Week 5.1 Flashcards
Where is mineralocorticoid produced & secreted?
Zona glomerulosa (cortex of adrenal gland)
Where is glucocorticoid produced…
Zona fasciculata (cortex)
Where is adrenal androgen produced…
Zona reticularis (cortex)
Where are catecholamines produced?
Medulla of Adrenal gland
What is the main GC:
cortisol / and some corticosterone
What is the main MC:
aldosterone
Pathway of aldosterone signalling
Renin -> Angiotensin (I/II) -> Aldosterone
The pathway of aldosterone synthesis (enzyme)
Cholesterol –> DOC –> Aldosterone
Enzyme: aldosterone synthase
Cortisol + corticosterone synthesis
Cortisol comes from cholesterol too
enzyme: 11-betaOH (hydroxylase)
Corticosterone comes from DOC (precursor of aldosterone)
is half life of aldosterone high or low?
low (minutes)
affinity of MR and GR
MR is higher than GR
is MR affected by cortisol?
yes
How is the high cortisol regulated in signalling to receptors
11beta-HSD2 in tissues, it blocks cortisol, so only MC will signal to MR
Drugs that inhibits mineralocorticoids action
Epi: no side effect
Spiro: side effect -> inhibits androgen receptors too
Drug – MC agonists
Fludro: substitutes for aldosterone.
Treat addison’s disease, low aldosterone.
aldosterone and Na+ reabsorption pathway
- Apical surface: aldosterone – MR – will let nucleus stimulate more ENaC (sodium inlet)
- Na+ is reabsorbed to circulation through Na/K pump, K+ comes in
- K+ will be pumped out through ROMK
Sodium reabsorption and aldosterone (side effects)
Hypertension:
Aldosterone will lead to reabsorption of sodium intra-cell becomes more negative.
Cl- is also pumped out -> increase in osmolarity due to ion accumulation.
releases ADH this will increase ECF and leads to hypertension.
Excessive aldosterone biochemical effect
Increased Na+ and Cl- pumped out.
Increased H+ and K+ cellular uptake.
Excessive aldosterone effect (symptom–)
- Hypertension
2.Hypokalaemia - muscle cramps
3.alkalosis.
Aldosterone deficiency leads to .. (biochem and symptom)
Due to decreased Na+ reabsorption and Cl- pumped into circulation:
1. Low BP
2. Decreased cellular uptake of K+ and H+.
How does renal artery stenosis affect aldosterone level
- High Renin and Aldosterone
- Blocked artery to kidney
- kidney senses low BP
- thinks it is low blood volume
- Kidney stimulates renin production -> aldosterone (secondary)
Adrenal overfunction and aldosterone
Primary
1. Adrenal gland produces a lot of aldosterone
2. Renin is turned off
3. High aldosterone/Renin ratio
Pseudo-hyperaldosteronism
It’s actually not high aldosterone
1. Genetic mutation that leads to increased BP and decreased circulating K+.
2. Low aldosterone and renin
Adrenal insufficiency disease
Addison’s
Adrenal insufficiency and aldosterone
The adrenal gland will lead to decreased aldosterone production.
High renin (small -ve feedback)
Pseudo-hypoaldosteronism
Apparent high K+ and low BP
Renin and aldosterone high.
Addison’s Disease (hormone change)
Adrenal disease:
Low MC - aldosterone and GC - cortisol
1. high Renin (low aldo)
2. high CRH and ACTH - hypothalamus & anterior pituitary.
Pathway of GC (cortisol) signalling
Hypothalamus -> Anterior Pituitary -> Adrenal cortex
Hypothalamus hormone to anterior pit.
CRH (corticotropin releasing hormone)
Anterior pituitary hormones
ACTH to adrenal gland
- Other hormones: LH, FSH, TSH, GH, prolactin, ADH.
Hypothalamus dysfunction and cortisol pathway (causes - consequences)
Destructive hypothalamic disease:
CRH low
& downstream hormones low
What could lead to anterior pituitary dysfunction
Large non-functional pituitary tumour:
The adenoma will not produce active hormones itself.
non-functional pituitary adenoma and cortisol pathway
Low ACTH & other pituitary released hormones
-> low downstream hormones
What is an apparent symptom of Addison’s disease
Adrenal gland dysfunction:
-> increased ACTH (along with CRH)
ACTH will lead to hyper-pigmentation
What will excessive ACTH cause???
melanocyte-stimulating hormone receptor (release melanin)
hyper-pigmentation.
Causes of Addison’s disease
Autoimmune, Metastasis, tuberculosis.
-> damage to the adrenal cortex
low Cortisol effects
vascular tone- Low blood pressure
Low glucose
Loss of Appetite
Pituitary ACTH deficiency
low cortisol and normal aldosterone (unaffected)
Short Synacthen Test
Synacthen is an ACTH-like drug
It should stimulate adrenal cortex to release cortisol
If abnormal -> adrenal cortex atrophy (dysfunction)
Inaccurate within 6 months of hypot/pit. damage. Adrenal gland needs 4-6 weeks to completely fail cortisol production.
What is Cushing’s syndrome
Excessive cortisol production
Cushing’s syndrome leads to –
Increased circulating glucose.
Increased protein catabolism.
- skin thinning
- easy bruising
High levels of cortisol: increased bone resorption and decreased bone formation: Osteoporosis
Causes of Cushing’s syndrome (3)
- Pituitary tumour -> excessive ACTH
- Ectopic ACTH.
Leads to increased cortisol, more -ve feedback to hypothalamus and anterior pituitary. - Adrenal tumour -> increased cortisol.
Diagnosis of cause of Cushing’s syndrome
Urine ACTH test:
1. low ACTH -> adrenal tumour
2. high ACTH -> pituitary/ectopic ACTH tumour
Ectopic ACTH vs Pituitary ACTH tumour
Pituitary ACTH tumour :
Can be suppressed by Dexamethasone suppression and CRH.
Ectopic ACTH is often more intense:
-Can have wait loss (weight gain is often the case for Cushing’s)
-ACTH is usually unaffected by dexamethasone suppression and CRH test.
CRH test
For pituitary ACTH tumour -> a dose of CRH can increase the ACTH.
For Ectopic ACTH tumour-> CRH cannot affect the ectopic tumour.
dexamethasone suppression
Dexamethasone -> synthetic glucocorticoid that aims to negative feedback to ACTH production.
- Can suppress in pituitary ACTH tumours.
- Cannot in ectopic ACTH tumours.
Adrenal insufficiency symptoms
low cortisol–low glucose
low BP - vascular collapse
low aldosterone–low Na+, high K+
very fatigue
weight loss
Conn’s tumour and bilateral adrenal hyperplasia
Excessive aldosterone.
Imaging might distinguish the two. Adrenal vein sampling where Conn’s tumour have more aldosterone on one side.
