The glucocorticoids Flashcards
are synthesised in the
Zona fasiculata
all corticosteroids are synthesised from
cholesterol (27 c)
- enzymes work at 20/21 junction
the RLS of corticosteroid synthesis is catalysed by
- sTAR
- contains a C transfer domain (sTAR related transfer domain)
- transport protein that regulates the uptake of cholesterol into the mitochondria
- activity can be increased by ACTH / luteinising hormone (cAMP)
- transported from outer MM to the inner MM
- can enter the mitochondrion which contains P450scc enzymes
The actions of the enzyme P450scc include
- activity increased by ACTH
- 2 hydroxylase reactions produce 20,22 - dihydroxyC
- final stage includes cleavage of bond between 20/22 to yield pregnenolone (21c)
- 27cā- 21c
- precursor for all other steroids
the regulation of P450scc
- requires electrons for function
- works in complex with 2 other proteins (andrenodoxin reductase and adrenodoxin)
- these provide e-
- always active but depends on supply of C
- ACTH up regulates all of these genes that are part of the complex
all steroids will contain how many carbon atoms?
21
the inactive form of cortisol is referred to as
- cortisone
CYP11B1 works by?
converting deoxycortisol to cortisol
cortisol is transported around the blood via?
- hydrophillic
- requires carrier proteins
- 90% bound to transcortin
- 10% to albumin
ACTH binds to which receptor?
- melanocortin 2 receptor
- activates 2nd messenger cascades via cAMP
the effects of cAMP cascades on the adrenal cortex include
- immediate actions, increased C transport into the M
- subsequent, increased gene transcription of hydroxylases
- increased LDLr
long term-
increased size and complexity of organelles (hypertrophy)
- increased number of cells (hyperplasia)
glucocorticoids bind to
- GR
- intracellular nuclear receptors
- dimerise upon binding
- translocate into the nucleus
- bind to GRE present on DNA
- increased protein synthesis
of lipocortin (inhibits PLA2 pathway)- anti-inflammatory - immunosuppression
the main effects of cortisol is to
- increase plasma glucose levels
- inhibits glucose entry into tissues
- increase hepatic glucneogenesis
metabolic effects of cortisol include
- Protein - muscles - increased breakdown of protein - AA > wasting/ growth retardation.
- Liver - increased uptake of AA - protein synthesis/ gluconeogenesis
- Fat - increased mobilization of FA from adipose tissues - more gluconeogenesis/ redistribution from extremities to the central trunk areas
- Cortisol- mobilizes fat and moves it into the central regions- evolution? Response to Long term stress
- Electrolyte balance - large amounts= MC activity
- Bones - reduced absorption of ca, enhanced excretion, inhibition of osteoblasts can lead to osteoporosis
- CNS- mood/cognition
- Immune system - reduce lymphocytes/ eosinophils , increase neutrophils, RBCs and platelets
Anti-inflammatory actions include
- reduced leukocyte action
- anti-allergic - inhibits histamine secretion and synthesis
- immunosuppressive
- anti-allergic medication (cortisol)
- can treat RA
cushings syndrome is characterised by
- XS cortisol levels
cushings disease is caused by
- pituitary tumour of corticotroph cells
- elevated ACTH levels
- negative feedback fails
- hyperplasia of cortex
- ectopic ACTH Producing tumor (lungs)
- autonomous adrenal adenoma
may be iatrogenic
- caused by a dr
- long term immunosuppression with synthetic cortisol analogues
- shrinkage of adrenal gland - decreased ACTH (NEG FEEDBACK)
- taken off these straight away can go into an adrenal crisis
the treatment of cushings syndrome
- surgery
- radiotherapy to target cancer
] - metyrapone (11-Bhydroxyalase inhibitor)
- Inhibits 11-deoxycortisol conversion to cortisol
symptoms of Cushings syndrome include
- central obesity
- thin arms/legs
- trunkal obesity
- mobilisation of fat to central regions
- muscle wastage
- increased bone resorption
- suppression of immune system
- increased risk of infection
- hypertension
- elevated plasma glucose
- suppression of glucose rendition capacity In kidney
primary cause of hypo-adrenal function
- Addisons disease
- 65% - autoimmune disease
secondary cause of hypo-adrenal function
- stopping long term glucocorticoid therapy
- or a disease of the pituitary gland (reduces ACTH)
