Endocrinology- Exam 3- Part 1- Cortisol/Androgens

CRH and ATCH use what mechanism?

Cortisol uses what mechanism of action?

-Adenyl Cyclase Mechanism

-Steroid Hormone Mechanism

ACTH is a ____________ stimulator of the zona glomerulosa.

ACTH is a __________ stimulator of the zona fasciculata.

ACTH is a ___________ stimulator of the zona reticularis.

weak; strong; strong

What enzymes are involved in classical conversion of cholesterol to cortisol? (long card)

1. Cholesterol to pregnolone via cholesterol desmolase

2. pregnalone to 17-a-hydroxy...via 17-alpha hydroxylase

3. 17-a hydroxypregnalone to 17-a hydroxyprogesterone via 3B-HDS

4. 17a-hydroxyprogesterone to 11 deoxycortisol via 21-a/b-hydroxylase

5. 11-deoxycortisol to cortisol via 11 beta-hydroxylase

best way to remember the enzymes involved in the converstion of cholesterol to cortisol (classical)

Chol, Preg, 17- HProg, 17-HPreg, 11-deoxycort, cortisol

CD, 17a, 3B-HDS, 21, 11B

What enzymes are involved in the alternative conversion of cholesterol to cortisol?

1. Cholesterol to pregnenolone via cholesterol desmolase

2. Pregnenolone to progesterone via 3B-HDS

3. Progesterone to 17-hydroxypogesterone via 17-alpha-hydroxylase

4. 17-hydroxypogesterone to 11-deoxycortisol via 21 a/b hydroxylase

5. 11-deoxycortisol to cortisol via 11 beta-hydroxylase

best way to remember enzymes involved in alternative conversion of cholesterol to cortisol

Chol, Preg, Prog, 17-Hydroxyprog, 11-deoxycort, Cortisol

CD, 3B-HDS, 17a, 21, 11B

When is cortisol released the lowest throughout the day?

When is it released in highest amounts?

-lowest= evening hours and right after falling asleep

highest= right before waking up (1/2 of total cortisol released)

How are cortisol levels regulated?

negative feedback

*cortisol has DIRECT to hypothalamus and AP

Long term stress increases the release of what? What does this lead to?

increases release of CRH and ACTH, leading to high cortisol levels

What is the role of the HPA axis and cortisol?

-ensures a quick response to stress

- ensures return to normal state quickly after stress

Cortisol has what effect on the following:

-Bone

-TGs

-Muscle

Bone-> resorption, gets AAs to fuel gluconeogenesis in the liver

TGs->lipolysis and decreased GLUT 4-> releases glycerol for gluconeogenesis and keeps glucose in blood

muscle-> catabolism into AA used in liver for gluconeogenesis

When cortisol increases, what happens to blood glucose levels?

increase

What is the main role of glucocorticoids (cortisol)? TQ

Stimulate gluconeogenesis and storage of glycogen

increased cortisol has what effect on lipolysis?

increases lipolysis

Cortisol has what effect on glucose utilization in tissues?

decreases (closes GLUT-4)

Hypercortisolism would have what effect on blood glucose levels?

What about Hypocortisolism?

-hyperglycemia

-hypoglycemia

Cortisol has what effects on our inflammatory immune response? TQ (3)

1. induces synthesis of lipocortin, which inhibits phospholipase A2 (enzyme needed for inflammatory response)

2. inhibits IL-2, suppressing proliferation of T cells

3. inhibits release of histamine and serotonin from mast cells/platelets

How does hypocortisolism affect blood pressure?

What about hypercortisolism?

hypo- hypotension

-hyper- hypertension

Cortisol has what effect on bone resorption/formation? (3)

-inhibits bone formation by decreasing type 1 collagen

-decreased formation of osteoblasts

-decreased intestinal Ca2+ absorption

What is the short-term affect of cortisol on glomerular filtration rate?

What is the chronic long-term affect?

short term= vasodilation, increases renal blood flow

long term- decrease GFR (bad filtering of blood)

Short term stress produces what type of effect from cortisol response?

Positive!

burst of energy, better memory, decreased pain sensitivity, anti-inflammatory effect

Long-term (chronic) stress can cause what type of effect from cortisol response?

Negative/problematic

-blood glucose imbalance, high BP, lowered immunity and bone density, depression, anxiety etc

When ACTH is released, which two zones are strongly stimulated?

Zona Fasciculata and Zona reticularis

Abnormal response to chronic stress has what affect on cortisol?

adrenal medulla emits catecholamines that signal to the hypothalamus for more ACTH, producing too much cortisol and adrenal androgens

What are the 3 phases of Hans Selye's General Adaptation Syndrome?

Stage 1) body releases stress hormones at first reaction to stress (Alarm reation)

Stage 2) chronic stress endures, the body adapts to ongoing threat and tries to return to normal function. Glucose levels increase and BP increases (Resistance)

Stage 3) Body has run out of reserve of energy and immunity, leading to exhaustion, body organ failure and death. (Exhaustion)

What is adrenal fatigue and what is it commonly mistaken for?

-Adrenal overdrive floods the body with cortisol and cannot keep up with constant demand

-hypothyroidism and depression

How would you test for adrenal fatigue?

Measure cortisol at home with saliva or urine test 4 times over 24 hrs (ex: DUTCH test)

Which enzyme is responsible for conversion of cortisol to cortisone?

11B-hydroxysteroid dehydrogenase type 2

What three metabolites are being measured when testing for adrenal fatigue?

A-THF

B-BTF

THE

conversion of cortisone to cortisol and accelerated metabolite conversion leads to what 5 effects?

-Insulin resistance

-Obesity

-Inflammation

- Decreased TH

-Leptin Resistance (satiety hormone)

Since there is no medical/pharmaceutical method to treat adrenal fatigue, what is recommended as treatment?

Adaptogens that help with HPA axis or help the body cope with stress

Licorice root has what effect with cortisol to cortisone conversion?

promotes conversion of cortisone to cortisol

T/F: Phosphatidylserine reduces cortisol

true

T/F: when free cortisol is low and symptomatic, the best treatment is hydrocortisone or prednisone.

FALSE: these can make the underlying issues worse!

The zona reticularis releases what when stimulated by ACTH?

adrenal androgens

What are the enzymes/pathway for conversion of cholesterol to DHEA? (adrenal androgen)

1. Cholesterol to pregnenolone via cholesterol desmolase

2. pregnenolone to 17a-hydroxypregnalone via 17-alpha-Hydroxylase

3. 17a-hydroxypregnalone to DHEA via 17, 20 lyase

4A. DHEA to androstenediol via 17B-HSD then to testosterone via 3B-HSD

4B. DHEA to androstenedione via 3B-HSD then to testosterone via 17B-HSD or estrogen via aromatase

what are the enzymes/pathway for conversion of cholesterol to androstenedione (adrenal androgen)

1. Cholesterol to pregnenolone via cholesterol desmolase

2. Pregnenolone to progesterone via 3B-HDS

3. Progesterone to 17-a hydroxyprogesterone via 17- a- hydroxylase

4. 17-a hydroxyprogesterone to androstenedione by 17,20 lyase

5. Androstadiene to testosterone via 17B-HSD or estrogen via aromatase

the onset of adrenal androgen production is called ___________ and begins to appear in circulation around age _____.

adrenarche; 6

T/F: Adrenal androgen levels peak in mid-20s and decline with age

TRUE

Androstenedione is converted to estrogen, and testosterone is converted to estradiol via which enzyme?

aromatase

testosterone is converted to dihydrotestosterone (DHT) via which enzyme?

5-alpha-reductase

What enzyme is always involved in the first step when producing adrenal hormones? **

cholesterol desmolase

Which hormone is involved in the production of all 3 hormones; aldosterone, cortisol, adrenal androgens? **

3- beta- hydroxysteroid dehydrogenase (3B-HSD)

What enzymes are only involved in the zona glomerulus and zona fasciculata? **

-21 alpha/beta hydroxylase

-11 beta hydroxylase

what enzyme is only active in the zona fasciculata for cortisol production and the zona reticularis for adrenal androgen production? **

17-alpha-hydroxylase

Which zone is aldosterone synthase present in? **

only in zona glomerulosa (final step of aldosterone production)

A deficiency of 11-Beta Hydroxylase would lead to what? TQ

-both aldosterone and cortisol levels decreased

-androgen production increased, causing virilization in females and early puberty for children

A deficiency of 17 alpha-hydroxylase would lead to what? TQ

-decreased cortisol and androgen production, but increased mineralocorticoids (aldosterone)

-Hypertension and hypokalemia

-decreased adrenal androgen production (lack secondary sex characteristics)

A deficiency of 21 alpha-hydroxylase would lead to what?

-reduced mineralocorticoid (aldosterone) and cortisol production

-salt wasting, increased androgens in females and early puberty in both sexes

T/F: The adrenal medulla is neural tissue with a neuroectodermal origin.

TRUE

What is the precursor for synthesis of catacholemines?

tyrosine

the chemical signal (Ach) is secreted from preganglionic sympathetic neurons and binds to ____________ receptors on ___________ cells of the adrenal medulla. TQ

nicotinic, chromaffin

What effect does Ach binding to nicotinic receptors on chromaffin cells of the adrenal medulla have?

secrete epinephrine (80%) and norepinephrine (20%)

Norepinephrine mainly excites ______ receptors while epinephrine excites both equally.

alpha

T/F: the effects that NE and Epinephrine have on a tissue is dependent on the receptor type (Beta/Alpha).

True

Beta receptors use which mechanism?

Alpha receptors use which mechanism?

-Adenylyl cyclase

-phospholipase C

Stimulation of alpha-adrenergic receptors has what effects?

-vasoconstriction (in gut)

-decreased insulin release

-sweating

-piloerection

-glycogenolysis and gluconeogenesis

-iris dilation

-sphincter contraction

-cardiac contraction

stimulation of beta adrenergic receptors has what effects?

-vasodilation (of heart/lungs/skeletal muscle)

-renin release for sodium reabsorption

- increased glucagon secretion

-inc. cardiac ctx and HR

-smooth muscle rlx in GI

-bronchodilation

Excess aldosterone causes what pathophysiology?

-increased K+ secretion (hypokalemia)

-ECF volume expansion and hypertension

Deficiency of aldosterone causes what pathophysiology?

-decreased K+ secretion (hyperhalemia)

-decreased volume expansion and hypotension

Excess adrenal androgens causes what pathophysiology in females?

- masculinization of females

Deficiency of adrenal androgens causes what pathophysiology in females?

-loss of body hair, decreased libido

Which adrenal pathology occurs from destruction of all 3 zones of the adrenal cortex?

Addison disease (aka primary adrenocortical insufficiency)

During primary adrenocortical insufficiency (Addison's disease) what are the most concerning symptoms?

-loss of cortisol leading to hypoglycemia

-loss of aldosterone, leading to hyperkalemia, acidosis and hypotension

*loss of adrenal androgens is not as concerning but does occur*

What is the primary cause of addison disease?

autoimmunity

A deficiency in cortisol in Addison Disease produces what main symptoms?

-Fatigue

-Muscle weakness

-weight loss

-vomiting

-hyperpigmentation

A deficiency in Aldosterone in Addison Disease produces what main symptoms?

-low BP

-Orthostatic Hypotension **

-craving salty food

A deficiency in adrenal androgens in Addison Disease produces what main symptoms?

loss of libido

Which test determines if cortisol is the problem or not in Addisons Disease vs. thyroid or any other hormone?

ACTH stimulation test

Insufficient CRH or ACTH leading to decreased levels of cortisol released is which adrenal pathology?

secondary adrenocortical insufficiency

What is the main difference between primary and secondary adrenocortical insufficiency (other than location of the problem organ)?

in primary, all three adrenal hormones are affected, whereas in secondary, aldosterone levels are not affected due to ACTH being a weak stimulator of the zona glomerulus

What is the difference in ACTH levels between primary and secondary adrenocortical insufficiency?

What is the difference in aldosterone levels?

What is the difference in hyperpigmentation?

1- ACTH is high, 2 ACTH is low

1 Aldosterone is low, 2 Aldosterone is normal

1 hyperpigmentation present, 2 no hyperpigmentation

What is the difference between Cushing Syndrome and Cushing Disease? TQ

Cushing syndrome- 1* problem (adrenal origin), normal ACTH, high cortisol

Cushing disease- 2* problem (hypothalamus of AP origin), high ACTH, high cortisol

What are the main symptoms of cushing syndrome / cushing disease?

-Hyperglycemia

-central obesity

- round "moon" face

-buffalo hump

-purplish abdominal striae

To decipher between cushing syndrome and cushing disease, what is the key indicator considering their symptoms are the same?

ACTH levels are low in cushing syndrome and high in cushing disease

How do you test for cushing syndrome? weird card, just read through and get idea

Urinary Free cortisol (UFC) at least two times, late night salivary control with at least two measurments, a 1mg overnight DST, or longer low-dose DST (2mg for 48 hrs)

How would you treat cushing syndrome?

ketoconazole or metyrapone (suppresses overproduction of cortisol)

How would you treat cushing disease?

removal of the ACTH tumor

Which pathology is where aldosterone levels are high due to an aldosterone-secreting tumor of the zona glomerulus? (primary*)

Conn Syndrome

What are the symptoms of conn syndrome?

- Na+ reabsorption (inc. ECF volume and high BP)

-K+ secretion (hypokalemia)

-H+ secretion (metabolic alkalosis)

What is the treatment for Conn syndrome?

An aldosterone antagonist ---Spironolactone

*may require surgical removal of aldosterone secreting tumor

What is a rare, benign tumor of the chromaffin tissue of the adrenal medulla?

pheochromocytoma

What is secreted in excess in pheochromocytoma (tumor of adrenal medulla)?

norepinephrine and epinephrine

What is the treatment for pheochromocytoma?

alpha and beta blockers