In our fast-paced lives, understanding how our body responds to stress is vital for maintaining overall well-being. One of the key players in our body's stress response system is cortisol, often called the "stress hormone." This hormone, produced by the adrenal glands, plays a central role in regulating various physiological processes, especially during stress. To gain insights into our stress levels and adrenal function, healthcare providers may order a cortisol urine test. This test measures cortisol levels over the course of a day, helping to diagnose adrenal pathologies and shed light on how our body copes with stressors. In this article, we will discuss the importance of the cortisol urine test and how it is utilized in clinical practice.

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The Role of Cortisol in the Body

Cortisol is a glucocorticoid (steroid) hormone produced by the adrenal glands, which are situated on top of each kidney. Its secretion is tightly regulated by the hypothalamic-pituitary-adrenal (HPA) axis, a complex network involving the hypothalamus, pituitary gland, and adrenal glands. The release of cortisol follows a diurnal pattern controlled by the body's internal clock, the circadian rhythm. Typically, cortisol levels peak early in the morning, helping individuals wake up and feel alert, and gradually decrease throughout the day, reaching their lowest levels at night to promote sleep. (12)

The HPA axis plays a vital role in responding to stress and maintaining various bodily functions. When the brain perceives stress, the hypothalamus releases corticotropin-releasing hormone (CRH), stimulating the pituitary gland to produce adrenocorticotropic hormone (ACTH). ACTH, in turn, signals the adrenal glands to secrete cortisol. 

Cortisol acts by binding to specific receptors in cells throughout the body, functioning to mediate the stress response, metabolism, inflammation, and immune function. Cortisol's effects can be observed in nearly every body system, including the nervous, immune, cardiovascular, respiratory, reproductive, musculoskeletal, and integumentary systems. Once cortisol has fulfilled its role, it is metabolized in the liver, where enzymes break it down into inactive compounds that are then excreted from the body through urine. (15, 18)

Why Measure Cortisol in Urine?

Measuring cortisol in urine is a valuable diagnostic tool due to its ability to provide insights into the body's adrenal function. Unlike blood tests, which only offer a snapshot of cortisol levels at a specific moment, urine testing allows for a comprehensive, 24-hour representation of cortisol production. This extended timeframe offers a more accurate reflection of adrenal function and total production of cortisol during 24 hours. 

Most cortisol circulates bound to cortisol-binding globulin (CBG) and albumin. Under normal circumstances, less than 5% of circulating cortisol is unbound to protein. Free (unbound) cortisol is the physiologically active form of the hormone and can be filtered and eliminated from the body by the kidneys. The concentration of free circulating cortisol in the body correlates well with urinary cortisol, making this a sensitive test for pathologic adrenal dysfunction. (13)

Functional laboratories provide alternative methods for cortisol testing, including urinary and salivary tests, which differ from the standard 24-hour urine cortisol test. Unlike the 24-hour test, these tests involve collecting 4-6 urine or saliva samples at various times throughout the day. While they don't provide a complete picture of daily cortisol secretion, they are valuable in assessing the cortisol secretion curve and the cortisol awakening response (CAR). The cortisol measurements derived from these functional tests offer insights into the body's stress response patterns. They help healthcare providers identify irregularities in the HPA axis and assess how an individual copes with stressors.

How to Collect a 24-Hour Urine Sample

Collecting a 24-hour urine sample for cortisol testing involves specific steps to ensure accurate results. First, gather all necessary materials, which the lab or your healthcare provider will provide. (5) 

To start the collection, discard the first-morning urine voided into the toilet and note the time. From this point onward, collect all urine in the provided container for the next 24 hours, including the first-morning urine on the following day. During this period, store the collection jug in a refrigerator to prevent the breakdown of cortisol. Ensure the lid is tightly sealed to avoid leakage and contamination. Label the container with your name, date, and the exact time you finish the collection. (5)

Understanding Your Results: High, Low, and Normal Ranges

Normal cortisol levels vary based on age and sex. Normal ranges may also vary slightly among different laboratories. The table below shows typical normal cortisol levels for a 24-hour urine cortisol collection. Reference ranges have not been established for infants up to one year of age. (6)

High Cortisol Levels

Elevated cortisol levels in urine often result from excessive production of cortisol by the adrenal glands or other factors that disrupt the normal regulation of cortisol secretion. Cushing's syndrome is a disorder characterized by prolonged exposure to high levels of cortisol. It can be caused by an overactive adrenal gland (Cushing's disease), adrenal tumors, or tumors in the pituitary gland, leading to excessive cortisol production. Some tumors outside the pituitary or adrenal glands can produce ACTH, which stimulates the adrenal glands to produce cortisol excessively; this condition is known as ectopic ACTH syndrome. (7)

Signs and symptoms of high cortisol levels include (10): 

• High blood pressure
• High blood sugar
• Weight gain in the trunk with thin arms and legs
• Pink or purple stretch marks on the abdomen, thighs, hips, breasts, and underarms
• A round, flushed face (sometimes called moon face)
• A fatty lump between the shoulders (called a buffalo hump)
• Bone weakness
• Easy bruising
• Muscle loss

Low Cortisol Levels

Low 24-hour urine cortisol levels can indicate an underproduction of cortisol, which can result from various medical conditions or factors that disrupt the normal functioning of the adrenal glands. Addison's disease, or primary adrenal insufficiency, is a rare but serious condition where the adrenal glands do not produce enough cortisol and aldosterone. This can result from autoimmune destruction of the adrenal glands, infections, or certain genetic disorders. Secondary adrenal insufficiency occurs when the pituitary gland fails to produce enough ACTH, so the adrenals lose their signal to secrete cortisol. Tumors, radiation therapy, infections, or surgery affecting the pituitary gland can lead to secondary adrenal insufficiency (11). 

Exogenous steroids have inhibitory effects on the release of CRH and ACTH, downregulating the body's natural production and secretion of cortisol. Patients who have been taking high-dose or long-term corticosteroid medications and stop suddenly can force the body into adrenal insufficiency. (3) 

Signs and symptoms of low cortisol levels that may warrant your doctor to order a 24-hour urine cortisol test include (10):

• Low blood pressure
• Low blood sugar
• Fatigue
• Dizziness
• Loss of appetite and unintended weight loss
• Salt cravings
• Muscle weakness
• Dark patches of skin
• Abdominal pain
• Changes in mood

It's important to note that low cortisol levels can be life-threatening, especially in cases of adrenal crisis, a medical emergency caused by extremely low cortisol levels. Symptoms include severe weakness, confusion, low blood pressure, and dehydration, requiring immediate medical attention.

Factors That Can Influence Your Results

Pseudo-Cushing syndrome refers to a group of conditions that display symptoms similar to Cushing's syndrome, but the elevated cortisol levels are due to factors other than adrenal tumors or pituitary disorders. Conditions such as depression, obesity, physical stress, malnutrition, eating disorders, polycystic ovary syndrome, uncontrolled diabetes, obstructive sleep apnea, and chronic alcoholism can mimic Cushing's syndrome and result in increased cortisol levels. (4) 

Conversely, falsely low cortisol levels can result from an incomplete urine collection or renal disease that reduces renal clearance. (13) 

Certain medications can interfere with test results. Examples include glucocorticoids, lithium, diuretics, ketoconazole, estrogens, and tricyclic antidepressants. (19) 

The accuracy of cortisol test results can be influenced by factors that affect the levels of CBG and albumin in the bloodstream. For instance, CBG levels increase during pregnancy but decrease during periods of acute stress. Since CBG binds to cortisol, changes in its levels directly impact the amounts of cortisol that are bound or unbound in the blood. When CBG levels rise, more cortisol becomes bound, potentially leading to lower levels of free, unbound cortisol. Conversely, decreased CBG levels, like during acute stress, can result in higher free cortisol levels. These fluctuations in protein levels can significantly alter the interpretation of cortisol test results, making it essential for healthcare providers to consider these factors when assessing cortisol levels in the body. (15) 

Next Steps: What to Do With Your Results

After receiving your urine cortisol test results, it is crucial to discuss them thoroughly with your healthcare provider. Proper interpretation of the results in the context of your overall health and medical history is essential. Depending on the findings, your healthcare provider may recommend additional tests or investigations to pinpoint the underlying cause of abnormal cortisol levels. For example, confirming a diagnosis of Cushing's syndrome requires a low-dose dexamethasone suppression or late-night salivary cortisol test. Addison's disease is diagnosed with a cosyntropin stimulation test. These tests should be performed under the care of an endocrinologist. Other blood tests and imaging can also help rule out alternative diagnoses that can present with abnormal cortisol levels. 

Treating Cushing's Syndrome

Conventional treatment of Cushing's syndrome involves the use of surgery, radiation, chemotherapy, and cortisol-inhibiting drugs to address the underlying cause of excess cortisol. Functional medicine providers will counsel patients on lifestyle modifications that encompass changes to diet, sleep, exercise, and stress management to naturally support a healthy HPA axis and address the unwanted consequences of elevated cortisol, such as high blood sugar. Supplements can also be used to manage complications of Cushing's. (20) 

Treating Addison's Disease

Patients with Addison's disease will require hormone therapy to replace the steroid hormones the adrenal glands aren't able to make enough of. A high-salt diet is also commonly recommended. Functional medicine doctors may additionally recommend adaptogenic herbs that support cortisol production and palliate symptoms commonly experienced by patients. (21) 

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Summary

The cortisol urine test is an important tool in diagnosing adrenal dysfunction and optimizing health through cortisol understanding. These results provide crucial insights into adrenal function, stress responses, and overall well-being. By realizing the implications of cortisol levels, individuals can make informed decisions about their health. Proactive management, tailored to these results, allows for targeted interventions, such as lifestyle adjustments, stress management techniques, or pharmacologic treatments.