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 **ultrad****ian**rhythm, also**stress** 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