Understanding Urine Cortisol and the Cortisol/Cortisone Ratio on the OAp™

By Betsy Redmond, Ph.D., MMSc, RDN

Posted On November 1st, 2024

Urine Cortisol

The OAp (Organic Acids Profile) includes cortisol and the cortisol/cortisone ratio to provide insight into how well the body regulates stress. Cortisol is the active form of the hormone that helps manage stress while cortisone is the inactive form. An unbalanced ratio has been associated with issues such as chronic stress, circadian misalignment, hypothalamic-pituitary-adrenal (HPA) axis dysfunction (“adrenal fatigue”), fatigue, cravings, or problems with hormone metabolism. Functional medicine practitioners use this information to better understand a person's stress response and overall hormonal balance.

Cortisol is a glucocorticoid. It is regulated by the HPA axis through the release of corticotrophin releasing hormone (CRH) from the hypothalamus and adrenocorticotrophin hormone (ACTH) from the anterior pituitary gland. Cortisol feedback can inhibit CRH and ACTH, which can inhibit cortisol production. Cortisol works to regulate metabolism, control blood sugar levels, and modulate the immune system response/inflammation. Cortisol is also involved in the sleep-wake cycle. Fluctuations in cortisol can be impacted by many factors such as anxiety, stress, immune challenges, physical activity, blood glucose, depression, sleep loss and awakening, exposure to light, etc.^1,2,3

Cortisol Circadian Rhythms: The central circadian pacemaker (CCP) in the suprachiasmatic nucleus (SCN) of the hypothalamus drives a 24-hour cortisol pattern. ACTH and cortisol levels rise to a peak in the morning (6:00 AM to 8:00 AM), decline throughout the day, and reach their lowest level around midnight. Cortisol’s rhythm is therefore described as a circadian rhythm. Circadian misalignment is characterized by desynchrony between the CCP and behavioral cycles (sleep/wake, feeding/fasting, activity/rest). Morning exposure to natural daylight and maintaining a consistent schedule supports well-being, alertness, circadian rhythms, and sleep.^4,5

Stress Response: Cortisol can initiate the “fight-or-flight” response. Cortisone is catalyzed to the active form, cortisol, by 11-β-hydroxysteroid dehydrogenases (11-β-HSD). ACTH is also involved in the secretion of epinephrine and norepinephrine. Epinephrine and norepinephrine are involved in executing the fight-or-flight response. Cortisol is required for the methylation of norepinephrine to epinephrine. The turnover of these neurotransmitters can be seen by evaluating their breakdown product, Vanillylmandelic acid (VMA). Elevated fasting urine cortisol can indicate prolonged exposure to chronic stress which can lead to cumulative physiological and psychological effects, increasing the risk of health problems such as cardiovascular disease, anxiety, and depression.^4,5

Urinary Cortisol: Urine measurements capture cortisol secretion over time and may be more reliable than plasma or salivary samples, which are subject to diurnal fluctuations. About 1% of plasma cortisol is excreted in the urine.^5,6 A morning spot-urine sample gives comparable results to 24-hour collection samples. The amount of cortisol in the urine reflects the average cortisol concentration in the blood.^7,8 There is a wide inter-individual variability in urinary cortisol excretion rate.⁹

Interpreting the Urine Cortisol/Cortisone Ratio on the OAp (Organic Acids Profile)

Elevated Urine Cortisol | High Cortisol/Cortisone Ratio

Elevated cortisol can impact functions such as digestion, reproduction, the immune system, and growth processes.
Stress can elevate urine cortisol:
- Elevated cortisol and VMA can reflect the activity of the HPA axis and the level of stress reaction.^2,10
- Research of older adults (n=6878) found elevated urine cortisol was associated with perceived stress and may be a useful marker for non-acute perceived stress in daily life.¹¹
- Physical activity and social support can help to balance cortisol due to stress. Exercise deepens breathing, helps relieve muscle tension, and aids mental focus.
There is a close relationship between adiposity and increased urine levels of cortisol.⁹
Excessive licorice consumption and use of carbenoxolone (a synthetic derivative of glycyrrhizinic acid used to treat gastroesophageal reflux disease), and phthalates may reduce the conversion of cortisol to cortisone, leading to increased cortisol.^4,12
Patients with T2D had a higher cortisol/cortisone ratio than healthy controls (n=275).¹³

Low Urine Cortisol | Low Cortisol/Cortisone Ratio

Urine cortisol values have been found lower in patients with chronic fatigue, in some studies.
Cortisol induces the enzyme that produces hydroxyproline, which may contribute up to 60% of total glycine requirement. This means that circulating levels of hydroxylproline may be reduced with lower cortisol. Animal studies have found lower levels of hydroxylproline in animals with fatigue (lack of sleep is a physical stress) or oxidative stress.¹⁴

Understanding Cortisol to Cortisone Interconversion

Cortisol is biologically active and can be converted to inactive cortisone via the 11-β-hydroxysteroid dehydrogenase (11-β-HSD) enzymes. The cortisol/cortisone ratio in urine is a surrogate marker of systemic 11β-HSD activity. Research has noted that 11-β-HSD activity can be accurately evaluated with cortisol and cortisone concentrations in spot urine samples.¹⁵

Cortisone + 11-β-hydroxysteroid dehydrogenase type 1 (11-β-HSD1) → Cortisol
- 11-β-HSD1 converts cortisone to cortisol in metabolically active tissue, such as the liver or adipose tissue, resulting in high local cortisol concentration.¹⁶
- Long-term weight loss favorably decreased activity of 11 β-HSD1.¹⁷
Cortisol + 11-β-hydroxysteroid dehydrogenase type 2 (11-β-HSD2) → Cortisone
- 11-β-HSD2 is present mainly in the kidneys, sweat glands, and intestinal epithelium tissues, and inactivates cortisol to cortisone.¹⁶
- The cortisol/cortisone ratio is primarily used to assess in vivo activities of 11-β-HSD2 activities.¹⁶

Elevated Cortisol/Cortisone Ratio: May Identify Increased 11-β-HSD1 or Decreased 11-β-HSD2

Inflammation is a potent inducer of 11-β‐HSD1 expression
Excessive licorice consumption and use of carbenoxolone (a synthetic derivative of glycyrrhizinic acid used to treat gastroesophageal reflux disease) may inhibit 11-β-HSD2 activity.¹²
Phthalates can inhibit 11-β-HSD2 activity, leading to higher cortisol.
Perceived stress was associated with reduced 11-β-HSD2 activity

Reduced Cortisol/Cortisone Ratio: May Identify Decreased 11-β-HSD1 or Increased 11-β-HSD2

Cortisone-Cortisol Vannilylmandelic Acid Figure

Treatment Considerations

Cortisol Levels	Supplements	Address Mood Disorders	Reset Circadian Rhythms
High Cortisol	Reduce stress; B3, Mg; consider adaptogenic herbs such as ashwagandha or rhodiola	• For anxiety, check HVA/VMA • For depression, check 5-HIAA	Establish circadian rhythms: sleep-wake cycles; eating & exercise patterns
Low Cortisol	Manage stress; consider adaptogenic herbs such as licorice root or cordyceps; consider glycine support (elevated pyroglutamic acid or benzoic acid may identify glycine need)

Case Examples Using the OAp (Organic Acids Profile)

Below is an example that has cortisol in the normal range, and a borderline high cortisol/cortisone ratio. The higher ratio identifies that cortisone is likely very low, and that 11-β‐HSD1 activity may be increased or 11-β-HSD2 may be decreased. Check for depression, glucose control, and/or licorice intake. In this example, the patient’s vanillylmandelic acid (VMA) was also elevated, indicating increased norepinephrine/epinephrine turnover, which is associated with increased stress.

Stress Hormone Sample 1

The example below shows cortisol below detectable limits, so a ratio could not be calculated. Reduced cortisol can be seen in chronic fatigue syndrome, renal disease, and impaired circadian rhythms.

Stress Hormone Sample 2

Literature Associations

High Urine Cortisol

A review found higher spot urine cortisol in those with schizophrenia spectrum and bipolar disorder compared to healthy controls (n=433).¹⁸
Average cortisol and cortisone levels were significantly higher in overweight children.¹⁶
Research of older adults (n=6878) found elevated urine cortisol was associated with perceived stress and may be a useful marker for non-acute perceived stress in daily life.¹¹
Patients with depression had higher urine cortisol measurements, compared to those with chronic fatigue syndrome and healthy controls (n=46).¹⁹

Low Urine Cortisol

Patients with chronic fatigue syndrome had lower urine cortisol in some studies but not others.²⁰
Low, or false low, urine cortisol may be seen in very high dose acetaminophen use, hypopituitarism, or in renal disease.²¹
The decreased ratio of the sum of cortisol metabolites to the sum of cortisone metabolites in urine may manifest in women with hirsutism, acne, menstrual disorders, infertility, and polycystic ovary syndrome (PCOS).²²
The buildup of visceral fat helps to extend the synthesis of adrenal cortical steroids. Android or central obesity, but not gynoid obesity, have been associated with reduced 11-β-HSD1 activity and lower cortisol. 11-β-HSD1 activity is highly related to body fat distribution.²³
- In overweight children, there was no significant difference in the cortisol/cortisone ratio and 11-β-HSD2 activities (n=105).¹⁶

Conclusion

Cortisol and the cortisol/cortisone ratio on the OAp (Organic Acids Profile) offers practitioners insight into the stress response. Results can be utilized to help personalized protocols as a part of an overall health plan, that may aid in relieving symptoms.

Author Betsy Redmond, Ph.D., MMSc, RDN

Dr. Redmond has 30 years experience in nutrition with a focus on functional laboratory assessment, research and application. She is a registered dietitian-nutritionist, with a Masters' degree in clinical nutrition from Emory University and a PhD in nutrition from the University of Georgia. Dr. Redmond is the past president of Dietitians in Integrative and Functional Medicine and the recipient of the Excellence in Practice award...

The opinions expressed in this presentation are the author's own. Information is provided for informational purposes only and is not meant to be a substitute for personal advice provided by a doctor or other qualified health care professional. Patients should not use the information contained herein for diagnosing a health or fitness problem or disease. Patients should always consult with a doctor or other health care professional for medical advice or information about diagnosis and treatment.

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