12.1 - Adrenal Glands + RAAS System Flashcards
Basics of the adrenal gland
- Two of these situated just above the kidney
- Has several layers – cortex (fibrous layer for protection), cortex (corticosteroid production) and medulla (catecholamine production)
- Contained within the renal fascia
Hormones of the adrenal cortex
☞ corticosteroids
- z. glomerulosa (nearest to capsule) producing mineralocorticoids eg aldosterone
- z. fasciculata producing glucogorticoids eg cortisol, corticosterone and cortisone
- z. reticularis (nearest to medulla) producing androgens eg androstenedione (key role in production of testosterone and oestrogens) and dehydroepiandrosterone
Steroid hormones
- These are synthesised from cholesterol in adrenal glands + gonads
- Lots of enzymes convert cholesterol into different enzymes
- Lipid soluble hormones
- Bind to receptors of the nuclear receptor family to modulate gene transcription
☞ glucocorticoids
☞ mineralocorticoids
☞ androgens
☞ oestrogens
☞ progestins
What does a deficiency in 21-hydroxylase cause
- An enzyme involved in the synthesis of cholesterol → cortisol, corticosterone and aldosterone
- Therefore deficiency in some androgens and an excess in others
- This causes renal hyperplasia
How do corticosteroids exert their actions
- Corticosteroids readily diffuse across the plasma membrane
- They then bind to glucocorticoid receptors
- Binding causes dissociation of chaperone proteins
- This allows the receptor-ligand complex to translocate to the nucleus where dimerisation with other receptors, such as GREs (glucocorticoid response elements) can occur
Aldosterone
- Most abundant mineralocorticoid
- Synthesised + released by z. glomerulosa fo adrenal cortex
- Steroid hormone so lipophilic ☞ needs to be transported using carrier protein
- Carrier protein= mainly albumin + sometimes transcortin
- Aldosterone receptor is intracellular
Exerts its actions using gene transcription
- Plays central role in regulation of plasma [Na+] and [K+] and therefore blood volume → arterial blood pressure
- Achieves this by acting on the distal tubules and collecting ducts of the kidney nephrons, where it promotes Na+ reabsorbtion and K+ excretion by the Na+/K+ ATPase pump, which causes an increase in water reabsorbtion
- This consequently causes an increase in blood volume and therefore blood pressure
The RAAS
the renin-angiotensin-aldosterone system
Liver releases angiotensinogen → angiotensin I → angiotensin II
- Angiotensinogen → angiotensin I stimulated by renin, which is released by kidney. The release of renin is in turn stimulated by hypotension + hypovolaemia (decrease in renal perfusion, drop in blood pressure, increased sympathetic tone)
- Angiotensin I → angiotensin II stimulated by ACE, which is released by lungs
-
Angiotensin II has following effects to increase blood volume + blood pressure…
☞ vascular system: vasoconstriction, leading to higher blood pressure
☞ ADH secretion from the posterior pituitary. This stimulates translocation of aquaporin channels, which aids water reabsorbtion back into blood (nephrons)
☞ stimulates adrenal gland to release aldosterone, increasing expression of Na+/K+ pump, increasing reabsorbtion of Na+ (and therefore water) back into blood
What is hyperaldosteronism (primary and secondary types + causes)
Too much aldosterone produced. Two types
primary
- Due to defect in adrenal cortex
- Bilateral idiopathic adrenal hyperplasia (ie increase in cell number in adrenal glands with no known cause)
- Aldosterone secreting adrenal adenoma (Conn’s syndrome)
- Low renin levels (high aldosterone : renin ratio)
secondary
- Due to overactivity of the RAAS
- Renin producing tumour (eg juxtaglomerular tumor) – very rare
- Renal artery stenosis… this causes high renin levels (low aldosterone : renin ratio)
How are primary and secondary hyperaldosteronism distinguished from one another
primary has high aldosterone : renin ratio
secondary has low aldosterone : renin ratio
Signs + treatment of hyperaldosteronism
signs
- High blood pressure
- Stroke (caused by high BP)
- Left ventricular hypertrophy (caused by high BP)
- Hypernatreaemia (increased Na+)
- Hypokalaemia (decreased K+)
treatment
- Depends on type + underlying cause
- Aldosterone-producing adenomas removed by surgery
- spironolactone (mineralocorticoid receptor antagonist)
Cortisol (actions on different card)
- Synthesised and released by z. fasciculata in response to ACTH
- Negative feedback to hypothalamus inhibits CRH and ACTH release
- Steroid hormone so need carrier protein for aqueous mediums ☞ transcortin
- Cortisol receptor exerts its actions by regulating gene transcription
Cortisol actions
Stress (eg pain, fever, hypoglycaemia, low BP) stimulates → hypothalamus releases CRH → this stimulates anterior pituitary to release ACTH → this stimulates adrenal cortex to release cortisol → cortisol has effect on…
☞ catabolic effects: increased proteolysis (in muscle) and increased lipolysis (adipose)
☞ increased gluconeogenesis (in liver), this increases available glucose to tissues
☞ resistance to stress (inc glucose supply, increase BP by making vessels more sensitive to vasoconstriction)
☞ anti-inflammatory affects (inhibits macrophage activity and mast cell degeneration)
☞ depression of immune response
What does cortisol have a negative feedback mechanism on
hypothalamus to release less CRH
anterior pituitary to release less ACTH
Glucocorticoid actions on metabolism
- Increase glucose production, increase proteolysis + redistribution of fat
- stimulates gluconeogenesis (in liver) by increasing the activity + amounts of enzymes. As a consequence of increased glucose ⇢ stimulates insulin ⇢ increased glycogen stores
- uptake of glucose in muscle inhibited (cortisol inhibits insulin-induced GLUT4 translocation in muscle). This prevents glucose uptake so has a glucose sparing effect
Cushing’s syndrome (signs and symptoms on other card)
umbrella term for several other conditions. Due to chronic excessive exposure to cortisol
☞ external causes are most common. This is where individual is prescribed glucocorticoids
☞ endogenous causes are much rarer. They include
- Benign pituitary adenoma secreting ACTH = Cushing’s Disease
- Excess cortisol produced by adrenal tumor = Adrenal Cushing’s
- Non pituitary-adrenal tumours producing ACTH (and/or CRH) eg small cell lung cancer
Why do people with Cushing’s have fat deposition
- Cortisol decreases sensitivity to insulin and increases lipolysis
- Cushing’s = chronic excessive exposure to cortisol
- Can result in re-distribution of fat, particularly in…
☞ abdomen: weight gain
☞ behind shoulders: ‘buffallo hump’
☞ on face: ‘moon face’
Signs and symptoms of Cushing’s syndrome
- Plethoric ‘moon-shaped’ face
- ‘buffallo hump’
- Abdominal obesity
- Purple striae (this is due to increased proteolysis which affects integrity of skin. Appears as just stretch marks on darker skin)
- Acute weight gain
- Hyperglycaemia (due to increased glucose production)
- Hypertension
Steroid drugs
- Eg prednisolone and dexamethasone
- Has anti-inflammatory and immunomodulatory effects
- Used to treat inflammatory disorders eg asthma, IBD, RA, and others
- Also can be used to supress immune reaction in response to organ transplantation
- Side effects are the same as the effects of high cortisol levels, plus can have a mineralocorticoid effect
Why do steroid doses need to be reduced gradually
- steroid dosage should be reduced gradually and not stopped suddenly
- this is because steroids dampen body’s own mechanism to produce cortisol
- body doesn’t have a chance to increase its own cortisol production
Addison’s disease + symptoms
- ie chronic adrenal insufficiency
- main cause used to be a complication of tuberculosis
- now most common cause is destructive atrophy from autoimmune response
- more common in women than men
- other rarer causes: fungal infection, adrenal cancer + adrenal haemorrhage
signs and symptoms
☞ postural hypotension (low BP when standing up)
☞ lethargy (unable to stimulate mobilisation of glucose)
☞ weight loss
☞ anorexia
☞ increased skin pigmentation (mechanism on next card)
☞ hypoglycaemia
Hyperpigmentation in Addison’s
POMC is a precursor of ACTH
decreased cortisol → negative feedback on anterior pituitary reduced → more POMC required to synthesise ACTH
☞ a by-product of ACTH breakdown is α-MSH which stimulates melanocytes to produce more melanin. ACTH itself can also stimulate melanocortin receptors and contribute to hyperpigmentation
☞ can present as skin getting overall darker, or pigmented areas such as gums, hands and tongue
Addisonian crisis (precipitated by, symptoms and treatment)
addison’s disease can go on to cause Addisonian crisis and it’s a life-threatening emergency due to adrenal insufficiency
precipitated by
- severe stress
- salt deprivation
- infection
- trauma
- cold exposure
- over-exertion
- abrupt steroid drug withdrawal
symptoms
- nausea
- vomiting
- pyrexia
- hypotension
- vascular collapse
treatment
- fluid replacement and cortisol
Androgens
- DHEA (dehydroepiandrosterone) and androstenedione are produced
- These are partially regulated by ACTH and CRH
- In males: DHEA → testosterone (in testes. After puberty this is insignificant as testes release more testosterone themselves)
- In females: adrenal adrogens → oestrogens (by other tissues. Also promote libido. After menopause this is the only source of oestrogens)
- In both, these promote axillary (armpit) and pubic hair growth in both sexes
Adrenal medulla
- Central region of adrenal glands
- Adrenal medulla is a modified sympathetic ganglion of the autonomic NS
- Contains chromaffin cells (CCs)
- CCs lack axons, but act as post-ganglionic nerve fibres
- These release catecholamines (produced from tyrosine) into the blood
- Most of these hormones released are adrenaline (converted from noradrenaline by N-methyl transferase enzyme)
- About 20% of CCs lack N-methyl transferase enzyme and secrete noradrenaline
- Adrenaline works through associated GPCR receptors (details in ICPP unit)
Hormonal actions of adrenaline
fight or flight via associated GPCR receptors
- Heart: increase heart rate and contractility (β1)
- Lungs: bronchodilation (β2)
- Blood vessels: vasoconstriction in skin / gut (α1) and vasodilation in skeletal muscle (α2) ☞ ie don’t need blood flow to GI while in fight/flight response, so blood is diverted to more useful tissues, such as muscle
- Kidney: increase renin secretion (β1, β2)
- Muscle: increase glycolysis and glycogenolysis (α1, β2)
- Liver: increase glycogenolysis and gluconeogenesis (α1, β2)
- Pancreas: increase glucagon secretion (α2) and decrease insulin secretion (α2, β2)
- Adipose: increase lipolysis (β2)
Phaeochromocytoma (inc signs and symptoms)
- Chromaffin cell tumor
- Rare, catcecholamine-secreting tumor (mainly noradrenaline)
- Histologically characteristic as they stain dark with chromium salts
- May precipitate life-threatening hypotension
- Primary treatment is surgical resection, but blocking receptors eg using α or β blockers might be useful
signs and symptoms - Headaches
- Palpitations
- Diaphoresis (excessive sweating)
- Anxiety
- Weight loss
- Elevated blood glucose
Adrenal hormones: corticosteroids vs catecholamines
corticosteroids
- Synthesised in cortex
- Cortisol, aldosterone and androgens
- Derived from cholesterol
- Endocrine
- Lipid soluble
- Nuclear receptors
- Effect on enzymes: regulates amount by gene expression
- Slow speed of response
- If adrenalectomy, patient must receive cortisol and aldosterone, otherwise will die
catecholamines
- Synthesised in medulla
- Adrenaline and noradrenaline
- Derived from tyrosine
- Neurocrine
- Stored in vesicles before release
- Water soluble
- Receptors are GPCRs (α and β)
- Regulates activity of existing enzymes
- Fast speed of response (seconds)
- If adrenalectomy, no apparent ill effect from lack of adrenal catecholamines
