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5-Alpha-Tetrahydrocortisol (a-THF) is a metabolite of cortisol, a hormone produced by the adrenal glands.  It is formed through the action of the enzyme 5-alpha-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 a-THF and 5beta-tetrahydrocortisol (b-THF), while cortisone is metabolized into 5beta-tetrahydrocortisone (b-THE).

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

Elevated a-THF levels can indicate increased cortisol production or metabolism, often seen in conditions like Cushing's syndrome, chronic stress, hyperthyroidism, or obesity.  They may also be associated with increased 5-alpha-reductase enzyme function.

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

Clinically, assessing a-THF levels helps evaluate adrenal function and hormone balance, particularly in conditions like PCOS, infertility, and obesity and metabolic disease.  

Additionally, a-THF testing provides insight into 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 a-THF?

5-Alpha-Tetrahydrocortisol (a-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 5-alpha-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-THF and 5-beta-tetrahydrocortisol (b-THF), while cortisone is metabolized into 5β-tetrahydrocortisone (b-THE).  Cortisol’s metabolism to a-THF occurs via the enzyme 5-alpha-reductase.  [11.] 

a-THF is excreted in the urine.

The levels of a-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 or PTSD, hyperthyroidism or obesity.  [1., 2., 4., 11., 12.] 

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.

a-THF’s Relationship with Metabolized Cortisol

Because all cortisol metabolites including a-THF and 5a-tetrahydrocortisol (b-THF), as well as the metabolite of cortisone, 5b-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 cortisol produced. 

Clinical Significance of a-THF Testing

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

Assessing Adrenal Function and Cortisol Metabolism  [1., 12.] 

a-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) or increased 5a-reductase activity, while low levels suggest impaired cortisol production or metabolism (e.g., Addison's disease), or decreased 5a-reductase activity. 

Testing a-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., 13.]

a-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.

Cortisol Metabolites and Their Association with PCOS  [6.]

The b-THF/a-THF ratio demonstrates the relative activity of the 5-beta-reductase vs. 5-alpha-reductase enzymes.  

In some women with PCOS, an increased b-THF/a-THF ratio is seen.

In a study of 90 women with PCOS, the women were categorized into three groups based on their adrenal androgen response to an ACTH (adrenocorticotropic hormone) stimulation test.  [6.] 

The groups are defined as follows:

High Responders (HR):

This group includes women whose responses for both androstenedione and DHEA (dehydroepiandrosterone) to ACTH1-24 were more than 2 standard deviations (SD) above the mean response observed in the control group. These women exhibited the highest levels of adrenal androgens following ACTH stimulation.

Intermediate Responders (IR):

This group includes women whose DHEA response to ACTH1-24 was similar to that of the high responders, but whose androstenedione response was lower. These women showed an elevated DHEA response but a normal androstenedione response to ACTH.

Normal Responders (NR):

This group includes women whose responses for both androstenedione and DHEA to ACTH1-24 were within 2 SD of the mean response seen in the control group. These women had adrenal androgen responses to ACTH that were within the normal range.

These categorizations were used to examine the relationship between cortisol metabolism and the extent of adrenal androgen hyper-secretion in response to ACTH in women with PCOS, independently of obesity.

In the study, it was found that the excretion of 5-beta metabolites (b-THF and 5b-THE) was significantly higher in high responders (HR) and intermediate responders (IR) groups compared to controls and normal responders (NR).  However, a-THF excretion did not significantly differ among these groups. 

Overall, the results of the study suggest a higher 5b-reductase activity relative to 5a-reductase activity in HR women with PCOS.

Increased 5β-reductase activity can lead to higher peripheral metabolism of cortisol, explaining the lower fasting cortisol levels and compensatory hypersecretion of adrenal androgens in certain PCOS women exposed to ACTH.  

This suggests that lower a-THF and a higher b-THF/a-THF ratio may be seen in women with PCOS, especially in the setting of elevated adrenal androgens.   

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

Hypothyroidism can impair cortisol metabolism, potentially leading to lower levels of metabolites like a-THF.  Testing a-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 a-THF.  

Obesity, Insulin Resistance, Fatty Liver, and Cortisol Metabolism  [3., 11., 12.] 

The relationship between cortisol metabolism and insulin sensitivity, particularly in the context of body fat distribution and non-alcoholic fatty liver disease (NAFLD), demonstrates the significance of glucocorticoids and insulin sensitivity.

Overall, a pattern of increased glucocorticoids is seen, which can be driven by the complex interplay of altered metabolism, insulin resistance, fatty liver, and fat deposition.  This correlates with alterations in the levels of cortisol and cortisone metabolites seen.      

One study found that higher cortisol clearance rates are seen in insulin resistance and fatty liver.  [3.]  This can be reflected in increased THF metabolites in urine, including a-THF.  

The enhanced cortisol clearance seen in insulin resistance and fatty liver is associated with higher intra-abdominal fat and altered activity of enzymes like 5a-reductase, 5b-reductase and 11b-reductase.  [3.]

In addition, the isoenzymes 11b-hydroxysteroid dehydrogenase type 1 (11b-HSD1) and type 2 (11b-HSD2) may have a differential activity in key insulin-sensitive tissues. 

In the liver, the activity of 11b-HSD1, which converts inactive cortisone to active cortisol, is decreased, while in adipose (fat) tissue, the activity is increased.  This imbalance contributes to altered cortisol metabolism and clearance in obesity and insulin resistance.

Another study showed that total glucocorticoid secretion and the activity of 5a-reductase (the enzyme responsible for a-THF production) decreased significantly after weight loss.  [12.] 

This reduction in 5a-reductase activity may contribute to lower hypothalamo-pituitary-adrenal (HPA) axis activation and reduced production of glucocorticoid metabolites, which results in decreased a-THF production.  [12.]

Relationship Between a-THF Levels and Body Fat Distribution  [11.]

For a given body mass index (BMI), mortality is higher in patients with central obesity compared to generalized obesity.  Glucocorticoids, particularly through the expression of 11β-hydroxysteroid dehydrogenase type 1 (11βHSD1) in omental adipose stromal cells, play a crucial role in body fat distribution by converting inactive cortisone to active cortisol.  [11.]

Increases in cortisol levels may correlate with increases in cortisol metabolites a-THF and b-THF.

This increased production of cortisol can drive the development of central obesity.  

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 a-THF

Test Information, Sample Collection and Preparation

a-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 a-THF Results

Optimal Levels of a-THF

a-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 a-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 a-THF as: 75-370 ng/mg  [10.] 

Clinical Significance of High a-THF Levels

High a-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.  [8.]

Clinical Significance of Low a-THF Levels

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

They may also be seen in conditions associated with decreased 5-alpha-reductase activity, as seen in some women with PCOS and excess adrenal androgens.  [6.]

Related Biomarkers to Consider Testing Alongside a-THF

Cortisol 

As a-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 a-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 a-THF because hypothyroidism can impair cortisol metabolism, potentially leading to lower a-THF levels.

Insulin 

High insulin levels have been linked to increased metabolism of cortisol into metabolites like a-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 a-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 a-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.

Frequently Asked Questions (FAQs) on a-THF

The FAQ section addresses common questions and concerns about 5a-Tetrahydrocortisol (a-THF), providing clear and concise answers for better understanding. Whether you're interested in its significance, testing, or health implications, this section covers essential information you need to know.

What Is a-THF?

5a-Tetrahydrocortisol (a-THF) is a metabolite of cortisol, a steroid hormone produced by the adrenal glands. It is involved in the metabolism of cortisol and can provide insights into adrenal function and the body's stress response.

Why Is a-THF Important?

a-THF is important because its levels can reflect the activity of the enzyme 5a-reductase, which converts cortisol into a-THF.  It also reflects the amount of cortisol circulating in the body, along with b-THF (another cortisol metabolite) and 5b-THE, a cortisone metabolite.  

Abnormal levels of a-THF can indicate issues with cortisol metabolism and adrenal function, providing valuable information for diagnosing and managing various health conditions.

What Is the Function of a-THF?

a-THF functions as a metabolite in the cortisol metabolism pathway. It helps in understanding how the body processes and regulates cortisol, a hormone essential for stress response, metabolism, immune function, and overall homeostasis.

How Is a-THF Measured?

a-THF levels are typically measured through urine tests, where a 24-hour urine collection is analyzed to determine the concentration of a-THF.  Blood tests may also be used, although urine tests are more common for assessing steroid metabolites.

What Are Normal Levels of a-THF?

Normal levels of a-THF can vary depending on factors such as age, sex, and overall health. Reference ranges are provided by the testing laboratory and should be interpreted by a healthcare provider in the context of the patient's health status and medical history.

What Can Cause Elevated Levels of a-THF?

Elevated levels of a-THF can be caused by conditions such as Cushing's syndrome, adrenal hyperplasia, and chronic stress, which lead to increased cortisol production and metabolism. Certain medications that affect adrenal function can also result in higher levels of a-THF.

What Can Cause Low Levels of a-THF?

Low levels of a-THF may indicate adrenal insufficiency, Addison's disease, or dysfunction in the enzyme 5a-reductase.  These conditions result in reduced production or impaired metabolism of cortisol, leading to lower levels of a-THF.

What Are the Symptoms of Abnormal a-THF Levels?

Symptoms of abnormal a-THF levels can vary depending on whether the levels are high or low. High levels may lead to symptoms such as weight gain, high blood pressure, fatigue, and muscle weakness. Low levels can cause symptoms like weight loss, low blood pressure, fatigue, and darkening of the skin.

How Are Abnormal Levels of a-THF Treated?

Treatment for abnormal levels of a-THF depends on the underlying cause. Hormone replacement therapy, medications to regulate adrenal gland function, and lifestyle changes to reduce stress are common approaches. 

It is essential to consult with a healthcare provider to determine the most appropriate treatment plan based on individual health needs.

Why Might a Doctor Order an a-THF Test?

A doctor might order an a-THF test to evaluate adrenal gland function, diagnose disorders related to cortisol metabolism such as Cushing's syndrome or Addison's disease, and monitor the body's response to stress. It can also be part of a comprehensive hormonal evaluation for patients with symptoms of adrenal imbalance.

Is the a-THF Test Safe?

Yes, the a-THF test is safe. The most common risk associated with the test is slight discomfort or inconvenience from the 24-hour urine collection process. Blood tests, if used, may cause slight discomfort or bruising at the site where blood is drawn.

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