Hypothalamic-pituitary-adrenal axis: clinical aspects

Question 1

What is shown in the image?

Answer 1

Hypothalamic-pituitary axis

Question 2

Hypothalamic-pituitary-adrenal axis

• Releasing factors are … and to a lesser extent …
• Trophic hormone is … (from pituitary)
• Adrenal gland principal hormone is …
• … feedback of cortisol at both the pituitary and hypothalamic levels

Answer 2

• Releasing factors are CRH, AVP to a lesser extent
• Trophic hormone is ACTH
• Adrenal gland principal hormone is cortisol
• negative feedback of cortisol at both the pituitary and hypothalamic levels

Question 3

What kind of circulation does the pituitary have?

Answer 3

portal capillary circulation

Question 4

• Label the image (Top left, top right, bottom left, bottom right)
• What scan is it? What plane? … weighted

Answer 4

• top left arrow = hypothalamus
• top right arrow = pituitary stalk
• bottom left arrow = optic chiasm
• bottom right arrow = pituitary gland with small adenoma (lower intensity)
• MRI scan, coronal plane, T1 weighted

Question 5

The adrenal cortex produces 3 different types of hormones, which are:

1. … e.g …
2. … e.g …
3. … e.g …

Answer 5

1. Glucocorticoid e.g cortisol
2. Mineralocorticoid e.g aldosterone (regulated by renin-angiotensin-aldosterone system)
3. Sex steroids e.g androgens

Question 6

In the blood, 90% of cortisol is bound to cortisol binding … (CBG)

Answer 6

• 90% is bound to cortisol binding globulin (CBG)

Question 7

Receptors - hypothalamic-pituitary-adrenal axis

• intracellular … and …. receptors

Answer 7

• intracellular glucocorticoid and mineralocorticoid receptors (GR & MR)

Question 8

Enzymes - hypothalamic-pituitary-adrenal axis

• 11-B-hydroxy… de… (11-B-HSD)

Answer 8

• 11-B-hydroxysteroid dehydrogenase (11-B-HSD)

Question 9

What is shown in the image?

Answer 9

Structure of steroid hormones

Question 10

Effects of glucocorticoids

• maintenance of … during times of … (give examples)
• anti-…
• energy balance / … (increase/maintain normal …)
• formation of … and …
• regulation of … …
• cognitive …, …, conditioning

Answer 10

• maintenance of homeostasis during times of stress (give examples)
• anti-inflammatory
• energy balance / metabolism (increase/maintain normal glucose)
• formation of bone and cartilage
• regulation of blood pressure
• cognitive function, memory, conditioning

Question 11

Circadian rhythms

Cortisol levels:

• rise during the …
• peak prior to …
• fall during …
• low in the …

Answer 11

• rise during the early morning
• peak prior to awakening
• fall during day
• low in the evening

Question 12

Ultradian rhythm

‘…’ of hormone release

Answer 12

• pulsatility of hormone release
• only when you average these do you get the circadian rhythm

Question 13

Ultradian rhythm - rats

• sponatenous … of varying amplitude
• amplitude decreases in the … trough

Answer 13

• sponatenous pulses of varying amplitude
• amplitude decreases in the circadian trough

Question 14

Ultradian rhythm - humans

• Hard to distinguish the … response

Answer 14

• Hard to distinguish the stress response

Question 15

What is shown in the image?

Answer 15

• Renin-angiotensin-aldosterone system

Question 16

Circulating Androgens

• include … and Andro… produced by the adrenal glands in both men and women

Answer 16

• DHEAS & Androstenedione

Question 17

• Cortisol crosses the cell membrane and links to the … receptor
• translocates into the … and binds there with …
• causes gene …

Answer 17

• Cortisol crosses the cell membrane and links to the glucocorticoid receptor
• translocates into the nucleus and binds there with coactivators
• causes gene transcription

Question 18

Enzymes - hypothalamic-pituitary-axis

• In vitro, the ‘…corticoid receptor’ has the same affinity for … and aldosterone
• … is conferred by a ‘pre-receptor’ mechanism
• 11-B-HSD-2 in the kidney inactivates …, enabling aldosterone to bind the … receptor

Answer 18

• In vitro, the ‘mineralocorticoid receptor’ has the same affinity for cortisol and aldosterone
• Specificity is conferred by a ‘pre-receptor’ mechanism
• 11-B-HSD-2 in the kidney inactivates cortisol, enabling aldosterone to bind the MR

Question 19

11-B-HSD enzymes

• tissue specificity - in kidney…
• ‘….’ of GC access to nuclear receptors
• in liver…
• ‘….’ of GC signal in target cells

Answer 19

• ‘gating’ of GC access to nuclear receptors - kidney - allows aldosterone to bind
• ‘amplification’ of GC signal in target cells - liver

Question 20

Too much cortisol

• … syndrome
  
  • leading to weight …
  • central …
  • …tension
  • insulin ….
  • neuropsychiatric …
  • osteo…

Answer 20

• Cushing’s syndrome
  
  • leading to weight gain
  • central obesity
  • hypertension
  • insulin resistance
  • neuropsychiatric problems
  • osteoporosis

Question 21

What syndrome is present?

Answer 21

• Cushing’s syndrome

Question 22

Cushing’s syndrome - pathogenesis

• excess …
  
  • pituitary … is commonest cause (has …-secreting cells)
  • Adrenal …: adenoma or carcinoma
  • ‘ectopic ACTH’: carcinoid, paraneoplastic - rare
  • Iatrogenic: steroid treatment - may become (‘…’)

Answer 22

• excess cortisol
  
  • pituitary adenomais commonest cause (hasACTH-secreting cells)
  • Adrenal tumour: adenoma or carcinoma
  • ‘ectopic ACTH’: carcinoid, paraneoplastic - rare
  • Iatrogenic: steroid treatment - may become (‘Cushingoid’)

Question 23

Cushing’s syndrome - Clinical features

• central obesity with thin … and …
• fat deposition over upper … known as a buffalo …
• rounded ‘moon’ …
• thin … with easy …, pigmented striae
• hirsutism
  
  • as previously mentioned…
• hypertension
• diabetes
• psychiatric manifestations
• osteroporosis

Answer 23

• central obesity with thin arms and legs
• fat deposition over upper back (buffalo hump)
• rounded ‘moon’ face
• thin skin with easy bruising, pigmented striae
• hirsutism
• hypertension
• diabetes
• psychiatric manifestations
• osteroporosis

Question 24

What syndrome is present?

what clinical features?

Answer 24

• cushing’s syndrome (Adrenal carcinoma)
• top left - buffalo hump
• top right - thin arms, brusing
• bottom left - striae on tummy
• bottom right - retaining salt and water - pitting oedema - rounded moon face

Question 25

Too little cortisol: Addison’s disease

The patient:

• Gradually falls off in general …
• becomes languid and …
• indisposed to either bodily or mental …
• body …
• slight pain is referred to …
• occasionally actual …
• … of skin
• (at length gradually sinks and expires) - in those days

Answer 25

• Gradually falls off in general health
• becomes languid and weak
• indisposed to either bodily or mental exertion
• body wastes
• slight pain is referred to stomach
• occasionally actual vomiting
• discolaration of skin
• at length gradually sinks and expires

Question 26

Pathogenesis of Addison’s disease

• Primary … insuffiency
  
  • usually … in the UK
  • Rare causes include … or …
  • decreased production of all … hormones
• Other causes of hypoadrenalism
  
  • … to pituitary disease (Rare)
  • … - patients on high dose, long term steroid, which is suddenly stopped at a time of stress

Answer 26

• Primary adrenal insuffiency
  
  • usually autoimmune in the UK
  • Rare causes include TB or metastases
  • decreased production of all adrenocortical hormones
• Other causes of hypoadrenalism
  
  • secondary to pituitary disease (Rare)
  • Iatrogenic - patients on high dose, long term steroid, which is suddenly stopped at a time of stress

Question 27

Addison’s disease - Clinical features

• malaise, …, anorexia, weight …
• increased skin … - in areas such as …, palmar …, around/inside the …, … areas, also …
• …/postural …
• …glycaemia

Answer 27

• malaise, weakness, anorexia, weight loss
• increased skin pigmentation - knuckles, palmar creases, around/inside the mouth, pressure areas, scars
• hypotension/postural hypotension
• hypoglycaemia

Question 28

Autoimmune polyendocrine syndromes: Type I vs Type II

• Type 1
  
  • common or rare?
  • onset is in …
  • single gene disorder?
  • Common phenotypes (3) are: …, …, …
• Type 2
  
  • common or rare?
  • onset is in …
  • single gene disorder?
  • Common phenotypes (cluster of) are: …, …, …

Answer 28

• Type 1
  
  • rare
  • onset is in infancy
  • Ar (AIRE gene) - single gene
  • Common phenotypes: Addison’s, hypoparathyroidism, candidiasis
• Type 2
  
  • commoner
  • infancy to adulthood
  • polygenic - not single gene
  • Common phenotype: Addison’s, T1 diabetes, autoimmune thyroid disease

Question 29

Autoimmune conditions that may occur together include:

• Type . ….
• autoimmune … disease (hypo or hyper)
  
  • also gestational / post-partum …
• … disease
• … disease
• … anaemia
• Alo…
• Vitiligo
• Hepatitis
• Premature … failure
• … gravis

Answer 29

• Type 1 diabetes
• Autoimmune thyroid disease (hypo or hyper)
  
  • also gestational / post-partum thyroiditis
• Coeliac disease
• Addison’s disease
• Pernicious anaemia
• Alopecia
• Vitiligo
• Hepatitis
• Premature ovarian failure
• Myasthenia gravis

Question 30

Clinical implications of autoimmune polyendocrine syndromes:

• … index of suspicion for additional autoimmune endocrine disorders
  
  • T1 Diabetes with fatigue, weight loss and hypoglycaemia - screen for … disease
  • T1 diabetes with non-specific GI symptoms/diarrhoea - screen for … disease
• Consider screening in patients with T1 DM and/or Addison’s disease
  
  • … screen
  • … function tests (especially in pregancy/post-partum)

Answer 30

• high index of suspicion for additional autoimmune endocrine disorders
  
  • T1 Diabetes with fatigue, weight loss and hypoglycaemia - screen for addison’s disease
  • T1 diabetes with non-specific GI symptoms/diarrhoea - screen for coeliac disease
• Consider screening in patients with T1 DM and/or Addison’s disease
  
  • Coeliac screen
  • Thyroid function tests (especially in pregancy/post-partum)

Question 31

Assessment of the hypothalamic-pituitary-adrenal axis

• Basal tests
  
  • … (cortisol, ACTH)
  • … (cortisol)
  • … (cortisol)
• Dynamic tests (… or …)

Answer 31

• Basal tests
  
  • blood (cortisol, ACTH)
  • urine (cortisol)
  • saliva (cortisol)
• Dynamic tests (stimulated or suppressed)

Question 32

Assessment of the hypothalamic-pituitary-adrenal axis

• Basal tests
  
  • blood (cortisol, ACTH) - important to remember … rhythm and … rhythm, also … response
  • urine (cortisol) - area under curve by using a … collection
  • saliva (cortisol) - … is important - but no stress - proportionate
• Dynamic tests
  
  • stimulated - e.g. …, … or stress using … to make them …
  • suppressed - … - a synthetic glucocorticoid

Answer 32

• Basal tests
  
  • blood (cortisol, ACTH) - important to remember circadian rhythm and ultradianrhythm, alsostress response
  • urine (cortisol) - area under curve by using a 24 hour collection
  • saliva (cortisol) - timing is important - but no stress - proportionate
• Dynamic tests
  
  • stimulated - e.g. ACTH,CRH, or stress using insulin to make them hypoglycaemic
  • suppressed - dexamethasone - a synthetic glucocorticoid

Question 33

What is shown here?

Answer 33

Assessment of the hypothalamic-pituitary-adrenal axis

Question 34

Too much cortisol? - tests would include:

• 24 hour urinary free cortisol - measure the …
• midnight cortisol (blood/saliva) - shows a ‘…’
• 9 am … (with paired cortisol) - pituitary/adrenal/ectopic? - negative feedback at pituitary
• … suppression - assessing sensitivity to GC … feedback at pituitary

Answer 34

• 24 hour urinary free cortisol - measure the area under curve
• midnight cortisol (blood/saliva) - trough
• 9 am ACTH (with paired cortisol) - pituitary/adrenal/ectopic? - negative feedback at pituitary
• dexamethasone suppression - sensitivity to GC negative feedback at pituitary (normally would get complete suppression of cortisol production with dexamethasone, not in patient with cushing’s syndrome)

Question 35

Dexamethasone suppression

• sensitivity to GC negative feedback at pituitary
• what would you expect in healthy individual?

Answer 35

• normally would get complete suppression of cortisol production with dexamethasone, but not in a patient with cushing’s syndrome

Question 36

• Pituitary cause of Cushing’s syndrome - expect ACTH to be … and cortisol to be …
• Adrenal cause of Cushing’s syndrome - expect ACTH to be … and cortisol to be …
• Ectopic cause of Cushing’s syndrome (lung cancer or carcinoma making ACTH) - expect ACTH to be … and cortisol to be …

Answer 36

• Pituitary cause of Cushing’s syndrome - expect ACTH to be high and cortisol to be high
• Adrenal cause of Cushing’s syndrome - expect ACTH to be low and cortisol to be high
• Ectopic cause of Cushing’s syndrome - expect ACTH to be high and cortisol to be high

Question 38

Too little cortisol? - tests would include:

• 9 am cortisol - looking for a …
• SynACTHen test - … response to ACTH - trophic effect on ACTH on adrenals
• … tolerance test to measure the response to … stress - but this can be dangerous
• U & E (… sodium, … potassium in Addison’s disease)
  
  • this is due to a … deficiency
  • can measure … (expecing to be high) & … (expecting to be low) concentrations - due to negative feedback
• decreased … levels

Answer 38

• 9 am cortisol - looking for a peak
• SynACTHen test - adrenal response to ACTH - trophic effect on ACTH on adrenals
• Insulin tolerance test to measure the response to hypoglycaemic stress - but this can be dangerous
• U & E (decreased sodium, increased potassium in Addison’s disease)
  
  • this is due to a mineralocorticoid deficiency
  • can measure renin & aldosterone concentrations
• decreased glucose levels

Question 39

Two golden rules - clinical aspects of hypothalamic-pituitary-adrenal axis

1. Never start investigating a patient for an endocrine condition unless their symptoms and signs suggest they have it due to …
2. Never image any endocrine gland until you have established the diagnosis biochemically! - risk of …

Answer 39

1. Never start investigating a patient for an endocrine condition unless their symptoms and signs suggest they have it - due to risk of false positive results
2. Never image any endocrine gland until you have established the diagnosis biochemically! - risk of discovering‘incidentalomas’

Question 40

Imaging - for Cushing’s syndrome/Addison’s disease

• Once you have confirmed a patient has Cushing’s syndrome, consider … (3 things)
• Patients with Addison’s disease - do they need imaging? When may they need it?

Answer 40

• Once you have confirmed a patient has Cushing’s syndrome, consider 1) CXR 2) MRI pituitary 3) CT adrenals
• Patients with Addison’s disease - do they need imaging? When may they need it?
  
  • Usuaully rare - unless concerned that they may have TB or metastatic cancer

Question 41

Management of Cushing’s syndrome

• largely …
  
  • adrenal cause = …
  • pituitary cause = … ….
• pituitary … as may be hard to cure surgically

Answer 41

• largely …
  
  • adrenal cause = adrenalectomy
  • pituitary cause = transphenoidal adenectomy
• pituitary radiotherapy - may be hard to cure with surgery alone

Question 42

Management of Addison’s disease

• … hormone replacement therapy (glucocorticoid) - usually this is …, but occassionally use …
• Patients with … adrenal insufficiency also need mineralcorticoid replacement therapy (…)
• patients with … adrenal insuffiency will often be taking other hormone replacement therapy so do not need this

Answer 42

• Steroid hormone replacement therapy (glucocorticoid) - usually this is hydrocortisone, but occassionally use prednisolone
• Patients with primary adrenal insufficiency also need mineralcorticoid replacement therapy (fludrocortisone)
• patients with secondary adrenal insuffiency will often be taking other hormone replacement therapy so do not need this

Question 43

Managing treatment of Addison’s disease in certain circumstances

• dose of glucocorticoids needs to be increased to cover ‘….’ such as intercurrent …
• …/…-… period - recommendations depend on the procedure
• Patients will require IV/IM … if unable to take tablets due to … or ‘… .. …’

Answer 43

• dose of glucocorticoids needs to be increased to cover ‘stresses’ such as intercurrent illness (like the flu)
• operations/post-op period - recommendations depend on the procedure
• Patients will require IV/IM steroids if unable to take tablets due to vomiting or ‘nil by mouth’

Question 44

Patients taking steroids for other reasons:

• patients may be treated with long-term high dose steroids for many reasons (glucocorticoids - usually …)
• usually the steroids are being used for what effects?
• Conditions include severe …/COPD, temporal … / polymyalgia … - these patients may look ‘…’ especially those with COPD

Answer 44

• patients may be treated with long-term high dose steroids for many reasons (glucocorticoids - usually prednisolone)
• usually the steroids are being used for what effects? - Anti-inflammatory
• Conditions include severe asthma/COPD, temporal arteritis/ polymyalgia rheumatica - these patients may look ‘Cushingoid’ especially those with COPD

Question 45

Patients taking steroids

• the endogenous … function of patients on long-term high dose steroid therapy may be suppressed:
  
  • they may not mount an adequate ‘…’ response
  • their steroid treatment should not be stopped …
  • if they need a major …, they require increased steroid cover as described
  • they should be given a ‘steroid … card’ to remind them (& their doctors) about this

Answer 45

• the endogenous adrenal function of patients on long-term high dose steroid therapy may be suppressed:
  
  • they may not mount an adequate ‘stress’ response
  • their steroid treatment should not be stopped suddenly
  • if they need a major procedure/an operation, they require increased steroid cover as described
  • they should be given a ‘steroid treatment card’ to remind them (& their doctors) about this