Endocrinology (3) - metabolic response to longer term stress Flashcards
thyroxine
axis running from hypo and Ant Pit
3 main axis and entire function
maintain metabolism
thyroid, adrenal cortex and growth H
adrenal gland H location
above kidney and v small
adrenal gland H - medulla
inner (neuronal) part - make catecholamines
produce adrenaline from deamination and modification
has huge BV - heavily vascularised of a.a
adrenal gland H - cortex
outer epithelium - make series of steroids
has 3 region
3 regions of cortex
outer - glomerulosa - produce aldosterone
middle - fascicular - bundle
largest - reticular - network both produce cortisol and androgens
cholesterol
branch and OH group - removed and changed
highly lipophilic - can’t be stored
oestrogen, progesterone, androgens, glucocorticoids and mineralocorticoids, vit D
hypothalamus function
release into small portal vessels
release H-G cortitropic
carried to Pit gland - bind to corticotropes - receptor for CRH = corticotrope release ACTH into blood supply carried to adrenal gland - bind to cortex cells
ACTH function
drives levels of cortisol made - only needed to produce amount of aldosterone and levels of being made
fascicular and reticular layer function for cholesterol and ACTH
more cholesterol brought into call and more released
E. cholesterol desmolase - activated cleaves cholesterol = intermediate
pregnenolone has 17 alpha hydroxylase
used to produce corisol
glomerulosa layer function for ACTH
activates desmolase and release cholesterol into cell
E hydroxylase not active
pushes to produce corticosterone
modification of aldosterone driven by aldosterone synthase which is regulated by angiotensin II
E produced and regulated causes
different steroid H secretion rates
cortisol
small MC effect (U.I) unlike aldosterone
MC
mineralocorticoids
GC
glucocorticoids
artificial - other steroids toles
modify immune system - anti flammatory
modifies - produce cortisone and dexamethasone
cortisone
weak GC and MC effect - strong inflammatory effect
synthetic - dexamethasone
high anti inflammatory effect compared to cortisol as dexamethasone - 0 - GC and 2.0 - MC effect
secretion of CRH - ACTH - cortisol pathway - cortisol released
1- circadian rhythm caused by feedback loop (long/short) - GC increases in morning
2- stress - increase cortisol level
secretion of CRH - ACTH - cortisol pathway - process as hypo responds to stress
release CRH binds to corticotropes in Pit
= POMC - cleaved by PC1 = ACTH - secreted and released to bind to receptors at adrenal cortex - release cortisol
POMC
pro-opiomelanocortin
prehormone
PC1
prohormone convertase 1
ACTH and other parts of POM cursor cuntion
cleaves in different ways = products
e.g. MSH - melanocytes stimulating H
controls for GC secretion
hypo responds to circadian/stress = CRH release to Ant
release ACTH to adrenal gland
release cortisol - -ve feedback
mechanism of andrenocorticoids
the slow release
cortisol carried by transcortin in blood
slow release - cross membrane and binds to receptor - carried into nucleus and bind to transcription factor into areas closes to promoter of specific gene/repressor/enhancer regions
HRE
H response element
GC RE - AGAACAnnnTGTTCT - palindromic - work as dimer
nnn
any nucleotide
RE
restriction enzyme
decrease in free H
cortisol bind to CrP (few hrs) - won’t get high peak (buffering)
stop being broken down
steroid H receptor has 3 functional domain
ligand binding
DNA binding
Ligand dependent transcription activating
1 - ligand binding domain
dependent nuclear translocation signal
chaperone bind to steroid
2 - DNA binding domain
contain2 Zn finger motif
3 - ligand dependent transcription activating domain
recruit transcriptional co-activator
bind to chaperone - masks
steroid binds to ligand binding domain - process
conformational change (CC) - lose chaperone = CC - COOH of ligand binding domain open = nuclear localisation
nuclear localisation occurs - process (1)
complex carried into nucleus with co activator protein - sits over 3 and 1 with receptor binding element = transcription regulating complex for target genes
change in expression of target genes
modification of receptor binding sequence - allows interactions when bind to it
e.g. GC RE
HRE short - function
acting sequences located within promoter/ enhancer of target genes - receptor interact with
receptor activation causes
induce modulation of transcription of specific gene with HRE
made of inverted repeats - specific to gene - acts upon
e.g. oestrogen and GC receptor
specification of system
dependent on receptor expressed by cell and co activator being made in cell
- steroids can go into every single cell type
receptor-binding element is present in all cells
GC - glucocorticoids function
drive catabolism
breakdown molecules and release energy
carbohydrate in metabolic pathway - GC cortisol (corticosterone)
save glucose - decrease its general use
gluconeogenesis in liver - breakdown protein and convert a.a. to glucose
make more glycogen - decrease use
increase blood glucose level - used for tissues needed
excess cortisol - adrenal diabetes - glucose can’t be absorbed
protein in metabolic pathway - GC cortisol (corticosterone)
increase breakdown of protein in liver - gluconeogenesis especially from muscles and collagen in bone and skin
decrease protein content of all tissues
lipids in metabolic pathway - GC cortisol (corticosterone)
increases use for fuel and a.a.
change lipid deposition
lose lipid being laid down in chest and lower neck
GC characteristic
v. potent anti flammatory effects hydro cortisone
increase if modified
decrease in inflammation
stabilises capillary membrane
decrease WBC activity and release lysosomal E and migration
decrease lymphocyte division or lysis
steroids used in disease
e.g. hydrocortisones - skin inflammation
Cushing’s disease
excessive GC - active tumour in hypo/pit/adrenal cortex
tumour in hypo/pit - secondary causes
in adrenal cortex - primary cause
giving high levels of steroid / give tumour
form GC - high blood glucose - can’t reabsorb
in filtration in kidney = increase urination and drinking
if tumour is caused of GC
produce more ACTH - make more androstenedione - androgen
increase in androgen production - precursor virilization
MC - aldosterone secretion
need ACTH but not regulated by it
from glomerulus
angiotensin 2 regulate level
MC-aldosterone - important for regulation NaCl and water reabsorption
increase absorption of EC fluid - increase arterial pressure and release aldosterone - reduce excretion of Na - increase reabsorption in kidney
aldosterone function in reabsorption
regulate NaCl and water reabsorption and loss of K+ - high ECK+
JG cells
juxtaglomerular cells
how aldosterone release is regulated - location
at the kidney - next to glomerulus - cell lining close to JG cells
smooth muscle cell sit around BV going into glomerulus and macular densa cell in walls of DCT of nephron
regulation of aldosterone - Renin-angiotensin system - decrease in BP - process
JG cells detect change - sit around BV - decrease pressure - sensed and get excited
decrease Na+/ increase K+
macular densa cells get excited stimulated JG cell - increase renin cleave angiotensin = angiotensin 1 and cleaved by ACE
= angiotensin 2 = adrenal zona glomerulosa = aldosterone
regulation of aldosterone - inhibitory pathway - ANF
increase in BP
produced by muscle cells in heart - atrium
stretch releases ANF - blocks formation of renin by JG cells
decrease Na+/ water reabsorption and hence BP
ANF
atrial natriuretic factor
ANP
atrial natriuretic peptide
DCT
distal convoluted tubule
regulation of aldosterone - minor direct effect
monitor [Na+] and [K+] in plasma by adrenal gland
Ant. Pit. gland - increase K+/ decrease Na+
release renin = angiotensin 2
direct effect overcome increase in BP = ANP factor
inhibitory = regulation of aldosterone
aldosterone function
has no carrier protein - effects are shorter
drives Na+ and water absorption = loss of K+
relatively slow
regulate metabolism
aldosterone - no carrier causes
produce Na+ channels - got into Apex of DCT cells
= Na+/K+ pump - increase metabolism
aldosterone - relatively slow means
does not make more aquaporin - through transcription pathway
aldosterone - change in metabolism - process
aldosterone diffuse into cell and bind to receptor and carried into nucleus
transcription = new protein and increase mitochondrial activity - metabolism increases
role of CRH/ACTH
AI - Addison’s disease - more antibodies against cells in adrenal cortex
make less GC and MC - survive longer without GC
without MC - can’t regulate EC K+ levels
action potential becoming excitable
resting membrane potential - closer to threshold then drives it into having action potential
failure in production of both corticoids - decrease in aldosterone = decrease in BP
increase EC K+ - excitable cells become more excitable
drive cardia arrhythmia - increase K+ - in EC fluid loss = muscle weakness
decrease in GC
can’t respond to stress - decrease blood system
unnoticeable - until stress - go into Addisonian crisis
increase ACTH lost (more POMc - ACTH precursor formed )
level of ACTH and POMC increases
feedback loop don’t work and try to compensate - CRH will increase as -ve feedback control don’t work - produce by byproduct by cleavage of POMC = MSH
more made - effect skin pigment
-ve loop in aldosterone function depend on 3 parts of body
keep regulated heart, kidney, Pit.
