Cortisol/Cortisone Ratio

Cortisol and cortisone are two closely related glucocorticoid hormones that play a crucial role in regulating various physiological processes, including metabolism, immune function, and stress response. The ratio of cortisol to cortisone, known as the cortisol/cortisone ratio, has emerged as a valuable biomarker for assessing adrenal function, metabolic health, and the body's response to stress. 

What is Cortisol?  [4., 5., 6., 13., 14.] 

Cortisol, a glucocorticoid hormone produced in the adrenal cortex, is essential for the body's stress response.  Synthesized from cholesterol, its production is regulated by the hypothalamic-pituitary-adrenal (HPA) axis. 

The hypothalamus releases corticotropin-releasing hormone (CRH), prompting the pituitary gland to secrete adrenocorticotropic hormone (ACTH), which then stimulates cortisol production in the adrenal cortex.  

This process is tightly controlled by a feedback loop to maintain homeostasis.

Cortisol influences various physiological functions by binding to glucocorticoid receptors throughout the body. It regulates metabolism by promoting gluconeogenesis and inhibiting glucose uptake. 

Cortisol also modulates the immune response with its anti-inflammatory properties and supports stress response by mobilizing energy reserves. 

Additionally, it regulates blood pressure, fluid and electrolyte balance, mood, cognition, and behavior. 

Cortisol plays a vital role in fetal development, the sleep-wake cycle, and bone health, underscoring its broad impact on overall health.

Cortisol levels fluctuate throughout the day in a diurnal rhythm, with higher levels promoting wakefulness in the morning and lower levels encouraging restful sleep at night.

What is Cortisone?  [9., 12.] 

Cortisone is the inactive form of the adrenal steroid hormone cortisol, which is converted back to its active form to exert physiological effects. 

This conversion primarily occurs in the kidneys through the action of the enzyme 11-beta-hydroxysteroid dehydrogenase (11beta-HSD), but it also takes place in the liver, salivary glands, adipose tissue, colon, and human placenta. 

As the inactive form, cortisone itself does not directly influence physiological functions. Its significance lies in its conversion to cortisol, which plays a crucial role in regulating metabolism, immune response, and stress management.

What is the Significance of the Cortisol/Cortisone Ratio?

Examining the levels of both cortisol and cortisone provides a more comprehensive picture of adrenal glucocorticoid output during a diurnal cycle.  

For example, an individual’s adrenal glands may secrete a healthy amount, or even a high amount, of cortisol, but if they are rapidly converting that cortisol to inactive cortisone, test results may demonstrate a false picture of adrenal insufficiency.  

Assessing the level of cortisol and cortisone production provides a comprehensive assessment of adrenal cortisol production in a 24 hour period.  

Cortisol and Cortisone Regulation: What Affects the Cortisol/Cortisone Balance?  [2., 9., 10., 13.] 

The conversion between the active cortisol and inactive cortisone is regulated by the enzyme 11β-hydroxysteroid dehydrogenase (11β-HSD), which exists in two isozyme forms. 

11β-HSD1 primarily catalyzes the reduction of cortisone to cortisol, while 11β-HSD2 catalyzes the oxidation of cortisol to cortisone. 

The activity of 11β-HSD1 is a key factor promoting the conversion of cortisone to cortisol. This enzyme is highly expressed in the liver, adipose tissue, and the central nervous system.  Its expression and activity can be induced by factors like stress, inflammation, and certain hormones like growth hormone and cytokines. 

Conversely, 11β-HSD2 expression in tissues like the kidney, colon, and placenta facilitates the inactivation of cortisol to cortisone.  Conditions that impair 11β-HSD2 activity, such as genetic mutations (apparent mineralocorticoid excess syndrome), inhibitors like licorice, or substrate saturation in Cushing's syndrome, can promote the accumulation of active cortisol. 

Additionally, factors that increase cortisol production, like exogenous glucocorticoid administration or ACTH stimulation in Cushing's disease, can drive the conversion of cortisone to cortisol by mass action. 

Therefore, the balance between the two 11β-HSD isozymes, their tissue-specific expression patterns, and the overall cortisol production rate are critical determinants of the interconversion between cortisol and cortisone.

Lab Testing for Cortisol/Cortisone Ratio

Test Procedure, Sample Collection, and Preparation 

Cortisol and cortisone levels can be measured in various biological samples including serum, saliva, and urine.  Each sample type typically requires multiple sample collections throughout the day to capture the diurnal rhythms of these hormones.  

Blood testing typically requires a blood draw in a clinical setting multiple times throughout the day, urine and saliva tests can be done from the comfort of the patient’s home.

Test preparation may be required including adjustment in the use of certain medications, hormones, or supplements, as well as avoidance of alcohol or excessive caffeine, extreme exercise, or during times of intense stress.

Interpretation of Cortisol/Cortisone Ratio

Optimal Levels of Cortisol/Cortisone Ratio

The interpretation of the cortisol/cortisone ratio should consider factors such as age, sex, time of day, and the specific sample type used for analysis.  

Laboratory assessment should be done in conjunction with the patient’s clinical picture and medical history, taking into account symptomatology as well as dietary, lifestyle and medical factors.  

One laboratory company states that, because the salivary glands convert cortisol to cortisone locally due to the presence of the 11β-hydroxysteroid dehydrogenase 2 (11β-HSD2) enzyme in salivary glands, the best way to assess an individual’s preference for cortisol vs cortisone production is to assess their metabolites in the urine: tetrahydrocortisol

(THF) and tetrahydrocortisone (THE).  [11.] 

Clinical Significance of Elevated Cortisol/Cortisone Ratio  [1., 3., 8., 9.] 

This may signify an increased amount of cortisol in the body, seen in conditions such as Cushing’s disease, or impaired 11β-hydroxysteroid dehydrogenase type 2 (11β-HSD2) activity.

Clinically, this can manifest in cardiometabolic symptoms and disorders including insulin resistance, hypertension, impaired glucose tolerance and visceral adiposity.  

It is important to consider excessive licorice ingestion, as this herb decreases 11β-HSD2 activity.  

Clinical Significance of Low Cortisol/Cortisone Ratio

A low cortisol/cortisone ratio may or may not have clinical relevance: for that reason, results should be interpreted within the context of an individual’s clinical picture.  

A low cortisol/cortisone ratio has clinical significance in settings of hypoadrenalism or adrenal insufficiency, where the adrenal glands are not producing adequate cortisol.  

Hyperthyroidism may also lower the cortisol/cortisone ratio, purportedly through the actions of thyroid hormones on the 11β-HSD2 enzyme and the 5-alpha-reductase enzyme (which is also involved in cortisol and cortisone metabolism).  [7.]  

This may also represent a normal physiological state, as long as the individual is not symptomatic.  

Cortisol/Cortisone Ratio Related Biomarkers

The cortisol/cortisone ratio should not be evaluated in isolation but rather in conjunction with other relevant biomarkers to provide a more comprehensive assessment of endocrine and metabolic health. 

Adrenocorticotropic Hormone (ACTH)

Adrenocorticotropic hormone (ACTH) is a pituitary hormone that stimulates the adrenal glands to produce cortisol. 

Measuring ACTH levels in conjunction with the cortisol/cortisone ratio can provide insights into the functioning of the hypothalamic-pituitary-adrenal (HPA) axis and help differentiate between primary and secondary adrenal disorders.

Dehydroepiandrosterone (DHEA) and DHEA-Sulfate (DHEA-S)

Dehydroepiandrosterone (DHEA) and its sulfated form, DHEA-S, are adrenal-derived steroid hormones that can be influenced by changes in cortisol levels.  Evaluating the cortisol/DHEA or cortisol/DHEA-S ratio may provide additional information about adrenal function and the body's response to stress.

Inflammatory Markers

Cortisol is known to have anti-inflammatory effects, and changes in the cortisol/cortisone ratio may be associated with alterations in inflammatory markers, such as C-reactive protein (CRP) and various interleukins. 

Assessing these markers alongside the cortisol/cortisone ratio can help elucidate the relationship between stress, inflammation, and metabolic health.

Insulin Resistance and Glucose Metabolism

Cortisol can antagonize the effects of insulin, leading to insulin resistance and dysregulation of glucose metabolism. 

The cortisol/cortisone ratio may be associated with markers of insulin resistance, such as fasting glucose, fasting insulin, and the homeostatic model assessment of insulin resistance (HOMA-IR).

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