Describe the diurnal pattern of cortisol release?
Three spikes correspond to meals (involved in glucose regulation)
Very low during early morning
Describe how cortisol is converted to cortisol, and vice versa?
In liver, 11b-HSD1 converts cortisone to cortisol
In kidney, 11b-HSD2 converts cortisol to cortisone
Cortisol has high affinity for mineralocorticoid receptors in the kidney. Describe why it does not activate these receptors?
11b-HSD2 colocalised with mineralocorticoid receptor in kidney > cortisol converted to inactive metabolite cortisone > cortisone does not activate receptors
Describe the difference in half-life between cortisol, cortisone, and cortisol regenerated from cortisone?
Cortisol: short (~30 mins)
Cortisone: longer (~60 mins)
Regenerated cortisol: longer (~60 mins) (similar to the cortisone that it was regenrated from)
PICTURE SLIDE 10
Describe the clinical presentation of cortisol deficiency?
In cortisol deficiency due to primary adrenal hypofunction, which other deficiency also occurs?
Describe the clinical signs of mineralocorticoid deficiency?
Why is adrenocortical insufficiency difficult to diagnose?
Presneting signs and symptoms are very nonspecific
Disorder rarely occurs without concomitant injury
Describe the consequences of untreated adrenocortical insufficiency?
Describe how treatment for adrenocortical insufficiency is administered?
Cortisol or cortisone
Short half-life > multiple doses a day
Divide doses to mimic physiological time course
Extra doses for infections and periods of stress (cortisol usually rises during these periods)
Add fludrocortisone if required (to replace aldosterone in primary adrenal insufficiency)
Describe the side effects of treatment with cortisol/cortisone?
No side effects from well managed treatment
But: Cushingoid syndrome, adrneal suppression, immunosuppression, peptic ulcers, osteoporosis, inhibition of linear growth in children
List the iatrogenic complications of glucocrticoid therapy?
Inhibition of linear growth in children
Why do iatrogenic complications of glucocorticoid therapy often occur?
Often given in supra-physiological doses
Describe why adrenal suppression may occur as an iatrogenic complication of glucocorticoid therapy?
Increased cortisool > negative feedback to ACTH
Why may immunosuppression be a problem as an iatrogenic complication of glucocorticoid therapy?
Reactivation of latent infection (eg. TB)
Describe why immunosuppression occurs with glucocorticoid therapy?
Glucocrticoids inhibit inflammatory cytokines released from macrophages amd other inflammatory mediators
Describe the effects of hypercortisolism?
Wasting of muscle, skin and bone
Inhibition of linear growth
Describe the difference between transactivation and transrepression?
Transactivation: activation of gene transcription via GREs
Transrepression: reduction of gene transcription via inhibition of AP-1 and NF-kB
What determines the level of adrenal suppression that occurs as an iatrogenic complication of glucocorticoid therapy?
Dose and duration of therapy
Varies between drugs
Varies between patients
How can adrenal suppression due to glucocorticoid administration be minimised?
Allow for ACTH secretion: avoid long lasting drugs, alternate day dosing, morning dosing
Minimise systemic absorption: inhaled or topical
Use third generation glucocorticoid drugs
Describe the third generation glucocorticoid drugs?
Have reduced systemic effects because they are pro-drugs, lipohilic, have low oral bioavailability and are highly protein bound in plasma
Describe the role that glucocorticoids play in the development of petic ulcers?
Causal role is debatable
Mostly occurs in patients also taking NSAIDs (possible synergistic action)
Cortisol seems to be protective in rats
Describe why glucocorticoid administration promotes osteoporosis?
Glucocorticoid administration leads to maturation of osteoclasts, via decreasing OPG and increasing RANKL
Osteoclast activation leads to bone resorption
(RANKL stimulates RANK receptor on osteoclast precursors, whereas OPG binds RANLK and prevents binding to RANK)
Describe the effect of glucocrticoid treatment on growth in childhood?
Children taking glucocorticoids lag a little in growth, but can recover later in treatment
Modest effect size with moderate dosing
However, growth suppression may be worse if disease is not treated