Endocrine Week 4 Flashcards
Describe brief anatomy of the adrenal glands:
- paired retroperitoneal organs, 5-8g each
- perinephric fat = covers adrenals and kidneys
- perirenal fat = separates kidneys and adrenals
- Gerota’s fascia = covers adrenals and kidneys and attaches to diaphragm
- Each gland supplied by three arteries
- > superior adrenal artery (br of inferior phrenic artery)
- > middle (br of abdominal aorta)
- > inferior (br of renal artery)
- drained by lumbar lymph nodes
- centrepetal blood flow
- veins gather forming a large medullary vein in the centre of each gland, and then each adrenal is drained by a R/L adrenal vein
- > R adrenal vein = into IVC
- > L adrenal vein = into L renal vein
Describe the anatomy of the adrenal cortex:
- derived from urogenital ridge of intermediate mesoderm
- 3 layers:
- > zona glomerulosa (irregular clusters of cells separated by trabeculae), secretes MINERALOCORTICOIDS e.g. ALDOSTERONE
- > zona fasiculata (largest area, lipid rich, narrow cell columns separated by capillaries) produces GLUCOCORTICOIDS e.g. CORTISOL AND ANDROGENS
- > zona reticularis (less lipid than ZF and produces same hormones but less amounts)
Describe the anatomy of the adrenal medulla:
- derived from neural crest cells of ectoderm
- part of sympathetic NS secreting A and NA
- makes 5x more adrenaline than noradrenaline
- has chromaffin cells = the secretory cells of the medulla
What type of hormones are cortisol and aldosterone and how are they produced?
Steroid hormones - from enzymatic modification of cholesterol
- All steroid hormones are lipid soluble and have a 4 ring structure -> means they are permeable to cell membranes and released as soon as they are formed
- bound to corticosteroid binding globulin to be carried in the blood
How is cortisol synthesised?
- stAR protein (steroidogenic acute regulatory protein) transports cholesterol in the cytoplasm of cells into the mitochondria
- CSCC (cholesterol side-chain cleavage, a P450 enzyme) is on the inner mitochondrial membrane and converts cholesterol -> pregnenolone
- Pregnenolone -> progesterone
- Pregnenolone/progesterone -> 17-alpha hydroxylase -> 17-OH pregnenolone/17-OH progesterone
- 17-OH progesterone -> deoxycortisol -> cortisol
What are cortisol functions?
PALM-B
Pancreas - cortisol is an insulin antagonist
Adipose - cortisol stimulates lipolysis
Liver - cortisol stimulates glucagon and gluconeogenesis
Muscle - stimulates protein breakdown
Bones - cortisol reduced OB activity so less bone formation
Also important for mood, memory, learning and immune suppression
What stimulates production of cortisol?
ACTH from AP
ACTH binds to G-protein coupled receptor -> adenyl cyclase -> cAMP -> PKA activation -> Ca influx
Ca influx stimulates cholesterol movement into the mitochondria to make cortisol
How is aldosterone produced?
Cholesterol -> pregnenolone -> progesterone -> 11-deoxycorticosterone -> corticosterone -> 18-OH-corticosterone -> aldosterone
What are the functions of aldosterone?
- Acts on mineralocorticoid receptors in DCT of kidney nephrons
- causes upregulation of ENaC channels so more Na reabsorption and therefore more water reabsorption
- also creates feelings of thirst
How is the production of aldosterone stimulated?
RAAS system -> AT2 made
AT2 causes production of aldosterone by adrenals
AT2 binds to G-protein coupled receptor and phospholipase C is activated -> secondary messengers activated -> Ca released
Rise in Ca stimulates transcription of stAR so more aldosterone production
Also increased K levels increase aldosterone action
Aldosterone then increases Na reabsorption and K excretion to eventually normalise K levels
How do cortisol/aldosterone bind to receptors and exert their effects on target tissues?
- steroid hormones bind to intracellular receptor and form hormone:receptor complex
- all steroid receptors belong to nuclear receptor superfamily and have 6 domains
A/B—C—D—E—(F)
A/B - controls which gene is activated
C - 2 zinc fingers and control what HRE on the DNA strand the hormone:receptor complex binds to
D - hinge region, controls movement of the hormone:receptor complex to the nucleus
E - ligand binding region, where steroid hormone binds to
F - variable and not always present
- Receptor:hormone complex binds to a specific region of DNA called hormone response element (HRE)
- This triggers gene transcription to make mRNA
- The mRNA is then translocated into a protein which acts on the target cell causing the desired response
Where are glucocorticoid/mineralocorticoid receptors found and how do they achieve their desired function?
Glucocorticoid receptors - very widespread
Mineralocorticoid receptors - distal nephron, salivary and sweat glands, large intestine
- both receptors are sensitive to overlapping hormones
- concentration of cortisol is much greater than aldosterone
- to stop cortisol binding to the MC receptors in the kidney, the enzyme 11-beta-HSD (hydroxysteroid dehydrogenase) is present and catalyses the conversion of active cortisol -> inactive cortisol
- This means that aldosterone can bind
- 11-B HSD is inactivated by liquorice
What is the relationship between the hypothalamus/AP/adrenal cortex?
Hypo releases CRH (corticotrophin releasing hormone)
This triggers AP to release ACTH (adrenocorticotrophic releasing hormone) - was initially POMC
ACTH triggers adrenal cortex to release cortisol
Cortisol has negative feedback on AP and Hypo
Why is it important to measure cortisol levels at the same time each day?
As levels fluctuate throughout the day as cortisol is released in a circadian rhythm
How do you test for adrenal insufficiency?
1) Biochemical tests for:
- High Na
- Low K (both due to lack of aldosterone)
- high renin (as body tries to make more aldosterone)
- low aldosterone
- hypoglycaemia (as normally cortisol suppresses insulin activity)
- raised ACTH levels
2) Short synACTHen test
- stimulate adrenals with ACTH and measure cortisol levels before and after, in insufficiency the adrenals will not respond and the cortisol level will remain low
3) Check for adrenal autoantibodies
How do you test for adrenal overactivity and cortisol XS?
1) Dexamethasone suppression testing
- is a steroid hormone like cortisol, that on administration would normally suppress ACTH release but in Cushing’s will not stop ACTH production
2) Measure urinary and plasma cortisol REGULARLY
3) Distinguish if cortisol XS is iatrogenic (low ATCH) or endogenous (high ACTH)
4) If endogenous, establish if the cause is pituitary / adrenal or ectopic cause
What are the differences between primary and secondary adrenal insufficiency?
Primary - an issue with the adrenal glands e.g. addison’s disease, tumour
Secondary - an issue with the pituitary gland / iatrogenic cause
What is the pathophysiology of addison’s disease and clinical features?
- commonest cause of primary adrenal insufficiency
- autoimmune destruction of adrenal cortex
- autoantibodies against 21-OH enzyme (enzyme involved in making cortisol and aldosterone)
- CRH and ACTH levels are high as they are trying to make the adrenals more active
Features:
- anorexia
- weight loss
- dizziness
- low BP
- fatugue
- abdo pain
- abnormal skin pigmentation (high ACTH production therefore lots of MSH also made from POMC)
How can hormones be replaced in adrenal insufficiency?
- If in doubt as to whether a patient has adrenal insufficiency, give steroids anyway as this will not do any harm
- Hydrocortisone - cortisol replacement (try to administer mimicking circadian rhythm)
- Fludrocortisone - aldosterone replacement
Why is patient education important in corticosteroid hormone replacement?
- must double up on hydrocortisone dosing if ill
- patients cannot stop treatment suddenly
- patients should wear identification/carry steroid card to warn others
- teach self injection techniques for HC (given IV or tablet)
What is the definition of Cushing’s disease?
Cushing’s syndrome caused by a pituitary adenoma
Describe the pathophysiology of cortisol XS:
1) ACTH dependant
- pituitary adenoma
- ectopic ACTH production eg. tumour
- ectopic CRH production e.g. tumour
2) ACTH independant
- adrenal carcinoma
- adrenal adenoma
- nodular hyperplasia
To distinguish between the two types you measure cortisol levels in the body
What are clinical signs of XS cortisol (i.e. stereotypical Cushing’s patient)?
Striae, thin skin, facial plethora, proximal limb myopathy, moon face, buffalo hump, euphoria, cataracts, poor wound healing, osteoporosis, increased appetite, central fat deposition
What is iatrogenic cushing’s syndrome?
Commonest cause of Cushing’s syndrome
Due to prolonged high dose steroid therapy (mainly from oral steroids but can be caused by inhalers and topical creams)
Drug use leads to chronic suppression of pituitary ACTH production -> adrenal atrophy occurs
