Adrenal Shit

Question 0

What does cortisol do?

Answer 0

Increases metabolic fuels: blood glucose, amino acids, and fatty acids. Increases catabolic reactions. Has multiple targets on the bone to decrease overall bike mass (less collagen synthesis, less osteoblasts and more osteoclasts). Anti inflammatory actions by blocking Phospholipase A2 and COX1 and 2 enzymes (by increasing the inhibitor Nexin A1). Competes with vitamin D3 to decrease calcium absorption. Also involved in birth. Decreases allergic response. Has neural effects as well.

Question 1

Summery of pathway

Answer 1

Hypothalamus releases CRH which acts on the anterior pituitary cells to release ACTH. ACTH acts on the adrenal cortex causing release of DHEA, aldosterone, and cortisol. These negatively regulate the release of CRH from the hypothalamus and the release of ACTH from the anterior pituitary. Stress leads to the release of epinephrine and norepinephrine from the medulla, which increases the release of ACTH. Angiotensin II increases the release of aldosterone.

Question 2

ACTH regulates cortisol synthesis but not it’s release, why?

Answer 2

Cortisol is a steroid which are membrane permeable. Once it’s synthesized it just goes across the plasma membrane.

Question 3

What is proopiomelanocortin the precursor for?

Answer 3

ACTH (adrenocorticotropic hormone), MSH (melanocyte stimulating hormone), and beta endorphins (opiate-like compounds). Pro= a precursor protein that is cleaved to give a final product. Different proteolytic cleavages occur in different regions of the pituitary.

Question 4

Why is cortisol released in the daytime as oppose to night?

Answer 4

Cortisol is involved in the stress response. Released in the morning cause it leads to increased glucose and can help handle stress throughout the day. Not needed at night.

Question 5

Why is CRH released and what is it’s ultimate effect?

Answer 5

Released in response to stress and works to increase glucose and metabolic fuels.

Question 6

Two system view of stress response

Answer 6

Two overall stress pathways in the body. Sympathetic nervous system mediates the short-term stress response and involves the adrenal medulla to release norepinephrine and epinephrine. The anterior pituitary pathway is involved in stimulating the release of glucocorticoids from the adrenal cortex, mediating the long-term response. This is the outer region of the gland.

Question 7

What does aldosterone do and why is it released?

Answer 7

Affects the kidney to regulate salt metabolism. Stimulated by angiotensin II and renin. Made in the outer most layer of the adrenal cortex (zona glomerulosa). Released in response to low blood pressure, low glomerula filtration rate in the kidney, and low salt content in the distal tubules. Promotes sodium reabsorption in the collecting duct by acting as a transcriptional regulator through binding of the mineralocorticoid receptor.

Question 8

What is DHEA?

Answer 8

Made in the zona reticularis of the adrenal cortex. Has weak androgen activity and is a precursor to testosterone, may be involved in fetal development but it’s functions are generally unknown. Source if testosterone-like compounds in females and would cause masculine features if given to women.

Question 9

What stimulates cholesterol to be converted to the different steroids? What inhibits?

Answer 9

ACTH and angiotensin II stimulate the conversion to pregnenolone which the steroids can be made out of. Aminoglutethimide inhibits this step.

Question 10

Trilostane

Answer 10

Inhibits pregnenolone to progesterone in the mineralocorticoid pathway to aldosterone.

Question 11

Metyrapone

Answer 11

Inhibits corticosterone to aldosterone in mineralocorticoid pathway. Angiotensin II stimulates the conversion. Metyrapone also inhibits the last step in cortisol synthesis in the glucocorticoid pathway.

Question 12

What are the effects of excess cortisol?

Answer 12

Cushing’s syndrome. Endogenous: 1. Pituitary tumor causes too much ACTH to be made resulting in excess cortisol (70% of causes). 2. Tumors of the adrenal cortex causing too much cortisol (30%).

Exogenous (most cases): usually due to giving a patient glucocorticoids to treat asthma and rheumatoid arrthritis and also used as an immune suppressor after organ transplants.

Question 13

How to treat cushing’s

Answer 13

If it’s due to a tumor in the pituitary or adrenal gland then remove it. Limited success in giving drugs that reduce glucocorticoid synthesis (metyrapone, trilostane, and aminoglutemide). These effect the synthetic pathway of cortisol synthesis.

Question 14

What does iantrogenic mean?

Answer 14

Side effect of a prescribed medicine.

Question 15

What are some symptoms of Cushing’s?

Answer 15

Euphoria (could sometimes be depression though), buffalo hump, hypertension, thinning of skin, muscle wasting (thin arms and legs), intracranial hypertension, cataracts, moon face, increased abdominal fat, avascular necrosis of femoral head, easy bruising and poor wound healing (due to suppressed immune system), osteoporosis. Sometimes diabetes can result from high levels of blood glucose exhausting the beta cells.

Question 16

Addison’s disease

Answer 16

Insufficient cortisol, main causes are tuberculosis in undeveloped countries and autoimmune disorders that destroy the adrenal gland in developed countries. These effect both the production of cortisol and aldosterone. Leads to carbohydrate imbalance, fatigue (low blood glucose), low blood pressure due to decreased sensitivity to epinephrine, high blood potassium bc aldosterone can’t be released basically mimicking a potassium sparing diuretic, increased skin pigmentation. Treated by giving cortisol and aldosterone.

Question 17

Congenital adrenogenital syndrome

Answer 17

Disease involving in born error of metabolism in which there is a deficiency in the enzyme beta-21 hydroxylase leading to decreased levels of cortisol and aldosterone (unrelated to Addison’s). Buildup of precursor due to lack of feedback inhibition so ACTH release is constantly stimulated. Precursors are shifted to another synthetic pathway to make DHEA androgens leading to premature masculination in babies. Treat with cortisol and aldosterone.

Question 18

When are glucocorticoids used therapeutically?

Answer 18

Used to reduce acute inflammation. They are applied topically to the skin for inflammatory conditions. Applied to the joints if inflammation of the joints occurs. Often used to treat asthma
and the late phase inflammatory effects by inhalation of aerosol to the lungs. This is nice because its possible to treat the lung tissue selectively and minimize side effects. Similar selection
when treating on the skin. Used before and after organ transplants to suppress immune system to reduce host rejection of foreign tissues. Also used to reduce allergic responses in some
conditions. Also used to treat adrenal insufficiency like Addison’s. Actually impairs wound healing due to the fact that it decreases inflammation.

Question 19

How can one minimize the suppression of the pituitary and adrenal cortex when administering glucocorticoids?

Answer 19

Administer in the morning after normal peak of release.

Question 20

feedback loops of synthesis and secretion of adrenal corticosteroids

Answer 20

Short negative feedback loop: ACTH inhibits release of CRF from hypothalamus.

Long feedback loop: glucocorticoids (cortisol) inhibit release of CRF from hypothalamus and inhibit the release of ACTH from the anterior pituitary. Exogenous glucocorticoids (prednisolone) has same feedback effect. Long feedback loop is more important because it had more of an effect on production of mineralocorticoids.

Question 21

Exogenous mineralocorticoid

Answer 21

Fludrocortisone.

Question 22

How can one test for hypothalamic-pituitary-adrenocortical function: test for adrenal excess (Cushing’s syndrome)

Answer 22

Dexamethasone suppression test. Dexamethasone is a potent glucocorticoid. Administer low dose and test to see if it suppresses ACTH and suppresses cortisol secretion due to long feedback inhibition of the hypothalamus and pituitary. Should suppress in normal patients. If it doesn’t suppress, could hint towards an ectopic source of ACTH or cortisol (adenoma).

Question 23

How can one test for hypothalamic-pituitary-adrenocortical function: test for adrenal insufficiency

Answer 23

1. Administer ACTH: check to see if cortisol increases (it should in normal patients).
2. Metyrapone enhancement test: block synthesis of cortisol in the adrenal cortex with metyrapone. Test for increased ACTH and increase in 11-deoxycortisol (precursor for cortisol) due to decreasing the long feedback inhibition of the hypothalamus and pituitary. If we don’t see an increase then it may indicate deficiency of hypothalamic-pituitary regulation.