Steroids Flashcards
steroid hormones that function to regulate inflammation/metaboolism
glucocorticoids
steroid hormones that function to regulate salt homeostasis
mineralcorticoids
where are corticosteroids produced?
adrenal cortex
what zone of the adrenal cortex makes glucocorticoids?
zona fasiculata
what are steroids derived from?
cholesterol
hypothalmic-pituitary axis
hypothalamus releases chemical stimulators (release hormones) that travel to pituitary gland via portal venous circulation and anterior pituitary then releases additional stimulatory mediators that cause tissues to release hormones
what hormone is secreted by the anterior pituitary that stimulates cortisol release?
ACTH
negate feedback in corticosteroid production
hypothalamus senses plasma concentration of corticosteroids and down regulates ACTH when it is high. ACTH also has its own negative feedback loop. FINE TUNE REGULATION
roles of glucocorticoids
metabolic, catabolic, immunosuppresive, anti-inflammatory, Na homeostasis, behavioral
metabolic role of glucocorticoids
gluconeogenesis, lipolysis (hormone sensitive lipase), lipogenesis (insulin)
catabolic role of glucocorticoids
protein, bone, etc
immunosuppresive role of glucocorticoids
cell mediated immunity (T cell impairment), reduced proliferation of lymphocytes/neutrophils/monocytes
anti-inflammatory role of glucocorticoids
inhibition of PLA2, decrease transcription of COX, decrease IL-2,3, decrease pro-inflammatory cytokines
four functional domains of glucocorticoid receptor
ligand binding domain (LBD), DNA binding domain (DBD), AF2, AF1
LBD of GR
where receptor interacts with chaperone proteins (HSP90/56) and glucocorticoid
DBD of GR
binds to specific DNA sequence called GRE on target gene
AF2 of GR
C terminal end, interacts with co-activator or suppressor proteins that modulate gene transcription
AF1 of GR
N terminal end, constitutively interacts with transcription machinery
mechanism of glucocorticoid action
enters cell, binds to GR, allowing it to dissociate from chaperone proteins. Steroid/receptor complex then enters nucleus, binds to GRE and amplifies/suppresses transcription of target gene
lipocortin
protein whose expression is unregulated by glucocorticoids. down regulates PLA2, leading to decreased prostanoids
IL6/8
proteins whose expression is inhibited by glucocorticoids.
property of synthetic steroids
alteration in some portion of chemical structure enhances either gluco or mineral corticoid function.
when would we treat someone with physiologic doses of corticosteroids?
during replacement therapy to treat adrenal insufficiency. don’t want to throw off the negative feedback loop
when would we treat someone with supra physiologic doses of corticosteroids?
for an anti-inflammatory or immunosuppresive effect
mechanism of anti-inflammatory role of corticosteroids
decreases t cell production of IFNy, macrophage production of IL1/TNFa, mast cell production of histamine/NO/prostaglandins, suppresses activity/activation of T cells and their cytokine production
toxicity of glucocorticoids on hypothalamic pituitary axis
with high doses of glucocorticosteroids, negative feedback turns off hypothalamic induction of ACTH. but sudden withdrawal of therapy can lead to acute adrenal insufficiency
acute adrenal insufficiency
Addisonian crisis
side effects of glucocorticoids
electrolyte imbalance aka sodium retention causing fluid retention and hypertension. immunosuppresion, myopathy or wasting of proximal muscles, behavioral changes (extra energy, insomnia, psychosis), osteoporosis, hyperglycemia (type 2 diabetes), cataracts, growth retardation
