Chapter 20: Adrenal Function
By Ryan Hungerford, A. Wayne Meikle
Copyright 2010 Wolters Kluwer Health | Lippincott Williams & Wilkins
Introduction
Adrenal Gland: An Overview
Produces steroid hormones & neuropeptides essential for life
Conditions affect blood pressure & electrolyte balance.
Hypofunction is treated with exogenous hormone replacement,
hyperfunction with pharmacologic suppression or surgery.
Embryology and Anatomy
Composed of outer adrenal cortex & inner adrenal medulla
Pyramid-shaped, located just above & medial to kidneys
Arterial supply is symmetric; axons reach medulla through cortex.
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Introduction (contd)
Adrenal gland by layer
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The Adrenal Cortex by Zone
Zona Glomerulosa (G-Zone) Cells (outer 10%)
Synthesize mineralocorticoids critical for sodium retention,
potassium, & acidbase homeostasis
Zona Fasciculata (F-Zone) Cells (middle 75%)
Synthesize glucocorticoids critical to blood glucose homeostasis
& blood pressure
Zona Reticularis (R-Zone) Cells (inner 10%)
Sulfate DHEA to DHEA-S
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The Adrenal Cortex by Zone (contd)
Cortex Steroidogenesis
All adrenal steroids are derived by sequential enzymatic conversion
of a common substrate, cholesterol.
Only free cholesterol can enter steroidogenic pathways in response
to ACTH.
Conversion of cholesterol to pregnenolone is a rate-limiting step in
steroid biosynthesis.
Decreased activity of any enzymes required for biosynthesis can
occur as an acquired or inherited trait.
Evaluation of adrenal function requires measuring relevant adrenal
hormones, metabolites, & regulatory secretagogues.
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The Adrenal Cortex by Zone (contd)
Congenital Adrenal Hyperplasia
An inherited family of enzyme disorders causing decreased cortisol &
aldosterone (Aldo) production
G-cells convert cholesterol to pregnenolone, & then into Aldo.
Aldo acts on kidney to increase blood pressure.
Isolated hypoaldosteronism
Caused by adrenal gland destruction, chronic heparin therapy,
unilateral adrenalectomy, & G-layer enzyme deficiencies
Hyperaldosteronism
Can lead to metabolic alkalosis, hypertension, & hypokalemia
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Diagnosis of Primary Aldosteronism
Three criteria
Plasma Aldo (PA)/plasma renin activity (PRA) > 25
Low plasma renin that fails to increase w/ volume depletion
High Aldo that fails to decrease w/ saline/angiotensin inhibition
Diagnosis Algorithm
Tests: 1) urinary potassium excretion, 2) upright PA/PRA ratio, 3)
captopril suppression, 4) 18-hydroxycorticosterone levels, 5) adrenal
imaging, & 6) adrenal vein sampling
Adrenal Cortical Physiology
Cortisol synthesis: critical to hemodynamic, glucose homeostasis
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Adrenal Insufficiency (Addisons Disease)
and Hypercortisolism
Adrenal Insufficiency
Cause: primary adrenal problem or ACTH deficiency
Symptoms: weakness, fatigue, anorexia, nausea, diarrhea,
abdominal pain, weight loss
Diagnosis: low baseline cortisol levels & ACTH > 200 pg/mL
Treatment: Synthetic steroids from G & R zones are replaced.
Hypercortisolism
Caused by overproduction of CRH, ACTH, adrenal glucocorticoid
secretion and exogenous intake
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Cushings Syndrome
Caused by excess glucocorticoid production or prolonged
exogenous steroid use
Determinations Necessary for Diagnosis
ACTH-dependent vs. ACTH-independent hypercortisolism (determined via
2-site IRMA assay for ACTH)
Pituitary vs. ectopic ACTH secretion (determined via high-dose
dexamethasone suppression test)
ACTH Source in Dexamethasone Non-Suppression
6070% of patients with non-suppressible ACTH secretion to high-dose
dexamethasone will have Cushings disease.
Scintinography may be used to localize neuroendocrine tumors.
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Cushings Syndrome (contd)
Inferior Petrosal Sinus Sampling
Source of ACTH hypersecretion can be investigated by
simultaneous sampling of blood from inferior petrosal sinus & a
peripheral vein.
Petrosal sinus to peripheral blood ACTH ratio of >23 is 97%
sensitive & 100% specific for ACTH hypersecretion from pituitary
gland, or Cushings disease.
Imaging with CT or MRI is used to localize pituitary or ectopic
ACTH-secreting tumors.
Outcome for patients with Cushings syndrome similar to that for
patients with type 1 diabetes
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Cushings Syndrome (contd)
Steps in Diagnosis
Document cortisol excess:
Urine free cortisol (and/or metabolites)
Random plasma cortisol levels
Baseline a.m. cortisol concentrations
Determine if diurnal rhythm is lost: late-night values remain
high.
Determine loss of normal cortisol suppression by
dexamethasone.
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Cushings Syndrome (contd)
CRH Stimulation Test to Determine ACTH Dependency
Distinguishes types of disease (central vs. primary adrenal)
CRH is injected, then cortisol & ACTH levels are measured.
Localization Procedures
Adrenal Cushings: adrenal CT (tumor vs. hyperplasia) & adrenal MRI
T2-weighted image to discern carcinoma
Pituitary Cushings: pituitary MRI
Ectopic Cushings: chest CT
Treatment (all types): surgery, radiation, and/or medications to
suppress adrenal cortisol production
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Cushings Syndrome (contd)
Algorithm for Cushings Workup
Day 1
8:00 a.m.: Empty bladder & start baseline urine collection.
11:00 p.m.: Collect saliva sample for cortisol level; ingest
dexamethasone (1 mg); empty bladder; end baseline urine
collection.
Optional extended workups: Begin overnight dexamethasonesuppressed urine collection.
Day 2
8:00 a.m.: Empty bladder; venous blood or saliva for cortisol;
ACTH; dexamethasone; hold samples until needed.
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Cushings Syndrome (contd)
Cushings syndrome workup
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Androgen Excess
Symptoms
Boys: penile enlargement, hair growth, precocious puberty
Girls: ambiguous genitalia (infants), hirsutism, acne, clitorimegaly,
short stature, precocious puberty
Women: infertility, hirsutism, acne, male pattern baldness,
menstrual irregularities, virility
Men: infertility & decreases in following: muscle mass, hair growth,
testes size, testosterone production, spermatogenesis
Diagnosis: high levels of DHEA-S, DHEA, testosterone
Treatment: surgical removal of tumors; exogenous DHEA
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The Adrenal Medulla
Functions
Secretes catecholamines directly into circulation in lieu of transmitting
messages via efferent axons
Acts as first responder to stress (within seconds) to promote fight-orflight response
Development
Sympathetic cells arise from primordial neural crest stem cells, which
differentiate into sympathoblasts or pheochromoblasts.
Biosynthesis of Catecholamines
Norepinephrine & epinephrine synthesized by conversion of phenylalanine
substrates in tightly regulated manner
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The Adrenal Medulla (contd)
Catecholamine Degradation
Three methods of catecholamine elimination: 1) reuptake into
secretory vesicles; 2) uptake in non-neuronal cells (mostly liver);
3) degradation
Two enzymes (COMT & MAO) produce metabolites from free
catecholamines.
Metabolites & free catecholamines are filtered into urine & excreted.
Urine and Plasma Catecholamine Measurements
Urine catecholamines are assayed using liquid chromatography,
fluorometrics, LC/MS/MS; 24-hour levels are more accurate.
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The Adrenal Medulla (contd)
Causes of Sympathetic Hyperactivity
Autonomic dysfunction
Panic attack (emotions)
Stress responses: hypoglycemia, injury, infection, psychosis,
seizures
Drugs: decongestants, appetite suppressors, stimulants,
bronchodilators, MAO inhibitors, thyroid hormone, cortisol, etc.
Foods containing tyramine: imported beer, red wine, soy
sauce, overripe/fermented foods, smoked or aged meats
Pheochromocytoma (catecholamine-producing tumor)
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The Adrenal Medulla (contd)
Diagnosis of Pheochromocytoma
Fractionated metanephrines & catecholamines (in a 24-hour
collection): best test for diagnosis
Total plasma catecholamines & urine metanephrines: most
sensitive screening profile
Plasma metanephrines (measured by HPLC or RIA): touted as most
specific & sensitive diagnostic test
Urine metanephrines: possibly most sensitive urine test
Serum chromogranin A & plasma catecholamines
Clonidine suppression test
Radiologic localization: CT, MRI, PET scanning
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The Adrenal Medulla (contd)
Treatment of Pheochromocytoma
Surgery, following appropriate medical preparation
Removal is a high-risk procedure.
Catecholamines fall to normal within 1 week of resection.
Perioperative alpha blockade is widely recommended.
Outcome and Prognosis
Patients with familial pheochromocytomas are more likely to have
recurrence.
Long-term monitoring is indicated in all patients.
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Adrenal Incidentaloma
Incidentaloma: adrenal mass, typically >1 cm in
diameter, found incidentally in CT, MRI, & ultrasound
imaging of abdomen
Autopsy studies report frequency of adrenal adenomas at
about 6%, & prevalence increases with age.
All lesions should be assessed for malignancy or
hypersecretion.
Surgery should be considered if adrenal mass is cancerous;
autonomously secreting cortisol, Aldo, or catecholamines;
4 cm in diameter; or growing.
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