Cortisol Urine Free

The hypothalamus secretes corticotrophin releasing hormone (CRF), which stimulates the pituitary to secrete ACTH.   ACTH then stimulates the adrenal gland to produce cortisol and contributes to skin pigmentation. Cortisol exerts a negative feedback effect on both the pituitary and the hypothalamus.  

Cushing syndrome is relatively rare; the prevalence is only 10 cases per 1 million people. It occurs most commonly in women between 30 and 50 years of age.  Early stages of the syndrome include hypertension and weight gain. Later, The more common manifestations become apparent including truncal obesity, moon face, buffalo hump, hirsutism, facial plethora, menstrual disorders, hyperglycemia, proximal muscular weakness, wide purple striae, acne, easy bruising and unexplained osteoporosis.  

Cushing syndrome is caused by any condition that produces an elevation in glucocorticoid levels.  There are 4 basic causes. 

• Administration of exogenous glucocorticoids
• Primary hypothalamic-pituitary diseases associated with hypersecretion of ACTH
• Adrenal hypersecretion of cortisol
• Ectopic secretion of ACTH by a nonendocrine neoplasm. 

Administration of exogenous glucocorticoids is the most common cause of Cushing syndrome seen in clinical practice. Topical preparations, such as hemorrhoid medications need to be considered.  Most cortisol immunoassays cross react with synthetic steroids. 

Primary hypersecretion of ACTH accounts for more than half of the cases of endogenous Cushing syndrome. Most of these cases are caused by a small ACTH producing adenoma in the pituitary gland. This pituitary form of Cushing syndrome is called Cushing disease. 

Approximately 15 to 30% of the cases of endogenous Cushing syndrome are caused by adrenal adenoma, carcinoma or cortical hyperplasia. This form of Cushing syndrome is also designated ACTH independent because the adrenals produce cortisol autonomously. Adrenal Cushing syndrome is characterized by high serum levels of cortisol but levels of ACTH.

Secretion of ectopic ACTH by nonpituitary tumors accounts for most of the remaining cases of Cushing syndrome. Small cell carcinoma of the lung , carcinoid tumors, medullary carcinomas of the thyroid and islet cell tumors of the pancreas have been associated with this syndrome. Occasionally ectopic tumors may secrete corticotropin releasing factor, which causes ACTH hypersecretion and hypercortisolism.  

Cushing syndrome is characterized by an increased 24-hour urinary free cortisol level and loss of the normal diurnal pattern of cortisol secretion. The best screening test is a 24-hour urine free cortisol. More than 90% of patients with Cushing syndrome have urinary cortisol values greater than 100 mcg/24 hours (reference range is less than 55 mcg/24 hours). Urine free cortisol is not increased in simple obesity, high estrogen states or by drugs such as phenytoin. However, chronic alcohol consumption increases urine cortisol.

If patients with depression, significant stress, and alcoholism are excluded, an elevated urine free cortisol has a sensitivity and specificity of close to 100% for Cushing's syndrome. Because this test has a higher sensitivity and specificity than the overnight dexamethasone suppression test, urine free cortisol is the test of choice when screening for Cushing's syndrome. 

 The main drawback of urine free cortisol is the timed 24-hour urine collection. Because urine free cortisol has no validity in patients with renal failure and a glomerular filtration rate <30 mL/min, renal function should be checked before testing.  

Although urine free cortisol may fall below the reference range, it is of little clinical use in evaluating adrenal reserve.  However, urine free cortisol is an accurate way to access the adequacy of corticosteroid therapy in patients with chronic adrenal cortical insufficiency.  Twenty four hour levels should be within the reference range.

The adult (18 years or older) reference range is 24108 ug/24 hours. The upper limit of normal for children between 0 and 17 years old is 91 ug/24 hours.  

Specimen requirement is a 24 hour urine collected in a container with 25 mL of 50% acetic acid.  Fifteen mL of acid should be added to containers for children <5 years old.

References

Loriaux DL, Diagnosis and Differential Diagnosis of Cushing’s Syndrome, New Engl J Med.2017;376:1451-1459.

Reincke M, Fleseriu M. Cushing Syndrome: A Review, JAMA 2023;330:170-181.