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)
What are the symptoms of Cushing’s syndrome?
adrenal overactivity leading to excessive cortisol
round face, fat deposition in trunk
muscle loss, osteoporosis - protein and bone catabolism
resection of adrenals or pituitary tumor, followed by gradual adjustment towards a maintenance dose of cortisol
understanding the features of Cushing’s disease is helpful to understand the side effects of GC treatment
symptoms resemble side effects of therapeutic doses of GCs
What causes the dark complexion in Addison’s disease?
it is a consequence of GC feedback mechanism
ACTH is generated in POMC neurons of the pituitary; cleavage of the POMC gene product generates multiple hormones, including melanocyte stimulating hormone
absence of feedback from cortisol causes hyperproduction of POMC and downstream products
What are the feedback loops involved in glucocorticoid overproduction?
in an individual with an adrenal tumor producing unregulated cortisol, there would be high cortisol, and low ACTH
in an individual with a pituitary tumor producing unregulated ACTH, there would be high cortisol, and high ACTH
What are glucocorticoids used to treat?
powerful anti-inflammatory, immunosuppressive actions of cortisol and analogs
allergic reactions (bee stings, contact dermatitis)
eye inflammation (uveitis, conjunctivitis)
reduction of pain and scarring after injury/surgery, by reducing inflammation
gastrointestinal diseases (inflammatory bowel syndrome)
hematologic disorders (leukemia, myeloma)
asthma
organ transplants (immunosuppression to avoid rejection)
What are Addison-like side effects of glucocorticoids?
Addison-like symptoms if stopped abruptly
negative feedback from glucocorticoid administration will suppress CRH and ACTH production
“Addisonian” crisis: Hypoglycemia, hyponatremia, hyperkalemia, low blood pressure
tapering is needed when stopping long-term course of glucocorticoids (i.e., you should not abruptly stop taking a glucocorticoid)
What are the metabolic side effects of glucocorticoid treatment?
hyperglycemia
care must be taken with diabetic patients
What are the immunosuppressive side effects of glucocorticoid treatment?
caution with patients carrying infections
latent infections can emerge (TB)
opportunistic infections can emerge
What are the catabolic side effects of glucocorticoid treatment?
osteoporosis, muscle wasting
What are the anti-inflammatory side effects of glucocorticoid treatment?
slow wound healing, ulcerations
What are the other side effects of glucocorticoid treatment?
hypertension considerations (non-specific MR effects of some GCs)
psychosis
