The Evaluation of Neuroendocrine Axis Disorders

what are the axes of the anterior pituitary?

hypothalamic-pituitary-prolactin axis, growth hormone/insulin-like growth factor axis, & hypothalamic-pituitary-adrenocortical axis

what do primary disorders have dysfunction of?

end-organs ex. thyroid

what do secondary disorders of dysfunction of?

pituitary (central)

what do tertiary disorders have dysfunction of?

hypothalamus (central)

what are posterior pituitary disorders primarily related to?

ADH

what structure produces ADH?

hypothalamus

what is ectopic hormonal secretion?

production of a hormone by a cell/tissue type that does not normally produce that hormonal substance ex. ectopic ACTH/ADH secretion, PTHrP secretion

what is paraneoplastic syndrome?

patients w/ cancers manifest w/ sxs of hormone dysfx due to their tumor

how do you test hyposecretion disorders (ex. GH deficiency)?

stimulation testing

how do you test hypersecretion disorders (ex. GH excess)?

suppression testing

what is the natural physiological state of prolactin?

inhibition

what hormone functions as prolactin inhibitory hormone?

dopamine

when prolactin is secreted, it has a suppressive effect on which other neuroendocrine axis?

hypothalamic-pituitary-gonadal (HPG)

what do elevated levels of serum prolactin (PRL) lead to?

pituitary adenoma: prolactinoma

what is the diagnosis if sxs are galactorrhea after b/l tubal ligation, negative pregnancy test, intermittent HA, and some difficulty w/ peripheral vision?

prolactinoma (PRL-secreting pituitary tumor)

how would you diagnose a prolactinoma?

serum PRL level (high) & pituitary MRI (sella turcica)

when would CNS destructive disease elevate serum prolactin levels instead of decreasing them?

if it impairs the natural inhibitory mechanisms of PRL secretion

what do elevated levels of serum growth hormone (GH) lead to?

pituitary adenoma -> gigantism/acromegaly or Laron dwarfism

what do decreased levels of serum growth hormone (GH) lead to?

dwarfism

what is most likely the location of the neoplasm for patients w/ gigantism or acromegaly?

anterior pituitary

what tests would be used to diagnose gigantism or acromegaly?

serum IGF-1 levels (vs GH), GH suppression test, & pituitary MRI

what is the MC diagnostic study for GH suppression testing?

oral glucose tolerance testing (OGTT)

what blood test is preferred in the evaluation of possible growth related pathologies?

IGF-1 (provides most accurate reflection of mean plasma GH)

what do elevated levels of IGF-1 lead to?

pituitary adenoma -> gigantism/acromegaly

what do decreased levels of IGF-1 lead to?

dwarfism or Laron dwarfism

what lab changes would be expected in Laron dwarfism?

high GH, low IGF-1

which stimuli used during the workup of potential GH deficiency is most reliable but rarely used now due to significant risks/complications?

insulin

what do elevated levels of adrenocorticotropic hormone (ACTH) lead to?

Cushing disease, ectopic ACTH secretion, or primary adrenal failure

what do decreased levels of adrenocorticotropic hormone (ACTH) lead to?

another form of Cushing syndrome

what is serum cortisol?

glucocorticoid stress hormone that is highest from 6-8am

what do elevated levels of serum cortisol lead to?

Cushing syndrome (primary = adrenal, secondary = pituitary, or ectopic ACTH secretion)

what do decreased levels of serum cortisol lead to?

primary adrenal failure or pituitary destruction

what is considered the best way to assess cortisol levels?

24-hr urinary cortisol (but it doesn't tell you the etiology)

is salivary cortisol a convenient way to assess a patient for hypocortisolism?

no, used to assess hyperfunction and is collected at midnight

what assessment for Cushing syndrome helps determine etiology?

dexamethasone suppression testing (DST)

what is step 1 for rapid DST?

administer low dose 1mg test, if results are <5 mcg/dL stop here (this is nL) & if >10 move to step 2

what is step 2 for rapid DST?

administer high dose 8mg test and see if there is + or - suppression

what could be the etiologies of negative suppression (still high cortisol) after step 2?

adrenal hypersecretion (primary) of cortisol OR ectopic ACTH secretion

how are adrenal hypersecretion of cortisol and ectopic ACTH differentiated?

draw the ACTH level (low in adrenal disease, high in ectopic ACTH)

what testing is used for suspected hypocortisolism to determine the etiology?

cosyntropin stimulation testing

what do you need to take into consideration with cosyntropin stimulation testing?

make sure you treat adrenal crisis first

how can you differentiate primary (adrenal) vs secondary (pituitary) causes in the cosyntropin stimulation test?

draw baseline ACTH level before testing, if high it is primary & if low it is secondary

what is serum aldosterone?

mineralocorticoid regulated by the RAA pathway, secreted in response to ACTH

what is serum aldosterone used to diagnose?

hyperaldosteronism

what do elevated levels of serum aldosterone lead to?

-primary causes: adrenal adenoma or b/l adrenal hyperplasia

-secondary causes: high ACTH, RAA stimulation

what do decreased levels of serum aldosterone lead to?

adrenal insufficiency/failure

what is the clinical usage of plasma renin activity?

ddx of hyperaldosteronism

which test is most sensitive for hyperaldosteronism?

24-hr urinary aldosterone

what are stimuli for aldosterone secretion?

low plasma volume, low Na+, high K+, & ACTH

will patients with primary/adrenal cause of hyperaldosteronism have normal, high, or low renin levels?

low

what is the most common aldosterone stimulation & suppression test?

posture stimulation test

what results would you expect for a posture stimulation test?

should see an increase in aldosterone

what are adrenal steroids?

cortisol, aldosterone, testosterone & estrogen (all made in adrenal gland in response to ACTH stimulation)

where can precursors to adrenal steroids and their metabolites be identified?

serum or urine (24-hr)

what happens to the precursors to hormones when enzyme defects occur along pathways of hormone synthesis?

those proximal to the pathway are elevated and those distal to the pathway are decreased

what are enzyme precursors used for clinically?

evaluate adrenal carcinoma or virilization syndromes (ex. CAH)

which autoantibodies would be expected to be positive in Addison's?

21-hydroxylase

what are the catabolic products for catecholamines found in 24-hr urine testing for pheo?

homovanillic acid, metanephrine & normetanephrine, and vanillylmandelic acid

what test is preferred for initial eval of a pt w/ suspected pheo because of its increased sensitivity & specificity?

plasma or 24-hr free metanephrine testing

what result proves diagnosis of pheo in the plasma free metanephrine testing?

>2000 pg/mL

what secretory protein is elevated in most pts w/ pheo?

serum chromogranin A

what is the safest way to f/u an abnormal/intermediate free metanephrine test?

clonidine suppression test

is glucagon stimulation test used anymore?

no because of risk of HTN crisis

where is ADH produced and stored?

hypothalamus; posterior pituitary

what 2 locations have V2-type ADH receptors & play a role in physiologic balance of water?

DCT & CD

what are the stimuli for ADH secretion?

low blood volume & high serum osmolality

when is ADH indicated?

-polyuria + polydipsia (but nL BG)

-abnormal sodium or osmolality levels

-workup for DI or SIADH

what conditions is ADH increased in?

SIADH & DI (nephrogenic)

what condition is ADH decreased in?

DI (central)

if pt had impaired thirst or issue obtaining necessary water to balance out polyuria, would electrolyte abnormality would you see?

hypernatremia

what are options for ADH stimulation testing?

water deprivation testing & modified vasopressin challenge testing

what biochemical test would confirm suspected diagnosis of central DI?

modified vasopressin challenge test (initial alt to full water deprivation testing)

how would modified vasopressin challenge test confirm central DI?

distinct reduction in polydipsia & polyuria after admin of DDAVP

will a pt with nephrogenic DI see improvement of symptoms w/ modified vasopressin challenge test?

no - problem is not w/ ADH production/secretion but tubular responsiveness to ADH (may benefit from full water deprivation testing)

what electrolyte abnormalities can also impair tubular responsiveness to ADH?

hypercalcemia & hypokalemia

what is the diagnosis of low Na+, low serum osmolality, high urine osmolality, & high urinary Na+?

SIADH

what type of hyponatremia does SIADH typically cause?

euvolemic hypotonic hyponatremia

is ADH a required component of assessment of a pt w/ SIADH?

no

would ADH suppression testing be clinically used?

not unless clinical scenario is confusing

if you were concerned of pituitary adenoma of infiltrative disease of the hypothalamus/pituitary, what imaging study would you order?

pituitary MRI

if you were concerned about adrenal adenoma/carcicnoma, pheo, or infiltrative/destructive disease of adrenals, what imaging study would you order?

abdominal CT/MRI

if you were concerned about an ectopic source of hormonal secretion (ADH or ACTH), where would you look first?

chest (xray or CT)

which test is a f/u of pt w/ suspected Cushing disease when pituitary MRI is nondiagnostic & confirms ACTH-secreting pituitary adenoma before surgery?

petrosal sinus sampling

which test assesses bone age in children w/ growth/development concerns?

plain x-rays of wrist & hands

which test confirms that adrenal mass is the source of hormonal hypersecretion prior to adrenalectomy & distinguishes b/l from u/l results?

adrenal petrous sampling

which test is a f/u of pt w/ non-MEN-related pheo when conventional adrenal imaging is nondiagnostic?

I-MBG scanning

which test confirms the secretory activity of masses present on CT of chest/abdomen or localization of any functional neuroendocrine tumor (metastatic or MEN-related pheos)

somatostatin receptor scintigraphy