Endocrine Topic 5 - Adrenal Glands Flashcards
(40 cards)
1
Q
Which diseases are often associated with Addison’s disease?
A
Other autimmune diseases e.g. T1DM, thyroid, pernicious anaemia
2
Q
Describe the mechanism of action of ACTH
A
- 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
3
Q
Describe the formation of ACTH
A
- 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
4
Q
How can primary and secondary adrenal insufficiency be distinguished?
A
- Short synacthen test
- Primary = low cortisol after ACTH
- Secondary = high cortisol after ACTH
5
Q
Describe the structure of the zona fasciculata
A
- Large cells arranged in cords - spongiocytes (appear empty)
- Parallel organisation - fenestrated capillaries run alongside
6
Q
Describe the hypothalamic-pituitary-adrenal axis
A
- 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
7
Q
Describe the mechanism of action of steroid hormones
A
- 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
8
Q
What activates the renin-angiotensin system?
A
Activated in response to low BP and/or high plasma potassium
9
Q
Describe the affinity of steroid hormone receptors for steroid hormones
A
- Mineralocorticoid receptor = aldosterone > deoxycorticosterone > corticosterone > cortisol > dexamethasone
- Glucocorticoid receptor = dexamethasone > corticosterone > cortisol = aldosterone
10
Q
What are the actions of the renin-angiotensin system?
A
Renin leads to production of angiotensin II - direct (vasoconstriction) and indirect (thirst/aldosterone) methods of increasing blood pressure
11
Q
Describe the structure of the adrenal medulla
A
- Chromaffin cells, medullary veins, splanchnic nerves
- Rounded cords with large secretory cells
- Blood from capillaries/sinusoids of cortex and arterioles from capsule
12
Q
Describe the embryological origin of the adrenal glands
A
- Cortex - genital ridge (mesoderm)
- Medulla - neural crest (sympathetic nerve system) - ectoderm
13
Q
List the types of steroid receptor
A
- Glucocorticoid receptor - widespread
- Minerlocorticoid receptor - distal nephron, salivary glanfs, sweat glands, large intestine
14
Q
Describe the venous drainage of adrenal glands
A
- Left adrenal vein, drains to left renal vein
- Right adrenal vein, drains to inferior vena cava
15
Q
Define Addison’s disease
A
- Primary adrenal insufficiency
- Autoimmune destruction of adrenal cortex - 90% destroyed before symptomatic, autoantibodies in 70%
16
Q
How are steroid hormones formed?
A
- 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)
17
Q
Which hormones are produced by each part of the adrenal glands?
A
- 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
18
Q
How is adrenal insufficiency managed?
A
- 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
19
Q
How does the action of angiotensin II lead to aldosterone release?
A
- 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
20
Q
Describe the innervation of the adrenal glands
A
Coeliac plexus and thoracic splanchnic nerves (innervate chromaffin cells)
21
Q
Describe the structure of the zona glomerulosa
A
Clusters of small cells, dark granules, close association with blood vessels
22
Q
Describe the gross structure of the adrenal glands
A
- 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
23
Q
Define Cushing’s syndrome
A
- Excess cortisol production
- High mortality, rare
- More common in women - 20-40 years old
24
Q
How is Addison’s disease diagnosed?
A
- 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
25
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
26
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
27
Describe the arterial supply of the adrenal glands
* Superior adrenal artery - inferior phrenic artery
* Middle adrenal artery - abdominal aorta
* Inferior adrenal artery - renal arteries
28
Describe the histological layers of the adrenal glands
* Mature adipose tissue surrounds for protection
* Fibrous capsule
* Zona glomerulosa
* Zona fasciculata
* Zona reticularis
* Medulla
29
Describe the structure of the zona reticularis
* Smaller cells, haphazard arrangement
* Stain darker, less lipids
30
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
31
How is hormone production in the adrenal gland regulated?
* Androgens regulated by ACTH
* Glucocorticoids regulated by ACTH
* Mineralocorticoids regulated RAS
32
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
33
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
34
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
35
How is Cushing's syndrome managed?
* Surgical - removal of ACTH source
* Transphenoidal pituitary surgery
* Laproscopic adrenalectomy
* Medical - metyrapone/ketaconazole - inhibit cortisol production, short-term
36
List the clinical features of Addison's disease
* Anorexia
* Weight loss
* Pre-syncope
* Low BP (postural hypotension)
* Abdominal pain
* Vomiting
* Diarrhoea
* Skin pigmentation
37
Where are the adrenal glands located?
In abdomen, superior to kidneys
Retroperitoneal
38
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
39
What causes secondary adrenal insufficiency?
* Pituitary/hypothalamus tumour/exogenous steroid use (predisolone, dexatriethasone, inhaled corticosteroid)
* No skin darkening, no need for fludrocortisone
40
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
