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1 - HPA Axis Flashcards

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1
Q

What are the 3 zones of the adrenal cortex?

A

Zona glomerulosa
Zona fasciculata
Zona reticularis

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2
Q

What hormones does the

zona glomerulosa make?

A

Mineralocorticoids

e.g. aldosterone

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3
Q

What hormones does the zona fasciculata make?

A

Glucocorticoids (e.g. cortisol)

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4
Q

What hormones does the zona reticularis make?

A

Sex steroids

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5
Q

What hormones does the adrenal make?

A

Catecholamines

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6
Q

Cortisol has systemic effects. What are the effects on the liver, muscle and adipose tissue?

A

Liver = gluconeogenesis

Muscle = release AA + block glucose uptake

Adipose = release of FFA (substrate for metabolism)

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7
Q

Name 3 environmental factors that alter CRH release?

A

Diurnal rhythm
Stress
Food (insulin?)

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8
Q

Diurnal variation of CRH release means which time has the highest cortisol level, and which has the lowest?

A

Highest = 6am

Lowest = midnight

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9
Q

CRH release occurs in what pattern?

A

Pulsatile

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10
Q

How frequently does pulsatile release occur for CRH?

A

Every 1-3h

7-8 per day

Fewer at night, more in day.

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11
Q

What effect does cortisol have on the immune system?

A

Suppresses lymphocyte function

Slows wound healing

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12
Q

What effect do interleukins have on CRH?

A

Stimulate its release

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13
Q

What is the pro-hormone to ACTH?

A

POMC

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14
Q

What receptor does CRH bind to?

A

CHR-R1

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15
Q

What G-protein coupled receptor is the CHR-R1?

A

GalphaS

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16
Q

How does activation of CHR-R1 results in POMC transcription?

A 
CRH binds
Stimulates adenylate cyclase
Increases cAMP
Activates PKA
Activates CREB
Binds to promoter region
Result in POMC transcription
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17
Q

What effect do glucocorticoids have on POMC production?

A

They inhibit it

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18
Q

What hormone is responsible for cleaviing POMC?

A

Pro-hormone convertase 1

PC1

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19
Q

Breakdown of POMC by PC1 results in what products?

A

1) Pro-ACTH

2) Beta-LPH

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20
Q

Pro-ACTH is then converted into what 3 products?

And by what enzyme?

A

N-POC (N-pro-opiocortin)
JP (joining peptide)
ACTH

By PC1

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21
Q

ACTH binds to what receptor in the adrenal cortex to stimulate glucocorticoid release?

A

Melanocortin 2-receptor (MC2-R)

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22
Q

What hormones can stimulate MC2-R?

A

ACTH
Pro-ACTH
POMC

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23
Q

Where are pro-convertase 1 and 2 found in the human body?

A

PC1 is found in hypothalamus

PC2 is found everywhere else.

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24
Q

What breakdown product of POMC results in pigmentation in the skin?

A

alpha-MSH

(melanocyte-stimulating hormone)

** think, clinical relevance of Cushing’s disease

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25
What receptor does alpha-MSH bind to?
Melanocortin receptors
26
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.
27
In the production of cortisol, what does the StAR protein do?
Moves cholesterol into mitochondria
28
What protein carries cortisol around the body?
Corticosteroid binding globulin (CBG)
29
CBG is responsible for binding to what % of cortisol and aldosterone?
90% cortisol 60% aldosterone
30
What pathologies cause CBG levels to fluctuate?
Hyperthryoidism | Diabetes
31
Which melanocortin receptors are found in the skin?
MCR1 | MCR5
32
Which melanocortin receptors are found in the hypothalamus?
MCR3 | MCR4
33
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
34
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)
35
What drugs can cause Cushing's syndrome?
Prednisolone Dexamethasone For immune suppression (asthma, UC), palliative care (cancer)
36
What causes pseudo-cushing's?
Alcohol
37
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)
38
What two cancers can you get in the adrenal cortex to produce excess cortisol?
Adenoma | Carcinoma
39
Describe the process of ubiquitination
Process that occurs post-translation, targeting proteins for degradation.
40
Give 3 examples of ectopic tumour sites
Lung Thymus Pancreas
41
Why might ectopic tumours not be able to produce ACTH, but can produce precursors?
Undifferentiated cells, therefore cannot carry out all the pathways.
42
What are the clinical features of an ectopic ACTH-producing tumour?
Cushing's features Metabolic (hypokalaemia) Pneumonia / infections (immunosuppressed)
43
What pathway results in pigmentation?
POMC Alpha-MSH / ACTH [high concentration] MC1R (and MC5R) = Skin pigmentation
44
What are the normal range values for ACTH production during the day and at night?
Day: 5-50mg/L Night: <5ng/L
45
What are the normal range values for cortisol production?
Day: 200-550 nmol/L Night: <50 nmol/L
46
What are the 3 ways to measure cortisol levels?
Immunoassay (single antibody) Salivary cortisol Urinary cortisol
47
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.
48
What is the overall benefit of measuring for ACTH precursors?
It helps distinguish between pituitary and ectopic tumours.
49
What two methods can help distinguish between a pituitary and an ectopic tumour?
High-dose dexamethasone CRH-stimulation (100ug) test
50
If both of those methods fail, what option remains?
Inferior petrosal sinus sampling
51
What are the disadvantages of IPSS?
Specialist centre Cause mortality / morbidity Cost Require very accurate ACTH assay
52
What 3 imaging modalities (in accuracy order) are used ?
X-ray High-res CT MRI
53
What clinical finding can help outline an ectopic ACTH producing tumour?
Hypokalaemia | possible hyperglycaemia
54
What pharmaceutical treatment can be used for an ectopic tumour? How does it work?
Metyrapone Cortisol production inhibitor
55
How do you treat pituitary / adrenal tumours?
Can use metyrapone Surgery (transphenoidal) Irradiation Adrenalectomy ?
56
How do you treat ectopic tumours?
If aggressive, chemotherapy. If benign, metyrapone.
57
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)
58
With GC-receptor transactivation, what 2 other receptors are activated within the liver?
Phosphoenolpyruvate carboxykinase (PEPCK) Tyrosine aminotransferase (TAT)
59
What is the function of PEPCK?
Control the rate of gluconeogenesis
60
What is the function of TAT?
Enzyme involved in gluconeogenesis
61
With GC-receptor transactivation, what receptor is activated in adipose tissue?
Enhancer binding-protein (CCAAT / C/EBPdelta)
62
What are the functions of enhancer binding-proteins?
Activate adipogenesis
63
In the context of immunosuppression, how do glucocorticoids cause it?
GR sequesters other transcription factors and prevents them from binding
64
In the context of bone mineralisation, what protein do GCs and their receptors inhibit?
Osteocalcin transcription
65
What pro-inflammatory groups of substances are also repressed?
Interleukins (IL-1B /8 /4) TNF-alpha GM-CSF (WBC growth factor)
66
What is the function of aldosterone?
Sodium retention by the kidney
67
What two triggers can stimulate the RAAS?
Hyponatraemia | Hypovolaemia
68
What enzyme is responsible for inhibiting glucocorticoids from stimulating the mineralocorticoid receptor?
11Beta-HSD2
69
What is the action of 11beta-HSD2?
Converts (Active) cortisol into (inactive) cortisone.
70
What enzyme converts cortisone back into cortisol?
11Beta-HSD1
71
Where is 11Beta-HSD1 found?
Liver | Peripheries
72
What features arise in Addison's disease?
Low Na High K Low Fluid Postural hypotension SKIN PIGMENTATION **Addisonian crisis
73
What is the treatment of Addison's disease?
Saline Hydrocortisone 2-3x Fludrocortisone
74
Why do you give fludrocortisone in Addison's disease?
Has a mineralocorticoid effect
75
What is Conn's syndrome?
High levels of aldosterone
76
What are 3 causes of Conn's?
Adenoma (z. glomerulosa) Adrenal hyperplasia Liquorice
77
How does liquorice cause Conn's syndrome?
11Beta-HSD2 inhibitor
78
Congenital adrenal hyperplasia is a condition which occurs from what pathology?
Enzyme defect
79
What analogy is best used to describe the pathology of congenital adrenal hyperplasia?
Motorway diversion. **At junction 21
80
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.
81
In regards to adrenal cortical hormones, what proportions do you get?
No glucocorticoids No aldosterone EXCESS androgens
82
Clinical features of excess androgens in girls?
- Virilised at birth - Rapid growth (tall/strong) - Amenorrhoea / oligmenorrhoea - Epiphyseal fusion earlier
83
Clinical features of excess androgens in boys?
- Normal genitalia - High initial growth rate (short final height) - Large penis - Small testes
84
How do you treat congenital adrenal hyperplasia?
``` Replace GC (hydrocortisone) Replace mineralocorticoid (fludrocortisone) ```
85
What effect does GC / mineralocorticoid treatment have on androgen production?
Suppresses it (negative feedback shit)
86
What inheritance pattern does 21-hydroxylase deficiency take?
Autosomal recessive disorder
87
What percentage of congenital adrenal hyperplasia have 21-hydroxylase deficiency as a cause?
90%
88
What is the incidence of 21-hydroxylase deficiency?
1/5000 - 1/15,000
89
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)

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