Endocrine Topic 5 - Adrenal Glands Flashcards
Which diseases are often associated with Addison’s disease?
Other autimmune diseases e.g. T1DM, thyroid, pernicious anaemia
Describe the mechanism of action of ACTH
- Binds to 7TMD G protein coupled receptor
- Conformational change - adenyl cyclase, increases cAMP, PKA activation, Ca2+ influx
- Rapid and long-term actions
- Rapid - stimulation of cholesterol delivery to mitochondria
- Long-term - transcription of genes coding for steroidogenic enzymes
- Increases cortisol/androgen production
Describe the formation of ACTH
- Peptide hormone formed from cleavage of pro-opiomelanocortin (POMC) in corticotropes in anterior pituitary
- Lipotropin (beta endorphin precursor), beta endorphin and metencephalin (opiod peptides - reduce pain, euphoria) and melanocyte stimulating hormone also released
How can primary and secondary adrenal insufficiency be distinguished?
- Short synacthen test
- Primary = low cortisol after ACTH
- Secondary = high cortisol after ACTH
Describe the structure of the zona fasciculata
- Large cells arranged in cords - spongiocytes (appear empty)
- Parallel organisation - fenestrated capillaries run alongside
Describe the hypothalamic-pituitary-adrenal axis
- Time of day (circadian), stress or illness stimulate release of corticotrophin releasing hormone (CRH) from the hypothalamus
- CRH stimulates adrenocorticotrophic (ACTH) hormone from the anterior pituitary
- ACTH stimulates cortisol/androgen release from the adrenal cortex
Describe the mechanism of action of steroid hormones
- Diffuse through plasma membrane
- Bind to intracellular cytosolic receptor - steroid receptor
- Receptor-hormone complex moves into nucleus, binds to glucocorticoid response element (DNA sequence) in 51 flanking region of target genes
- Binding causes gene transcription of mRNA sequences, translation produces proteins which modulate the response
What activates the renin-angiotensin system?
Activated in response to low BP and/or high plasma potassium
Describe the affinity of steroid hormone receptors for steroid hormones
- Mineralocorticoid receptor = aldosterone > deoxycorticosterone > corticosterone > cortisol > dexamethasone
- Glucocorticoid receptor = dexamethasone > corticosterone > cortisol = aldosterone
What are the actions of the renin-angiotensin system?
Renin leads to production of angiotensin II - direct (vasoconstriction) and indirect (thirst/aldosterone) methods of increasing blood pressure
Describe the structure of the adrenal medulla
- Chromaffin cells, medullary veins, splanchnic nerves
- Rounded cords with large secretory cells
- Blood from capillaries/sinusoids of cortex and arterioles from capsule
Describe the embryological origin of the adrenal glands
- Cortex - genital ridge (mesoderm)
- Medulla - neural crest (sympathetic nerve system) - ectoderm
List the types of steroid receptor
- Glucocorticoid receptor - widespread
- Minerlocorticoid receptor - distal nephron, salivary glanfs, sweat glands, large intestine
Describe the venous drainage of adrenal glands
- Left adrenal vein, drains to left renal vein
- Right adrenal vein, drains to inferior vena cava
Define Addison’s disease
- Primary adrenal insufficiency
- Autoimmune destruction of adrenal cortex - 90% destroyed before symptomatic, autoantibodies in 70%
How are steroid hormones formed?
- All synthesised from cholesterol - taken up from circulation (as LDL through LDL receptors then esterified to free cholesterol) or synthesised de novo from acetyl coA (rate limiting enzyme is HMG coA reductase)
- Rate limiting step - cholesterol transported from cytoplasm into mitochondria by steroidogenic acute regulatory protein (StAR)
Which hormones are produced by each part of the adrenal glands?
- Cortex
- Zona glomerulosa - mineralocorticoids e.g. aldosterone
- Zona fasiculata - glucocorticoids e.g. cortisol
- Zona reticularis - adrenal androgens e.g. DHEA, DHEAS
- Medulla
- Catecholamines - adrenaline, noradrenaline
How is adrenal insufficiency managed?
- Hydrocortisone as cortisol replacement
- If unwell IV
- Then 15-30mg daily - split dose (oral tablets)
- Mimic diurnal rhythm
- Fludrocortisone as aldosterone replacement
- Monitor BP and plasma K+
- Education - increase dose when unwell
- Cannot stop suddenly
- Need identification to show long-term steroid treatment
How does the action of angiotensin II lead to aldosterone release?
- Binds to 7TMD G-coupled receptor
- Activates phospholipase C
- Hydrolyses PIP2 to IP3 and DAG
- IP3 causes stored calcium to be released
- Increased calcium activates Ca2+ calmodulin dependent protein kinases (CaMKs), causes StAR transcription, increased cholesterol movement into the mitochondria
- Increased aldosterone production
Describe the innervation of the adrenal glands
Coeliac plexus and thoracic splanchnic nerves (innervate chromaffin cells)
Describe the structure of the zona glomerulosa
Clusters of small cells, dark granules, close association with blood vessels
Describe the gross structure of the adrenal glands
- Endocrine glands (4-6cm, 6-8g) - rich blood supply
- Pyramidal
- Yellow due to high cholesterol
- Outer cortex and inner medulla
- Outer cortex - zones, secrete different hormones
- Inner medulla - embryologically/histologically distinct
Define Cushing’s syndrome
- Excess cortisol production
- High mortality, rare
- More common in women - 20-40 years old
How is Addison’s disease diagnosed?
- Biochemistry - low Na+, high K+, hypoglycaemia
- Short synacthen test
- Measure plasma cortisol before and 30 minutes after ACTH injection
- Normal - baseline >250nmol/L, post-ACTH >480nmol/L
- ACTH level - high
- Renin high, aldosterone lw
- Adrenal autoantibodies
Why does skin pigmentation occur in Addison’s disease
High levels of ACTH (no negative feedback) - bind to melanocortin 1 receptors on the surface of dermal melanocytes
List the effects of cortisol
- Increased gluconeogenesis
- Permissive effect on glucagon
- Increased lipolysis in adipose tissue to produce free fatty acids (used for energy or in gluconeogenesis)
- Insulin antagonist
- Increased skeletal muscle protein breakdown
- Memory, learning, mood
- Immune suppression
Describe the arterial supply of the adrenal glands
- Superior adrenal artery - inferior phrenic artery
- Middle adrenal artery - abdominal aorta
- Inferior adrenal artery - renal arteries
Describe the histological layers of the adrenal glands
- Mature adipose tissue surrounds for protection
- Fibrous capsule
- Zona glomerulosa
- Zona fasciculata
- Zona reticularis
- Medulla
Describe the structure of the zona reticularis
- Smaller cells, haphazard arrangement
- Stain darker, less lipids
List the effects of aldosterone
- Bind to mineralocorticoid receptors on principle cells of DCT and collecting ducts
- Upregulates Na+/K+ ATPase, ENaC, H+/ATPase (intercalated cells), K+ secretion into lumen, SGK-1 (increased Na+/K+ ATPase)
- Causes
- Increased Na+ reabsorption by the kidneys, therefore increased water reabsorption and an increase in BP
- Increased K+ excretion by the kidneys
- Increased H+ excretion by the kidneys
How is hormone production in the adrenal gland regulated?
- Androgens regulated by ACTH
- Glucocorticoids regulated by ACTH
- Mineralocorticoids regulated RAS
Describe the causes of Cushing’s syndrome
- ACTH dependent
- Pituitary adenoma (68%)
- Ectopic ACTH - carcinoid/oma
- Ectopic CRH
- ACTH independent
- Adrenal adenoma
- Adrenal carcinoma
- Nodular hyperplasia
What is the cause of iatrogenic Cushing’s syndrome?
- Prolonged high dose steroid therapy, usually oral (can be inhaled/injected)
- In asthma, rheumatoid arthritis, inflammatory bowel disease, transplants etc.
- Chronic suppression of ACTH production and adrenal atrophy
- Unable to respond to stress/illness - need extra doses when ill
- Cannot stop steroid therapy suddenly - gradual withdrawal of steroid therapy if 4-6+ weeks
Describe the clinical features of Cushing’s syndrome
- Euphoria (or depression/psychosis)
- Hypertension
- Buffalo hump
- Thinning of skin
- Wasting of arm + leg muscles
- Easy bruising
- Avascular necrosis of femoral head
- Increased abdominal fat
- Moon face and red cheeks
- Cataracts
- Striae
How is Cushing’s syndrome managed?
- Surgical - removal of ACTH source
- Transphenoidal pituitary surgery
- Laproscopic adrenalectomy
- Medical - metyrapone/ketaconazole - inhibit cortisol production, short-term
List the clinical features of Addison’s disease
- Anorexia
- Weight loss
- Pre-syncope
- Low BP (postural hypotension)
- Abdominal pain
- Vomiting
- Diarrhoea
- Skin pigmentation
Where are the adrenal glands located?
In abdomen, superior to kidneys
Retroperitoneal
How is Cushing’s syndrome diagnosed?
- Establish cortisol excess
- Dexamethasone suppression testing
- 24 hr urinary free cortisol
- Late night salivary cortisol
- Establish course of cortisol excess
- Measure ATCH
- Undetectable - adrenal scan
- Normal/high - CRH stimulation test
- No change - CT chest/abdomen/pelvis - ectopic
- Exaggerated rise in ACTH - pituitary MRI
- Measure ATCH
What causes secondary adrenal insufficiency?
- Pituitary/hypothalamus tumour/exogenous steroid use (predisolone, dexatriethasone, inhaled corticosteroid)
- No skin darkening, no need for fludrocortisone
Compare cortisol and aldosterone concentration
- High concentration of cortisol compared with aldosterone
- Cortisol converted to cortisone (inactive), catalysed by 11 beta-hydroxysteroid dehydrogenase in selected tissues e.g. kidneys to allow aldosterone to function
