Adrenal Physiology Flashcards
(116 cards)
1
Q
True or false: the adrenal cortex and medulla are completely independent of one another
A
False–not completely, but mostly
2
Q
What are the two major hormone types that are secreted by the adrenal glands?
A
Steroid hormones
Catecholamines
3
Q
What are the steroid hormones that are secreted by the adrenal glands?
A
Glucocorticoids
Mineralocorticoids
Androgens
4
Q
What are the catecholamines secreted by the adrenal glands?
A
Epi and NE
5
Q
What part of the adrenal glands secretes aldosterone?
A
The zona glomerulosa
6
Q
What controls the secretion of aldosterone?
A
Fluctuations in the extracellular levels of angiotensin II and K
7
Q
What percent of the output of the adrenal cortex comes from the zona fasciculata and zona reticularis? What are the products of each of these areas?
A
75% and 10% respectively
Cortisol, corticosterone, and DHEA
8
Q
Where are chromaffin cells located? What do they do? What regulates this?
A
- Within the adrenal medulla
- Synthesize and secrete epi and NE
- ANS
9
Q
When during the day are the highest cortisol levels?
A
In the morning, with a subsequent peak around 1300
10
Q
What percent of glucocorticoid activity comes from cortisol?
A
95%
11
Q
What is the signal for the release of CRH?
A
Diurnal patterns, stresses, and emotional stress
12
Q
Where does CRH travel once released from the hypothalamus?
A
Down the hypophyseal portal venous plexus
13
Q
What is the G protein that is activated once CRH reaches the pituitary? What does this cause?
A
Gs
Release of ACTH
14
Q
What is ACTH a breakdown product of? What is the significance of this?
A
POMC
If ACTH levels are high, then melanocyte-stimulating hormone increases as well, which causes the hyperpigmentation of addison’s disease
15
Q
What is the receptor that ACTH binds to? Where is this located, and what does this do?
A
MC2R
Surface of the adrenal cortex causing Gs activation, and cholesterol ester hydrolase
16
Q
What are the enzymes that are activated in the adrenal cortex by ACTH binding? What do these do?
A
Cholesterol ester hydrolase–Elevates the availability of free cholesterol that feeds directly into the steroidogenesis pathways
StAR–increases cholesterol demolase
17
Q
True or false: ACTH is released in a pulsatile fashion
A
True
18
Q
How long does it take cortisol production to begin once ACTH binds?
A
15 minutes
19
Q
How do glucocorticoids exert a negative feedback on the HPA axis?
A
Binding to the glucocorticoid receptor in the cytoplasm of both corticotroph cells in the pituitary and the CRH secreting cells of the hypothalamus
20
Q
What are the intracellular events that occur when Glucocorticoid receptors are bound in the corticotrophs and hypothalamic CRH secreting cells? How fast is this, and what is the significance of this speed?
A
Translocate to the nucleus, where they modulate the expression of genes, and inhibit the synthesis of ACTH and CRH receptor
Slow, so does not account for the rapid feedback inhibition seen
21
Q
What is the mechanism by which cortisol causes fast suppression of ACTH and CRH?
A
Unknown
22
Q
When CRH binds to corticotrophs, is there a release of preformed ACTH, an increase in synthesis of ACTH, or both?
A
Both
23
Q
ACTH causes hypertrophy of the adrenal glands. What is the significance of this?
A
Exogenous glucocorticoids will decrease size, whilst an ACTH secreting tumor will increase in size
24
Q
Draw out the pathway
A
Pathway
25
What is the precursor molecule for all of the steroid hormones?
Cholesterol
26
What are the two source of cholesterol for steroid secreting cells?
LDL (80%)
| De Novo synthesis (20%)
27
What is the first step in steroid synthesis from cholesterol?
Cholesterol desmolase (aka p450scc, or CYP11A1) cleaves cholesterol to pregnenolone
28
What is the protein that facilitates the transport of cholesterol into the mitochondria of steroid producing cells?
StAR protein
29
What is the rate limiting step of steroidogenesis?
Cholesterol cleavage to pregnenolone via cholesterol desmolase
30
Where in the cell does the conversion of pregnenolone to 17 hydroxypregnenolone take place?
sER
31
What is the enzyme that converts 17-OH pregnenolone into 17-OH progesterone?
3beta hydroxysteroid dehydrogenase
32
What is the order of enzymes from cholesterol to the end of each of the synthesis pathways of mineralocorticoids and glucocorticoids? (3)
3beta
21
11
33
What prevents the formation of cortisol and androgens in the zona glomerulosa?
The zona glomerulosa does not contain 17-hydroxylase
34
What is the enzyme that converts corticosterone into aldosterone?
Aldosterone synthase (18 hydroxylase/dehydrogenase)
35
What is the first step of synthesis of androgens, starting with pregnenolone?
17-alpha-hydroxylase converts it to 17 hydroxypregnenolone
36
What happens to 17 hydroxypregnenolone in the zona glomerulosa?
Converted to DHEA by 17-alpha hydroxylase, which is then converted to androstenedione by 17-alpha-hydroxylase 17,20 lyase
37
What is the majority of cortisol in the plasma found as?
Bound to cortisol binding globulin (aka transcortin)
38
What percent of cortisol is bound to cortisol binding globulin? Albumin? Free?
```
CBP = 40-70%
Albumin = 20-50%
Free = 10%
```
39
Where is the glucocorticoid receptor located on target cells? What type of receptor is this?
Nuclear hormone receptor that is free in the cytoplasm in complex with chaperone proteins
40
What happens when cortisol binds its receptor?
binding
causes a conformational change in GRs that allows them to disassociate from the chaperone proteins
and translocate to the nucleus where they homodimerize and bind to promoters or the intragenic
regions of glucocorticoid target genes
41
The genomic effects of GRs can occur within what time frame?
hours
42
What are the four main categories of glucocorticoid effects?
1. Metabolic
2. Anti-inflammatory
3. Immunosuppressive
4. Vascular reactivity
43
Glucocorticoids (cortisol) can increase the rate of gluconeogenesis by 6 to 10-fold by doing what?
```
Increasing the
expression of
gluconeogenic enzymes
in the liver and
liberating amino acids
by causing the
degradation of muscle
and preventing new
protein synthesis
```
44
What is the effect of cortisol in fat cells?
Induces lipolysis
45
What is the effect of cortisol on amino acid and glucose uptake on non-hepatic cells?
Reduces
46
The overall effect of cortisol's reducing non hepatic uptake of glucose and amino acid, and inducing lipolysis is to do what?
Shunt all products to the liver to increase gluconeogenesis and thus BG levels
47
What is the effect of cortisol on liver glycogen synthesis? How?
Increases by increasing expression and activity of hepatic glycogen synthase
48
What is the enzyme that converts testosterone into DHT? What drug inhibits this enzyme?
5-alpha-reductase
Finasteride
49
What is the enzyme that converts testosterone into estrogen? What is the drug that inhibits this enzyme?
Aromatase
Anastrozole
50
What is the main regulated step of glucocorticoid synthesis? What chemical regulates this?
p450scc
ACTH increases the expression of this enzyme
51
What is the order of enzymes that converts cholesterol to cortisol?
17
3beta
21
11
52
How does cortisol get into the cell?
It's lipophilic, therefore it passes through the lipid bilayer
53
What particular part of the 17-alpha-hydroxylase enzyme converts 17 OH-pregnenolone into DHEA/androstenedione?
17-20 lyase
54
What percent of testosterone comes from the adrenal glands in males?
Less than 5%
55
What is the role of the adrenal androgens?
Maintaining normal axillary and pubic hair, as well as some metabolic actions
56
When in a woman's life are the androgens produced by the adrenal cortex particularly important?
Post menopausal
57
What type of G protein is the melanocortin-2-receptor?
Gs
58
What are the two ways in which ACTH increases the production of adrenal products?
Increases the expression/activity of:
- p450ss
- StAR protein
59
What is the effect of cortisol on bones?
Increases resorption
60
How does cortisol decrease inflammation/the immune response? (3)
-decreasing the synthesis and
release of a precursor to prostaglandins and leukotrienes
-decreasing the permeability of capillaries
-decreasing the production of platelet activating factor and nitric oxide
61
How does cortisol regulate BP?
maintaining responsiveness of vascular smooth muscle to the
| catecholamines by increasing alpha receptor
62
What is a major reason to give premature infants cortisol?
Increases lung maturation
63
What is the effect of cortisol on RBC production?
Increases
64
What is the effect of cortisol on appetite?
Increases
65
How does Cushing's syndrome cause DM II?
Chronically increased BG levels, and decreased sensitization of cells to insulin
66
Why is it that giving pressors to a patient with adrenal insufficiency will not cause as large of an increase in BP as a normal pt?
Loss of alpha receptors that are usually maintained by cortisol
67
What is the main mineralocorticoid produced by the body?
Aldosterone
68
What are the cellular effects of aldosterone binding its receptor?
Once the MR is bound and
activated by aldosterone, it stimulates the expression of the amiloride sensitive epithelial sodium channel (ENaC) and the basolateral Na+, K+-ATPase pump
69
What, generally, are the renal effects of aldosterone?
Increase in the reabsorption of Na and water, and secretion of K in the collecting ducts of the kidney tubule
70
MRs and GRs have a high degree of homology. What is the significance of this?
Blood levels of cortisol are at least 100-fold greater than aldosterone. Therefore, if no other factors existed, aldosterone would have little utility, as MRs would be continuously regulated by cortisol
71
MRs and GRs have a high degree of homology, and cortisol has a much, much higher concentration in the blood than aldosterone. How do the aldosterone target cells prevent their regulation by cortisol?
aldosterone target cells express the type 2
isoform of 11β-hydroxysteroid dehydrogenase (11β-HSD2), which converts active cortisol into inactive
cortisone, while not acting on aldosterone
72
What happens to aldosterone regulation with Cushing's?
11β-HSD2 is overwhelmed, causing cortisol to stimulate Mineralocorticoid receptors, leading to increases in BP, Na, water and hypokalemia
73
Aldosterone synthesis and
release from the adrenal
zona glomerulosa is primarily
regulated by what?
angiotensin II (ANG II) and extracellular K+
74
What triggers angiotensin release? What cells release this, and what are its effects?
Decreases in blood volume trigger the juxtaglomerular cells to secrete renin
Renin cleaves angiotensinogen to ANG I
75
What are the steps of the renin-angiotensin system?
Renin released by juxtaglomerular cells cleaves angiotensinogen to ANG I, which is then converted by ACE to ANG II
76
What are the effects of ANG II?
- Induces the synthesis and secretion of aldosterone
| - Causes vasoconstriction
77
What is the half-life and breakdown product of ANG II?
less than 1 min
ANG III (which still maintains some physiological effects)
78
What happens when ANG II binds to AT receptor on the plasma membrane of the adrenal glomerulosa cells? What type of G protein?
Gq, causes the release of aldosterone
79
What is the relative strength of the adrenal androgens (DHEA and androstenedione)?
Weak (i.e., they bind to the androgen receptor with
| a lower affinity than testosterone)
80
What is the major cell type in the adrenal medulla? How are these cells stimulated to release catecholamines?
Chromaffin cells
| Function like ANS--ACh stimulates them to release and synthesize catecholamines
81
What is percent of the adrenal medulla's secretions are epi/NE?
```
Epi = 80%
NE = 20%
```
82
What is the enzyme located in the cytoplasm of chromaffin cells that converts NE to epi? What can increase the expression/activity of this enzyme?
phenylethanolamine-N-methyltransferase (PNMT)
Cortisol increases the expression
83
How is it that cortisol deficiencies can lead to catecholamine deficiencies?
Loss of PMNT expression (converts NE to Epi) if there is no cortisol
84
What happens to epi/NE that leaks out of the secretory vesicles of chromaffin cells?
Continuously metabolized by COMT
85
What are the breakdown products of epi/NE?
Epi - metanephrine
| NE - normetanephrine
86
Do 11-deoxycorticosterone (DOC) and corticosterone have mineralocorticoid activity?
Slightly, but yes
87
How does elevated [K] lead to the secretion of aldosterone?
Depolarizes the glomerulosa cells by increasing Ca levels
88
What causes renin release?
Decrease perfusion of juxtaglomerular cells
89
Where is angiotensinogen found?
Circulating in the plasma
90
Are ACE inhibitors K sparing? Why or why not?
Yes, because blocking of ANG lower aldosterone production, which would normally excrete K in exchange for Na and water
91
What are the peripheral effect of aldosterone?
Prevents Na lost in sweat
| Prevents loss of Na in stools
92
What are the enzymes that activate and deactivate cortisone/cortisol respectively?
11-beta-HSD1 activates
| 11-beta-HSD2 deactivates
93
What are the tissues that have 11-beta-HSD2?
Kidney
Colon
Salivary glands
94
What are the tissues that have 11-beta-HSD1?
Liver
Brain
Lung
Adipose tissue
95
What is "Apparent mineralocorticoid excess" (AME)?
rare genetic mutation causing an inactivation of 11-beta-HSD2
This translates into an apparent mineralocorticoid excess d/t cortisol stimulation of MR receptors
96
What is congenital adrenal hyperplasia
Genetic defect in adrenal steroid biosynthetic enzymes, leading to reduced cortisol levels, and an increase in ACTH
97
What is the half-life of catecholamines?
0.5-2 minutes
98
What happens when catecholamines enter into their target cells?
Metabolized into vanillylmandelic acid (VMA) by MAO and COMT
99
What is the normal proportion of urine catecholamines? (3)
50% metanephrines
35% VMA
10% conjugated catecholamines
100
What is Cushing's disease?
ACTH secreting pituitary tumor
101
How does ACTH increase the synthesis of androgens?
binding to MC2Rs on the adrenal cortex
102
How does Cushing's lead to HTN?
Saturation of 11-beta-HSD2
103
What is the most commonly affected enzyme in the cortisol synthesis pathway? What happens when this enzyme is defective/deficient?
21-hydroxylase
Cholesterol is shunted down the androgen pathway
Low cortisol = increased ACTH secretion
104
What is the effect of 21-hydroxylase deficiency in newborn females?
masculinization of genitalia d/t overproduction of adrenal androgens
105
What happens with 17-alpha-hydroxylase deficiency?
Deficiency in adrenal glucocorticoids and androgens, and an excess in aldosterone. This leads to HTN and hypokalemia
106
What happens with 11-beta-hydroxylase deficiency? How is this different from 21-alpha-hydroxylase deficiency?
Loss of aldosterone and cortisol, but increased adrenal androgen synthesis. However, there is not salt-wasting and low BP d/t the activity of DOC--there is actually HTN
107
What is the usual presentation of 17-alpha-hydroxylase deficiency in males and females?
Ambiguous genitalia in males
| Lack of secondary sex characteristics in females
108
Name the disease:
- High mineralocorticoids
- Low [K]
- Low cortisol
- Low androgens
- HTN
17-alpha-hydroxylase deficiency
109
Name the disease:
- Low mineralocorticoids
- High [K]
- Low cortisol
- High androgens
- Low BP
21-alpha hydroxylase deficiency
110
Increased levels of 17-OH-Progesterone is characteristics of what disease?
21-alpha hydroxylase deficiency
111
Name the disease:
- Low mineralocorticoids
- Low [K]
- Low cortisol
- High androgens
- HTN
- Increased DOC
11-beta-hydroxylase
112
How do you differentiate pituitary hypersecretion of ACTH vs ectopic ACTH production?
Dexamethasone will suppress pituitary ACTH production
113
What is the cofactor for DOPA production of Y-hydroxylase?
THF***
114
What is the enzyme that converts epi into metanephrine, and NE into Normetanephrine?
COMT
115
What is the enzyme that converts NE and epi into Dihydroxymandelic acid, which is then converted to VMA by COMT?
MAO
116
Which has a greater Alpha receptor stimulation: NE or epi?
NE
