b-Tetrahydrocortisol

Beta-Tetrahydrocortisol (b-THF) is a metabolite of cortisol, a hormone produced by the adrenal glands.  It is formed through the action of the enzyme 5β-reductase during cortisol metabolism. 

Cortisol, initially synthesized from cholesterol in the adrenal cortex, circulates mainly bound to cortisol-binding globulin (CBG) in the bloodstream.  The free cortisol can be converted to cortisone by the enzyme 11β-hydroxysteroid dehydrogenase (11βHSD). 

Both cortisol and cortisone undergo further metabolism, with cortisol being converted into 5α-tetrahydrocortisol (5α-THF) and b-THF, while cortisone is metabolized into 5β-tetrahydrocortisone (b-THE).

b-THF levels provide critical insights into cortisol production and metabolism, serving as a biomarker for various health conditions.  

Elevated b-THF levels can indicate increased cortisol production or metabolism, often seen in conditions like Cushing's syndrome, chronic stress, hyperthyroidism, or obesity. 

Conversely, reduced b-THF levels may suggest impaired cortisol production or metabolism as observed in Addison's disease, certain medications, or hypothyroidism. 

Clinically, assessing b-THF levels helps evaluate adrenal function and hormone balance, particularly in conditions like PCOS, infertility, and obesity and metabolic disease.  Additionally, b-THF testing is significant in understanding the impact of thyroid health on cortisol metabolism and in exploring the relationship between cortisol metabolism and body fat distribution. 

This testing is typically done through 24-hour urine samples, providing a comprehensive view of cortisol metabolism and guiding therapeutic decisions.

What is b-THF?  [1., 4.,11.] 

Beta-Tetrahydrocortisol (b-THF) is a metabolite of the hormone cortisol, which is produced by the adrenal glands. It is formed when cortisol is metabolized by enzymes in the body, specifically through the action of 5β-reductase.

Cortisol is first produced from cholesterol in the adrenal cortex, with the majority (80-90%) bound to cortisol-binding globulin (CBG) in the bloodstream.  The unbound or free cortisol can then be converted to the inactive form cortisone by the enzyme 11β-hydroxysteroid dehydrogenase (11βHSD). 

Both cortisol and cortisone are further metabolized, with cortisol being converted into 5α-tetrahydrocortisol (5α-THF) and b-THF, while cortisone is metabolized into 5β-tetrahydrocortisone (b-THE).  Cortisol’s metabolism to b-THF occurs via the enzyme 5beta-reductase.  [10.] 

b-THF is excreted in the urine.

The levels of b-THF in urine or blood can provide insight into the body's cortisol production and metabolism.  

High levels of b-THF may indicate increased cortisol production or increased metabolism, which can be seen in conditions like Cushing's syndrome, chronic stress, hyperthyroidism or obesity.  [1., 2., 4., 10., 11.] 

Conversely, low levels of b-THF could suggest impaired cortisol production or metabolism, as in Addison's disease, certain medications or hypothyroidism.  [1., 4.] 

In summary, b-THF is a key metabolite of cortisol that serves as a biomarker for assessing adrenal function and cortisol metabolism in the body.

b-THF’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-THF Testing

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

Assessing Adrenal Function and Cortisol Metabolism  [1., 11.] 

b-THF is a metabolite of cortisol, and its levels can provide insight into cortisol production and metabolism by the adrenal glands.  High levels may indicate increased cortisol production (e.g., Cushing's syndrome), while low levels suggest impaired cortisol production or metabolism (e.g., Addison's disease). 

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

Assessing Hormone Balance and Metabolism  [5., 12.]

b-THF levels can be used in conjunction with other hormone metabolites to assess the overall balance and metabolism of steroid hormones in the body.  Imbalances or dysregulation in hormone metabolism can contribute to various conditions such as polycystic ovary syndrome (PCOS), infertility, and hormone-related cancers.

Assessing the Impact of Thyroid Health on Cortisol Metabolism  [4.] 

Hypothyroidism can impair cortisol metabolism, potentially leading to lower levels of metabolites like b-THF. Testing b-THF levels in individuals with hypothyroidism may provide insights into the interplay between thyroid function and cortisol metabolism.

In contrast, hyperthyroidism may also increase cortisol clearance, raising the levels of b-THF.  

Obesity, Metabolic Health and Cortisol Metabolism  [9., 11.] 

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

Other studies have also shown that the metabolism of cortisol to metabolites like b-THF is decreased as insulin resistance worsens.  [3.]   

This suggests an inhibition of the enzyme 11β-hydroxysteroid dehydrogenase type 1 (11βHSD1) in obesity, which is involved in cortisol metabolism.

The reduced THF/THE ratio indicates impaired conversion of inactive cortisone to active cortisol in obese individuals. This results in increased metabolic clearance of cortisol, potentially explaining the increased cortisol secretion rate observed in obesity despite normal circulating cortisol levels.

Relationship Between b-THF Levels and Body Fat Distribution  [10.]

ONe study found a significant inverse relationship between the THF/THE ratio (including b-THF) and central or android obesity (fat distribution around the abdomen and waist).  [10.] 

However, there was a direct relationship between the THF/THE ratio and gynoid or peripheral obesity (fat distribution around the hips and thighs).

This suggests that reduced 11βHSD1 activity, as reflected by lower b-THF levels, is associated with central obesity but not peripheral obesity.  Testing b-THF levels may provide insights into the role of cortisol metabolism in different patterns of body fat distribution.

Assessing Liver Clearance and Function  [9.] 

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-THF

Test Information, Sample Collection and Preparation

b-THF 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-THF Results

Optimal Levels of b-THF

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

Cortisol clearance should align with free cortisol levels, meaning that the amount of THF produced should roughly align with free cortisol levels.  Low free cortisol with a higher THF level may signify increased clearance as seen in conditions like obesity and hyperthyroidism.  

Alternately, high free cortisol levels alongside a lower THF level may indicate conditions of decreased clearance, including hypothyroidism or decreased clearance at the liver, which may signify liver congestion. 

For reference, one laboratory company recommends 24 hour urine levels of b-THF as: 1050-2500 ng/mg  [9.] 

Clinical Significance of High b-THF Levels

High b-THF levels may be seen in conditions such as obesity, insulin resistance, hyperthyroidism, chronic stress, or conditions of increased cortisol production such as Cushing’s disease.  

Additionally, substances that inhibit 11β-HSD2 activity such as licorice root inhibit the inactivation of cortisol to cortisone, increasing cortisol levels and therefore THF levels as well.  [7.]

Clinical Significance of Low b-THF Levels

Low b-THF levels may be seen in conditions such as hypothyroidism, or in conditions of decreased cortisol production such as Addison’s disease.

Related Biomarkers to Consider Testing Alongside b-THF

Cortisol 

As b-THF is a metabolite of cortisol, measuring cortisol levels provides insight into cortisol production and metabolism as well as the balance between the two. 

Cortisone 

Cortisone is another metabolite of cortisol, and the ratio of cortisol metabolites (like b-THF) to cortisone metabolites 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-THF because hypothyroidism can impair cortisol metabolism, potentially leading to lower b-THF levels.

Insulin 

High insulin levels have been linked to increased metabolism of cortisol into metabolites like b-THF, so testing insulin can help understand the impact of insulin resistance on cortisol metabolism.

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

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

Sex Hormones (e.g. Estrogen, Testosterone) 

Cortisol metabolism and the hypothalamic-pituitary-adrenal (HPA) axis are closely linked to the hypothalamic-pituitary-gonadal (HPG) axis, which regulates sex hormone production. Testing sex hormones can provide insights into the interplay between these systems.

Vitamin B12 and Folate

Methyl-vitamin B12 and methylfolate are involved in homocysteine metabolism and methylation reactions, which are important for proper cortisol metabolism.  Deficiency in proper methylation can impair cortisol breakdown and may affect cortisol, and therefore b-THF levels.  [6.] 

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 metabolism.

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.

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