L09 - Hypothalamic-pituitary-adrenal axis: Clinical Aspects Flashcards
what does the adrenal cortex produce
what is cortisol bound to
what are the receptors
what is the enzyme involved
• Adrenal cortex hormone production GLUCOCORTICOID • CORTISOL MINERALOCORTICOID • ALDOSTERONE (renin-angiotensin-aldosterone system) SEX STEROIDS • ANDROGENS
• Binding proteins
90% cortisol bound to cortisol binding globulin (CBC)
• Receptors
— Intracellular glucocorticoid and mineralocorticoid receptors (GR
and MR)
Enzymes
1 1 -ß-hydroxysteroid dehydrogenase (11- ß-HSD)
What are the various effects of glucocorticoids
Maintenance of homeostasis during stress
— e.g. haemorrhage, infection, anxiety
Anti-inflammatory
Energy balance / metabolism
— incr / maintain normal [glucose]
Formation of bone and cartilage
Regulation of blood pressure
Cognitive function, memory, conditioning
How does circadian rhythm effect cortisol levels
• Cortisol levels: — rise during the early morning — peak just prior to awakening fall during the day — are low in the evening
tell me about ultradian rhythm
describes the pulsality of hormone release
they are spontaneous pulses of varying amplitude
the amplitude decreases in the circadian trough
it is hard to distinguish the stress response
what do the adrenal glands secrete and how does this relate to the testes
secrete DHEAS
these convert to androstenedione
this converts to test/oestro
what are the enzymes involved with glucocorticoids
what does this have the same affinity for
what is specificity conferred by?
what is the enzyme that inactivates cortisol? what does this enable?
In vitro, the ‘mineralocorticoid receptor’ (MR) has the same affinity for aldosterone and cortisol
Specificity is conferred by a ‘pre-receptor’ mechanism
11-ß-HSD-2 in the kidney inactivates cortisol, enabling aldosterone to bind the MR
How do 11-ß-HSD enzymes work
through tissue specificity
they gate GC access to nuclear receptors
they amplify GC signal in target cells
WHat happens with too much cortisol? condition
what are the big signs of it
Cushing's Syndrome — Weight gain — Central obesity ---Hypertension — Insulin resistance — Neuropsychiatric problems — Osteoporosis
CUSHING’s
what is the pathogenesis - how does it happen?
(different ways)
Excess cortisol:
— Pituitary adenoma: ACTH-secreting cells
(‘Cushing’s disease’)
— Adrenal tumour: adenoma (or carcinoma)
—‘Ectopic ACTH’: carcinoid, paraneoplastic
— Iatrogenic: steroid treatment (‘Cushingoid’)
what are the clinical features of cushings
— 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
— Osteoporosis
What happens with too little cortisol?
what are the main signs of this
Too little cortisol:
Addison’s disease
• The patient
— gradually falls off in general health
—becomes languid & weak
— indisposed to either bodily or mental exertion
— the body wastes
—slight pain is referred to the stomach
—there is occasionally actual vomiting
— discoloration of the skin
—at length he gradually sinks and expires
what is the pathogenesis of addison’s disease
ie what causes it
what are rare cases.
also what are other causes of hypoadrenalism
Pathoqenesis — Primary adrenal insufficiency • 'Addison's disease' • Usually autoimmune in UK • Rare causes include metastases or TB • decr in Production of all adrenocortical hormones
— Other causes of hypoadrenalism • Secondary to pituitary disease (rare) • 'Iatrogenic' — patients on high dose, long term steroid Rx, which is suddenly stopped at a time of stress
ADDISONS DISEASE
clinical features
— Malaise, weakness, anorexia, weight loss
— Increased skin pigmentation:
knuckles, palmar creases, around / inside the mouth, pressure areas, scars
— Hypotension / postural hypotension
— Hypoglycaemia
describe the two types of autoimmune polyendocrine syndromes
, Type 1 — Rare — Onset in infancy — Ar (AIRE gene) — Common phenotype: • Addison's disease • Hypoparathyroidism • Candidiasis
, Type Il — Commoner (still rare!) — Infancy to adulthood — Polygenic — Common phenotype: • Addison's disease • Tl diabetes • Autoimmue thyroid disease
What other autoimmune conditions may occur together
autoimmune polyendocrine syndromes
Type 1 diabetes — Autoimmune thyroid disease (hypo- or hyper-) • Also gestational / postpartum thyroiditis — Coeliac disease — Addison's disease — Pernicious anaemia — Alopecia — Vitiligo ---Hepatitis — Premature ovarian failure ---Myasthenia gravis
what would you query for these cases:
Tl DM with fatigue, weight loss & hypos
Tl DM with non-specific GI symptoms / diarrhoea
what screening should you consider for T1DM and addisons?
Clinical implications:
— High index of suspicion for additional autoimmune
endocrine disorders
• Tl DM with fatigue, weight loss & hypos:
— ? Addisons disease
• Tl DM with non-specific GI symptoms / diarrhoea:
— ? Coeliac disease
— Consider screening in patients with Tl DM and/or
Addison’s disease
• Coeliac screen
• Thyroid function tests (esp in pregnancy / post-partum)
Assessment of the HPAA
basal tests? what are they and what is tested
what things (timings and conditions) are considered
BLOOD
–cortisol
–ACTH
account for timing (circ rhythm), ultradian rhythm, stress
urine
–cortisol
do 24 hour collection and fins area under the curve
saliva
–cortisol
timing, no stress
Assessment of the HPAA
what are the dynamic tests
what is being looked for for each
stimulated:
ACTH, CRH., “stress” - hypoglycaemia
suppressed:
dexamethasone
If you had too much cortisol, what would you notice for:
midnight cortisol for blood/saliva
9am ACTH with paired cortisol?
dexamethasone suppression
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
what happens with too little cortisol
what is 9am cortisol at?
what tests are done
what are Na and K levels like and why
also glucose?
• 9 a.m. 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 (UNa, t K) in Addison’s disease
Due to mineralocorticoid deficiency
Can measure renin & aldosterone concentrations
decr in glucose
what are two golden rules when it comes to investigating and diagnosing such patients
and why
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
what is needed for cushings and addisons
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
CUSHINGS
what are the management options
— Surgical (depending on the cause)
• Transphenoidal adenectomy
• Adrenalectomy
— Pituitary radiotherapy
ADDISON’S
what are the management options
what meds would they be on
what would patients with primary adrenal insufficiency also need?
what would patients with secondary adrenal insuff require?
— 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).
ADDISONS
future care
when would dosages need to be adjusted and why and when would they need changing
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 / 1M steroid if unable to take
their tablets:
— Vomiting
— ‘Nil by mouth’
what reasons would people have to be treated with long term and high dose steroids
(conditions)
what would they be treated with. what properties do these things have
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
what is a consequence of taking long term steroids?
what do you need to be careful with this
— 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.
