b-Tetrahydrocortisone

What is b-THE?  [8., 9., 10.] 

b-Tetrahydrocortisone (b-THE) is produced when the hormone cortisone is metabolized.  Cortisone itself is an inactive form derived from cortisol, the primary stress hormone produced by the adrenal glands.

b-THE is formed as a byproduct when cortisone undergoes metabolism by enzymes like 5β-reductase in various tissues throughout the body.

Cortisol is first produced from cholesterol in the adrenal cortex.  A portion of cortisol is converted to the inactive form cortisone by the enzyme 11β-hydroxysteroid dehydrogenase (11βHSD). This cortisone is then metabolized into b-THE by 5β-reductase.  

The cortisone metabolite b-THE is eventually excreted from the body through urine.

While b-THE itself does not have any direct biological activity, its levels in urine can provide valuable information about cortisol metabolism and the overall balance between active cortisol and inactive cortisone in the body.

The ratio of cortisol metabolites (like b-THF) to cortisone metabolites (like b-THE) is often used to assess the overall dominance of active cortisol or inactive cortisone.  This ratio can give insights into conditions related to cortisol dysregulation such as Cushing's syndrome, Addison's disease, or other adrenal disorders.

b-THE’s Relationship with Metabolized Cortisol

Because all cortisol metabolites including 5α-tetrahydrocortisol (5α-THF) and b-THF, as well as the metabolite of cortisone, 5β-tetrahydrocortisone (b-THE), came from cortisol produced in the adrenal glands, the sum total of all of these metabolites can be considered the sum total of all metabolized cortisol.  

Clinical Applications of b-THE Testing

Testing for b-THE levels can provide clinical insights in a variety of settings and conditions:

Assessing Adrenal Function, Cortisol Inactivation and Metabolism  [1., 10.] 

b-THE is a metabolite of cortisone, the inactive form of cortisol, while b-THF is a metabolite of cortisol.  Measuring b-THE alongside b-THF, free cortisone and free cortisol can provide insight into cortisol production and metabolism by the adrenal glands.  

High levels of many of these biomarkers may indicate increased cortisol production (e.g., Cushing's syndrome), while low levels suggest impaired cortisol production or metabolism (e.g., Addison's disease).

High levels of b-THE with normal or low levels of b-THF suggests a preference for the inactive cortisone over cortisol.   

Testing b-THE along with other cortisol metabolites in a 24-hour urine sample can comprehensively evaluate the activity of the hypothalamic-pituitary-adrenal (HPA) axis.

Assessing the Impact of Thyroid Health on Cortisone Metabolism  [3.] 

Hyperthyroidism can increase cortisol clearance, raising the levels of b-THF; there is evidence that hyperthyroidism can also increase cortisone clearance, increasing levels of b-THE.  

Obesity, Metabolic Health and Cortisol Metabolism  [9., 10.] 

Obese individuals have demonstrated a significant reduction in the ratio of tetrahydrocortisol (THF) metabolites to tetrahydrocortisone (THE) compared to lean individuals.  [9.] 

In obesity, the conversion of cortisone to cortisol is dysregulated, primarily due to changes in 11βHSD1 activity.  This enzyme’s activity is increased locally in visceral adipose tissue but reduced overall, leading to a decreased THF+5α-THF/THE ratio. 

The body compensates for faster cortisol clearance by increasing its secretion, contributing to the maintenance of normal cortisol levels but also promoting central fat accumulation and insulin resistance.  These mechanisms underline the complex role of cortisol metabolism in the pathogenesis of obesity and its metabolic consequences.

Assessing Liver Clearance and Function  [6.]

Studies on the metabolism and clearance of glucocorticoid medications such as prednisone show slowed metabolism in settings of liver dysfunction.  This implies that slowed or sluggish liver function would slow metabolism of endogenous glucocorticoids such as cortisol and cortisone, decreasing the levels of THF and b-THE.  

Laboratory Testing for b-THE

Test Information, Sample Collection and Preparation

b-THE is typically assessed in urine samples, often in 24-hour urine collections.  The samples can be easily collected from home.

It is important to consult with the ordering provider for preparation instructions, as it may be recommended to avoid certain supplements, medications or foods prior to testing.  

Interpretation of b-THE Results

Optimal Levels of b-THE

b-THE levels should be interpreted in the context of other biomarkers including THF levels, cortisol, cortisone, and possibly other markers such as sex or thyroid hormone levels to gain an understanding of optimal levels of b-THE for an individual’s physiology.  

Cortisol and cortisone clearance should align with free cortisol and cortisone levels respectively, meaning that the amount of THF produced should roughly align with free cortisol levels, and the same pattern should be expected with b-THE and cortisone.  

For reference, one laboratory company recommends 24 hour urine levels of b-THE as: 1550-3800 ng/mg  [7.] 

Accurate measurement of b-THE levels is crucial for its effective utilization as a biomarker. Various laboratory techniques have been developed and optimized for this purpose.

Clinical Significance of High b-THE

High b-THE often means that the enzyme 11b-HSD2 is rapidly converting cortisol to cortisone in peripheral tissues including the kidneys, salivary glands and colon.  Higher cortisone levels will be reflected in higher b-THE levels, unless cortisone is subsequently re-activated to cortisol.  

High b-THE levels may be seen in conditions involving excessive cortisol production including Cushing’s disease, chronic stress, or obesity, as well as in hyperthyroidism.  [1., 2., 3., 4., 10.]  

Clinical Significance of Low b-THE

Low THE level may indicate conditions of decreased cortisol production such as Addison’s disease, or decreased inactivation of cortisol to cortisone via the 11β-HSD2 enzyme, which may happen with certain genetic mutations or with inhibitors like licorice.  [5.]

A low THE level may also mean decreased cortisone metabolism in the liver, which may signify liver congestion. 

Related Biomarkers to Consider Testing Alongside b-THE

Cortisol and Its Metabolites

As cortisol is the parent hormone of cortisone, measuring cortisol levels as well as its metabolites provides insight into cortisol production and metabolism as well as the balance between the two. 

Cortisone

Cortisone is metabolized to b-THE.  Measuring cortisone,cortisol and its metabolites alongside b-THE illuminates the ratio of cortisol metabolites to cortisone metabolites which can indicate the overall balance between active cortisol and inactive cortisone.

TSH, T3, and T4 

Thyroid hormones like TSH, T3, and T4 should be tested alongside b-THE because hypothyroidism and hyperthyroidism can alter cortisol metabolism, potentially affecting cortisone metabolism.

Insulin 

Insulin resistance affects cortisol and cortisone metabolism, which has profound effects on hormone levels and their metabolism, and is implicated as part of the pathogenesis of obesity and central weight gain.

Inflammation markers (e.g., C-Reactive Protein, ESR, hs-CRP) 

Chronic inflammation can affect cortisol production and metabolism, potentially influencing b-THE levels.

Melatonin 

Melatonin is a hormone produced by the pineal gland and is involved in regulating sleep-wake cycles. It has been shown to interact with the HPA axis and may influence cortisol production and therefore b-THE levels.

Organic Acids 

Organic acids like pyruvate, lactate, and citrate can provide insights into energy metabolism and mitochondrial function, which may be affected by cortisol dysregulation, which can manifest in altered b-THE levels.

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