Adrenal Physiology

Question 1

What hormone is released by the hypothalamus to activate the adrenal axis?

Answer 1

corticotropin releasing hormone (CRH)

Question 2

Where are the cells have have the receptor for CRH (CRHR1)?

Answer 2

anterior pituitary corticotrophs

Question 3

What kind of receptor of the CRFR1?

Answer 3

a Gs GPCR with adenylate cyclase activity

Question 4

What types of mediators will promote release of CRH?

Answer 4

proinflammatory cytokines and chronic stress

Question 5

What is the preprohormone that is synthesized to make ACTH?

Answer 5

pro-opiomelanocortin (POMC)

Question 6

What are the two other products of POMC?

Answer 6

melanostimulating hormone and lipotropin

note that other tissues can further break down ACTH and lipotropin into other types of MSH and some other things

Question 7

What cells synthesize POMC?

Answer 7

the anterior pituitary corticotrophs

Question 8

What receptor does ACTH prefer to bind to? Where?

Answer 8

the melanocortin-2 receptor in adrenal cortical cells

Question 9

What type of receptor is the melanocortin 2 receptor?

Answer 9

Gs-alpha protein, which elevates cAMP to initiate a signal transduction cascade

Question 10

What does ACTH binding to MC2 receptor do?

Answer 10

it rapidly promotes side-chain cleavage enzyme synthesis in the adrenal cortex

Question 11

Why is this side-chain cleavage enzyme so important?

Answer 11

It converts cholesterol to pregnenolone, which is the first and rate-limiting step in all adrenal steroid synthesis

Question 12

What receptor is the primary melanocortin receptor in the skin? What does it regulate?

Answer 12

MC1 receptor

it regulates pigmentation

Question 13

What does MC1-R prefer to bind - ACTH or MSH?

Answer 13

It prefers most MSH isoforms, but ACTH at high levels can also bind to it

Question 14

So what are the two ways that excessive POMC levels can stimulate hyperpigmentaiton?

Answer 14

1. excess POMC will make excess MSH

2. the excess PMC will make ACTH, which can also activate MC1 at high concentrations

Question 15

Where is MC3-R expressed?

Answer 15

the brain

regulates food intake and energy homeostasis

Question 16

Where is MC4-R expressed?

Answer 16

central nervous system (mainly hypothalamus)
GI tract (it’s the primary melanocortin receptor for regulating food intake)
Placenta

Question 17

Where is MC5-R expressed?

Answer 17

adrenals, skin, stomach, lung and spleen

involved in sebum preduction

Question 18

What is the primary active glucocorticoid?

Answer 18

cortisol

Question 19

What do the glucocrticoids do in terms of glucose?

Answer 19

1. mobilizes amino acids from protein for the liver to use i gluconeogenesis
2. so raises blood glucose

Question 20

What receptor does cortisol prefer to bind to?

Answer 20

the glucocorticoid receptor

Question 21

What is the primary mineralocorticoid?

Answer 21

aldosterone

Question 22

What are the three main sex steroids produced in the adrenals?

Answer 22

dehydroepiandrosterone (DHEA)
androstenedione
testosterone

only a very minor site for estrogen synthesis

Question 23

What percentage of cortisol is free in the blood? What binds the bound stuff?

Answer 23

10% circulates free

of the 90% that’s bound, 60% is bound to corticotropin binding globulin (transcortin), and 30% is bound to albumin

Question 24

What is the half life for the glucocorticoids like cortisol?

Answer 24

70-90 minutes (longer than the peptide hormones)

Question 25

What are two situtations where the total cortisol hormone level is varied by the amount of transcorting that's produced?

Answer 25

Transcortin is decreased in liver cirrhosis or elevated cortisol Transcortin is increased in pregnancy and other times of high estrogen

Question 26

The glucocorticoid receptors belong to what receptor family?

Answer 26

the nuclear receptor superfamily

Question 27

What hormone has the highest affinity and potency for the glucocorticoid receptors?

Answer 27

cortisol other glucocorticoids will bind but have less affinity and potency

Question 28

What tissues are the mineralocorticoid receptor located?

Answer 28

kidney, colon, sweat glands, heart, hippocampus, brown adipose

Question 29

The mineralocorticoid receptor has about equal affinity for what two hormones?

Answer 29

aldosterone and cortisol

Question 30

So if it has equal affinity for both, how do tissues make sure to only respond to the aldosterone - like the kidney?

Answer 30

The kidney will have enzymes that inactivate the cortisol (convert to cortisone) such that the aldosterone can act on the MC receptor

Question 31

What enzyme will do intracellular conversion of active glucocorticoid ot inactive steroid?

Answer 31

11 beta hydroxylase type 2

Question 32

WHat enzymes will do intracellular conversion of inactive steroids to active steroids?

Answer 32

11 beta hydroxylase type 1

Question 33

How is it determined whether steroid hormone will be enzymatically activated or inactivated?

Answer 33

the tissue location of 11 beta hydroxylase type 1 and type 2 will define the net result in that particular tissue

Question 34

True or false: most synthetic glucocorticoids are already in the active form and thus do not require any of the hydoxylase activity.

Answer 34

false - many needs to be reduced to their 11beta hydroxy derivatives to attain biological activity

Question 35

Most metabolism of glucocorticoids occurs in what organ?

Answer 35

the liver - will be conjugated to form tetrahydrocortisone and tetrahydrocortisol glucuronid eof sulfate these are then excreted by the kidneys (what we measure in 24 h urine collections)

Question 36

What will happen to urinary nitrogen excretion if glucocorticoids are on board?

Answer 36

increase - because they promote proteolysis to free up AA for gluconeogenesis in the liver so you get muscular atrophy

Question 37

Again, what is the first and rate limiting step in adrenal hormone synthesis?

Answer 37

side chain cleavage hormone converts cholesterol to pregnenolone

Question 38

What is the hydroxylase that promtoes conversion of pregnenolone to the sex hormones? So where in the cortex will this enzyme have the highest activity?

Answer 38

17alpha hydroxylase (or CYP17) highest in the zona reticularis (the inner layer), while the zona glomerulosa (outer layer) has none

Question 39

What is the most common adrenal enzyme deficiency? second most common?

Answer 39

21alpha hydroxylase is the most common 11beta hydoxylase is the second most comon

Question 40

What syndromes do 21 hydroxylase deficiency and 11beta hydrosylase deficiency cause?

Answer 40

congenital adrenal hyperplasia

Question 41

So we use pregnenolong to make progesteron derivatives which are then used to make both cortisol and aldosterone. Which works in thei pathway first - 21 or 11 hydroxylase?

Answer 41

21 works first

Question 42

What does 21 turn the progesterone into?

Answer 42

11-deoxycortisol

Question 43

True or false: 11-deoxycortisol is inactive.

Answer 43

false it does have some mineralocorticoid effects

Question 44

What does the 11 hydroxylase do to the 11 deoxycortisol?

Answer 44

converts it to cortisol

Question 45

So if you have a 21 hydroxylase deficiency, what will the level of cortisol be? aldosterone? sex hormones?

Answer 45

decreased cortisol and decreased aldosterone (can't even get to the 11-deosycortisol) you have an increase in ACTH, enzymes, precurors, and androgen synthesis

Question 46

So what are the symptoms of a 21 hydroxylase deficiency?

Answer 46

virilization and hypotension

Question 47

How about if you have an 11 hydroxylase deiciency - what will the hormone levels be like?

Answer 47

decreased cortisol, corticosteron and aldosteron however, you get increased deoxycorticosteroid and 11 deoxycortisol, which have mineralocorticoid activity!!! increased ACTH and sex hormones as well

Question 48

So what are the symptoms of an 11 hydroxylase defiiency?

Answer 48

virilization and HYPERTENSION (because of the excess mineralocorticoid activity of deoxycorticosterone and 11 doexycortisol

Question 49

True or false: aldosterone feeds back to inhibit the axis like cortisol does?

Answer 49

false

Question 50

Normal ACTH is tonic to aldosterone production, but at high levels it is stimulatory. What else is stimulatory for aldosterone production?

Answer 50

angiotensin II