1 - HPA Axis Flashcards
What are the 3 zones of the adrenal cortex?
Zona glomerulosa
Zona fasciculata
Zona reticularis
What hormones does the
zona glomerulosa make?
Mineralocorticoids
e.g. aldosterone
What hormones does the zona fasciculata make?
Glucocorticoids (e.g. cortisol)
What hormones does the zona reticularis make?
Sex steroids
What hormones does the adrenal make?
Catecholamines
Cortisol has systemic effects. What are the effects on the liver, muscle and adipose tissue?
Liver = gluconeogenesis
Muscle = release AA + block glucose uptake
Adipose = release of FFA (substrate for metabolism)
Name 3 environmental factors that alter CRH release?
Diurnal rhythm
Stress
Food (insulin?)
Diurnal variation of CRH release means which time has the highest cortisol level, and which has the lowest?
Highest = 6am
Lowest = midnight
CRH release occurs in what pattern?
Pulsatile
How frequently does pulsatile release occur for CRH?
Every 1-3h
7-8 per day
Fewer at night, more in day.
What effect does cortisol have on the immune system?
Suppresses lymphocyte function
Slows wound healing
What effect do interleukins have on CRH?
Stimulate its release
What is the pro-hormone to ACTH?
POMC
What receptor does CRH bind to?
CHR-R1
What G-protein coupled receptor is the CHR-R1?
GalphaS
How does activation of CHR-R1 results in POMC transcription?
CRH binds Stimulates adenylate cyclase Increases cAMP Activates PKA Activates CREB Binds to promoter region Result in POMC transcription
What effect do glucocorticoids have on POMC production?
They inhibit it
What hormone is responsible for cleaviing POMC?
Pro-hormone convertase 1
PC1
Breakdown of POMC by PC1 results in what products?
1) Pro-ACTH
2) Beta-LPH
Pro-ACTH is then converted into what 3 products?
And by what enzyme?
N-POC (N-pro-opiocortin)
JP (joining peptide)
ACTH
By PC1
ACTH binds to what receptor in the adrenal cortex to stimulate glucocorticoid release?
Melanocortin 2-receptor (MC2-R)
What hormones can stimulate MC2-R?
ACTH
Pro-ACTH
POMC
Where are pro-convertase 1 and 2 found in the human body?
PC1 is found in hypothalamus
PC2 is found everywhere else.
What breakdown product of POMC results in pigmentation in the skin?
alpha-MSH
(melanocyte-stimulating hormone)
** think, clinical relevance of Cushing’s disease
What receptor does alpha-MSH bind to?
Melanocortin receptors
What is the link between a POMC mutation and obesity within children?
Arcuate nucleus within hypothalamus contains both PC1 and PC2.
Also produces POMC.
alpha-MSH inhibits food intake
Therefore, obese kids have POMC mutation because can’t stop eating.
In the production of cortisol, what does the StAR protein do?
Moves cholesterol into mitochondria
What protein carries cortisol around the body?
Corticosteroid binding globulin (CBG)
CBG is responsible for binding to what % of cortisol and aldosterone?
90% cortisol
60% aldosterone
What pathologies cause CBG levels to fluctuate?
Hyperthryoidism
Diabetes
Which melanocortin receptors are found in the skin?
MCR1
MCR5
Which melanocortin receptors are found in the hypothalamus?
MCR3
MCR4
What is the difference between Cushing’s syndrome and Cushing’s disease?
Cushing’s disease refers to the ACTH-producing pituitary adenoma.
Cushing’s syndrome refers to a state of hypercortisolism
What are the 4 causes of Cushing’s syndrome?
Cushing’s disease (ACTH-producing pituitary tumour)
Non-pituitary (ectopic) tumour (produced ACTH-related peptides)
Adrenal tumour (producing cortisol)
Ectopic tumour producing CRH (VERY RARE)
What drugs can cause Cushing’s syndrome?
Prednisolone
Dexamethasone
For immune suppression (asthma, UC), palliative care (cancer)
What causes pseudo-cushing’s?
Alcohol
What are the relative proportions of Cushing’s syndrome causes?
Cushing’s disease - 70%
Adrenal tumour - 17%
Ectopic tumour - 13%
CRH producing ectopic (very rare)
What two cancers can you get in the adrenal cortex to produce excess cortisol?
Adenoma
Carcinoma
Describe the process of ubiquitination
Process that occurs post-translation, targeting proteins for degradation.
Give 3 examples of ectopic tumour sites
Lung
Thymus
Pancreas
Why might ectopic tumours not be able to produce ACTH, but can produce precursors?
Undifferentiated cells, therefore cannot carry out all the pathways.
What are the clinical features of an ectopic ACTH-producing tumour?
Cushing’s features
Metabolic (hypokalaemia)
Pneumonia / infections (immunosuppressed)
What pathway results in pigmentation?
POMC
Alpha-MSH / ACTH [high concentration]
MC1R (and MC5R)
= Skin pigmentation
What are the normal range values for ACTH production during the day and at night?
Day: 5-50mg/L
Night: <5ng/L
What are the normal range values for cortisol production?
Day: 200-550 nmol/L
Night: <50 nmol/L
What are the 3 ways to measure cortisol levels?
Immunoassay (single antibody)
Salivary cortisol
Urinary cortisol
What is the issue with taking an ACTH assay in the of an ectopic tumour?
ACTH assay cannot detected ACTH precursors - of which the tumour may only be producing.
What is the overall benefit of measuring for ACTH precursors?
It helps distinguish between pituitary and ectopic tumours.
What two methods can help distinguish between a pituitary and an ectopic tumour?
High-dose dexamethasone
CRH-stimulation (100ug) test
If both of those methods fail, what option remains?
Inferior petrosal sinus sampling
What are the disadvantages of IPSS?
Specialist centre
Cause mortality / morbidity
Cost
Require very accurate ACTH assay
What 3 imaging modalities (in accuracy order) are used ?
X-ray
High-res CT
MRI
What clinical finding can help outline an ectopic ACTH producing tumour?
Hypokalaemia
possible hyperglycaemia
What pharmaceutical treatment can be used for an ectopic tumour?
How does it work?
Metyrapone
Cortisol production inhibitor
How do you treat pituitary / adrenal tumours?
Can use metyrapone
Surgery (transphenoidal)
Irradiation
Adrenalectomy ?
How do you treat ectopic tumours?
If aggressive, chemotherapy.
If benign, metyrapone.
What are the 6 main functions of cortisol?
1) Increases blood glucose (gluconeogesis / glycogenolysis)
2) Increase lipolysis
3) Increases amino acid availability (reduced protein synthesis / increase hepatic protein metabolism)
4) Immunosuppressive
5) Metabolic (Increase Na, Decrease K)
6) Bone (osteoporosis)
With GC-receptor transactivation, what 2 other receptors are activated within the liver?
Phosphoenolpyruvate carboxykinase (PEPCK)
Tyrosine aminotransferase (TAT)
What is the function of PEPCK?
Control the rate of gluconeogenesis
What is the function of TAT?
Enzyme involved in gluconeogenesis
With GC-receptor transactivation, what receptor is activated in adipose tissue?
Enhancer binding-protein (CCAAT / C/EBPdelta)
What are the functions of enhancer binding-proteins?
Activate adipogenesis
In the context of immunosuppression, how do glucocorticoids cause it?
GR sequesters other transcription factors and prevents them from binding
In the context of bone mineralisation, what protein do GCs and their receptors inhibit?
Osteocalcin transcription
What pro-inflammatory groups of substances are also repressed?
Interleukins (IL-1B /8 /4)
TNF-alpha
GM-CSF (WBC growth factor)
What is the function of aldosterone?
Sodium retention by the kidney
What two triggers can stimulate the RAAS?
Hyponatraemia
Hypovolaemia
What enzyme is responsible for inhibiting glucocorticoids from stimulating the mineralocorticoid receptor?
11Beta-HSD2
What is the action of 11beta-HSD2?
Converts (Active) cortisol into (inactive) cortisone.
What enzyme converts cortisone back into cortisol?
11Beta-HSD1
Where is 11Beta-HSD1 found?
Liver
Peripheries
What features arise in Addison’s disease?
Low Na
High K
Low Fluid
Postural hypotension
SKIN PIGMENTATION
**Addisonian crisis
What is the treatment of Addison’s disease?
Saline
Hydrocortisone 2-3x
Fludrocortisone
Why do you give fludrocortisone in Addison’s disease?
Has a mineralocorticoid effect
What is Conn’s syndrome?
High levels of aldosterone
What are 3 causes of Conn’s?
Adenoma (z. glomerulosa)
Adrenal hyperplasia
Liquorice
How does liquorice cause Conn’s syndrome?
11Beta-HSD2 inhibitor
Congenital adrenal hyperplasia is a condition which occurs from what pathology?
Enzyme defect
What analogy is best used to describe the pathology of congenital adrenal hyperplasia?
Motorway diversion.
**At junction 21
What is the most common enzyme defect and what part of the metabolic pathway is disrupted?
21-hydroxylase
Converts progesterone
into
11-deoxycorticosterone
and
17alpha-OH progesterone
into
11-deoxycortisol
Respectively.
In regards to adrenal cortical hormones, what proportions do you get?
No glucocorticoids
No aldosterone
EXCESS androgens
Clinical features of excess androgens in girls?
- Virilised at birth
- Rapid growth (tall/strong)
- Amenorrhoea / oligmenorrhoea
- Epiphyseal fusion earlier
Clinical features of excess androgens in boys?
- Normal genitalia
- High initial growth rate (short final height)
- Large penis
- Small testes
How do you treat congenital adrenal hyperplasia?
Replace GC (hydrocortisone) Replace mineralocorticoid (fludrocortisone)
What effect does GC / mineralocorticoid treatment have on androgen production?
Suppresses it (negative feedback shit)
What inheritance pattern does 21-hydroxylase deficiency take?
Autosomal recessive disorder
What percentage of congenital adrenal hyperplasia have 21-hydroxylase deficiency as a cause?
90%
What is the incidence of 21-hydroxylase deficiency?
1/5000 - 1/15,000
What are the clinical, PRESENTING features of Congenital adrenal hyperplasia?
Salt-wasting crisis in neonates Failure to gain weight Vomiting Dehydration Shock
Death (adrenal crisis)
