L9 - The hypothalamic pituitary axis - clinical aspects Flashcards
Releasing factors
CRH
AVP
Tropic hormones
ACTH
Target organ hormones
Cortisol
What two types of factors does the hypothalamus produce?
releasing factors
inhibiting factors
to the pituitary
Pituitary releases?
tropic hormones
to target organ
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 in HPA
11-B-hydroxysteroid dehydrogenase (11-B-HSD)
Effects of glucocorticoids (6)
Maintenance of homeostasis during stress
-e.g. haemorrhage, infection, anxiety
Anti-inflammatory
Energy balance/metabolism
-increases/maintains normal (glucose)
formation of bone and cartilage
regulation of BP
cognitive function, memory, conditioning
Circadian rhythm and cortisol levels
rise during the early morning
peak just prior to awakening
fall during the day
are low in the evening
Ultradian rhythm - ‘pulsatility of hormone release’
spontaneous pulses of varying amplitude
amplitude decrease in the circadian trough
it is hard to distinguish the stress response
Circulating androgens: what do the adrenal glands release?
DHEAS
Circulating androgens: what do the testes release?
testosterone
How is testosterone converted into oestrogen?
the enzyme aromatase
How is testosterone converted into dihydrotestosterone
the enzyme 5-a-reductase
DHEAS and testosterone both converted into?
androstenedione
Enzymes - MR receptor
In vitro, the MR receptor has the same affinity for aldosterone and cortisol
Enzymes - what is specificity conferred by?
a ‘pre-receptor’ mechanism
What inactivates cortisol in the kidneys?
11-B-HSD-2 in the kidney inactivates cortisol, enabling aldosterone to bind the MR
11-B-HSD enzymes: tissue specificity
gating of GC access to nuclear receptors
amplification of GC signal in target cells
Features of Cushing’s syndrome
weight gain central obesity hypertension insulin resistance neuropsychiatric problems osteoporosis
Cushing’s syndrome: pathogenesis
excess cortisol:
-pituitary adenoma: ACTH-secreting cells (‘Cushing’s disease’)
- adrenal tumour: adenoma (or carcinome)
- ‘ectopic ACTH’: carcinoid, paraneoplastic
- iatrogenic: steroid treatment (‘cushingoid’)
Cushing’s syndrome: clinical features
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
osteoporosis
What disease is too little cortisol?
Addison’s
Addison’s disease: the patient
- gradually falls of 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
- discolouration of the skin
- at length pt gradually skins and expires
Addison’s disease: pathogenesis
Primary adrenal insufficiency
- addisons disease
- usually autoimmune in UK
- rare causes include metastases or TB
- decreased production of all adrenocortical hormones
Other causes of hypoadrenalism
- secondary to pituitary disease (rare)
- iatrogenic
- patients on high does, long term steroid Rx, which is suddenly stopped at a time of stress
Addison’s 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
Autoimmune polyendocrine syndromes: Type 1
rare
onset in infancy
Ar(AIRE gene)
common phenotype
- addisons disease
- hypothyroidism
- candidiasis
Autoimmune poluendocrine syndromes: Type 2
commoner (still rare)
infancy to adulthood
polygenic
common phenotype
- addisons disease
- T1 diabetes
- autoimmune thyroid disease
Autoimmune conditions that may occur together?
Type 1 diabetes
Autoimmune thyroid disease (hypo- or hyper-)
-Also gestational / post-partum thyroiditis
Coeliac disease
Addison’s disease
Pernicious anaemia-low B12
Alopecia
Vitiligo
Hepatitis
Premature ovarian failure
Myasthenia gravisAutoimmune polyendocrine syndromes: clinical implications
high index of suspicion for additional autoimmune endocrine disorders
- T1 DM with fatigue, weight loss and hypos: addisons?
- T1 DM with non-specific GI symptom/diarrhoea: coeliac disease?
Assessment of the HPAA: BASAL
blood
- cortisol
- SCTH
urine
-cortisol
saliva
-cortisol
Assessment of the HPAA: dynamic tests
stimulated
- ACTH
- CRH
- ‘Stress’
- hypoglycaemia
suppressed
- dexamethasone
- synthetic glucocorticoid
Assessment of the HPAA: basal collecting data
blood
- timing
- circadian rhythm
- ultradian rhythm
- stress
urine
- 24hr collection
- ‘area under curve’
saliva
- timing
- no stress!
Too much cortisol?
24hr urinary free cortisol
-area under the curve
Midnight cortisol (blood/saliva) -trough
9am 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 (decreased Na, increased K) in Addisons
- due to mineralocorticoid deficiency
- can measure renin & aldosterone concentrations
Decreased glucose
2 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
CXR
MRI pituitary
CT adrenals
Patients with Addison’s disease seldom need imaging unless you are concerned they may have TB/metastatic cancer
Cushing’s syndrome: management
Surgical (depending on cause)
- transphenoidal adenectomy
- adrenalectomy
Pituitary radiotherapy
Addison’s disease: management 1
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)
Addison’s disease: management 2
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’
Why may patients be treated with long-term steroids?
such as glucocorticoids usually prednisolone
usually the steroids are being used for their anti-inflammatory/immunosuppressive effects
conditions include severe asthma/COPD, temporal arteritis/polymyalgia rheumatics
-these patients may look ‘cushingoid’ especially those with COPD
Why might the endogenous adrenal function of patients on long-term high dose steroid therapy 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 and doctors about this
