH?

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

6

What produces CRH and what does it stimulate

produced in parvocellular neurons of PVN

stimulates anterior pituitary

7

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

8

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

9

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

10

How is AVP involved in HPA axis feedback?

Cortisol inhibits the synthesis of AVP in the CNS

11

Where is ACTH synthesized, and from what?

produced in the anterior pituitary (corticotroph)

precursor is pro-opiomelanocortin (POMC)

12

What regulates ACTH?

regulated by CRH and AVP from hypothalamus

13

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

14

What intracellular signal is increased upon ACTH binding MC2R?

cAMP

15

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

16

What are the subsequent effects of ACTH binding MC2R?

increased transcription of P450s
increased adrenoxin, LDL and HDL receptors

17

What are the long term effects of ACTH binding MC2R?

increased size and functional complexity of organelles
increased size and number of cells

18

What is functionally unique about the adrenal gland?

it is functionally two glands

19

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

derived from mesoderm, produces steroids

20

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

derived from neural crest cells, produces catecholamines

21

What does sympathetic innervation synapse on in the adrenal gland?

medullary cells - epi/norepi

22

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)

23

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

24

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

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