Steroids of the adrenal cortex Flashcards
State the 3 steroids of the adrenal cortex?
Glucocorticoids: principally cortisol in mammals
Mineralocorticoids: aldosterone
Androgens
What does hypercortisolism cause?
Cushing’s syndrome
What does primary adrenal insufficiency cause?
Addison’s disease
What results from the synthesis of layer-specific enzymes in
during adrenal blood flow?
Steroid synthesis in one layer can inhibit different enzymes in subsequent layers
Describe how the adrenal blood flow results in functional
zonation ?
Blood flows from outer cortex to inner medulla
- Layer-specific enzymes are found between these regions
Results in functional zonation of cortex with different hormones made in each layer
State the structure of the adrenal gland in terms of tissue
and which steroid is formed
From cholestrol -> Pregnenolone
Capsule: Zona glomerulosa -> mineralocorticoids (aldosterone)
Cortex:
Zona fasciculata -> Glucocorticoids (cortisols)
Zona reticularis -> (androgens)
State action of mineralcorticoids?
Salt and water balance
- Aldosterone (MC)
State action of Glucocorticoids?
Metabolism and immune function
- Stress increases release, but minimal levels essential for normal function
State action of androgens?
So called ‘weak androgens’
State the functions of mineralcorticoids in order to balance
salt and water?
1) Sodium retention (whole body sodium) via
- Active reabsorption of sodium (with associated passive reabsorption of water)
- Active secretion of potassium
2) Volume regulation (part of RAAS)
Why does aldosterone not regulate sodium concentration?
Due to the fact water follows passively with sodium at the sites.
- To change concentration requires loss or gain of pure water, which in turn requires ADH action.
State the action of aldosterone on ascending LoH, DCT, CD
of kidney?
Aldosterone binds to its receptor the mineralocorticoid receptor (MR).
- Nuclear receptor, works by control of gene transcription.
Leads to activation of serum/glucocorticoid regulated kinase 1 (SGK1) ,
mainly by phosphorylating and inactivating a factor that keeps plasma membrane ENaC channels expressed at low levels.
Describe the difference in affinity and circulating conc. of cortisol and aldosterone for
adlosterone receptor
Similar affinity
Cortisol has significantly higher levels of circulating conc. than aldosterone
Why doesn’t cortisol stimulate salt and water balance, even though
circulating conc. of cortisol is higher than aldosterone
When cortisol reaches the kidney
Cortisol is rapidly metabolized to inactive cortisone
What enzyme is required for the metabolism of cortisol in the kidney?
11beta-hydroxysteroid dehydrogenase type 2 (11B-HSD2)
what occurs if mutation of 11B-HSD2 happens?
syndrome of apparent mineralocorticoid excess (AME)
What item has a compound which can block 11B-HSD2?
liquorice contains glycyrrhizinic acid, a molecule that inhibits 11-beta-hydroxysteroid dehydrogenase
Don’t need to know compound name
Describe the 3 major functions of glucocorticoids?
- Decreased glucose utilization (maintenance of blood glucose during fasting)
- Cardiovascular
- Anti-inflammatory, immunosuppresive
State the ways glucocorticoids decreases glucose utilization?
Decreased glucose utilization (glucose sparing)
- Proteolysis
- Gluconeogenesis (mainly from amino acids)
- Lipolysis
Overall: maintenance of blood glucose – essential for survival during fasting
Why is the glucocorticoids required to impact the CVS?
Required for vascular integrity
- Capacity of the vessel to hold everything inside
What can be the impact of CVS from hypocortisolism
inappropriate vasodilation, hypotension
What can be the impact of CVS from hypercortisolism
hypertension
State the effect glucocorticoids have on inflammatory mediators?
Glucocorticoids inhibit IF response
- Increases production of annexin-1
- This inhibits phospholipase A2
- Stops production of arachidonic acid (IF mediators are derived from this)
- Therefore inhibits induction of COX-2 preventing production of IF mediators e.g. prostaglandins or thromboxane
What member is the glucocorticoid receptor part of and describe its structure?
Member of the nuclear receptor super-family
Characteristic 3-domain structure
- Ligand-binding
- DNA-binding
- N-terminal transcription co-factor binding
State the 2 isoforms of the glucocorticoid receptor and how this arises?
GR alpha and beta
- Arises from alternate splicing of the 9th exon
What are many of the anti-IF effects from GCs caused by?
Transrepression - major theurpeutic target
Draw or describe the control of glucocorticoid and androgen production cycle?
“VP: vasopressin (ADH)
Corticotropin-releasing hormone
- (CRH)
Adrenocorticotropic hormone
- (corticotropin, ACTH)
“
Describe briefly what occurs action of ACTH receptor when ACTH binds to it?
“ACTH receptor: G-protein coupled, via cAMP
- Stimulates cholesterol uptake and steroid synthesis
“
What is ACTH synthesised from?
Pro-opiomelanocortin prohormone
Which group of receptors is the ACTH receptor a part of?
“member of the melanocortin group of receptors (group of hormones released from pituitary gland)
“
Describe the relationship between ACTH and melanocortin receptors?
“Different forms of melanocyte-stimulating hormones bind to melanocortin receptors
ACTH can also bind to other melanocortin receptors
“
What can excess circulating ACTH cause?
Skin pigmentation
What can secondary adrenal insufficiency cause?
“Hypopituitarism; secondary to failure in RAAS
“
What causes adrenal insufficiency?
“Enzyme defect in steroid synthesis pathways
“
State 5 clinical features of addison’s disease?
“Addison’s: Primary adrenal insufficiency
Low circulating adrenal steroids
Plasma [Na+]: normal to low
High ACTH
Plasma [K+]: normal to high
Elevated plasma renin
“
State symptoms of addisons’ disease?
“Significant stress or illness
- shock
- hypotension
- volume depletion (adrenal crisis)
“
What is the cause of addisons disease decribed as?
“Autoimmune
“
State how the coritsol -ve feedback cycle is affected during addisons disease?
“Primary adrenal failure
- Loss of cortisol, androgens and aldosterone
High ACTH and CRH/VP”
Describe how cushing’s syndrome occurs via ACTH-dependent?
”- Cushing’s disease: due to increased ACTH secretion (typically due to pituitary adenoma: secondary)
- Ectopic ACTH-secreting tumour
Pituitary adenoma: Growth of pituitary
“
Describe how cushing’s syndrome occurs via ACTH-independent?
“Adrenal adenoma or carcinoma (primary)
- Growth or tumour of adrenal glan
iatrogenic; effect of GC therapy
“
State 6 clinical features of hypercortisolism?
“Hypertension
Hyperglycaemia
Truncal obesity (fat is mainly stored around abdomen)
Fatigue, muscle weakness
Virilization (hirsutism in females) - development of opposite sex physical characteristics
Depression, mood or psychiatric disturbances
“
State the first step required to diagnose Hypercortisolism?
“First step: confirm hypersecretion of cortisol
- 24-hour urinary cortisol (due to variance of C due to circadian rhythm)
- Cortisol at nadir of secretion (around midnight)
Nadir= Lowest point
“
State the second step required to diagnose Hypercortisolism?
“Next, determine the cause
- Check Plasma ACTH
- Dexamethosone suppression test
“
WHat is the most common cause of cushing’s disease?
iatrogenic : side effect of medical treatment
Describe how iatrogenic causes cushing’s disease?
“iatrogenic : side effect of medical treatment
Exogenous glucocorticoids activate cortisol receptor
At high doses will shut down HPA
Adrenal cortex atrophies (slows) with lack of ACTH stimulation
Several days may be required for adrenal to become responsive to ACTH again
“
“What is the effect of ACTH-secreting pituitary adenoma from cushing disease on the
feedback loop?”
“pituitary adenoma results in increased ACTH secretion, which drives excess cortisol production from adrenal cortex
. Negative feedback loop is still intact, but greater mass of ACTH-secreting pituitary cells means set point is higher.
“
What is the effect of ecoptic ACTH source from cushing disease on the
feedback loop?
Excess ACTH, but source is ectopic (not from pituitary, but ACTH secreting tumour elsewhere in body). Excess cortisol would shut down ACTH secretion from pituitary, but pituitary is not the source of ACTH: feedback loop is by-passed
“What is the Dexamethasone suppresion test
“
“If ACTH is high, used to find out if
- CUshing disease from pituitary adenoma
OR
- ecotopic ACTH source”
State and describe the different scenarios involved in the dexamethasone suppression test?
“Dexamethasone: Dosage of exogenous steroid (activates GC receptor)
Low doses will normally supress ACTH secretion via negative feedback
Low dose fails to supress ACTH secretion with pituitary disease (Cushing’s)
Higher dose will supress ACTH secretion in Cushing’s
No supresssion with low or high dose: suggests ectopic source of ACTH (e.g., tumour elsewhere
“
