Tetrahydrocortisone

Tetrahydrocorticosterone (THE) is a key metabolite of corticosterone, a corticosteroid produced in the adrenal cortex from cholesterol.  

THE is also known as 5-beta-tetrahydrocorticosterone, or 5-beta-THE. 

THE is formed by the action of 5β-reductase enzymes primarily in the liver and plays a crucial role in the metabolism of corticosterone. 

Unlike 5-alpha-THE, 5-beta-THE binds minimally to glucocorticoid receptors, indicating limited biological activity.  However, monitoring the levels of THE in urine can provide valuable insights into adrenal function and the activity of steroidogenic enzymes, making it a significant biomarker for diagnosing and understanding metabolic and endocrine disorders. 

Elevated or decreased levels of THE can signal various conditions such as Cushing's syndrome, adrenal hyperplasia, or Addison’s disease, thus emphasizing its clinical importance in evaluating adrenal health and hormonal imbalances.

What is THE?  [9., 15.] 

THE is the terminal metabolite of corticosterone.  Corticosterone is a corticosteroid, which is a steroid hormone produced from cholesterol in the adrenal cortex. THE refers to 5-alpha-THE and 5-beta-THE.

5β-tetrahydrocorticosterone and 5α-tetrahydrocorticosterone are stereoisomers, differing in the configuration of the hydrogen atoms at the 5th carbon position of the steroid backbone.  

5β-tetrahydrocorticosterone and 5α-tetrahydrocorticosterone are metabolites of corticosterone, but they are produced by different enzymes.

5β-tetrahydrocorticosterone is formed by the action of 5β-reductase enzymes on corticosterone, while 5α-tetrahydrocorticosterone is formed by the action of 5α-reductase enzymes on corticosterone.

THE Production

THE (THE) is a metabolite derived from corticosterone through the action of 5-alpha- or 5b-reductase and subsequent steps involving 3α-hydroxysteroid dehydrogenase (HSD3B) and 3b-hydroxysteroid dehydrogenase (AKR1C1/C2).  [10.] 

5b-Reductase is primarily expressed in the liver and to a lesser extent in the testis and colon.  [8.] 

Biological Activity of THE

5-beta-THE binds minimally to glucocorticoid receptors compared to corticosterone and 5a-reduced metabolites.  [9.] 

These 5-beta-reduced metabolites did not activate glucocorticoid receptors in cell assays and showed lower binding affinities, suggesting limited biological activity.  [9.]  However, 5-alpha-THE may have more glucocorticoid activity.

Clinical Relevance of THE  [10.] 

THE is a significant urinary metabolite that can be used to assess steroidogenic activity and enzyme functions, especially when assessed with 5-alpha- and 5-beta-tetrahydrocortisol.

The presence and levels of THE in urine provide insights into the metabolic pathways active in steroid hormone metabolism, especially those involving corticosterone.

Monitoring THE levels in urine is relevant for understanding various metabolic disorders and enzyme deficiencies.  Along with other steroid hormone metabolites, it serves as a biomarker for disorders affecting steroidogenesis and can help diagnose enzyme deficiencies such as 5b-reductase deficiency.

It is important to understand the differential presence of THE in serum and urine, illustrating how the steroid metabolomes in these biological fluids can provide complementary information. 

While THE is a prominent urinary metabolite, its presence in serum is less pronounced, underscoring the importance of urinary analysis for specific steroid metabolites.

Factors Affecting Levels of THE

The production and levels of THE are influenced by various factors, including:

Adrenocorticotropic hormone (ACTH) Stimulation  [12.] 

ACTH, released by the pituitary gland, is a key regulator of adrenal steroidogenesis, including the synthesis of cortisol and its metabolites.

Circadian Rhythms  [7.] 

The biosynthesis of adrenal steroids and their metabolites, including THE, exhibits a diurnal pattern.  

Age and Developmental Stage  [5., 11.]

Steroid hormone levels, including those of THE, can vary depending on age and developmental stage, such as during fetal development, childhood, and aging.

Genetic Factors  [4.] 

Variations in genes encoding enzymes involved in steroidogenesis, such as CYP11B1 and AKR1D1, can influence the production and levels of THE.

Pathological Conditions  [1., 2., 6., 16.]

Certain diseases and disorders affecting adrenal hormones such as adrenal hyperplasia, Cushing's syndrome, adrenal insufficiency including Addison’s disease, or congenital adrenal hyperplasia, can lead to altered levels of THE and other steroid metabolites.

Altered levels may also be seen in PCOS, as it may alter the enzymatic function of the 5-alpha and 5-beta reductase enzymes.  [2.] 

Lab Testing for THE

Test Information, Sample Collection and Preparation

Cortisone metabolites such as THE are often tested in the urine, commonly over 24 hours.  They may also be tested in the blood.

It is important to consult with the ordering provider regarding preparation for sample collection, as certain supplements or medications may need to be avoided.

Interpreting THE Levels

Optimal Levels of THE

It is important to assess levels of adrenal hormones in the broader context of overall hormone levels; imbalances may signal a genetic or functional issue affecting hormone production or metabolism.  

Additionally, interpretation should take into account the presence of any symptoms of hormone excess or deficiency.

One lab reports the following optimal levels for THE: 58-240 ng/mg Creatinine/Day.  [13.]

Clinical Significance of Elevated THE

Elevated levels of THE can be seen in conditions associated with increased cortisol production and adrenal activity, including Cushing syndrome as well as elevated cortisol output in stress or inflammation.  [3., 17.]

Chronic or excessive alcohol use can also raise cortisol levels and, therefore, its metabolites including THE.  [14.]

Clinical Significance of Decreased THE

Decreased levels of THE may signal decreased cortisol output due to Addison’s disease, adrenal insufficiency, or congenital adrenal hyperplasia.  [1., 12., 16.] 

Related Biomarkers to Test Alongside THE

Cortisol and Other Adrenal Hormones

Cortisol, the primary glucocorticoid hormone produced by the adrenal glands, is closely related to THE in terms of biosynthesis and metabolism.  

Measuring cortisol levels alongside THE can provide valuable insights into adrenal function and the regulation of the hypothalamic-pituitary-adrenal (HPA) axis.  

Other adrenal hormones, such as aldosterone and dehydroepiandrosterone (DHEA), may also be evaluated in conjunction with THE to assess adrenal disorders. 

Steroid Metabolites

Several steroid metabolites including tetrahydrocortisone (THE) and tetrahydrocortisol (THF), are closely related to THE and may serve as complementary biomarkers. 

These metabolites are formed through similar enzymatic pathways and can provide additional information about steroid metabolism and potential dysregulation in various disease states. 

Frequently Asked Questions (FAQs) on Tetrahydrocorticosterone

The FAQ section addresses common questions and concerns about Tetrahydrocorticosterone, providing clear and concise answers for better understanding. 

What Is Tetrahydrocorticosterone?

Tetrahydrocorticosterone is a metabolite of corticosterone, a steroid hormone produced by the adrenal glands.  It plays a role in the metabolism of corticosterone and is involved in the regulation of stress responses and immune function.

Why Is Tetrahydrocorticosterone Important?

Tetrahydrocorticosterone is important because it serves as an indicator of adrenal gland function and corticosterone metabolism.  Abnormal levels can provide insights into various health conditions related to adrenal and endocrine function.

What Is the Function of Tetrahydrocorticosterone?

Tetrahydrocorticosterone functions as a metabolite in the corticosterone metabolism pathway.  It does not have any biological activity, but monitoring its levels may provide insight into endocrine imbalances or pathologies.

How Is Tetrahydrocorticosterone Measured?

Tetrahydrocorticosterone levels are typically measured through urine tests, often involving a 24-hour urine collection.  Blood tests may also be used, but urine tests are more common for assessing steroid metabolites.

What Are Normal Levels of Tetrahydrocorticosterone?

Normal levels of Tetrahydrocorticosterone 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 Tetrahydrocorticosterone?

Elevated levels of Tetrahydrocorticosterone can be caused by conditions such as adrenal hyperplasia, Cushing's syndrome, and chronic stress.  These conditions lead to increased production and metabolism of corticosterone.

What Can Cause Low Levels of Tetrahydrocorticosterone?

Low levels of Tetrahydrocorticosterone may indicate adrenal insufficiency, Addison's disease, or dysfunction in the enzymes involved in steroid metabolism.  These conditions result in reduced production or impaired metabolism of corticosterone.

What Are the Symptoms of Abnormal Tetrahydrocorticosterone Levels?

Symptoms of abnormal Tetrahydrocorticosterone levels can vary depending on whether 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 Tetrahydrocorticosterone Treated?

Treatment for abnormal levels of Tetrahydrocorticosterone depends on the underlying cause. 

Common approaches include hormone replacement therapy, medications to regulate adrenal gland function, and lifestyle changes to manage stress. 

It is essential to consult with a healthcare provider to develop an appropriate treatment plan based on individual health needs.

Why Might a Doctor Order a Tetrahydrocorticosterone Test?

A doctor might order a Tetrahydrocorticosterone test to evaluate adrenal gland function, diagnose disorders related to corticosterone 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 Tetrahydrocorticosterone Test Safe?

Yes, the Tetrahydrocorticosterone 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.

Order THE Testing

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