Urinary Free Cortisol

Urinary free cortisol measurements are used primarily in the diagnosis of hypercortisolism caused by Cushing syndrome. ^{[1, 2, 3]}

Reference ranges for urinary free cortisol vary by age, as follows:

• Age 0-2 years - Not established

• Age 3-8 years - 1.4-20 µg/24 h

• Age 9-12 years - 2.6-37 µg/24 h

• Age 13-17 years - 4-56 µg/24 h

• Age 18 years or older - 3.5-45 µg/24 h

Conversion factor

Cortisol: µg/24 h X 2.76 = nmol/24 h (molecular weight = 362.5)

Urinary free cortisol measurements are used primarily in the diagnosis of hypercortisolism caused by Cushing syndrome. ^{[4, 5]} Stress and exogenous glucocorticoid usage are other factors that can affect urinary free cortisol levels.

Using a cortisol-to-cortisone ratio, urinary free cortisol testing can also be used to diagnose inherited or acquired abnormalities of 11-beta-hydroxy steroid dehydrogenase such as pseudohyperaldosteronism, licorice consumption, and chewing tobacco use.

Albeit rarely, urinary free cortisol can also be used to diagnose adrenal insufficiency.

Collection details are as follows:

• Container/tube - Plastic 10-mL urine tube

• Specimen volume - 5 mL

• Collection instructions - Collect urine for 24 hours; at the start of collection, 10 g of boric acid is added as preservative

• Additional information - 24-Hour volume is required

Description

The main adrenal glucocorticoid is cortisol, and it has a central role in the metabolism of glucose and in the body's response to stress. Corticotropin regulates adrenal cortisol production. Corticotropin is synthesized in the pituitary gland in response to hypothalamic corticotropin-releasing hormone (CRH). In turn, the production of both CRH and corticotropin are inhibited by serum cortisol (negative feedback loop). The system self-regulates to control proper levels of cortisol production. These coordinated stimulatory and inhibitory connections between CRH, corticotropin, and cortisol are termed the hypothalamic-pituitary-adrenal (HPA) axis.

Most cortisol circulates bound to cortisol-binding globulin (CBG, also known as transcortin) and albumin. Elevated estrogen levels are the most common cause of increased CBG levels; therefore, higher levels of cortisol are found in women, during pregnancy, and in persons on estrogen therapy.

In normal circumstances, less than 5% of circulating cortisol is free (unbound). Free cortisol is the physiologically active form of cortisol and is filterable by the renal glomerulus. With increased levels of plasma cortisol, free cortisol levels increase, which is then filtered through the glomerulus.

The concentration of plasma free cortisol correlates well with urinary free cortisol. Urinary free cortisol values represent the excretion of the circulating, biologically active, unbound (free) cortisol. Urinary free cortisol is a sensitive test for the various types of adrenocortical dysfunction, particularly hypercortisolism (Cushing syndrome).

Indications/Applications

The primarily use for urinary free cortisol measurements is to diagnose hypercortisolism (states of excess cortisol); however, urinary free cortisol measurements are less helpful for diagnosing hypocortisolism (cortisol deficiency).

While hypercortisolism is uncommon, the signs and symptoms are common and include obesity, high blood pressure, and increased blood glucose concentration.

The cause of Cushing syndrome (endogenous hypercortisolism rather than exogenous hypercortisolism resulting from medication) is overproduction of cortisol due to either a primary adrenal disease (eg, adenoma, carcinoma, nodular hyperplasia) or an excess of corticotropin (from a pituitary tumor or an ectopic source). The most frequently diagnosed subtype of hypercortisolism is corticotropin-dependent Cushing disease resulting from a pituitary corticotroph adenoma. It most commonly occurs in women in the third to fifth decades of life. Insidious in onset, it usually occurs 2-5 years before a clinical diagnosis is made.

A study by Otsuka et al reported that the ratio of urinary free cortisol to the urinary aldosterone concentration can be used to detect adrenocortical dysfunction–related metabolic and inflammatory complications. The ratio was found to correlate more significantly with metabolic and inflammatory status markers, including hemoglobin A1c, albumin, C-reactive protein (CRP), ferritin, and D-dimer, than did levels of serum cortisol levels or urinary free cortisol by themselves. With cutoff values of approximately 12, the ratio was determined to indicate the risk for diabetes, hypoalbuminemia, hyper-CRPemia, and thrombophilia. ^[6]

Considerations

Elevated baseline urinary free cortisol levels can result from situations of acute stress (eg, hospitalization, surgery), from alcoholism, from depression, and as a side effect of many drugs (eg, exogenous cortisones, anticonvulsants).

Urinary free cortisol testing is not a reliable diagnostic tool for adrenal insufficiency.

Falsely low values can result from an incomplete urine collection or from renal disease with decreased renal clearance.

Cross-reactivity with some exogenous glucocorticoids (eg, prednisone) can occur, depending on the assay method (radioimmunoassay, high-performance liquid chromatography, or liquid chromatography–tandem mass spectrometry [LC-MS/MS]). The preferred assay is LC-MS/MS because it eliminates analytical interferences with substances such as carbamazepine (Tegretol) and synthetic corticosteroids that may affect immunoassay-based cortisol results. ^[3]

Pseudo-Cushing syndrome is increased production of cortisol without true clinical manifestations of hypercortisolism. It occurs in certain conditions, such as depression, alcoholism, anorexia nervosa, and pregnancy, among others. In such situations, HPA axis overactivity is similar to Cushing syndrome.