Version May 2024
INTRODUCTION — Measurement of urinary excretion of corticosteroids (any steroid hormone produced by the adrenal cortex) and their metabolites has been used to evaluate adrenal function for more than 50 years. Currently, these measurements are used to evaluate cortisol excretion of exogenous glucocorticoids or cortisol and its metabolites in the context of Cushing syndrome or adrenal cancer.
Evaluating daily urinary cortisol (and corticosteroid) excretion has the advantage of providing an integrated index of steroid production over a period of 24 hours, whereas measurements of serum cortisol only provide information about an instant in time. This is important because corticotropin (ACTH) and cortisol are secreted in discrete pulses, resulting in plasma concentrations that rise and fall episodically. This is true not only for normal subjects but also for patients with Cushing syndrome caused by pituitary or adrenal tumors [1,2].
Other methods of cortisol measurement are discussed separately. (See "Establishing the diagnosis of Cushing syndrome" and "Measurement of cortisol in serum and saliva" and "Basic principles in the laboratory evaluation of adrenocortical function".)
URINE COLLECTION — The validity of the results depends on normal renal function [3]. Individuals with moderate (creatinine clearance less than 60 mL/min) and severe renal impairment (creatinine clearance less than 20 mL/min) have progressively lower cortisol excretion [3].
Additionally, over or under-collection of the 24-hour specimen can bias the results. Because of this, measurement of cortisol excretion must include concurrent measurement of creatinine excretion. The accuracy of the collection (and the reproducibility of a series of collections) can be estimated from knowledge of the normal rate of creatinine excretion (which is equal to creatinine production in the steady state). In adults under the age of 50 years, daily creatinine excretion should be 20 to 25 mg/kg (177 to 221 mmol/kg) lean body weight in men and 15 to 20 mg/kg (133 to 177 mmol/kg) lean body weight in women.
From the ages of 50 to 90 years, there is a progressive decline in creatinine excretion (to as low as 10 mg/kg in men), due primarily to a decrease in muscle mass (see "Calculation of the creatinine clearance"). However, the excretion of cortisol and its metabolites varies diurnally, whereas creatinine excretion does not. Thus, inadequate urine collections cannot be corrected on the basis of the creatinine value. Furthermore, creatinine excretion is not affected by fluid intake, while cortisol excretion increases with increased fluid intake in both children and adults [4,5]. The importance of appropriately timed collection and avoidance of high fluid intake should be stressed to the patient. (See "Patient education: Collection of a 24-hour urine specimen (Beyond the Basics)".)
24-HOUR URINARY FREE CORTISOL — The 24-hour urinary free cortisol (UFC) is one of the first-line diagnostic tests for Cushing syndrome [6-9]. Serum cortisol measures both cortisol bound to corticosteroid-binding globulin (CBG) and free hormone, while UFC measures only non-CBG-bound cortisol (which is filtered by the kidney unchanged). Therefore, UFC is unaffected by medications and medical conditions that affect CBG, such as oral estrogen use, which increases CBG and serum cortisol concentrations, while UFC is unchanged. (See "Dexamethasone suppression tests", section on 'Sources of error'.)
The use of the 24-hour UFC test in the diagnostic evaluation of Cushing syndrome is discussed in detail separately. (See "Establishing the diagnosis of Cushing syndrome", section on '24-hour urinary cortisol excretion'.)
Types of assays — We suggest liquid chromatography-tandem mass spectrometry (LC-MS/MS) [10] to measure 24-hour UFC. Normal ranges vary even within analytic methods so it is essential to interpret test results in this context.
Antibody based — Some immunoassays are relatively nonspecific because of cross-reaction with other steroids and steroid metabolites (eg, prednisolone, the biologically active metabolite of prednisone, 6-beta-hydroxycortisol, an inactive metabolite of cortisol and A-ring dihydro- and tetrahydro metabolites [11-13]). This is typically reflected by a higher upper limit of the reference range. Nonspecific urine cortisol immunoassays have reference ranges of 20 to 90 to 100 mcg/day or greater (55 to 250 to 285 nmol/day), considerably higher than the reference ranges for more specific immunoassays and LC-MS/MS (10 to 55 mcg/day [27 to 150 nmol/day]).
However, there is significant variability in cross-reactivities between different assays. Online catalogs and laboratory result forms provide the reference range and (sometimes) the test methodology. The laboratory may need to be consulted to investigate unusual or unexpected results. It is prudent to request a referral of such a sample for analysis by LC-MS/MS. Laboratories typically only retain samples for one to two weeks, so fast action by the clinician is needed.
Results obtained with nonspecific immunoassays should be interpreted with caution, recognizing the possibility that other glucocorticoids (endogenous and exogenous) and their metabolites are being measured [12-17]. Interestingly, immunoassay crossreactivity may be a diagnostic advantage or, at least, non-inferior for identification of mild glucocorticoid excess [9,18,19].
Structurally based — Urinary cortisol is assayed by structurally based assays that do not use antibodies, such as LC-MS/MS or gas chromatography-mass spectrometry (GC-MS; and previously by high-performance liquid chromatography [HPLC]). These methods are more specific than immunoassays, have a lower reference range (10 to 55 mcg/day [27 to 150 nmol/day]), and correlate well with each other [12]. Most reference laboratories use LC-MS/MS for the evaluation of urinary cortisol and its metabolites and synthetic precursors.
Normal values — As noted above, urinary cortisol excretion in normal subjects without excess fluid intake ranges from approximately 10 to 55 mcg/day (27 to 150 nmol/day), measured by specific immunoassays or LC-MS/MS.
Interpretation — Urinary cortisol excretion results from glomerular filtration of serum free cortisol (unbound minus some that is reabsorbed) and is therefore an index of the integrated 24-hour serum free cortisol concentration. Although urinary cortisol represents less than 1 percent of the cortisol secreted each day, it provides a valid index of cortisol secretion. Because it reflects 24-hour serum cortisol concentrations, one should be suspicious of a high urinary cortisol value in a patient with a normal bedtime serum or salivary cortisol concentration and of a low urinary cortisol value in a patient with a normal morning serum or salivary cortisol concentration.
Hypercortisolism — Serum total cortisol concentrations exceed the binding capacity of CBG at approximately 25 mcg/dL, reflecting the normal circadian peak level (690 nmol/L); above this concentration serum free cortisol concentrations increase rapidly, leading to a rapid increase in urinary cortisol excretion.
Patients with modest increases in cortisol production may have normal 24-hour UFC. (See "Establishing the diagnosis of Cushing syndrome".)
Adrenal insufficiency and glucocorticoid replacement — Urinary cortisol excretion is low in patients with primary and secondary adrenal insufficiency [20] and in those with congenital adrenal hyperplasia (CAH). However, values in these patients overlap the lower part of the normal reference range. Therefore, UFC alone is not reliable for diagnosis of these conditions.
Urinary cortisol assays are not a good indicator of the adequacy of cortisol or cortisone replacement [21]. The same daily replacement dose of cortisol (eg, 30 mg) results in a greater increase in 24-hour urinary cortisol excretion when given as a single dose than when given in multiple divided doses.
●A single dose of hydrocortisone is absorbed within 20 to 30 minutes. As a result, serum cortisol concentrations temporarily exceed the binding capacity of CBG and serum free cortisol concentrations are temporarily high. This free cortisol is excreted in the urine until the serum total cortisol concentration, falling rapidly, reaches the binding capacity of CBG.
●When multiple doses are used to give the same total amount of hydrocortisone, serum cortisol concentrations may never exceed the binding capacity of CBG. As a result, the 24-hour urinary cortisol excretion is lower and more representative of the integrated serum free cortisol concentrations to which the patient's cells have been exposed.
Monitoring adrenal steroidogenesis inhibition for Cushing syndrome — UFC is used to monitor the efficacy of steroidogenesis inhibitors to decrease cortisol production in Cushing syndrome. When used to monitor inhibitors of CYP11B1 (metyrapone and osilodrostat), LC-MS/MS assays should be used to avoid immunoassay cross-reactivity with increased 11-deoxycortisol resulting from those agents [22]. (See "Medical therapy of hypercortisolism (Cushing's syndrome)", section on 'Osilodrostat'.)
ACTH/CRH stimulation tests — Urinary cortisol excretion is also disproportionately high after major episodes of endogenous cortisol secretion, as may occur during corticotropin (ACTH) and corticotropin-releasing hormone (CRH) stimulation tests. Because of this, measurement of urinary cortisol excretion for the diagnosis of Cushing syndrome should be avoided after recent administration of these compounds.
DETECTING FACTITIOUS OR IATROGENIC CUSHING SYNDROME — The urinary excretion of exogenous synthetic steroids can be measured using liquid chromatography-tandem mass spectrometry (LC-MS/MS) or gas chromatography-mass spectrometry (GC-MS) [23,24]. This approach can be very helpful in patients suspected of having adrenal suppression or glucocorticoid excess on the basis of iatrogenic or factitious steroid use [25,26].
OTHER CORTISOL PRECURSORS AND METABOLITES — A variety of other corticosteroids can be measured by mass spectrometry [27]. Some of these involve profiling of multiple steroids (the metabolome) to produce diagnostic "signatures" for congenital adrenal hyperplasia (CAH) [28] or other conditions as below. However, not all are available for clinical use.
●Adrenal carcinomas are relatively inefficient producers of steroids and may secrete excessive amounts of several adrenal steroid metabolites and precursors, including androgens (pregnanediol, pregnanetriol, androsterone, etiocholanolone) or glucocorticoids (17-hydroxyproesterone, tetrahydro-11-deoxycortisol, 6-hydroxy-cortisol, tetrahydrocortisol, and alpha-cortol). This pattern distinguishes them from cortisol-secreting adenomas, which produce cortisol, but little androgens [29-31]. Although the method was originally developed using gas chromatography-mass spectrometry (GC-MS), these adrenal urinary steroid panels are now clinically available by liquid chromatography-tandem mass spectrometry (LC-MS/MS) high-resolution accurate mass (HRAM) [32].
●Cortisone can be measured in urine by LC-MS/MS [27,33,34]. Its daily excretion is increased in patients with Cushing syndrome; results of this test may be combined with urinary cortisol to aid in the diagnosis of factitious Cushing syndrome produced by ingestion of hydrocortisone. In such patients, urinary cortisol excretion is high, but urinary cortisone excretion is low. It is decreased in patients with the syndrome of apparent mineralocorticoid excess in whom the ratio of urinary cortisol to cortisone may aid in the diagnosis [35,36].
OUTMODED ASSAYS FOR MEASUREMENT OF URINARY STEROIDS — Assays for 17-hydroxycorticosteroids, 17-ketogenic steroids, and 17-ketosteroids were previously used for the diagnosis of Cushing syndrome or various types of congenital adrenal hyperplasia (CAH). Because of the availability of more specific assays described above and elsewhere, these are no longer recommended. (See "Establishing the diagnosis of Cushing syndrome" and "Clinical manifestations and diagnosis of classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency in infants and children".)
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Diagnosis and treatment of Cushing syndrome".)
SUMMARY
●Measurement of 24-hour urinary cortisol excretion is a first-line test for the diagnosis of hypercortisolism. (See '24-hour urinary free cortisol' above.)
●Urinary free cortisol (UFC) measures only non-corticosteroid binding globulin (CBG)-bound cortisol (which is filtered by the kidney unchanged). Therefore, UFC is unaffected by medications and medical conditions that affect CBG, such as oral estrogen use, which increases CBG and serum cortisol concentrations, while UFC is unchanged. (See '24-hour urinary free cortisol' above and "Dexamethasone suppression tests", section on 'Sources of error'.)
●UFC is measured by immunoassay or liquid chromatography-tandem mass spectrometry (LC-MS/MS), with the latter being the preferable approach. Clinicians should pay careful attention to the reference ranges for UFC as they vary considerably depending on the assay method used. (See 'Types of assays' above.)
●The most important clinical use of 24-hour UFC is for the diagnosis of hypercortisolism and for monitoring the efficacy of steroidogenesis inhibitors. It is not useful for determining adequacy of glucocorticoid replacement regimens. (See 'Hypercortisolism' above and "Establishing the diagnosis of Cushing syndrome".)
ACKNOWLEDGMENT — The views expressed in this topic are those of the author(s) and do not reflect the official views or policy of the United States Government or its components.
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