• CRH and ACTH regulated it
• released in secretory pulses throughout the day, with most happening during the later half of sleep
  • partially regulated by pineal melatonin
• if someone works irregular shifts, travels from one time zone to antoher, it takes days to weeks to adjust melatonin synthesis patterns to match new waking hours
  • after adjustment, they have different diurnal cortisol patterns than "normal" people

• difficult to due effects of stress and diurinal variation
• to fix this, we use dynamic testing (evaluate response to stimuli or suppressants)

• increase by:
  • estrogens
  • pregnacy
• decrease by:
  • liver disease
  • malnutrition
  • protein losing states

• almost all of it is bound to CBG (changes in CBG mean abnormal cortisol levels)
• highest when waking up
  • even higher with acute illness or critical illness (cortisol increases dramatically)
  • diurnal variation is lost in illness

• usually excreted unchanged in the urine
• when the plasma levels are elevated to the upper limits of normal, binding capacity is exceed and unbound cortisol increases in urine
• this is a way to quantify the degree to which plasma cortisol exceeds protein binding capacity
  • slight increases in average cortisol cause marked increases in UFC (ex: plasma cortisol in Cushing could be 2x normal while UFC can be 50x normal)

• purpose: evaluate for suspected congenital adrenal hyperplasia or adrenal carcinoma
  • where there is a block in synthesis to prevent formation of active compound
• 17-hydroxysteroids
  • includes cortisol, its immediate precursor, and their metabolites
• 17 ketosteroids
  • most adrenal androgens (NOT testosterone)

Many compounds interfere with both assays, resulting in falsely increased urine levels

• problems with it
  • difficult due to episodic bursts
  • quite labile in plasma (special collection and handling needed to prevent falsely low results)
  • show varying levels in patients with ectopic ACTH production
• current techniques for sampling
  • direct sinus sampling (used to determine pituitary origin and side of pituitary affected in patients with Cushings)
    • requires highly skilled interventional radiologist to be able to successfully catheterize sinus
    • based off fact that ACTH is released from pituitary into blood reaching the inferior petrosal sinus

• this works because it is a GCS that inhibits ACTH and DOES NOT cross react with cortisol assays
• process
  1. overnight DST
     • give 1 mg (slightly above physiologic levels) given before bedtime, right before most ACTH production occurs
     • normal response rules out Cushings (plasma cortisol less than 5 micrograms/ dL at 8 AM)
  2. low dose DST
     • supraphysiologic dose (0.5 mg every 6 hrs for two days) should prevent normal individuals from having pituitary ACTH production
     • determine by measuring UFC (normal: less than 20 micrograms during the second day of administration)
  3. high dose DST
     • greatly supraphysiologic dose (2 mg every 6 hrs for 2 days) will decrease ACTH production in pituitary tumors (UFC fall below 20% of basal)
     • in other causes of Cushing's, no other change in cortisol production
     • could also be done by giving 8 mg of dexmethasone at bedtime with morning cortisol being 50% of basal
     • some patients with pituitary tumors may need 16-32 mg to show suppression

• overnight DST
  • hopsitalized, acutely ill individuals
  • stress
  • depression
  • obesity (lower plasma dexamethasone levels),
  • drugs increasing metabolism (dilantin, ethanol)
  • poor absorption (renal failure)
• low dose DST
  • more likely Cushings
  • other causes of abnormal overnight DST usually do not effect low dose test
• high dose DST
  • Cushings
  • pituitary tumors

• process
  1. administer 250 micrograms of corrosyn (bioactive, synthetic ACTH fragment) in IV bolus
  2. measure plasma cortisol at 0, 30, and 60 minutes
     • if increase plasma cortisol with at least 7 micrograms/dL with peak over 18-20 micrograms is normal
• differential dx
  • if you fail to respond to 1 mg cortrosyn:
    • pituitary tumor
    • long term steroid therapy

More recently 1 mg is sometimes used. Dont need cortrosyn stimulation of basal cortisol level is 18-20 micrograms/dL.

• process
  1. inhibits last step of cortisol synthesis, removing feedback inhibition of ACTH
  2. increase in ACTH lead to increase in 11 deoxycortisol to rise by at least 7 micrograms/dL
• warnings- dangerous with low basal cortisol, and may produce adrenal crisis if the patient is not pretreated with dexamethasone

• process
  1. IV insuline reduces glucose below 40 mg/dL
  2. leads to increase ACTH
     • normal: cortisol should increase by at least 7 micrograms/dL with peak over 18-20

Most sensitive test to document inadequate pituitary ACTH production

1. 100 micrograms synthetic CRH given via IV bolus
2. should cause increase of 2-4 fold in ACTH
3. cortisol should increase by 7 micrograms/dL with peak over 18-20 micrograms/dL

NOT commercially available

• cortrosyn stimulation
• metyrapone test
• insulin hypoglycemia
• CRH stimulation

• cause- excess GCS due to:
  • high dose steroid tx
  • disease (RARE)
• symptoms
  • obesity
  • HTN
  • virilization
  • poor wound healing
  • hyperglycemia
  • hypokalemia and metabolic alkalosis (activation of Ald R's by cortisol)
  • possible low lymphocyte count

1. overnight DST or UFC (UFC has fewere fals positives)
   • if UFC greater than 20, possible Cushings
2. low dose DST (many fals negatives)
   • if greater than 20 micrograms/dL, confirms Cushings syndrome
3. high dose DST or inferior petrosal sinus ACTH (sinus test more reliable: 3 fold gradient between two sides indicates Cushings)
   • if more than 50% fall, Cushing DISEASE
   • if no or fewer than 50% fall, do ACTH levels
     • if higher end: ectopic ACTH
     • if lower end: adrenal tumor

• adrenal hyperplasia (usually bilateral)
  • with increase ACTH, cause enlargement of zona fasciculata and reticularis (not really to glomerulosa)
• unliateral enlargement due to neoplasms
  • adrenal adenoma
    • often incidental finding at autopsy
    • gross- solitary, yellow nodules reaching 50 grams with surrounding cortex and opposite adrenal often atropy
    • microscopy- lipid containing cells stain pale with significant pleomorphis
  • adrenal carcinoma (RARE)
    • often do not produce function steroids or only produce androgens without cortisol
    • usually detected as adrenal mass rather than by symptoms of excess steroid
    • gross- very larg yellow tumors with gross evidence of necrosis and hemorrhage often present

• minerocorticoid deficiency lead to:
  • dehydration
  • hyponatremia
  • hyperkalemia
  • non anion gap metabolic acidosis
• glucocorticoid defiency lead to:
  • hypotension
  • weight loss
  • nausea
  • vomiting
  • weakness
  • occasional hypoglycemia

• primary adrenal insufficiency (Addison's disease)
  • high POMC production leads to increase pigmentation of skin and mucus membranes
• secondary adrenal insufficiency (due to pituitary disease) or tertiary adrenal insufficiency (due to hypothalamic dysfunction)
  • no excess ACTH or mineralcorticoid problems
  • hypoglycemia more common (due to deficiencies in GH and thyroid hormone)
  • dx often delayed due to non specific symptoms of glucocorticoid deficiency

• if stable patient, measure plasma cortisol levels
  • cortisol greater than 18-20 micrograms/dL rules out adrenal insufficiency
  • cortisol less than 3 in ill patient confirms adrenal insufficiency
• if values between 3-20, do a cortrosyn stimulation test or ACTH measurement for further evaluation
• if signs and symptoms suggest hypoadrenalism, tx should be started ASAP
• administer dexamethasone to tx adrenal insufficiency after drawing basal cortisol and ACTH then rapid infusion with cosyntropin to determine adrenal response
• measure ACTH in equivocal cases
  • marked elevation confirms primary adrenal failure
  • low ACTH and low cortisol is secondary failure

• requires destruction of over 90% of cortex
• most commonly, adrenal insufficiency associated with autoimmune adrenalitis
• gross
  • small adrenal glands
  • adrenal medulla uneffected
  • if granuolamatous disease or carcinomas causing insufficienc, look for enlarged glands replaced with nonadrenal tissue

1. adrenal hemorrhage caused by Neisseria meningitidis infection causin gram negative shock
2. leadss to DIC and extensive petechial hemorrhage in skin
3. also cause adrenal insufficiency

• corticosterone accumulates
• increased mineralcorticoids, decreased glucocorticoids and sex steroids cause
  • hypoglycemia
  • HTN
  • hypokalemia
  • males with female external genitalia

• pregnanetriol accumulates
• decrease in sex steroids (except DHEA), mineralcorticoids, and glucocorticoids cause:
  • Addison's disease
  • males with female external genitalia in complete form
  • impotence and infertility in partial form

• 17 OH progesterone accumulates
• decreased glucocorticoids and mineralcorticoids, increase sex steroids lead to:
  • Addisons in complete form
  • females with masculinized external genitalia (hypertrophy of clitoris with partial fusion of labia)
  • normal adrenal function
  • hirsutism
  • menstrual abnormalities in women in partial form

• accumulation of 11 deoxycortisol and deoxycorticosterone
• decrease glucocorticoids and mineralcoritcoids (except deoxycorticosterone), increase sex steroids leads to:
  • hypoglycemia
  • HTN
  • hypokalemia
  • females with masculinized external genitalia

• renin and Ald lows in morning and rise when standing
• testing levels
  • some tissues due produce inactive precursor (prorenin) which can be converted to renin after specimens are collected
  • normal Ald:renin ratio is 5:1-20:1
    • if high, primary Ald
    • if low, adrenal insufficiency

Must interpret in light of volume status, so NEVER do random testing without preperation like taking patients off all drugs affecting renin and Ald levels

• clinical signs
  • hypokalemia
  • metabolic alkalosis
  • marked sodium retention
  • excessive potassium excretion
• dx
  • discontinue all meds affecting Ald and liberalize salkt intake
  • if HTN and hypokalemia found, test 24 hour urine potassium (more than 30 mmol)
  • measure morning supine renin, Ald
    • high renin, high Ald = secondary hyperAld
    • low renin, high Ald = primary hyperAld

• adrenal adenoma
  • lateralizing aldosterone gradient
  • no change in Ald levels upon change in posture
  • iodocholesterole scan shows unilateral uptake
  • CT/MRI show tumor if > 10 mm
• essential hyperAld
  • Ald levels increase with no gradient
  • CT/MRI show normal or bilateral enlargement
  • increases in Ald when upright
  • iodocholesterol scan show bilateral enlargement

1. synthesize and release catecholamines (mainly epi is made exclusively here)
2. broken down by MAO and COMT
   • makes metanephrings (ex: VMA is end product of both)
   • HVA is end product of dopamine metabolism

• measuring direct catecholamines not always good because adrenal cortex not the only source of catecholamines
• metanephrines are most widely used chemical assay of catecholamine production
  • usually measure total metanephrins with most derived from norepi metabolism and ucan measure metanephrine and normetanephrine separately (this increase sensitivity for detecting epinephrine tumors)
  • VMA is least senstivie test of catecholamine production
  • HVA (final product of dopamine breakdown)
    • usually only produced by neuroblastomas
    • may be only evaluation and follow up tool of neuroblastoma
• fractionated urine catecholamines are most sensitive urine test for catecholamine production
• fractionated metanephrines recently became available (most sensitive for PHEO but more prone to false positives)
• must discontinue drugs or any sympathomimetic agents before testing
• also acute stress should delay testing (acute illness, psyc disease, anxiety)

• epidemiology
  • most common tumor of adrenal medulla
  • rare cause of HTN
  • rule of 10% (recently called ino question)
    • 10% malignant
    • 10% bilateral
    • 10% extraadrenal
    • 10% familial (MEN)
    • 10% in kids
    • 10% calcify
• clinical presentation (5 P's)
  • pressure (elevated bp)
  • pain (headache)
  • perspiration
  • palpitation (tachycardia)
  • pallor

• gross
  • gray to brown tumors
  • very vascular
  • may have hemorrhage or necrosis
• histo
  • nuclear pleomorphism with frequent mitoses
  • NOTHING to help distinguish benign or malignant (can only do via metastases)
• tx- surgery for the benign, although patients must be premedicated with catecholamine blockers before surgery or other invasive procedures to prevent tachycardia or HTN

• epidemiology
  • most common adrenal tumor of children
  • peak age of tumor development below five years of age (1/3 in first 2 yrs of life)
  • 10% outside adrenal gland
• dx- usually due to mass affects
  • measure VMA and HVA useful at baseline and for follow up after tx to detect residual or recurrent tumor (one or both will be elevated a great majority of the time)
• prognosis
  • behave in malignat fashion
  • stage is important predictor of prognosis
  • microscopic metastases to certain sites (skin, liver, marrow) do not affect prognosis
  • rarely in infants, neuoblastoma can spontaneously mature into benign ganglioneuroma
  • also related to degree of amplification of N-myc oncogene (more copies equals worse prognosis)

• gross
  • soft, gray masses
  • often with hemorrhage and necrosis
• histo
  • sheets of small, blue cells
  • form small circular spaces without true gland lumen (aka Homer Wright rosettes)
  • similar to appearance of neuroblast
  • closely related to ganglioneuromas)