9. Hypothalamic-pituitary-adrenal axis: clinical aspects Flashcards
Describe the cortisol HPA axis pathway
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
Describe a generic HPA axis pathway
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.
List some stuff which is found along the HPA axis
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)
Effects of glucocorticoids
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
Circadian rhythms of cortisol
- rise during early morning
- peak just prior to awakening
- fall during the day
- low in the evening
What is an ultradian rhythm?
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).
RAAS system
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
Describe
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
How is the mineralocorticoid receptor’s specificity conferred?
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
11-beta-HSF enzymes
determine tissue specificity
Gating of GC access to nuclear receptors
Amplification of GC signal in target cells
Too much cortisol?
Cushing’s syndrome:
- weight gain
- central obesity
- hypertension
- insulin resistance
- neuropsychiatric problems
- osteoperosis
Cushing’s syndrome causes
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)
Clinical features of Cushing’s syndrome
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
Addison’s disease
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)
Pathogenesis of Addison’s disease
Primary adrenal insufficiency
Usually autoimmune in the UK
Rare causes include metastases or TB
Decreased producction of all adrenocortical hormones
Other causes of hypoadrenalism (not Addison’s)
Secondary to pituitary disease (rare)
Iatrogenic - patients on high dose, long term steroid Rx, which is suddenly stopped at a time of stress
Clinical features of Addison’s disease
Malaise, weakness, anorexia, weight loss
Increased skin pigmentation: knuckles, palmar creases, around/inside the mouth, pressure areas, scars
Hypotension/postural hypotension
Hypoglycaemia
Autoimmune polyendocrine syndromes
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
Autoimmune conditions that may occur together
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
Clinical complications of autoimmune endocrine conditions
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)
Assessment of the HPAA
Basal: blood - cortisol, ACTH urine - cortisol saliva - cortisol Dynamic: stimulated suppressed
Timing of basal tests
Blood - circadian rhythm, ultradian rhythm, stress
Urine - 24 hour collection - area under curve
Saliva - timing, no stress
Stimulated HPAA assessment
ACTH, CRH, stress - hypoglycaemia
Suppressed HPAA assessments
Dexamethasone - synthetic glucocorticoid
Too much cortisol?
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
Too little cortisol?
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
Two golden rules
- Never start investigating a patient for an endocrine condition unless their symptoms & signs suggest they may have it!
Risk of false positive results - Never image any endocrine gland until you have established the diagnosis biochemically!
Risk of discovering ‘incidentalomas’
Imaging
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
Management of Cushing’s disease
Surgical (depending on the cause):
- transphenoidal adenectomy
- adrenalectomy
Pituitary radiotherapy
Management of Addison’s disease
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’
Patients taking steroids
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.
