LM 2.1: Adrenal Physiology

Question 1

what 3 classes of corticosteroid hormones are produced by the adrenal cortex?

Answer 1

1. glucocorticoids
2. mineralocorticoids
3. adrenal androgen precursors

Question 2

what is the function of glucocorticoids and mineralocorticoids?

Answer 2

they act through specific nuclear receptors, regulating aspects of the physiologic stress response as well as blood pressure and electrolyte homeostasis

Question 3

what is the function of adrenal androgen precursors?

Answer 3

they are converted to sex steroids that act via nuclear androgen and estrogen receptors

Question 4

what hormones are produced by the adrenal medulla?

Answer 4

catecholamines

they affect cardiovascular and metabolic processes via G protein-coupled cell-surface receptors

Question 5

where do the cells forming the adrenal cortex originate from?

Answer 5

intermediate mesoderm

the cells derive from the urogenital ridge and have a common embryologic origin with the gonad and the kidney

urogenital ridge –> adrenal-gonadal primordial –> arden-cortical primordial at 8 weeks gestation –> fetal adrenal –> adrenal

Question 6

when does the adrenal cortex form embryologically?

Answer 6

8 weeks gestation

Question 7

when does the adrenal medulla form embryologically?

Answer 7

9 weeks

at this time, the adrenal blastema encapsulates and the adrenal medulla develops when neural crest cells migrate into the adrenal gland

so the adrenal medulla forms at 9 weeks gestation when neural crest cells migrate into the adrenal gland

Question 8

what are the two layers of the adrenal cortex? how do they develop?

Answer 8

the ad­renocortical primordium develops at approximately 8 weeks of gestation and can be differentiated into two distinct layers, the inner fetal zone (FZ) and the outer definitive zone (DZ)

during the second trimester, the FZ enlarges, becomes larger than the fetal kidney, and secretes abundant amounts of dehydroepiandrosterone (DHEA) and dehydroepiandrosterone sulfate (DHEAS) –> concentrations of these hormones abruptly decline postnatally, in parallel with the postnatal involution of the FZ

the neocortex develops over the subsequent years into the adult adrenal gland

the fetal life and up to 12 months of age, two distinct zones are evident, an inner prominent FZ and an outer DZ that differentiates into the adult adrenal gland

after birth, the FZ regresses and the DZ, which contains an inner zona fasciculata (ZF) and an outer zona glomerulosa (ZG), proliferates – the innermost zone, the zona reticularis (ZR), is evident after 2 years of life.

Question 9

what are the functional consequences of the differentiation of the adrenal cortex into distinct zones?

Answer 9

adrenarche is an early sexual maturation stage, at which the inner zone (ZR) thickens, corresponding with increased production of adrenal androgens

clinically, adrenarche becomes apparent at 6 to 8 years of age

Question 10

what is the arterial supply of the adrenal gland?

Answer 10

12 small arteries form the aorta and inferior phrenic, renal and intercostal arteries

these arteries branch to form a subcapsular arteriolar plexus from which radial capillaries penetrate deeper into the cortex

in the ZR, a dense sinusoidal plexus is created, which empties into a central vein

Question 11

what is the venous drainage of the adrenal gland?

Answer 11

in the ZR, a dense sinusoidal plexus is created, which empties into a central vein

the right adrenal vein is short, draining directly into the inferior vena cava, whereas the longer left adrenal vein usually drains into the left renal vein

Question 12

how much of the adrenal gland is the zone glomerulosa vs inner fasiculata vs. zone reticular?

Answer 12

beneath the capsule, the ZG makes up approximately 15% of the cortex –> cells are clustered in spherical nests and are small, with smaller nuclei in comparison with cells in other zones

zona fasciculate makes up 75% of the cortex –> cells are large and lipid-laden and form radial cords within the fibrovascular radial network

innermost zona reticularis is sharply demarcated from both the ZF and the adrenal medulla –> cells there are irregular with little lipid content

Question 13

what are the 3 main types of hormones produced by the adrenal cortex? which zones produces which?

Answer 13

1. mineralocorticoids = aldosterone, deoxycorticosterone (DOC) –> zona glomerulosa
2. glucocorticoids = cortisol, coticosterone –> zona fasiculata
3. sex steroids = androgens –> zona reticularis

catchomalines like epinephrine and NE are produced in the adrenal medulla

Question 14

which hormones control the secretion of hormones form the zona glomerulosa?

Answer 14

mineralocorticoids are secreted from the ZH under the control of angiotensin II, K and a little bit by ACTH

mineralocorticoids are secreted in low concentrations

Question 15

which hormones control the secretion of hormones form the zona fasciculata?

Answer 15

glucocorticoids are secreted in high amounts from the ZF under the influence of ACTH

Question 16

which hormones control the secretion of hormones form the zona reticulata?

Answer 16

DHEA, DHEAS, and androstenedione are the most abundant steroids secreted from the ZR under the control of ACTH

Question 17

what structure are all steroid hormones derived from?

Answer 17

all steroid hormones are derived from the cyclopentanoperhydrophenanthrene structure, that is, three cyclohexane rings and a single cyclopentane ring

Question 18

what is the precurosr for adrenal steroidgenesis?

Answer 18

cholesterol

it is provided principally from the circulation, in the form of LDL

uptake is by specific cell-surface LDL receptors present on adrenal tissue –> LDL is then internalized via receptor-mediated endocytosis, the resulting vesicles fuse with lysozymes, and free cholesterol is produced after hydrolysis

Question 19

which enzymes in the zona glomerulosa are responsible for minerlocorticoid production?

Answer 19

secretion of aldosterone and its intermediary 18-hydroxylated metabolites is restricted to the ZG because of the zone-specific expression of CYP11B2 (aldosterone synthase)

Question 20

which enzymes in the zona fasciculata are responsible for glucocorticoid production?

Answer 20

17α-hydroxylation by CYP17A1 is an essential prerequisite for glucocorticoid synthesis, and the ZG does not express 17α-hydroxylase

Question 21

which enzymes in the zona reticulata are responsible for androgen production?

Answer 21

CYP17A1 also possesses 17,20-lyase activity, which results in production of the C19 adrenal androgens DHEA and androstenedione

Question 22

what is the normal negative feedback regulation of cortisol secretion?

Answer 22

ACTH is secreted from the anterior pituitary under the influence of CRH and arginine vasopressin –> ACTH then goes to the adrenals and stimulates secretion of cortisol

CRH secretion is regulated by an inbuilt circadian rhythm and by addition stressors operating through the hyothalamus

secretion of CRH and ACTH is inhibited by cortisol via negative feedback

Question 23

what is the effect of cortisol on metabolism?

Answer 23

1. increased gluconeogeneisis
2. increased glycogenolysis
3. increased proteolysis
4. increased lipolysis

Question 24

what is the effect of cortisol on the cardiovascular system?

Answer 24

1. increased myocardial contractility
2. increased cardiac output
3. increased catecholamine pressor effect

Question 25

what is the normal negative feedback regulation of aldosterone secretion?

Answer 25

renin is secreted from the juxtaglomerular cells in the kidney dependent on renal arterial blood pressure, B-adrenergic action and prostaglandin levels

renin converts angiotensinogen to angiotensin I which is converted in the lungs to angiotensin II via ACE

angiotensin stimulates adrenal aldosterone synthesis

a low extracellular fraction of K has an important direct inhibitory influence on aldosterone secretion from the adrenal glands – ANP and dopamine inhibit renin release from the kidneys

Question 26

what are the 4 factors that control renal renin release?

Answer 26

1. macula densa, a specialized group of convoluted distal tubular cells that function as chemoreceptors for monitoring the sodium and chloride loads present in the distal tubule
2. juxtaglomerular cells acting as pressure transducers that sense stretch of the afferent arteriolar wall and thus renal perfusion pressure
3. the sympathetic nervous system, which modifies the release of renin, particularly in response to upright posture
4. humoral factors, including potassium, angiotensin II, and atrial natriuretic peptides. Renin release is maximized in conditions of low renal perfusion pressure or low tubular sodium content (e.g., renal artery stenosis, hemorrhage, dehydration). Renin release is suppressed by elevated perfusion pressure at the kidney (e.g., hypertension) and a high-sodium diet. Renin release is increased directly by hypokalemia and decreased by hyperkalemia

Question 27

how does angiotensin II maintain normal BP?

Answer 27

1. increased aldosterone synthesis and secretion from ZG via increased transcription of CYP11B2
2. increased constriction of vascular smooth muscle
3. increased release of NE and E from adrenal medulla
4. increased central sympathetic outflow
5. increased release of vasopressin

Question 28

where are mineralocorticoid receptors located?

Answer 28

highest in the distal nephron, colon and hippocampus

lower levels of mineralocorticoid receptors are found in the rest of the GI tract and heart

Question 29

what binds to mineralocorticoid receptors?

Answer 29

GC and MC bind equally to the mineralocorticoid receptor

specificity of action is provided by the presence of GC inactivation enzyme, 11B-hydroxysteroid dehydrogenase the 2 which prevents GC from interacting with MR

Question 30

what happens if 11B-hydroxysteroid dehydrogenase is deficient of inhibited?

Answer 30

an apparent mineralocorticoid excess state may occur

cortisol will bind avidly to the MR and may induce a mineralocorticoid excess state or apparent mineralocorticoid excess

without 11β-HSD2, cortisol isn’t inactivated into cortisone and it’s free to bind to the MR

Question 31

what are the nonclassic effects of aldosterone?

Answer 31

in nonpeithelial cells, it results in the expression of:
1. several collagen genes

2. genes of tissue growth factors
3. genes mediating inflammation

resultant actions leads to microangiopathy, necrosis, and fibrosis

on non epithelial

Question 32

where does feedback control for plasma cortisol levels occur?

Answer 32

1. pituitary gland
2. hypothalamic corticotropin-releasing center
3. locus coeruleus

Question 33

what is ACTH secretion controlled by?

Answer 33

secretion of ACTH stimulated by:
1. CRH from the hypothalamus

2. vasopressin
3. biological clock
4. stress

inhibition of ACTH secretion by:
1. feedback inhibition by cortisol

Question 34

how is cortisol effected by circadian rhythm?

Answer 34

ACTH, and hence cortisol, is secreted in a pulsatile fashion with a circadian rhythm

levels are highest on wakening and decline throughout the day, reaching nadir values in the evening

Question 35

what are the actions of the mineralocorticoids?

Answer 35

1. regulates ECFV
2. K+ metabolism
3. rebaosprfton of Na+ in exchange for K+

Question 36

what are the actions of the glucocorticoids?

Answer 36

1. intermediary metabolism –> regulation of carbohydrate, protein, lipid and nucleic acid metabolism; increased blood glucose, protein breakdown, nitrogen excretion and FA mobilization
2. skin, muscle and connective tissue
3. bone/calcium metablism –> inhibits osteoblast function, induces osteocyte apoptosis, negative calcium balance
4. anti-inflammatory effects
5. protects organism under stress
6. regulates ECFV
7. weak mineralocorticoid-like properties
8. influences behavior and emotion
9. growth/development
10. endocrine effects

Question 37

what is the action of androgens?

Answer 37

1. regulates male secondary sexual characteristics
2. can cause virilizing symptoms in women
3. regulated by CTH, not by gonadotropins

Question 38

what are the consequences of glucocorticoid excess?

Answer 38

1. depression/psychosis
2. decreased LH, FSH, TSH and GH secretion
3. glaucoma
4. peptic ulcers
5. increased hepatic glycogen deposition, peripheral insulin resistance, gluconeogenesis, and free fatty acid production; overall diabetogenic effect
6. salt and water retention
7. HTN
8. promotes visceral obesity
9. decreased bone formation and bone mass; osteoporosis
10. protein catabolism/collagen breakdown; skin thinning
11. anti-inflammatory action; immunosuppression
12. decreased growth

Question 39

what happens to the adrenal medulla in response to cortisol?

Answer 39

chromatin cells differentiate in the center of the adrenal gland in response to cortisol

Question 40

what is the innervation of the adrenal medulla?

Answer 40

axons from lower thoracic and lumbar preganglionic neurons, via splanchnic nerves, directly innervate the cells of adrenal medulla

Question 41

what is stored in the adrenal medulla?

Answer 41

dpinephrine is synthesized and stored in adrenal medulla

norepinephrine is synthesized and stored both in adrenal medulla and in peripheral sympathetic nerves

Question 42

where are catecholamines synthesized and stored?

Answer 42

catecholamines are synthesized from tyrosine by a process of hydroxylation and decarboxylation

tyrosine is derived from ingested food or synthesized from phenylalanine in the liver, and it enters neurons and chromaffin cells of the adrenal medulla by active transport

tyrosine is converted to 3,4-dihydroxyphenylalanine (dopa) by tyrosine hydroxylase, the rate-limiting step in catecholamine synthesis

aromatic l -amino acid decarboxylase (AADC) converts dopa to dopamine. Dopamine is hydroxylated to norepinephrine by dopamine β-hydroxylase (DBH)

norepinephrine is converted to epinephrine by phenylethanolamineN -methyltransferase (PNMT). Cortisol serves as a cofactor for PNMT, which explains why epinephrine-secreting neoplasms are almost exclusively localized to the adrenal medulla

Question 43

how are catecholamines metabolized?

Answer 43

metabolism of catecholamines occurs through two enzymatic pathways. Catechol- O -methyltransferase (COMT) converts epinephrine to metanephrine and converts norepinephrine to normetanephrine through meta- O -methylation

metanephrine and normetanephrine are oxidized by monoamine oxidase (MAO) to vanillylmandelic acid (VMA) by oxidative deamination. MAO also may oxidize epinephrine and norepinephrine to dihydroxymandelic acid, which is then converted by COMT to VMA

dopamine is also metabolized by MAO and COMT to the final metabolite, homovanillic acid (HVA)

Question 44

what is the enzyme that catalyzes the first and rate-limiting step in the biosynthesis of all steroid hormones?

Answer 44

cholesterol side chain cleavage

enzymatic reaction catalyzed by CYP11A. CYP11A catalyzes three sequential oxidation reactions followed by cleavage of the six carbon side chains. Each oxidation reaction requires one molecule of oxygen and one molecule of NADPH and uses the mitochondrial electron transfer system.

Question 45

what combination of factors increases aldosterone synthesis and secretion?

A. hypernatremia and hypokalemia

B. decreased renal perfusion and elevated ANP

C. decreased ACTH and hyperkalemia

D. hypervolemia and elevated catecholamines

E. hypovolemia and elevated angiotensin II

Answer 45

hypovolemia and elevated angiotensin II

Question 46

epinephrine is synthesized and stored in adrenal medulla while norepinephrine is synthesized and stored both in adrenal medulla and in peripheral sympathetic nerves. This is because which enzyme is expressed only in adrenal medulla?

Answer 46

phenylethanolamine n-methyltransferase

norepinephrine is converted to epinephrine by phenylethanolamineN -methyltransferase (PNMT)