Adrenal Phys [TRH] Flashcards
What are the 3 zones of the adrenal cortex and what does each synthesize?
- Zona Glomerulosa [outermost]
- synthesizes: mineralcorticoid; aldosterone
- Zona Fasciculata [middle]
- synth= glucocorticoids, cortisol
- Zona Reticularis [innermost]
- synthesizes: androgens; DHEA & androstenedione,
***the 3 zones make up 90% of the adrenal gland [medulla = 10%]
What is the adrenal medulla derived from?
What is its “structure” & what does it secrete?
- derived from neural crest
- it can be thought of as a modified sympathetic ganglion that secretes catecholamines directly into circulation
Corticotropin Releasing H/Factor [CRH]
- where is it made?
- what promotes its release?
- short t1/2 [9 mins]
- synthesized in the hypothalamus
- ant pit corticotrophs have CRFR1 receptor
- GPCR
- proinflammatory cytokines & chronic stress promote release of CRF
When is ectopic produxn of ACTH possible?
in cancer
What is the enzyme required for cholesterol conversion to pregenelone?
What is it a rate limiting step for?
side-chain cleavage enzyme [CYP11A=P450scc]
**made in adrenal cortex
rate limiting in: adrenal steroid synthesis
What R does predominantly ACTH bind?
-where is it?
MC2-R: melanocortin 2 receptor
- located 1’ in adrenal cortex
- also in skin melanocytes
- adipocytes –> where it medi8s stress induced lipolysis via ACTH release
Where is MC1-R 1’ located?
- what does it bind?
- what does ^^ACTH levels do?
- MC1-R is the 1’ MCR in the skin [regulates pigmentation]
- high affinity binding for most MSH isoforms
- ACTH @ high levels will also bind MC1-R
- chronically high ACTH levels can induce skin & gum hyperpigmentation
What does excess POMC cause?
- ^^MSH & ^^ACTH levels
- –> both can stimul8 hyperpigmentation
MC3-R, where is it located?
Where is MC4-R is it located?
What do MC3 & 4 R’s regulate?
MC3-R: in the brain
- knockouts for MC3-R are obese
MC4-R: in CNS [esp. hypothalamus], placenta, & GIT
- 1’ MCR for food intake regulation
- inactivating mutations of MC4-R cause obesity in mice & ppl
**Both MC3&4 R’s in CNS regulate food intake but MC3R also regulates energy homeostasis
Where is MC5R located? What does it do?
MC5R: expressed in adrenals, skin, stomach, lung & spleen
-involved in sebum prodxn
What are the 3 types of adrenocorticoids?
“adrenal cortical steroids”
- glucocorticoids
- mineralocorticoids
- sex steroids, mostly androgens
glucocorticoids…
bind?
do?
are recognized when?
- recognized: early to cause an ^^glu in circulation levels
- CORTISOL: mobilizes AA’s 4m proteins for hepatic GNeo
- cortisol is 1’ active glucocorticoid
- deficiency = hypoglycemia
- CORTISOL: mobilizes AA’s 4m proteins for hepatic GNeo
- bind glucocorticoid R’s [GR]
mineralcorticoids…
are?
do?
bind?
- ALDOSTERONE is main example
- little activity as a glucoC
- promote salt & H20 retention in the kidney
- bind to mineralocorticoid R’s [MR]
Sex steroids, mostly androgens…
are?
bind?
do?
- DHEA [dehydroepiandrosterone], androstenedione, some testosterone
- bind androgen R’s [AR]
- minor role in estrogen synthesis
How does cortisol circulate?
10% circulates as free cortisol
90% bound:
- -60% CBG [aka transcortin]
- -30% w/ albumin
What increases & decreases CBG?
^^^CBG = esrtogens & pregnancy
decreased CBG = ^^^cortisol & liver cirrhosis
What happens after a glucocorticoid [usually cortisol] binds a R?
- R’s are usually cytoplasmic
- Bound H R moves to nucleus –> forms homodimer
- Homodimer acts as transcription factor –> bind to genes w/ glucocorticoid response elements [GRE]
- recruits transcription co-factors
- then inti8s transcription or inhibits it
what is the aldosterone receptor?
NR3C2
nuclear R subfamily 3, grpC, member 2
Where are Mineralocorticoid R’s [MR’s] found?
what does it bind?
- kidney, colon, sweat glands, heart, hippocampus, brown adipose
-
binds: equal affinity for aldosterone & cortisol
- but in some tissues, cortisol will bind and become inactive–/.thus not “working” on mR’s
4 steps of glucocorticoid metabolism
- intracellular active glucocorticoid –> inactive
- via 11 beta hydroxylase type 2 [in K, colon, placenta, fetus, & salivary gland]
- inactive steroid cannot activate MC2R
- inactive steroids converted to active
- via 11 beta hydroxylase type 1 [in liver, adipose, lung, vascular tissue, CNS, & mac’s]
- tissue location of 11BhT1 & 2 defines net result of metabolism
**many synthetic glucoC’s [prednisolone/cortisone etc] are 11-ketosteroids that must be reduced to get biologically active
Where does most of glucoC metabolism occur?
- most happens in the liver
- conjugated cortisol/-sone are soluble & excreted by K’s
- use these to measure adrenal steroid prodxn w/ 24hrU
- other conversion enzymes are in the K, colon, & salivary gl.
which is an active steroid, cortisol or cortisone?
CORTISOL!!!
- in mineralC-responsive tissues [K for ex], convert cortisol to inactive cortisone
how do glucoC’s affect metabolism?
by increasing plasma glucose!!
What are the effects of aldosterone?
aka what does it do?
- stimulates K retention of Na+ & h20
- stimulates Na+ & h20 reabsorption in the colon, salivary glands & sweat glands
- enhances K excretion of K+
- hypersecretion of aldosterone–> HTN
