9. Hypothalamic-pituitary-adrenal axis: clinical aspects

Question 1

Describe the cortisol HPA axis pathway

Answer 1

Hypothalamus releases CRH and AVP, stimulate pituitary to release ACTH which acts on the adrenal cortex to produce cortisol. Cortisol then produces a negative feedback effect on the pituitary to decrease the level of ACTH released

Question 2

Describe a generic HPA axis pathway

Answer 2

Hypothalamus releases releasing hormone down axons to the pituitary gland which releases a stimulating hormone which acts on the target organ to release its hormones and exert its biological effects. This hormone also exerts a negative feedback effect on the pituitary, resulting in less stimulating hormone released.

Question 3

List some stuff which is found along the HPA axis

Answer 3

Adrenal cortex hormone production - glucocorticoid, cortisol

Mineralocorticoid - aldosterone, RAAS

Sex steroids - androgens

Binding proteins - 90% cortisol bound to cortisol binding globulin (CBG)

Receptors - intracellular glucocorticoid and mineralocorticoid receptors (GR and MR)

Enzymes - 11-b-hydroxysteroid dehydrogenase (11-b-HSD)

Question 4

Effects of glucocorticoids

Answer 4

Necessary for life!

• Maintain homeostasis during stress e.g. haemorrhage, infection anxiety
• Anti-inflammatory
• Energy balance/metabolism (increase/maintain normal [glucose])
• Formation of bone and cartilage
• regulation of blood pressure
• cognitive function, memory, conditioning

Question 5

Circadian rhythms of cortisol

Answer 5

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

Question 6

What is an ultradian rhythm?

Answer 6

A recurrent period or cycle which is repeated during a 24 hour period, representing the pulsatility of hormone release. A circadian rhythm is the mean of many ultradian rhythms

Spontaneous pulses of varying amplitude, which decrease in the circadian trough (usually around 4am).

Question 7

RAAS system

Answer 7

Angiotensinogen released by liver, turned into angiotensin I by renin from kidney, ACE from lungs turns angiotensin I into angiotensin II.
Angiotensin II acts on adrenal cortex to release aldosterone which reabsorbs Na+ and Cl-, excreted K+ and retains water, on the pituitary gland to release ADH which absorbs H2O from collecting duct, and on arterioles to cause vasoconstriction and increase BP, and increases sympathetic activity.

Results in water and sodium retention, increased circulating volume and increased renal perfusion

Question 8

Describe

Answer 8

Adrenal glands make DHEAS which is made into androstenedione. This is made into testosterone whcih is also made by the testes. Testosterone is then made into oestrogen by aromatase, and dihydrotestosterone by 5-alpha-reductase

Question 9

How is the mineralocorticoid receptor’s specificity conferred?

Answer 9

In vitro, the mineralocorticoid receptor (MR) has the same affinity for aldosterone and cortisol. Specificity is conferred by a pre-receptor mechanism.

11-B-HSD-2 in the kidney inactivates cortisol, enabling aldosterone only to bind the MR

Question 10

11-beta-HSF enzymes

Answer 10

determine tissue specificity
Gating of GC access to nuclear receptors
Amplification of GC signal in target cells

Question 11

Too much cortisol?

Answer 11

Cushing’s syndrome:

• weight gain
• central obesity
• hypertension
• insulin resistance
• neuropsychiatric problems
• osteoperosis

Question 12

Cushing’s syndrome causes

Answer 12

Due to excess cortisol:
pituitary adenoma - ACTH-secreting cells (Cushing’s disease)
Adrenal tumour: adenoma (or carcinoma)
Ectopic ACTH: carcinoid, paraneoplastic
Iatrogenic: steroid treatment (Cushingoid)

Question 13

Clinical features of Cushing’s syndrome

Answer 13

Central obesity with thin arms & legs
Fat deposition over upper back (buffalo hump)
Rounded moon face
Thin skin with easy bruising, pigmented striae
Hirsutism
Hypertension
Diabetes
Psychiatric manifestations
Osteoperosis

Question 14

Addison’s disease

Answer 14

To little cortisol
Patient falls off in general health, becomes languid and weak
indisposed to either bodily ot mental exertion
body wastes
slight pain is referred to the stomach
occasionally actual vomiting
discolouration of the skin (darker pigmentation)

Question 15

Pathogenesis of Addison’s disease

Answer 15

Primary adrenal insufficiency
Usually autoimmune in the UK
Rare causes include metastases or TB
Decreased producction of all adrenocortical hormones

Question 16

Other causes of hypoadrenalism (not Addison’s)

Answer 16

Secondary to pituitary disease (rare)

Iatrogenic - patients on high dose, long term steroid Rx, which is suddenly stopped at a time of stress

Question 17

Clinical features of Addison’s disease

Answer 17

Malaise, weakness, anorexia, weight loss
Increased skin pigmentation: knuckles, palmar creases, around/inside the mouth, pressure areas, scars
Hypotension/postural hypotension
Hypoglycaemia

Question 18

Autoimmune polyendocrine syndromes

Answer 18

Type I: rare, onset in infancy, Ar (AIRE gene)
Common phenotype: Addison’s disease, hypoparathyroidism, Candidiasis

Type II: commoner (still rare), infancy to adulthood, polygenic.
Common phenotype:
Addison's disease
T1 diabetes
Autoimmune thyroid disease

Question 19

Autoimmune conditions that may occur together

Answer 19

Type 1 diabetes
Autoimmune thyroid disease (hypo or hyper, and gestastional/post-partum thyroiditis)
Coeliac disease
Addison's disease
Pernicious anaemia
Alopecia
Vitiligo
Hepatitis
Premature ovarian failure
Myasthenia gravis

Question 20

Clinical complications of autoimmune endocrine conditions

Answer 20

High index of suspicion for additional autoimmune endocrine disorders

T1DM with fatigue, weight loss & hypos -> Addison’s?

T1 DM with non-specific GI symptoms/diarrhoea -> Coeliac?

Consider screening in patients with T1DM and/or Addison’s disease:
Coeliac screen
Thyroid function tests (esp in pregnancy/post partum)

Question 21

Assessment of the HPAA

Answer 21

Basal:
blood - cortisol, ACTH
urine - cortisol
saliva - cortisol
Dynamic:
stimulated
suppressed

Question 22

Timing of basal tests

Answer 22

Blood - circadian rhythm, ultradian rhythm, stress
Urine - 24 hour collection - area under curve
Saliva - timing, no stress

Question 23

Stimulated HPAA assessment

Answer 23

ACTH, CRH, stress - hypoglycaemia

Question 24

Suppressed HPAA assessments

Answer 24

Dexamethasone - synthetic glucocorticoid

Question 25

Too much cortisol?

Answer 25

24 hour urinary free cortisol
-> ‘AREA UNDER THE CURVE’

Midnight cortisol (blood / saliva)
->‘TROUGH’

9 a.m. ACTH (with paired cortisol)
->PITUITARY / ADRENAL / ECTOPIC?
NEGATIVE FEEDBACK AT PITUITARY

DEXAMETHASONE SUPPRESSION
-> Sensitivity to GC negative feedback at pituitary

Question 26

Too little cortisol?

Answer 26

9AM cortisol
-> ‘PEAK’

SynACTHen test

• > Adrenal response to ACTH
• > Trophic effect ACTH on adrenals

Insulin tolerance test
-> Response to hypoglycaemic stress. Can be dangerous

U&E (decrease Na, increase K) in Addison’s disease

• > Due to mineralocorticoid deficiency
• > Can measure renin & aldosterone concentrations
• > Decrease in glucose

Question 27

Two golden rules

Answer 27

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

Question 28

Imaging

Answer 28

Once you have confirmed that a patient has Cushing’s syndrome, consider
- CXR
- MRI pituitary
- CT adrenals
Patients with Addison’s disease seldom need imaging unless you are concerned they may have TB / metastatic cancer

Question 29

Management of Cushing’s disease

Answer 29

Surgical (depending on the cause):

• transphenoidal adenectomy
• adrenalectomy

Pituitary radiotherapy

Question 30

Management of Addison’s disease

Answer 30

Steroid hormone replacement therapy (‘glucocorticoid’):
- Usually hydrocortisone (sometimes prednisolone)

Patients with primary adrenal insufficiency also need mineralocorticoid replacement therapy (fludrocortisone).

Patients with secondary adrenal insufficiency will often be taking other hormone replacement therapy (do not need fludrocortisone).

Dose of glucocorticoids needs to be increased to cover ‘stresses’:
- Intercurrent illnesses (e.g. ‘flu)

Operations / post-op period
- Recommendations depend on the procedure

Patients need IV / IM steroid if unable to take their tablets:

• Vomiting
• ‘Nil by mouth’

Question 31

Patients taking steroids

Answer 31

Patients may be treated with long-term high dose steroids for many reasons
• Glucocorticoids
• Usually prednisolone
Usually the steroids are being used for their anti-inflammatory / immunosuppressive effects
Conditions include severe asthma / COPD, temporal arteritis / polymyalgia rheumatica
• These patients may look ‘Cushingoid’, especially those with COPD

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.