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AE > 1 - HPA Axis > Flashcards

1 - HPA Axis Flashcards

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
Q

What receptor does alpha-MSH bind to?

A

Melanocortin receptors

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26
Q

What is the link between a POMC mutation and obesity within children?

A

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.

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27
Q

In the production of cortisol, what does the StAR protein do?

A

Moves cholesterol into mitochondria

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28
Q

What protein carries cortisol around the body?

A

Corticosteroid binding globulin (CBG)

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29
Q

CBG is responsible for binding to what % of cortisol and aldosterone?

A

90% cortisol

60% aldosterone

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30
Q

What pathologies cause CBG levels to fluctuate?

A

Hyperthryoidism

Diabetes

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31
Q

Which melanocortin receptors are found in the skin?

A

MCR1

MCR5

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32
Q

Which melanocortin receptors are found in the hypothalamus?

A

MCR3

MCR4

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33
Q

What is the difference between Cushing’s syndrome and Cushing’s disease?

A

Cushing’s disease refers to the ACTH-producing pituitary adenoma.

Cushing’s syndrome refers to a state of hypercortisolism

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34
Q

What are the 4 causes of Cushing’s syndrome?

A

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)

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35
Q

What drugs can cause Cushing’s syndrome?

A

Prednisolone
Dexamethasone

For immune suppression (asthma, UC), palliative care (cancer)

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36
Q

What causes pseudo-cushing’s?

A

Alcohol

37
Q

What are the relative proportions of Cushing’s syndrome causes?

A

Cushing’s disease - 70%

Adrenal tumour - 17%

Ectopic tumour - 13%

CRH producing ectopic (very rare)

38
Q

What two cancers can you get in the adrenal cortex to produce excess cortisol?

A

Adenoma

Carcinoma

39
Q

Describe the process of ubiquitination

A

Process that occurs post-translation, targeting proteins for degradation.

40
Q

Give 3 examples of ectopic tumour sites

A

Lung
Thymus
Pancreas

41
Q

Why might ectopic tumours not be able to produce ACTH, but can produce precursors?

A

Undifferentiated cells, therefore cannot carry out all the pathways.

42
Q

What are the clinical features of an ectopic ACTH-producing tumour?

A

Cushing’s features

Metabolic (hypokalaemia)

Pneumonia / infections (immunosuppressed)

43
Q

What pathway results in pigmentation?

A

POMC

Alpha-MSH / ACTH [high concentration]

MC1R (and MC5R)

= Skin pigmentation

44
Q

What are the normal range values for ACTH production during the day and at night?

A

Day: 5-50mg/L

Night: <5ng/L

45
Q

What are the normal range values for cortisol production?

A

Day: 200-550 nmol/L

Night: <50 nmol/L

46
Q

What are the 3 ways to measure cortisol levels?

A

Immunoassay (single antibody)

Salivary cortisol

Urinary cortisol

47
Q

What is the issue with taking an ACTH assay in the of an ectopic tumour?

A

ACTH assay cannot detected ACTH precursors - of which the tumour may only be producing.

48
Q

What is the overall benefit of measuring for ACTH precursors?

A

It helps distinguish between pituitary and ectopic tumours.

49
Q

What two methods can help distinguish between a pituitary and an ectopic tumour?

A

High-dose dexamethasone

CRH-stimulation (100ug) test

50
Q

If both of those methods fail, what option remains?

A

Inferior petrosal sinus sampling

51
Q

What are the disadvantages of IPSS?

A

Specialist centre
Cause mortality / morbidity
Cost
Require very accurate ACTH assay

52
Q

What 3 imaging modalities (in accuracy order) are used ?

A

X-ray
High-res CT
MRI

53
Q

What clinical finding can help outline an ectopic ACTH producing tumour?

A

Hypokalaemia

possible hyperglycaemia

54
Q

What pharmaceutical treatment can be used for an ectopic tumour?

How does it work?

A

Metyrapone

Cortisol production inhibitor

55
Q

How do you treat pituitary / adrenal tumours?

A

Can use metyrapone

Surgery (transphenoidal)
Irradiation

Adrenalectomy ?

56
Q

How do you treat ectopic tumours?

A

If aggressive, chemotherapy.

If benign, metyrapone.

57
Q

What are the 6 main functions of cortisol?

A

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
Q

With GC-receptor transactivation, what 2 other receptors are activated within the liver?

A

Phosphoenolpyruvate carboxykinase (PEPCK)

Tyrosine aminotransferase (TAT)

59
Q

What is the function of PEPCK?

A

Control the rate of gluconeogenesis

60
Q

What is the function of TAT?

A

Enzyme involved in gluconeogenesis

61
Q

With GC-receptor transactivation, what receptor is activated in adipose tissue?

A

Enhancer binding-protein (CCAAT / C/EBPdelta)

62
Q

What are the functions of enhancer binding-proteins?

A

Activate adipogenesis

63
Q

In the context of immunosuppression, how do glucocorticoids cause it?

A

GR sequesters other transcription factors and prevents them from binding

64
Q

In the context of bone mineralisation, what protein do GCs and their receptors inhibit?

A

Osteocalcin transcription

65
Q

What pro-inflammatory groups of substances are also repressed?

A

Interleukins (IL-1B /8 /4)
TNF-alpha
GM-CSF (WBC growth factor)

66
Q

What is the function of aldosterone?

A

Sodium retention by the kidney

67
Q

What two triggers can stimulate the RAAS?

A

Hyponatraemia

Hypovolaemia

68
Q

What enzyme is responsible for inhibiting glucocorticoids from stimulating the mineralocorticoid receptor?

A

11Beta-HSD2

69
Q

What is the action of 11beta-HSD2?

A

Converts (Active) cortisol into (inactive) cortisone.

70
Q

What enzyme converts cortisone back into cortisol?

A

11Beta-HSD1

71
Q

Where is 11Beta-HSD1 found?

A

Liver

Peripheries

72
Q

What features arise in Addison’s disease?

A

Low Na
High K
Low Fluid

Postural hypotension
SKIN PIGMENTATION

**Addisonian crisis

73
Q

What is the treatment of Addison’s disease?

A

Saline
Hydrocortisone 2-3x
Fludrocortisone

74
Q

Why do you give fludrocortisone in Addison’s disease?

A

Has a mineralocorticoid effect

75
Q

What is Conn’s syndrome?

A

High levels of aldosterone

76
Q

What are 3 causes of Conn’s?

A

Adenoma (z. glomerulosa)

Adrenal hyperplasia

Liquorice

77
Q

How does liquorice cause Conn’s syndrome?

A

11Beta-HSD2 inhibitor

78
Q

Congenital adrenal hyperplasia is a condition which occurs from what pathology?

A

Enzyme defect

79
Q

What analogy is best used to describe the pathology of congenital adrenal hyperplasia?

A

Motorway diversion.

**At junction 21

80
Q

What is the most common enzyme defect and what part of the metabolic pathway is disrupted?

A

21-hydroxylase

Converts progesterone
into
11-deoxycorticosterone

and

17alpha-OH progesterone
into
11-deoxycortisol

Respectively.

81
Q

In regards to adrenal cortical hormones, what proportions do you get?

A

No glucocorticoids
No aldosterone

EXCESS androgens

82
Q

Clinical features of excess androgens in girls?

A
  • Virilised at birth
  • Rapid growth (tall/strong)
  • Amenorrhoea / oligmenorrhoea
  • Epiphyseal fusion earlier
83
Q

Clinical features of excess androgens in boys?

A
  • Normal genitalia
  • High initial growth rate (short final height)
  • Large penis
  • Small testes
84
Q

How do you treat congenital adrenal hyperplasia?

A 
Replace GC (hydrocortisone)
Replace mineralocorticoid (fludrocortisone)
85
Q

What effect does GC / mineralocorticoid treatment have on androgen production?

A

Suppresses it (negative feedback shit)

86
Q

What inheritance pattern does 21-hydroxylase deficiency take?

A

Autosomal recessive disorder

87
Q

What percentage of congenital adrenal hyperplasia have 21-hydroxylase deficiency as a cause?

A

90%

88
Q

What is the incidence of 21-hydroxylase deficiency?

A

1/5000 - 1/15,000

89
Q

What are the clinical, PRESENTING features of Congenital adrenal hyperplasia?

A 
Salt-wasting crisis in neonates
Failure to gain weight
Vomiting
Dehydration
Shock

Death (adrenal crisis)

AE (7 decks)

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