Lecture 25: Adrenocorticosteroids Flashcards
What are secretions of the medulla?
adrenaline
catecholamine/amino acid hormone
What are secretions of the cortex?
zona glomerulosa
zona fasciculata
zona reticularis
steroid hormones
What are mineralocorticoids?
salt balance
aldosterone
zona glomerulosa
What are glucocorticoids?
metabolic and immune effects
cortisol
zona fasciculata
What are androgens?
DHEA
Precursors for strong androgens (testosterone) and estrogens
zona reticularis
What are the “HPA” axis and steroidogenesis?
“HPA” axis controls cortisol release from the zona fasciculata
ACTH (pituitary) stimulates steroid production: after meals, circadian rhythm (high just before waking)
ACTH is controlled by CRH from the hypothalamus
steroid hormones cannot be stored like peptides; ACTH stimulates cortisol synthesis
What is negative feedback in the HPA xis?
cortisol exerts negative feedback on: CRH (hypothalamus)and ACTH (ant. pituitary)
cortisol suppresses stress signals like cytokines involved in the stress response (“other regulatory signals”)
cortisol acts on glucocorticoid target tissues – stress response, catabolism and immuno-suppression - “glucocorticoid response”
What is the RAAS system in aldosterone release?
RAAS: renin - angiotensin - aldosterone system
renin: released by the juxtaglomerular apparatus (kidney; generates AT1 from angiotensin
ACE (angiotensin converting enzyme) converts AT1 to AT2
AT2 triggers aldosterone release
aldosterone: primary target is kidneys, promotes Na+/water reabsorption, K+ excretion “mineralocorticoid response”
the primary role of RAAS is control of blood pressure/volume
What is the generalized mechanism of steroid hormone action?
cytoplasmic unliganded receptor in complex with Hsp90
binding of hormone causes dissociation from Hsp, transport into nucleus
dimerized receptors, interact with DNA and influence transcription of target genes
GRE - Glucocorticoid receptor / response element
What are the receptors for corticosteroids?
glucocorticoid receptor (stimulates GC response)
mineralocorticoid receptor (stimulates a MC response)
“spectrum”: steroids have different affinities for either receptor
each receptor activates/represses transcription of different sets of genes (and unique target tissues)
What are mechanisms for in vivo specificity?
many glucocorticoid target tissues (adipose, muscle, liver) express 11beta-hydroxysteroid dehydrogenase, type 1, “activates” cortisol
corticosteroid specificity arises from affinity of the compound/receptor, and metabolism in target tissues
What is prednisone?
not very effective topically
widely used (oral intake, injection)
must be metabolized to prednisolone to become effective
What is prednisolone?
strong topical effect
active form of prednisone
Cortisol activates the GR and MR but was weak mineralocorticoid effects in vivo. Why?
kidney cells (mineralocorticoid targets), express an enzyme (11beta-hydroxysteroid dehydrogenase, type 2) that renders cortisol inactive
What is pseudohyperaldosteronism?
licorice contains an inhibitor of 11beta-hydroxysteroid dehydrogenase, type 2
this allows glucocorticoids to have an inappropriate effect in aldosterone target tissues like the kidney
a “licorice overdose” can cause high blood pressure (due to aldosterone-like effects including Na+ and water reabsorption
genetic disease called Apparent Mineralocorticoid Excess, arising from mutations in the 11beta-hydroxysteroid dehydrogenase, type 2 gene
What are the short term/acute metabolic effects of glucocorticoids?
carbohydrate metabolism –> increases circulating glucose
fat/lipid balance –> promotes fat breakdown
muscle –> promotes breakdown of muscle, overall “catabolic” effects, loss of muscle and bone mass in limbs
inhibit action of insulin (inhibits glucose uptake in muscle, adipose)
What are the long term/prolonged effects of glucocorticoids?
features include enhanced fat deposition (especially in the trunk)
characteristic physical appearance of adipose accumulation in the trunk, but loss of mass in limbs
likely partly due to increased insulin levels in response to elevated glucose caused by corticosteroid
also potential tissue specific actions of cortisol
What are the key glucocorticoid-mediated mechanisms in inflammation?
inhibit AA generation
inhibit prostanoid synthesis
these two effects have widespread downstream effects on inflammatory reactions
What is cyclooxygenase-2?
COX-2 is an important inflammatory mediator, early in the process of inflammation
COX-2 plays an early step in the metabolism of Arachadonic Acid to various prostanoids (depending on the cell type)
glucocorticoid regulation of COX-2 does not involve direct receptor antagonism
Glucocorticoids influence (suppress) transcription of the COX-2 gene, leading to a long-term suppression of COX-2 expression (protein levels)
they do not directly inhibit cyclooxygenase activity
What are lipocortins/annexins?
are a large family of proteins characterized by “annexin repeats”
Annexin A-I plays an important anti-inflammatory role for what two important reasons?
- direct effects on Leukocytes inhibits their tissue infiltration
- suppression of phospholipase A2 activity; this prevents AA generation, and thereby suppresses downstream generation of prostanoids
these effects are very early in the inflammatory response, so they have broad powerful anti-inflammatory efefcts
What is lipocortin?
lipocortin is a protein – expression is induced by GC receptor activation
mechanism of inhibition of PLA2 is debated - could be by sequestering lipid substrates, or direct inhibition of PLA2
What is Addison’s disease?
chronic adrenocortical insufficiency (fatigue, salt balance, sugar balance problems, skin discoloration)
low production of glucocorticoids, and often mineralocorticoids
typically treated with GC/MC supplementation (hyrocortisone/cortisol)
What are the causes of Cushing’s syndrome?
adrenal tumor (cortisol producing)
pituitary tumor (ACTH production, stimulation of adrenal cortex)
drug-induced (long course of GC treatment)
ectopic tumor (ACTH producing)
