Lec 12 Adrenal gland Flashcards
What does the adrenal cortex produce?
- outer zona glomerulosa –> aldosterone
- zona fasciculata –> cortisol
- zona reticularis –> androgens that get converted peripherally to major androgens, testosterone, and DHT
What is the origin of adrenal cortex?
mesoderm
What is the origin of adrenal medulla?
neural crest tissue
What is structure of the fetal adrenal cortex?
- fetal zone –> produces DHEA and DHEA-sulfate [DHEA-S]
What does the zona glomerulosa make?
aldosterone
What does the zona fasciculata make?
cortisol
What does the zona reticularis make?
androgens
What is starting point for all adrenal hormones?
cholesterol
Where does the adrenal vein empty on L and R sides?
right –> into vena cava
left –> into left renal vein
What is the first step in steroid hormone synthesis? enzyme? 2 things that regulate it?
- cholesterol desmolase catalyzes cholesterol –> pregnenolone in the inner mitochondrial membrane
- activated by ACTH
- inhibited by ketoconazole
What 3 reactions are catalyzed by 3B-hydroxysteroid dehydrogenase?
zona glomerulosa: pregnenolone –> progesterone
zona fasciculata: 17-hydroxypregnenolone –> 17-hydroxyprogesterone
zona reticularis: dehydroepiandrosterone [DHEA] –> androstenedione
What is function of StAR [steroidogenic acute regulator protein]?
mediates reaction of cholesterol to pregnenolone; induced by high cAMP after binding of ACTH
What parts of adrenal cotex have 21-hydroxylase activity?
- zona glomerulosa [aldosterone]
- zona fasciuclata [cortisol]
What parts of adrenal cortex have 11B-hydoxylase activity?
- zona glomerulosa [aldosterone]
- zona fasciculata [cortisol]
What parts of adrenal cortex have 17a-hydroxylase activity?
just the zona glomerulosa
What regulates cortisol and androgen secretion from the adrenal gland?
ACTH from pituitary
What regulates aldosterone secretion from zona glomerulosa?
JG apparatus in kidney that produces renin –> angiotensin II stimulates adrenal aldosterone secretion
thus high Na; high K; volume depletion increase aldosterone
Where does ACTH come from?
synthesized from POMC in pituitary
What 3 proteins are created from POMC in anterior pituitary?
- beta-lipoprotein
- ACTH
- melanocyte stimulating hormone [MSH]
What is action of cortisol?
stimulates conversion of AA to glucose = gluconeogenesis lipolysis proteolysis increased BP increased insulin resistance
Is cortisol anabolic or catabolic?
catabolic
What is effect of high levels of cortisol?
- central weight gain
- Na and H2O retention
- suppression of inflammation and immune responses
- inhibition of fibroblasts
- loss of connective tissue
- thin skin
- easy bruising
- impaired wound healing
- growth failure in kids
- decreased Ca absorption
- osteoblast inhibition
- bone loss
When is cortisol highest?
has a circadian rhythm –> highest amount in early AM; lowest in late PM
What are three sources of cholesterol for adrenal steroid hormone synthesis?
- LDL from blood that is internalized
- cholesterol generated de novo in cortex from acetyl CoA
- HDL
What causes the increased pigmentation in Addison’s disease?
ACTH binding to melanocortin-2 receptor
What are some things that stimulate cortisol secretion?
- stress
- circadian rhythm
- inflammatory cytokines
What are the main actions of aldosterone?
- increases Na reabsorption
- excretes K and H
- increased intravascular volume
What stimulates secretion of aldosterone?
- RAAS by high vascular volume or high Na
- increased sympathetic activity
- hyperkalemia
- ACTH = very minor effect
What is path of action of cortisol/aldosterone?
bind receptor –> translocate to nucleus –> bind cofactors and hormone-response elements in promotors of target genes –> enhance transcription
What is the difference hormone-response elements [HREs] of aldosterone vs coritsol?
they are identical
What determines specificity of cortisol vs aldosterone effects since they have such similar structure?
aldosterone receptors [mineralocorticoid receptors = MR] = expressed heavily in kidney
MR-expressing cells in kidney express high levesl of 11-beta-hdroxysteroid-dehydrogenase [11-beta-HSD] so they convert cortisol to cortisone which cannot bind the MR
What adrenal androgens are produces?
- DHEA, DHEA-S, and delta-4-androstenedione
= weak androgens; converted peripherally to more potent androgens
What is effects of high adrenal androgens in males vs females?
males = insignificant b/c have more potent androgens
females: can cause hirsuitism or virilization at high level
What is cushings disease?
ACTH-secreting pituitary adenoma causing overproduction of cortisol
What is cushings syndrome?
syndrome of excess cortisol; can be exogenous or endogenous cause
What are clinical manifestations of cushings syndrome?
- hypertension
- obesity
- moon facies
- truncal obesity
- buffalo hump
- hyperglycemia
- skin changes [thinning/striae]
- osteoporosis
- amenorrhea
- immune suppression
- muscle weakness
- hirsuitism
What are two major classes of cause of cushings disease?
ACTH dependent = include pituitary tumors, ectopic ACTH production
ACTH independent = adrenal cortical neoplasm, exogenous glucocorticoid administration
What are 2 most common sources of ectopic ACTH production?
carcinoid tumors and small cell cancers of lung
What are the four screening tests for cushings syndrome?
- 24 hours urinary free cortisol
- midnight salivary or serum cortisol [should be low]
- dexamethasone suppression test
- CRH stimulation test
What happens to ectopic ACTH in dexamethasone suppression test?
ectopic secretion will not increase with CR b/c pituitary ACTH is suppressed
What does high dose dexamethasone suppression test tell you?
give dexamethasone at bedtime and check AM coritsol the next morning
if its not suppressed –> ectopic ACTH secretion
if its suppressed –> cushings disease [pituitary adenoma]
What does low vs high ACTH with cushings symptoms tell you?
low ACTH = tells you probably adrenal tumor
high ACTH = either cushing disease or other ectopic ACTH secretion
What does CRH stimulation test tell you?
increase in ACTH/cortisol with CRH –> cushing disease [pituitary adenoma]
no increase in ACTH/cortisol with CRH –> ectopic ACTH secretion
What is petrosal vein sampling?
compare levels of ACTH in the petrosal veins vs periphery
if source is pituitary –> higher ACTH in petrosal than periphery
but be bilateral and simultaneous
> 3:1 central: peripheral to establish pituitary source of ACTH
> 2:1 from one side to other to lateralize pituitary tumor
What is treatment for cushings syndrome?
if adrenal tumor: remove
if pituitary tumor: try removal or treat with focused radiation
medical: give ketoconazole [glucocorticoid synthesis inhibitor] or glucocorticoid receptor antagonist [mifepristone]
What is problem with doing adrenalectomy for cushings?
cures cushings but causes addisons
What is problem with radiation therapy for pituitary tumor?
has delayed therapeutic effects and may cause panhypopoituitarism
What is mech of action mifespristone?
glucocorticoid receptor antagonist; to treat cortisol excess
What is mech of action ketoconazole?
inhibits glucocorticoid synthesis
