Adrenal Physiology

Question 1

How do the adrenal glands develop?

Answer 1

begins to develop around week 6.
the inside medulla develops from neural crest cells
the cortex from mesothelium adjacent to dorsal mesentery? I think they come from primary germ cells that migrate from the hindgut. Until the late fetal period, there aren’t different layers to the cortex- it’s just fetal cortex

Question 2

What does the fetal adrenal cortex do?

Answer 2

produce huge amounts of DHEA-S, an androgen precursor

Question 3

What are the layers of the adrenal cortex?

Answer 3

zona glomerulosa, fasiculata, reticularis

Question 4

What does each layer of the adrenal cortex make? What are the regulatory signals for each layer of the adrenal cortex?

Answer 4

glomerulosa: “salt.” makes aldosterone. regulated by angiotensin II
zona fasiculata: “sugar” makes cortisol. regulated by ACTH
zona reticularis: “sex” makes DHEA and androstenedione. also regulated by ACTH

Question 5

What are the biochemical highlights in the synthesis of aldosterone?

Answer 5

cholesterol is converted to pregnenolone (regulated by StAR)
pregnenolone goes to progesterone by 3 beta HSD (enzyme not that important)
progesterone converted by 21 HYDROXYLASE
other enzymes: 11B2 hydroxylase and 11B2 oxidase.
final product: Aldo

Question 6

What are the biochemical highlights in cortisol synthesis?

Answer 6

cholesterol is converted to pregnenolone (regulated by StAR)
pregnenolone is converted, either directly or indirectly, to 17-OH preg or 17-OH progesterone by Cyp 17 hydroxylase.
(basically cholesterol to pregnenolone by StAR to eventually 17 OH progesterone)
17-OH progesterone is converted by an enzyme called 21 HYDROXYLASE (to 11-deoxycortisol). 11B1 HYDROXYLASE is responsible for the final conversion to cortisol

Question 7

What are the biochemical highlights in androstenedione synthesis?

Answer 7

cholesterol to pregnenolone (regulated by StAR)
pregnenolone to 17-oH pregnenolone
(or preg to progesterone to 17OH progesterone).
Cyp17 lyase with B5 cofactor converts 17 OH pregnenolone to DHEA and 17-OH progesterone to androstenedione.
DHEA can be converted to androstenedione (3 beta HSD)

Question 8

How is cortisol biosynthesis regulated in the short-term?

Answer 8

in seconds-minutes, StAR is responsible regulating the conversion of cholesterol to pregnenolone. It provides cholesterol to the inner mitochondrial membrane- a site of side chain cleavage
it is the rate-limiting step

Question 9

How is cortisol biosynthesis regulated in the long term?

Answer 9

ACTH induces and maintains transcription of all the steroidogenic genes

Question 10

What does aldosterone do?

Answer 10

acts on distal tubules and collecting ducts
increases water and sodium resorption
causes secretion/loss of potassium
at normal physiologic levels has no role in acid base. At very high levels causes proton secretion and alkalosis
also has similar effects in colon, salivary glands, and sweat glands

Question 11

How is aldosterone regulated (details)? Where is ACE found?

Answer 11

decreased renal blood flow causes renin secretion by the juxtoglomerular apparatus
renin activates angiotensin I
ACE converts angiotensin I to angitogensin 2
ACE is found in lung
Angiotensin II promotes aldosterone secretion by the adrenals. aldo increases blood Na, decreases K, and increases blood volume to raise BP

Question 12

Why does the zona fasciculata preferentially make cortisol?

Answer 12

this zone has the cyp17 hydroxylase enzyme, which rapidly converts pregenolone and progesterone to 17-OH preg and 17-OH-prog, respectivly. this promotes the cortisol rather than the aldo pathway.

Question 13

Why does the zona reticularis preferentially make sex steroids?

Answer 13

like the zona fasculata, the zona reticularis has cyp 17, to bring preg and progesterone to 17-OH preg and 17-OH progesterone.
Uniquely, it also has B5 cofactor. this helps cyp 17 to act as cyp17 lyase, which converts 17 OH preg to DHEA and 17OH pros to androstenedione

Question 14

what are the main sex hormones made by the zona reticularis and what is there role

Answer 14

DHEA and DHEA-s&raquo_space; androstenedione

they can all serve as a substrate for testosterone made in other cells?

Question 15

Basic facts about regulation of the HPA axis, top to bottom. What influences the top?

Answer 15

CRH is the principal ACTH secretogogue
some pacemaker generates a circadian rhythm for HPA axis
stress increases CRH, ACTH, and cortisol secretion
glucocorticoids exert negative feedback
arginine vasopressin/ADH acts synergistically with CRH at pituitary corticotroph cells

Question 16

What should I know about changes temporal changes in ACTH secretion? Implications for testing?

Answer 16

it is diurnal and depends on light. cortisol is highest when you first get up. If you think a person has too much cortisol, test it at night
If you think they don’t have enough, test it in the morning (peak level)

Question 17

How do glucocorticoids exert their effects, biochemically?

Answer 17

cortisol circulates loosely bound to a binding globulin
only free molecule can enter cells
cortisol enders and binds the glucocorticoid receptor
GR-cortisol is translocated to the nucleus to regulate gene expression

Question 18

How do mineralocorticoids exert their effects, biochemically?

Answer 18

the mineralocorticoid receptor recognizes cortisol and alodsterone with equal affinity
alodsterone target tissues cotain an enzyme that inactivates cortisol by converting it to cortisone and allows aldo exclusive access to mineralocorticoid receptor.

Question 19

What does cortisol do? 7 effects

Answer 19

1. incr. lipolysis in fat cells
2. incr glycogen and gluconeogenesis in liver
3. mobilizes gluconeogenesis aas in skeletal muscle
4. decr. REM sleep and impact mood in brain
5. decre. bone formation and wound healing
6. promote lung development and renal medullary differentiation during development
7. Immunosuppression via redistribution/demargination of leukocytes

Question 20

How is cortisol inactivated?

Answer 20

it is turned into cortisone

Question 21

What is the histology of the adrenal medulla?

Answer 21

columna cells clustered around venules

Question 22

What does the adrenal medulla make? What does it express?

Answer 22

expreses PNMT, which converts NE to epinephrine
makes NE and epinephrine
epinephrine&raquo_space; NE

Question 23

How is the adrenal medulla regulated?

Answer 23

preformed catecholamines are stored in secretory granules. stress results in an ACh signal to the medulla from preganglionic sympathetic fiberse that synapse on the chromaffin cells of the medulla

Question 24

How is catecholamine activity stopped?

Answer 24

1. desensitazation of target cells by down regulation of receptors
2. reuptake by presynaptic terminals- though not really for circulating catecholamines
3. metabolism by MAO and COMT in adrenals and perphery to yield metanephrines