Cortisol (Urine)

Diagnostic Use

Urine free cortisol reflects mean serum free cortisol (unbound to cortisol binding globulin). Free unbound cortisol in plasma fluctuates in Cushing syndrome. The 24 hour urine free cortisol reflects the average serum free cortisol (unbound to cortisol binding globulin) filtered by the kidneys. This is one of the recommended screening tests for Cushing syndrome.

Note that genuine Cushing syndrome is very uncommon when iatrogenic causes are ruled out.

Measurements of urine cortisol are not useful in diagnosing adrenal insufficiency, as there is a large overlap between patients with adrenal insufficiency and normal subjects. Urine cortisol testing is of no value in chronic fatigue syndrome.

Interpretation

The use of spot urine cortisol/creatinine ratio is not endorsed by expert bodies such as the US Endocrine Society, and may be misleadingly affected by factors such as pulsatile cortisol release, which a 24hr urine collection is intended to reduced. Late night salivary cortisol measurement is a better index of free cortisol levels at night, and is part of the recommended algorithm for investigation of suspected Cushing’s syndrome (1).

However, diagnosis of Cushing syndrome can be difficult. As with all screening tests, false positives and negatives may occur. Careful correlation with clinical background and other tests (dexamethasone suppression, salivary cortisol) is recommended (1).

Cortisol excretion can vary widely from day to day, with biological variation (within-person CV) averaging about 50% (2). It can be influenced by numerous physical/psychological stimuli and the general health, stress level, exercise habits etc of the patient. Mild-moderate elevation can occur with any acute or chronic physical and/or psychological stress or illness, depression/insomnia, anorexia, alcoholism, or significant exercise, and inaccurate collection timing, as well as in Cushing syndrome. Depending on clinical suspicion and the initial result, additional follow-up measurement(s) may be needed (1,2).

In the absence of high dose exogenous steroid intake, more than four-fold elevation of UFC is strongly suggestive of Cushing’s syndrome (3).

Excretion may be increased in states of renal hyperfiltration (e.g. high daily fluid intake, pregnancy). However, production of cortisol is also increased in pregnancy and diagnosis of Cushing’s syndrome is more difficult (the above reference interval is for non-pregnant patients).

Conversely, the test may be falsely negative in patients with reduced glomerular filtration, progressively falling from eGFR <60 mL/min/1.73m2, and more as eGFR declines further. It should be interpreted with caution in this context and more reliance placed on other means of diagnosis (4).

Intake of some steroids causes elevation of urine cortisol measurement, especially hydrocortisone and prednisone/prednisolone, which can cross-react in the assay. There is very little assay cross-reaction with other exogenous/endogenous steroids. Intake (oral, inhaled, transdermal) of supra-physiological doses of high potency non-cross reacting steroids (e.g. dexamethasone, betamethasone, fluticasone) can cause physiological suppression of cortisol production and reduced urine cortisol measurement. Intake and dose of relevant steroids should be checked before requesting the sample.

Dexamethasone can be measured by specific request (see separate entry). In rare situations where presence of other adrenal steroids is suspected (e.g. adrenal carcinoma, congenital adrenal hyperplasia, other rare genetic disorders) a urine steroid profile may be appropriate. Please consult the laboratory. Requests are only approved with clinical justification.

Urine free cortisol correlates with daily dose in patients on steroid replacement and can be used as a guide in patients being treated with replacement hydrocortisone to avoid excessive replacement therapy. It is also useful in patients with established Cushing’s syndrome being treated medically with blockers of adrenal steroidogenesis.

Reference Intervals