Interpretive Handbook

Cortisol is a steroid hormone synthesized from cholesterol by a multienzyme cascade in the adrenal glands. It is the main glucocorticoid in humans and acts as a gene transcription factor influencing a multitude of cellular responses in virtually all tissues. It plays a critical role in glucose metabolism, maintenance of vascular tone, immune response regulation, and in the body's response to stress. Its production is under hypothalamic-pituitary feedback control.

Only a small percentage of circulating cortisol is biologically active (free), with the majority of cortisol inactive (protein bound). As plasma cortisol values increase, free cortisol (ie, unconjugated cortisol or hydrocortisone) increases and is filtered through the glomerulus. Urinary free cortisol (UFC) correlates well with the concentration of plasma free cortisol. UFC represents excretion of the circulating, biologically active, free cortisol that is responsible for the signs and symptoms of hypercortisolism. UFC is a sensitive test for the various types of adrenocortical dysfunction, particularly hypercortisolism (Cushing syndrome). A measurement of 24-hour UFC excretion, by Liquid Chromatography-Tandem Mass Spectrometry (LC-MS/MS), is the preferred screening test for Cushing syndrome. LC-MS/MS methodology eliminates analytical interferences including carbamazepine (Tegretol) and synthetic corticosteroids, which can affect immunoassay-based cortisol results.

Cortisone, a downstream metabolite of cortisol, provides an additional variable to assist in the diagnosis of various adrenal disorders, including abnormalities of 11-beta-hydroxy steroid dehydrogenase (11-beta HSD), the enzyme that converts cortisol to cortisone. Deficiency of 11-beta HSD results in a state of mineralocorticoid excess because cortisol (but not cortisone) acts as a mineralocorticoid receptor agonist. Licorice (active component glycyrrhetinic acid) inhibits 11-beta HSD and excess consumption can result in similar changes.

Investigating suspected hypercortisolism, when a 24-hour collection is prohibitive (ie, pediatric patients).

The cortisol to cortisone ratio can assist in diagnosing acquired or inherited abnormalities of 11-beta-hydroxy steroid dehydrogenase (11-beta HSD).

Diagnosis of pseudo-hyperaldosteronism due to excessive licorice consumption.

Most patients with Cushing's syndrome have increased urinary excretion of cortisol and/or cortisone. Further studies, including suppression or stimulation tests, measurement of serum corticotrophin (ACTH) concentrations, and imaging are usually necessary to confirm the diagnosis and determine the etiology.

Values in the normal range may occur in patients with mild Cushing's syndrome or with periodic hormonogenesis. In these cases, continuing follow-up and repeat testing are necessary to confirm the diagnosis.

Patients with Cushing's syndrome due to intake of synthetic glucocorticoids should have both suppressed cortisol and cortisone. In these circumstances a synthetic glucocorticoid screen might be ordered (SGSU/81035 Synthetic Glucocorticoid Screen, Urine).

Suppressed cortisol and cortisone values may also be observed in primary adrenal insufficiency and hypopituitarism. However, random urine specimens are not useful for evaluation of hypocorticalism.

Patients with 11-beta HSD deficiency may have cortisone to cortisol ratios less than 1, whereas a ratio of 2 or 3:1 is seen in normal patients. Excessive licorice consumption and use of carbenoxolone, a synthetic derivative of glycyrrhizinic acid used to treat gastroesophageal reflux disease, also may suppress the ratio to less than 1.

Random urine cortisol results are less reliable than results obtained from properly collected and complete 24-hour urine specimens, which are not affected by diurnal variations in cortisol levels.

This test has limited usefulness in the evaluation of adrenal insufficiency.

Acute stress (including hospitalization and surgery), alcoholism, depression, and many drugs (eg, exogenous cortisone, anticonvulsants) can obliterate normal diurnal variation, affect response to suppression/stimulation tests, and increase baseline levels.

Liquid chromatography-tandem mass spectrometry (LC-MS/MS) methodology eliminates analytical interferences including carbamazepine (Tegretol) and synthetic corticosteroids.

Random urine specimens may yield falsely elevated values when patients have a high urinary output.

Renal disease (decreased clearance) may cause falsely low values.

Values may be elevated to twice normal in pregnancy.

Patients with exogenous Cushing syndrome caused by ingestion of hydrocortisone will not have suppressed cortisol and cortisone values.

CORTISOL

Males

0-2 years: 3.0-120 mcg/g creatinine

3-8 years: 2.2-89 mcg/g creatinine

9-12 years: 1.4-56 mcg/g creatinine

13-17 years: 1.0-42 mcg/g creatinine

> or =18 years: 1.0-119 mcg/g creatinine

Females

0-2 years: 3.0-120 mcg/g creatinine

3-8 years: 2.2-89 mcg/g creatinine

9-12 years: 1.4-56 mcg/g creatinine

13-17 years: 1.0-42 mcg/g creatinine

> or =18 years: 0.7-85 mcg/g creatinine

CORTISONE

0-2 years: 25-477 mcg/g creatinine

3-8 years: 11-211 mcg/g creatinine

9-12 years: 5.8-109 mcg/g creatinine

13-17 years: 5.4-102 mcg/g creatinine

18-29 years: 5.7-153 mcg/g creatinine

30-39 years: 6.6-176 mcg/g creatinine

40-49 years: 7.6-203 mcg/g creatinine

50-59 years: 8.8-234 mcg/g creatinine

60-69 years: 10-270 mcg/g creatinine

> or =70 years: 12-311 mcg/g creatinine

Use the conversion factors below to convert each analyte from mcg/g creatinine to nmol/mol creatinine:

Conversion factors

Cortisol: mcg/g creatinine x 413=nmol/mol creatinine

Cortisone: mcg/g creatinine x 415=nmol/mol creatinine

Cortisol molecular weight=362.5

Cortisone molecular weight=360.4

Creatinine molecular weight=149.59

1. Findling JW, Raff H: Diagnosis and differential diagnosis of Cushing's syndrome. Endocrinol Metab Clin North Am 2001;30:729-47

2. Boscaro M, Barzon L, Fallo F, Sonino N: Cushing's syndrome. Lancet 2001;357:783-791

3. Taylor RL, Machacek D, Singh RJ: Validation of a high-throughput liquid chromatography-tandem mass spectrometry method for urinary cortisol and cortisone. Clin Chem 2002;48:1511-1519