"Medical Physiology Adrenal Gland Huaiyu Hu" 3/20

Question 1

The adrenal cortex is derived from what embryologic tissue?

Answer 1

The adrenal cortex is derived from mesoderm.

The adrenal medulla is derived from neural crest cells.

Question 2

T/F: The total loss of the adrenal cortex is fatal within 4-14 days, whereas the total loss of the adrenal medulla is not.

Answer 2

True

Question 3

What is the common precursor of adrenal cortical hormones?

Answer 3

Cholesterol, LDL

Question 4

What is the rate-limiting step in adrenal cortical hormone pathways?

Answer 4

The rate limiting step to forming androgens, testosterone (not part of adrenal repertoire), cortisol and aldosterone is a shared step from cholesterol –> pregnenolone

This step occurs in the mitochondria, and is catalyzed by 20,22 desmolase, aka “side chain cleavage enzyme”

Question 5

What family do most adrenal cortical hormone-synthesizing enzymes belong to?

Answer 5

Except for cytosolic 3-beta-hydroxysteroid dehydrogenase, all enzymes belong to the cytochrome P-450 oxidase family.

Question 6

Why is the rate of secretion of aldosterone by the adrenal gland limited by the rate at which the glomerulosa cells can synthesize the hormone?

Answer 6

Because there is no amount of preformed aldosterone ready for secretion

Question 7

Why does the glomerulosa layer lack the ability to synthesize cortisol or androgens, even though all synthesis pathways of adreno-corticohormones are related?

Answer 7

The zona glomerulose lacks the enzyme to make androgens/cortisol, which is 17-alpha-hydroxylase.

Question 8

What is the function of aldosterone?

Answer 8

The main action of aldosterone is stimulating the kidney (distal tubule) to increase Na (Cl) absorption. It does this by increasing protein transcription to put in more apical Na channels, and Na/K pump. A side effect of this is K secretion.

Aldosterone has similar effects in the colon, salivary and sweat glands.

Question 9

Cortisol inhibits transcription of what gene?

Answer 9

POMC

Question 10

How is cortisol transported in the plasma?

Answer 10

90% of cortisol is bound to CBP (cortisol binding protein or transcortin)
7% is bound to albumin
3% is free, and it is this cortisol that can diffuse into a cell and affect transcription.

Question 11

What is the precursor to testosterone that is made in the adrenal cortex (zona fasciculata and reticularis)?

Answer 11

Androstenedione, which is converted to testosterone in peripheral tissues such as skin and fat.

DHEA is also a precursor to testosterone, but not directly. It has a peak in 20’s and declines throughout life. It is thought to be important in maintenance of sex drive in postmenopausal females.

Question 12

What are the two negative feedback targets of cortisol?

Answer 12

1. In the AP, cortisol inhibits expression of POMC gene and inhibits release of premade ACTH.
2. In the hypothalamus, cortisol decreases mRNA and peptide levels of CRH and inhibits release of premade CRH.

Question 13

What are the major metabolic effects of cortisol?

Answer 13

Cortisol:

1. stimulates gluconeogenesis in the liver
2. Enhances protein breakdown in muscle cells to provide aa’s for gluconeogenesis
3. Stimulates lipolysis in adipose tissue
4. Decreases osteoblastic activity in trabecular bone
5. Interferes with Ca absorption in gut

Question 14

What are the major anti-inflammatory effects of cortisol?

Answer 14

Cortisol:

1. Inhibits cytokine production (inhibits cyclooxygenase activity and histamine release)
2. Inhibits production of chemo-attractant molecules
3. Stabilizes lysosomal enzymes
4. Contributes to vasoconstriction and decreased capillary permeability

Also, in the are of immunosuppression, cortisol:

1. decreases lymphocyte proliferation
2. inhibits hypersensitivity reactions, esp cell-mediated ones

Question 15

T/F: Cortisol blocks glucose uptake except in the brain.

Answer 15

True. The brain has a diff glucose transporter than cortisol has no effect on.

Question 16

What is the most potent mineralcorticoid?

Answer 16

Aldosterone

Question 17

What is the most potent exogenous glucocorticoid?

Answer 17

Dexamethasone

Question 18

T/F: Cortisol is an equal mineralcorticoid and glucocorticoid.

Answer 18

True

Question 19

What kind of receptor does ACTH use in the adrenal cortex?

Answer 19

Melanocortin-2 receptor.

ACTH stimulates all kinds of enzyme synthesis and is also a trophic factor for adrenal cortex survival (is needed for cortex cells to proliferate). Notably, ACTH increases P450 activity and stimulates the rate limited step in cortisol synthesis.

Question 20

What is the difference between ACTH and cortisol?

Answer 20

ACTH is a peptide, whereas cortisol is a steroid.

CRH causes secretion of ACTH by the AP (GPCR pathway), and ACTH acts on the adrenal cortex to stimulate cortisol synthesis (cholesterol –> pregenolone).

Question 21

Why does excessive licorice intake cause hypertension and kypokalemia?

Answer 21

Licorice contains “Glycyrrhetic acid,” an inhibitor of 11-beta-hydroxysteroid dehydrogenase type II.
This enzyme typically converts cortisol to cortisone in the kidney.
Cortisol, but not cortisone, can bind with equal affinity to aldosterone receptors as aldosterone. If there is too much cortisol, there is falsely high aldosterone activity, wasting of K and too much retention of salt and water.

Question 22

What is POMC?

Answer 22

POMC, pro-opiomelanocortin, is a pre-peptide that ca form many different peptide hormones in the corticotrophs of the AP. Notably, POMC becomes ACTH and beta-lipotropin.

During fetal development, POMC becomes alpha MSH and beta-endorphin.

Question 23

When is cortisol highest in the blood, and what effect does this have?

Answer 23

Cortisol is highest in the blood in the early morning, owing to the diurnal variation of cortisol release. Cortisol stimulates gluconeogenesis which is why many people feel more alert in the morning (more brain food). Cortisol also increases appetite by inhibiting the anorexigenic center in the brain and stimulating nueropeptide Y.
Rhythmic secretion of ACTH influences cortisol production.

Question 24

What is the effect of hypoglycemia on cortisol?

Answer 24

Stresses, including hypoglycemia, influence CRH secretion, enhanced ACTH secretion and cortisol synthesis. The result is increased blood glucose levels.

Question 25

What is the effect of 21-alpha-hydroxylase deficiency?

Answer 25

21-alpha-hydroxylase deficiency, also called congenital adrenal hyperplasia, is a genetic mutation that causes decreased production of cortisol and aldosterone.

As a result, ACTH is increased, and causes adrenal hyperplasia, and these hormone precursors are instead shunted to produce androgens, which causes ambiguous genitalia in females. Other symptoms include hypotension due to salt loss, hypoglycemia and dehydration.

Prednisone can be used as a cortisol substitute to reduce ACTH levels.

Question 26

How would you treat 17-alpha-hydroxylase deficiency?

Answer 26

17-alpha-hydroxylase deficiency is a genetic mutation that causes decreased production of cortisol and androgen synthesis bc this enzyme is common to all pathways but aldosterone.

Symptoms include increased ACTH, adrenal hyperplasia, hypokalemia and hypertension (because hormone precursors are shunted to aldosterone), pseudohermaphrodism/sexual infantilism in males.

Treatment includes glucocorticoidreplacement, plus estrogen for females. Males also benefit from testosterone and possibly surgery

Question 27

What is the difference between Cushing’s syndrome and Cushing’s disease?

Answer 27

Cushing’ syndrome is any etiology that causes hypercortisolism or hyperadrenocorticism. Symptoms include change in body fat distrbution, weight gain, osteopenia, muscle wasting and weakness, Skin thinning, glucose intolerance, hypokalemia and hypertension, increased length/severity of infections.

Cushing’s Disease is an ACTH producing tumor or adrenal adenoma. Treat with surgery and prednisolone

Question 28

Can dexamethasone feedback to inhibit cortisol synthesis?

Answer 28

Yes, bc it is an analog.

This is the dexamethasone suppresion test, which can distinguish between Cushing’s syndrome and Cushing’s disease. If dexamethasone is admin to a Cushing’s syndrome patient, their cortisol remains high, but ACTH will drop due to feedback inhibition.

Question 29

What is the defect in Addison’s Disease?

Answer 29

Addison’s is caused by an autoimmune attack on cells containing 21-hydroxylase, or TB infection.

The effect is lack of aldosterone, causing hypotension and hyperkalemia. The second effect is lack of cortisol, which causes weakness, weight loss, poor stress tolerance, and hypoglycemia. The third effect caused by ACTH increase is hyperpigmentation of the skin and mucous membranes.

When synthetic ACTH is given to these patients, there is no corresponding rise in cortisol levels.

Treat with cortisol and sometimes fludrocortisone (tp replace aldosterone).