Hellekant Adrenal Cortex Physiology and Pharm Flashcards
What zone of the adrenal cortex produces aldosterone?
Glomerulosa
What zone of the adrenal cortex produces glucocorticoids?
Fasiculata
What zone of the adrenal cortex produces androgens?
Reticularis
What causes the release of CRH? Where is it released from?
Stress and circadian rhythm cause CRH release from hypothalamus
What promotes the production of aldosterone?
Angiotensin II (due to low BP), high K+, and high levels of ACTH
What is the difference between aldosterone and cortisol in the HPA axis?
Cortisol has a negative feedback; aldosterone does not
What cells does CRH bind? What is the receptor type CRH binds?
Binds Gs receptor on corticotrophs in the anterior pituitary
CRH increases synthesis of what?
Preprohormone POMC - which is cleaved into ACTH and MSH and lipotropin
What is POMC cleaved into?
ACTH, MSH, lipotropin
How do melanocytes in the skin cleave POMC?
Into MSH, but not ACTH
What cells synthesize ACTH?
Corticotrophs
ACTH binds what receptor in adrenal cortical cells?
Melanocortin-2 receptor (MC2R)
What kind of receptor is melanocortin receptor type 2? What binds it?
Gs coupled receptor; ACTH binds it
ACTH binding MC2R promotes what?
Synthesis of side-chain cleavage enzyme (CYP11A) in adrenal cortex
What is the function of the enzyme CYP11A1?
Conversion of cholesterol to pregnenolone
What is the rate limiting step in adrenal steroid synthesis?
CYP11A - p450scc enzyme converting cholesterol to pregnenolone
What receptor can ACTH bind on melanocytes?
Melanocortin 1 receptor
Where in the cell are glucocorticoid receptors found?
Cytosol
Where are mineralocorticoid receptors found?
Kidney, colon, sweat glands, heart, hippocampus, brown adipose
Mineralocorticoid receptor has affinity for what?
Equal affinity for mineralocorticoid and glucocorticoids
How to mineralocorticoid responsive tissues regulate the equal affinity of glucocorticoids and mineralocorticoids for the MR?
Mineralocorticoid responsive tissues (eg kidney) convert cortisol to inactive cortisone so there is no effect from cortisol
What is the inactive form of cortisol?
Cortisone
What is the active form, cortisol or cortisone?
Cortisol
What increases the level of corticotropin binding globulin?
Estrogens and pregnancy
What is the function of 11 beta hydroxylase 2?
Converts active glucocorticoid to inactive steroid (eg cortisol converted to cortisone)
What tissues convert active glucocorticoids to inactive steroids?
Kidney, colon, salivary glands, placenta, fetus
What enzyme can convert inactive steroids to active steroids?
11 beta hydroxylase type 1
What tissues convert inactive steroid to active steroids?
Liver adipose, lung, vascular tissue, CNS, macrophages
What is cushing disease?
Excess ACTH secretion, usually due to pituitary adenoma, resulting in hypercorticolism
What is cushing syndrome?
Iatrogenic or due to primary glandular excess production of cortisol (adrenal tumors); increased cortisol, decreased ACTH
What are the levels of ACTH and cortisol in cushing disease?
Both elevated
What are the levels of ACTH and cortisol in cushing syndrome?
Elevated cortisol, decreased ACTH
17 alpha hydroxylase is important in synthesis of what?
Glucocorticoids and androgens
What region of the adrenal cortex lacks 17 alpha hydroxylase?
Zona glomerulosa; expresses aldosterone synthase instead
What are the hormone level changes seen in congenital 21 hydroxylase def?
Decreased mineralocorticoids and glucocorticoids; elevated androgens; increased ACTH
11 beta hydroxylase deficiency effects the adrenal cortex hormone levels how?
Low aldosterone, but elevated 11-deoxycorticosterone (weak mineralocorticoid), low cortisol, elevated sex hormones
What CAH results in low aldosterone and cortisol, but high BP?
11 beta hydroxylase def; 11-deoxycorticosterone increases BP
What CAH results in low cortisol and androgens, but elevated aldosterone?
17 alpha hydroxylase def
What is Addison disease?
Adrenal insufficiency
What are the symptoms of adrenal insuff?
Fatigue, anorexia, diarrhea, hyperpigmentation
What is tetracosactide?
Synthetic ACTH
What is the short ACTH stimulation test?
Give tetracosactide, measure cortisol one hour later; if increased above normal or 2x, adrenal gland is functioning
When do you do the long ACTH stimulation test?
If the short test reveals cortisol is subnormal
How is the long ACTH stimulation helpful in diagnosis?
Differentiates between primary and secondary adrenal insufficiency
If tetracosactide is administered multiple times, and the cortisol level is measured at 1, 4, 8, and 24 hours and at all time points the cortisol levels are decreased, what is the diagnosis?
Primary adrenal insuff (Addison disease for example)
If tetracosactide is administered multiple times, and the cortisol level is measured at 1, 4, 8, and 24 hours and there is a delayed but normal increase in cortisol, what is the diagnosis?
Secondary corticoadrenal insufficiency
What does high levels of cortisol in the urine confirm?
Hypercortisolism
If late night saliva test reveals increased cortisol, what does this mean?
Hypercortisolism
How can hypercortisolism be tested?
24 hr urine measure of free cortisol; late night salivary cortisol; low dose dexamethasone test
Once hypercortisolism is established, what is the next test?
Plasma ACTH levels are obtained
What is the high dose dexamethasone used for?
High dose dexamethasone suppresses ACTH production by a pituitary adenoma (serum cortisol is lowered) but will not suppress ectopic ACTH
If cortisol is still elevated after a high dose dexamethasone test, what is the cause?
Ectopic ACTH production
What is cushing disease?
Cushing syndrome caused by pituitary tumor secreting ACTH
What can the CRH stimulation test be used for?
Distinguish between pituitary tumors vs ectopic/adrenal tumors
Pituitary tumors are responsive to CRH; ectopic and adrenal show no response
What is the active form? Prednisolone or prednisone?
Prednisolone
What happens when prednisone is the substrate for 11 beta hydroxydehydrogenase?
Prednisone (inactive) is converted to prednisolone (active)
What is fludrocortisone?
Mineralocorticoid
Why do glucocorticoids increase susceptibility to infection?
Lymphocyte levels decrease (T cells > B cells)
What are the hematologic effects of glucocorticoids?
Lymphocytes, basophils, eosinophils decreased, neutrophils increased, erythrocytes increased
What effect do glucocorticoids have on the CNS?
Lowers seizure threshold; behavioral changes
What are the effects of glucocorticoids on the GI system?
Increased gastric acid and pepsin; decrease Ca++ absorption
What is pasireotide? What is it used for?
Somatostatin analog; used for suppression of ACTH
What is cabergoline?
D2 analog
What is mifepristone?
Glucocorticoid receptor antagonist
What is mitotan?
Glucocorticoid receptor antagonist
What enzyme is inhibited by ketoconazole?
Cyp11A1
What is the MOA of etomidate?
Inhibits 11 beta hydroxylase CYP11B1
What is metyrapone?
Inhibits 11 beta hydroxylase CYP11B1 in adrenal gland
Pituitary tumors that secrete ACTH usually express what receptors?
SST and D2
What can mitotane be used for the treatment of?
Adrenal carcinoma
