Dr.Fondel - Adrenal Physiology

Question 1

What is made in the adrenal medulla? Adrenal cortex?

Answer 1

Medulla - Epi and norepi

Cortex - mineralocorticoid, glucocorticoids, androgens

Question 2

How are Epi/norepi made/stored?

Answer 2

it starts with a Tyrosine. From there it is altered many times by various enzymes in order to have an end product of norepi and eventually Epi. One of these enzymes is tyrosine hydroxylase, which if stimulated can upregulate catecholamine (Epi and norepi) synthesis. Also, cortisol can upregulate the conversion of norepi –> Epi. Eventually they are stored in what is called chromaffin granules and eventually secreted.

Question 3

How is the adrenal medulla similar to / different than a sympathetic ganglion?

Answer 3

Similar: Both release norepi
Different: the adrenal gland secretes it directly into the blood stream, while smypathetic ganglions secrete it into a synaptic cleft.

Question 4

Beta adrenergic receptor

Answer 4

Mostly responds to Epi.
Induces gluconeogenesis, glycogenolysis, increased contractility, lipolysis, glucose utilization, heart rate, and arteriolar dilation of active skeletal muscle and smooth muscle surrounding bronchial airways.

Question 5

Alpha adrenergic receptor

Answer 5

Mostly responds to norepi.
Response is gluconeogenesis, glycogenolysis, cardiac contractility, and arteriolar vasoconstriction in visceral organs, renal, cutaneous and genitals.

Question 6

What is cortisol made out of? What is the process?

Answer 6

Made out of our cholesterol, which is from the liver or our diets. There is then a 5 step process: 1) cholesterol is hydrolyzed and transported. To outer mitochondrial membrane 2) Cholesterol is brought inside of mitochondria. 3) Cholesterol is converted into pregmenolone. 4) Pregmenolone is shuttled to the ER where it undergoes enzymatic modifications. 5) Pregmenolone gets shuttled back into mitochondria where it undergoes its final modifications.

Question 7

What is the rate limiting step in cortisol biosynthesis? Where does it occur?

Answer 7

Rate limiting step is the conversion of cholesterol into pregmenolone, which is done by 22, 22 DESMOLASE in order to cleave side group of cholesterol off for the proper pregmenolone sidechain. This occurs in the inner mitochondrial membrane.

Question 8

Where is CPY17 expressed?

Answer 8

Only in zona fisciculata and zona reticularis. This is because CYP17 is used to convert pregmenolone into the precursors for cortisol and androgens.

Question 9

Where does CRH come from? ACTH? What does ACTH do?

Answer 9

CRH comes from the hypothalamus, which causes ACTH secretion from the anterior pituitary and acts on the adrenal cortex. ACTH then causes rapid conversion of pregmenolone from cortisol because it Speeds up The rate-limiting step. This causes the creation of all 3 steroidal hormones: aldosterone, cortisol, and androgen precursors (ACTH actually doesn’t play a major role in aldosterone release but it does for the other two)

Question 10

How exactly does ACTH exert its effects?

Answer 10

Acute - activation of the enzyme responsible for the rate limiting step of conversion into pregmenolone (20,22-desmolase).
Chronic - 1) selectively upregulates enzymes involved in cortisol biosynthesis. Possibly at the expense of other hormones from the adrenal cortex. This is one reason why prolonged stress is bad. 2) Increases the amount of LDL receptors

Question 11

What is CBG and why is it important?

Answer 11

CBG binds to cortisol and allows it to be a mobile reservoir of cortisol in the body. It also extends the half-life of cortisol by not allowing it to be metabolized by the liver.

Question 12

What’s the deal with cortisol vs.. Cortisone?

Answer 12

They are in an equilibrium and can be altered from one to another through the action of 11-HSD. Type 1 is expressed pretty much everywhere and can make cortisone into cortisol and type 2 is expressed only in the kidney and can make cortisol into cortisone.

Question 13

So what exactly does cortisol do Metabolically?

Answer 13

We know it raises blood sugar levels but how?

1) Essentially it. Can break down muscle in order to use the AA’s for the creation Of glucose which is then stored in the liver as glycogen and eventually released into the blood.
2) In adipose tissue, it breaks down triglycerides into FFA and glycerol, which are turned into glucose and stored in the liver. eventually though, prolonged cortisol will increase the appetite and cause fat storage around the trunk, abdomen, and face.
3) Cortisol also inhibits insulin.

Question 14

What else can cortisol do?

Answer 14

1) it can inhibit bone formation and causes bone resorption.
2) inhibits collagen formation in the skin.
3) can act like aldosterone in the kidneys to hold onto Na+.
4) antiinflammatory and immunosuppressive.

Question 15

How does cortisol affect inflammation?

Answer 15

Basically, there are three inflammatory proteins: prostaglandins, thromboxanes, and leukotrienes.

1) They are all made from phosphatidyl choline, which needs phospholipase to convert it. Cortisol inhibits phospholipase so that these inflammatory proteins can’t be made.
2) Additionally, it inhibits the enzyme cyclooxygenase, which makes prostaglandins and thromboxanes.
3) It also inhibits leukotrienes chemotactic abilities.
4) inhibits vasoactive, proteolytic enzymes - inhibits swelling

Question 16

How does cortisol impact immunosupression?

Answer 16

In summary cortisol lowers the amount of T-cells in circulation.

1) cortisol inhibits the role of interleukins so that T cells aren’t made
2) cortisol causes t-cell apoptosis.

Question 17

What is cortisols action in the kidneys and how is it halted?

Answer 17

Cortisol, under certain circumstances, can act like aldosterone in the kidneys in that it will hold onto Na+. This is not always on because we have Type 2 11-HSD to turn cortisol Into cortisone.

Question 18

What would a mutation in the Type 2 11-HSD protein cause?

Answer 18

Hypertension because now nothing will be holding cortisol back from exerting its sodium retention affects on the kidneys.

Question 19

Adrenal cortex disorders - hyper function – Cushing’s syndrome

Answer 19

Excessive production or secretion from the adrenal corte that does not respond to inhibition. Number one cause is hyper secretary ACTH tumors that affects the adrenal cortex secondarily (Cushing’s disease). Another cause is a non-pituitary tumor that causes secretion of ACTH (ectopic ACTH syndrome). You can also have an adrenal cortex tumor in which case you can have hyper secretion in one or all 3 types of steroids.

Question 20

What are the symptoms of cortisol Excess? (Cushing’s DISEASE)

Answer 20

Obesity, hyperglycemia, high BP, truncal fat, facial fat, muscle atrophy, insulin resistance, poor wound healing, susceptibility to infection, easily bruised, osteoporosis, hypogonadism.

Question 21

Symptoms of excess aldosterone?

Answer 21

High BP, hypokalemia.

Question 22

Symptoms of excess androgen precursors?

Answer 22

Only in females –> facial hair, acne, depending of voice, altered menses, increased muscular tone, regression of breast tissue.

Question 23

Adrenal Cortex Disorders - Hypofunction - Addisons

Answer 23

Any loss or deficiency of normal steroid hormone secretion from the adrenal cortex. Most common. Cause is the autoimmune destruction of the adrenal cortex. Major sign is hypo pigmentation in this primary form of addisons.
- other ways to get addisons are HypoACTH secreting tumors or brain tumors that are hypoCRH secreting.

Question 24

Symptoms of Cortisol deficiency?

Answer 24

Weight loss, loss of appetite, fatigue, nausea, vomitting, diarrhea, hypoglycemia, impaired gluconeogenesis, increased insulin sensitivity, HYPERPIGMENTATION.

Question 25

Symptoms of aldosterone deficiency?

Answer 25

Low BP, Hyperkalemia, weight loss, excessive renin production.

Question 26

Symptoms of too little androgens?

Answer 26

Only in females –> reduction in pubic,axillary hair.

Question 27

Why would Addisons cause HYPERPIGMENTATION?

Answer 27

Remember that cortisol causes feedback on CRH and ACTH, so if no cortisol, then more ACTH. ACTH can actually be broken down into MSH (melanocyte secreting hormone).

Question 28

Difference between hydrophobic and hydrophilic hormones

Answer 28

The hydrophobic ones - steroid hormones - are able to traverse the plasma membranes of their target cells and exert direct effects on their receptors which are transcription factors and are found at the promoter or enhancer regions.
The hydrophilic ones - peptide hormones - usually bind to the receptors on the outside portion of the cell are cause downstream affects such as phosphorylation of tyrosine residues or cause the action of secondary messengers.

Question 29

How do steroid hormones Work? Where are their receptors? What do their receptors do?

Answer 29

Essentially steroid hormones are NP and therefore go right through the cell membrane and bind to their receptors, which are called nuclear hormone receptors. These receptors then bind to the hormone response element at the promoter or enhancer region of the DNA and exert their effects there.

Question 30

What does aromatase do?

Answer 30

It converts testosterone into estradiol.

Question 31

How should we treat Cushing’s?

Answer 31

A K+ sparing diuretic in order to lower the BP. ALso give a glucocorticoid receptor antagonist (metheprozone).

Question 32

Embryological origin of adrenal Medulla? Adrenal Cortex?

Answer 32

Medulla - neuroectodermal tissue

Cortex - mesoderm

Question 33

How is cortisol similar to GH and how is it different?

Answer 33

Similar - 1) both raise plasma glucose levels 2) both antagonize he action of insulin
Different - 1) GH cause the buildup of muscle in that it does not allow proteolysis. Cortisol on the other hand causes proteolysis to occur and the AAs are converted into glucose. 2) cortisol cause bone resorption whereas GH causes bone mineralization

Question 34

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

Answer 34

Disease - anterior pituitary ACTH secreting tumor
Syndrome - a pathological condition caused by the excessive secretion of adrenocortical steroid hormones that does not respond to negative feedback.