L7 - HPA Axis: Clinical Features

Question 1

HPA AXIS

i) name two releasing factors produced by the hypothalamus
ii) name a trophic hormone released from the pituitary gland
iii) what is produced by the adrenal cortex and negatively feeds back to the PG, HT and brain?
iv) do hypothalamic hormones get into the systemic circulation?

Answer 1

i) CRH and AVP/ADH
ii) ACTH
iii) adrenal cortex produces cortisol which allows negative feedback
iv) no they dont - only go to the PG

Question 2

ADRENAL HORMONES/RECEPTORS/ENZYMES

i) what three hormones does the adrenal cortex produce? Give an example of each
ii) how does 90% of cortisol travel in the blood?
iii) where are receptors for adrenal hormones found?
iv) which enzyme catalyses the conversion of inactive cortisone to active cortisol?
v) what molecule are steroid hormones synthesised from?

Answer 2

i) 1) glucocorticoids - cortisol
2) mineralocorticoids - aldosterone
3) sex steroids - androgens (testosterone)

ii) most cortisol is bound to CBG in the blood
iii) GC and MC receptors are found intracellularly
iv) 11b-HSD catalyses cortisone to cortisol
v) cholesterol

Question 3

EFFECTS OF GLUCOCORTICOIDS

what effects to do GCs have in relation to

i) stress
ii) inflammation
iii) metabolism/energy balance
iv) bone and cartilage
v) BP
vi) name three other things that GCs affect

Answer 3

i) maintain homeostasis during stress eg haemmorhage, infection, anxiety
ii) anti inflammatory (balance out pro-inflam cytokines)
iii) maintain energy balance and metab in stress - increase glucose levels in stress
iv) formation of bone and cartilage
v) regulate BP eg in fight or flight
vi) also affect cognitive function, memory, conditioning

Question 4

RHYTHMS OF CORTISOL PRODUCTION

i) at what time of day do cortisol levels rise?
ii) when do they peak?
iii) when do they fall?
iv) what time of day are they the lowest?
v) what do you need to think about hen examining rhythms of cortisol release? why?

Answer 4

i) cortisol levels rise in the early morning
ii) peak just after waking
iii) fall during the day
iv) lowest in the evening
v) need to think about stress when examining rhythms as there is pulsatile release and a minor stressor can affect pulsatility

Question 5

ULTRADIAN RHYTHMS

i) what is an UR?
ii) when does amplitude of the waves decrease?
iii) what can it be used to measure?
iv) what are its limitations for using them to distinguish stress response in humans?

Answer 5

i) spontaneous pulses of varying amplitude
ii) amplitude decreases in the circadian trough (when cortisol is the lowest)
iii) can be used to measure pulsatility of hormone release
iv) limitations = hard to distinguish stress response due to pulsatility

Question 6

ENZYMES CONTROLLING RECEPTOR BINDING

i) which intracellular receptor has the same affinity of aldosterone and cortisol?
ii) what mechanism confers specificity?
iii) which enzyme works to allow aldosterone to bind? where is this enzyme found?
iv) why is this required?

Answer 6

i) mineralocorticoid receptors have the same affinity for aldo and cortisol
ii) a pre receptor mechanism confers specificity
iii) 11-B-HSD2 in the kidney allows aldo to bind by inactivating cortisol
iv) 11-b-HSD2 activity is required as there are higher levels of cortisol than aldo in the blood (so inactive some cortisol to allow aldo to bind the MC receptor)

Question 7

11-B-HSD ENZYMES

i) what is the principle role of 11-B-HSD2?
ii) what is the principle role of 11-B-HSD1?
iii) what action can it have of glucocorticoid signals in target cells? name two places this can occur

Answer 7

i) HSD2 converts active cortisol to inactive cortisone
ii) HSD1 converts inactive cortisone to active cortisol
iii) 11BHSD can amplify GC signals in target cells such as liver and adipose tissue

Question 8

CUSHINGS SYNDROME

i) name to key symptoms
ii) name four more symptoms
iii) what is the principle underlying this condition?
iv) name four things that can cause this
v) give four clinical features of CS

Answer 8

i) weight gain and central obesity
ii) hypertension, insulin resistance, neuropsych problems, osteoporosis
iii) excess cortisol

iv) excess cortisol can be caused by
1) pituitary adenoma (ACTH secreting)
2) adrenal tumour
3) ectopic ACTH ie produced by a tumour that stimulates the adrenals to produce lots of cortisol
4) iatrogenic - steroid treatment (cushingoid)

v) clin features = central obesity with thin arms and legs
- deposition of fat on upper back
- rounded moon face
- thin skin, easy brusing
- hirtuism (dark hair on women)

Question 9

ADDISONS DISEASE

i) what is the underlying cause of this disease?
ii) what organ is the problem usually primarly in?
iii) is the condition autoimmune? name two other rare causes
iv) name two causes of secondary disease
vi) which adrenocortical hormones does it affect?

Answer 9

i) too little cortisol
ii) primary adrenal insufficiency

iii) condition is usually autoimmune in the UK
two other rare causes are mets and TB

iv) secondary disease can be caused by pituitary disease or iatrogenic (patients on high dose steroids that are suddenly stopped at a time of stress)
vi) affects all of them (decreases them)

Question 10

CLINICAL FEATURES OF ADDISONS DISEASE

i) name four clinical features
ii) how is skin pigmentation affected? why?
iii) how is blood pressure affected?
iv) how is blood sugar affected? at what stage of disease is this seen?

Answer 10

i) malaise, weakness, anorexia, weight loss
ii) increased skin pigmentation as reduced cortisol = increased ACTH which is co-secreted with MSH which stimulates melanocytes
iii) hypotension/postural hypotension
iv) hypoglycaemia - seen in severe adrenal insuff

Question 11

AUTOIMMUNE POLYENDOCRINE SYNDROMES

i) what condition can these cluster with?
ii) which type is monogenic and which is polygenic?
iii) which gene is implicated in the monogenic disease?
iv) what is the age of onset in type I and type II?
v) name 6 of the autoimmune conditions that can occur together in this syndrome

Answer 11

i) can cluster with addisons
ii) type I is monogenic and type II is polygenic
iii) monogenic implicates AIRE gene
iv) age of onset is infancy in type I and infancy-adulthood in type II
v) T1DM, thyroid disease, coeliac, addisons, pernicious anaemia, alopecia, vitligo, hepatitis, myasthenia gravis, premat ovarian failure

Question 12

AUTOIMM POLYENDO SYNDROMES - CLINICAL IMPLICATS

i) if a patient has T1DM with fatigue, weight loss and hypoglycaemia - which condition would you screen for?
ii) if a patient has T1DM and non specific GI symp and diarrhoea - which other condition would you screen for?

Answer 12

i) screen for addisons disease
ii) screen for coeliac disease

Question 13

NAME THE CONDITION

i) central obesity, thin arms & legs, moon face, thin skin, hirsutism and may have hypertension, diabetes, psych manifestation, osteoporosis
ii) malaise, weakness, anorexia, weight loss, increased skin pigmentation, hypotension, hypoglycaemia

Answer 13

i) cushings syndrome - excess cortisol
ii) addisons disease - too little cortisol

Question 14

ASSESSMENT OF THE HPA AXIS - BASAL TESTS

i) name three basal tests and what hormone would be measured by each test
ii) what is important to bear in mind when taking blood tests?
iii) why is urine taken over a 24 hr period?
iv) are there higher levels of cortisol in the saliva or the blood

Answer 14

i) blood - cortisol and ACTH
urine - cortisol
saliva - cortisol

ii) when taking blood test - think about time of day due to circadian/ultradian rhythm of cortisol (can have normal adrenal function but high cortisol if stressed)
iii) urine over 24hrs as cortisol levels vary over this time
iv) higher levels of cortisol in the blood than saliva

Question 15

ASSESSMENT OF THE HPA AXIS - DYNAMIC TESTS

i) what does using ACTH in the stimulated test allow testing of?
ii) what parameter can be measured when the body is stimulated with stress?
iii) what can be used in a supressed test? what does this do physiologically and in disease?

Answer 15

i) stimulate with synthetic ACTH to see if adrenals can mount a cortisol response
ii) stimulate with stress and monitor blood sugar - cortisol should increase blood sugar (opposes insulin)

iii) use dexamethasone in a supressed test
- synthetic GC which will normally supress cortisol production
- pathologically (cushings) it will not supress cortisol production

Question 16

HPA AXIS & TREATMENT

i) what are the conditions labelled A and B?
ii) what may be given to patients that have high levels of cortisol? where does this act?
iii) what may be given to patients with adrenal insufficiency? where does this act?

Answer 16

I) A = Cushings (too much cortisol)
B = Addisons (too little cortisol)

ii) patients with high levels of cortisol may be given dexamethasone which acts on the pitutiary gland
ii) patients with adrenal insufficiency may be given synthetic ACTH (synACTHen) which acts on the adrenal

Question 17

TOO MUCH CORTISOL

i) what test would be conducted over 24 hrs?
ii) which two things would be sampled at midnight? what is usually seen at this time?
iii) what would be sampled at 9am?
iv) what would be seen if there is a) pituitary b) adrenal or c) ecotpic problems in relation to ACTH and cortisol
v) what is seen in these patients when given dexamethasone?

Answer 17

i) urine test (free cortisol)
ii) blood and saliva would be sampled at midnight (saliva is good because doesnt cause stress on sampling) and usually see a trough at this time
iii) sample ACTH at 9am

iv) a) pit problem = both ACTH and cortisol are increased
b) adrenal problem = high cortisol but low ACTH (due to negative feedback to PG)
c) ectopic eg lung cancer = both ACTH and cortisol are increased

v) usually when giving dex you see a reduction in cortisol but not in cushings patients

Question 18

TOO LITTLE CORTISOL

i) what time would you expect to see the cortisol peak?
ii) what do the synACTHen and insulin tolerance test measure?
iii) what is seen on U&E tests in Addisons patients? why?
iv) what may be seen when renin and aldosterone concs are measued?
v) what is seen to be reduced in severe addisons

Answer 18

i) 9am

ii) synACTHen - measure the adrenal response to ACTH
insulin tolerance - make patient hypoglycaemic and measure cortisol response (not really done)

iii) on blood tests see low Na+ and high K+ due to mineralocorticoid deficiency
iv) high renin and low aldosterone
v) see hypoglycaemia in severe addisons

Question 19

IMAGING

i) what three imaging tests may be done once a patient has confirmed cushings?
ii) under which two conditions would you image a patient with addisons disease?

Answer 19

i) CXR, MRI pituitary, CT adrenals
ii) if you suspect the patient to have TB or metastatic cancer (otherwise dont image)

Question 20

MX OF CUSHINGS SYNDROME

i) what is the mainstay of treatment?
ii) what root cause would a a) transphenoidal adenectomy and b) adrenalectomy be done for?
iii) what other treatment may be given in addition to surgery?

Answer 20

i) surgery but depends on the cause

ii) a) pituitary
b) adrenals

iii) RT to pit gland

Question 21

MX OF ADDISONS DISEASE

i) what type of therapy is mainstay of treatment? high or low dose?
ii) what drug is usually given? what pattern is it given in and why
iii) what other therapy may patients with primary adrenal insuffiency need? name a drug
iv) which drug do patients with secondary adrenal insuffiency need? why?

Answer 21

i) medical - steroid hormone replacement therapy
- high dose to cover stresses such as flu

ii) a glucocorticoid eg hydrocortisone (sometimes prednisolone)
- give in divided doses to mimick circadian rhythms

iii) primary insuffiency may also need mineralocorticoid replacement therapy eg fludrocortisone
iv) secondary insufficency only need hydrocortisone as they dont have an adrenal problem so make normal amounts of aldosterone (dont need MC replacement)

Question 22

PATIENTS TAKING STEROIDS

i) what is the most common glucocorticoid given to patients long term?
ii) what effect are steroids usually utlised for? give two conditions where this may happen
iii) what conditions may it look like these patients have?
iv) what effect can long term high dose steroid therapy have on adrenal function? what does this mean for their ability to mount a stress response?
v) what needs to happen to their steroid doses if they need a major procedure/operation?

Answer 22

i) prednisolone

ii) used for anti-inflammatory and immunosupressive effects
- in rheumatoid arthritis and COPD

iii) may look like these patients have cushings but they dont (prednis is similar to cortisol)
iv) long term high dose steroid therapy can supress endogenous adrenal function therefore they cant mount an endogenous stress response