Hypothalamus and Pituitary Disorders Flashcards
Basic physiology
Releasing/inhibitory peptides synthesised in hypothalamus and released in response to neurotransmitters that regulate pituitary hormones
6 anterior pituitary hormones
- TRH –> TSH –> T4, T3 feedback
- LHRH –> LH –> E2, Testosterone feedback
- LHRH –> FSH –> inhibin, E2, Testosterone feedback
- GHRH, SMS (inhibitory) –> GH –> IGF-1 feedback
- PIF (dopamine) –> Prolactin
- CRH, ADH –> ACTH –> Cortisol feedback
Posterior pituitary hormones
- ADH
- Oxytocin
Pituitary problems
Excessive states involving single hormone e.g. adenoma
- PRL cell adenoma 30%, GH cell 15%, non-functioning 25% (TSH cell least common)
Progressive pituitary damage e.g. SOL, irradiation –> sequential hypo secretion (LH/FSH and GH first, then ACTH and TSH) and secondary failures of target organs
Mass effects:
- hypopituitarism
- bitemporal hemianopia
- CN3,4,6 palsy – opthalmoplegia
- headache
Stimulatory tests for assessing pituitary reserves using releasing hormones
e.g. CRH, GnRH, TRH, TRIPLE FUNCTION TEST (GnRH, TRH + Insulin)
Normal: increase then decrease after 30 min
Primary organ failure: higher baseline pituitary hormones (no feedback), exaggerated response to RH
Pituitary failure/ primary organ hyperactivity: no response to RH
Hypothalamus failure: slow, sluggish rise (from 0-60 min) in response to RH (no reserves in pituitary, need to synthesise)
Stimulatory tests for assessing pituitary reserves using other pathways
Insulin tolerance test/ Glucagon stimulation test –> GH and ACTH through inducing reactive hypoglycaemia/stress
- cortisol >450, GH up to 20 (120-180 min)
Exercise, sleep, amino acids –> GH
Water deprivation test –> ADH
Inhibitory tests for hyperactive pituitary
Cushing’s disease – Dexamethasone suppression test (should suppress ACTH normally)
Acromegaly/ Gigantism – oral glucose suppression test or somatostatin (should suppress GH normally)
ADH and DI
Synthesised in supraoptic nuclei of hypothalamus
- released in response to increased plasma osm and activation of osmoreceptors
Enhances water reabsorption in collecting ducts
Deficiency = Diabetes Insipidus (cranial or nephrogenic)
- water deprivation test (inappropriately dilute urine in the presence of high serum Osm due to water restriction)
- causes: cranial (pituitary surgery, supersellar tumour, vascular, encephalitis, skull base fracture), nephrogenic (Li, hypoK, hyperCa, chronic renal failure)
Prolactin
Lactation and inhibits Gn release
Normally under inhibitory control by dopamine
TRH increases PRL (hypothyroidism)
(macroprolactin formed when PRL-IgG complex formed – biologically inactive)
Pituitary stalk obstruction may impede dopamine
GH tumours often co-secrete PRL
- excess causes reproductive problems, amenorrhea, galactorrhea, low libido
Dynamic function tests:
- stimulatory - TRH, domperidone (dopamine antag)
- inhibitory - bromocriptine (dopamine agonist used in Tx of hyperPRL)
DDx of hyperPRL
- pregnancy, lactation, stress
- pituitary disorders (tumour)
- prolactinoma
- hypothalamic stalk disorder
- drugs: SSRI, estrogen, dopamine antagonists, PPIs, antipsychotics
- systemic: hypothyroid, chronic renal failure, cirrhosis
Prolactinoma vs hypothalamic stalk disorder
- stalk disorder in older age, have visual defects, GH deficiency, PRL <5000, extrasellar tumour extension on presentation (prolactinoma symptomatic during micro adenoma stage)
GH
GHRH stimulatory
SMS inhibitory
- in response to glucose, sleep, exercise
–> promotes growth via IGF-I (levels should also be established)
Deficiency state leads to dwarfism
Excessive state: gigantism (before puberty), acromegaly (after puberty)
Stimulatory test: ITT or GST, sleep induced rise, severe exercise, amino acids
Inhibitory test: oral glucose suppression test
Hypothalamic-pituitary-adrenal axis
CRH –> zona fasciculata and zona reticularis under ACTH control
Negative feedback by glucocorticoids
(zona glomerulosa under regulation by RAAS for producing mineralocorticoids)
Stimulatory test: Synacthen test (synthetic ACTH)
- normal = rise of 200 nM at 30 min, exceeding 550 nM
- low cortisol and no response = Addison’s or adrenal insufficiency –> extra tests to delineate causes
Suppression test: Dexamethasone
Dexamethasone suppression test interpretations
Synthetic glucocorticoid with 25x cortisol potency –> suppress ACTH and lowers cortisol
To distinguish aetiology of Cushing’s syndrome (hypercortisolism)
- Overnight Dex (low dose: 2mg)
- normal: suppresses cortisol
- Cushing’s: no suppression
Once Cushing’s syndrome established,
- High dose Dex (2mg Q6H 2/7)
- 50% reduction of cortisol = Cushing’s disease (pituitary ACTH secreting tumour)
- no suppression
- -> low ACTH = adrenal tumour (autonomous cortisol; ACTH independent)
- -> high ACTH = ectopic ACTH (e.g. SCLC)
Endocrine Ix pre-analytical factors
Initially measure hormones related to axis at fault, if necessary dynamic tests to assess reserve and responsiveness
Pre-analytical factors
- collection time (daily circadian rhythm for cortisol - high in morning, low at night)
- menstrual cycle - estradiol, progesterone, LH, FSH
- labile hormones/enzymes - ACTH, renin, PTH (need to be processed immediately or else will be degraded)
- venipuncture - fear may cause stress hormones to rise so insert indwelling catheter and wait for 30 min before taking blood sample
Hormone measurement methods, pitfalls
Need sensitive methods due to low concentrations of blood hormones
- -> radioimmunoassays (RIA)
- -> newer non-radioactive labels e.g. enzymes, fluorophores, chemiluminescent labels
Immunoassays to measure free biologically active hormone fractions e.g. T4. T3
Pitfalls:
- cross reactivity e.g. alpha subunit of LH, FSH, TSH and hCG are identical; PRL, GH and hPL (pregnancy)
- fragments of labile hormones may be immunoreactive (with longer t1/2 and affected by renal clearance) but biologically inactive
- radioisotopes given for imaging may interfere with counting in RIA
