Pregnanetriol

Pregnanetriol is produced in the adrenal glands from 17-hydroxyprogesterone, an intermediate in the biosynthetic pathway of cortisol.

The levels of Pregnanetriol, typically measured in urine, can indicate disruptions in steroidogenesis pathways such as those seen in congenital adrenal hyperplasia (CAH) and adrenal insufficiency. 

Monitoring these levels helps in diagnosing and managing endocrine disorders, and they reflect the broader metabolic and hormonal balance within the body.

What is Pregnanetriol?

Pregnanetriol, also known as 5β-pregnane-3α,17α,20α-triol, is an inactive metabolite of progesterone.  It is excreted in urine and its levels are often measured over a 24-hour period.  [6., 7.]

Metabolism and Function of Pregnanetriol  [9.]

Pregnanetriol is primarily produced from 17-hydroxyprogesterone.  17-hydroxyprogesterone is derived from progesterone, which is produced by the corpus luteum of the ovary, the human placenta, and the adrenal gland.

The conversion of 17-hydroxyprogesterone to pregnanetriol is primarily associated with the adrenal gland.  This conversion occurs due to an inability of the adrenal gland to produce sufficient enzyme for C-21 hydroxylation, leading to an accumulation of 17-hydroxyprogesterone, which is then converted to pregnanetriol.  [2.]

This metabolic pathway is disrupted in conditions like adrenal hyperplasia, where the enzyme deficiencies prevent normal hydroxylation processes, causing increased levels of 17-hydroxyprogesterone and subsequently pregnanetriol.  [2., 5.]

Pregnanetriol can be directly excreted in the urine.

In individuals with normal adrenocortical function, daily urinary excretion of pregnanetriol ranges from 0.13 to 1.0 mg.  [9.]  There is relatively little accumulation of pregnanetriol under normal circumstances.

Pregnanetriol itself is an inactive metabolite, although its levels are tested for diagnosis and monitoring of conditions such as congenital adrenal hyperplasia and adrenal insufficiency. 

Clinical Significance of Pregnanetriol

High Pregnanetriol in Congenital Adrenal Hyperplasia  [1., 8., 9.]

CAH is primarily caused by 21-hydroxylase deficiency, leading to more than 90% of CAH cases. Early diagnosis and treatment are vital to prevent complications like genital virilization in females and adrenal insufficiency in males. 

Newborn screening programs help identify affected infants by measuring 17-hydroxyprogesterone, and sometimes Pregnanetriol, levels.  They may also be tested in amniotic fluid.

Steroid 21-hydroxylase (CYP21, P450c21) hydroxylates 17-hydroxyprogesterone and progesterone to produce cortisol and aldosterone precursors. 

Deficiency in this enzyme leads to cortisol and aldosterone deficiencies, resulting in high ACTH levels, adrenal hyperplasia, and overproduction of cortisol precursors, some of which convert to sex steroids.

Accordingly, elevated 17-hydroxyprogesterone and Pregnanetriol can also be seen.  

The main symptoms of congenital adrenal hyperplasia caused by 21-hydroxylase deficiency are due to lack of cortisol (leading to salt-wasting crisis), lack of aldosterone (salt-wasting), and excess androgens causing virilization in females and premature puberty in both sexes.  [8.]

Severity depends on the degree of 21-hydroxylase deficiency.  [8.]

Classic Salt-Wasting Form:

• In newborns: Dehydration, poor feeding, vomiting, diarrhea, low blood pressure, low blood sodium, low blood glucose, metabolic acidosis, weight loss 

• Adrenal crisis: Confusion, irritability, rapid heart rate, coma 

• In both sexes: Premature pubarche, rapid growth, early puberty, acne, hirsutism, advanced bone age 

• Females: ambiguous genitalia with enlarged clitoris, fused labia at birth; irregular menses, infertility, deepening voice 

• Males: Large phallus, testicular adrenal rest tumors, infertility 

Classic Simple Virilizing Form:

• In females: Ambiguous genitalia with enlarged clitoris at birth

• In both sexes: Premature pubarche, rapid growth, early puberty, acne, hirsutism, advanced bone age

Non-Classic Form:

• Premature pubarche, rapid growth in childhood, short adult stature

• Females: Hirsutism, irregular menses, acne, infertility

• Males: Precocious pseudo-puberty 

Low Pregnanetriol in Adrenal Insufficiency  [5.]

Low levels of 17-hydroxyprogesterone (17-OHP) and pregnanetriol can be indicative of adrenal insufficiency. 

17-OHP is an intermediate in the adrenal biosynthetic pathway from cholesterol to cortisol.  It is converted to cortisol in the adrenal glands via the enzyme steroid 21-hydroxylase. 

In cases of adrenal insufficiency, the production of 17-OHP and its downstream metabolites, including pregnanetriol, is diminished due to impaired adrenal function.  

This impairment can be due to inherited enzyme deficiencies or other conditions affecting adrenal health, leading to insufficient cortisol synthesis and consequently low levels of 17-OHP and pregnanetriol in the body.

Symptoms of untreated adrenal insufficiency or adrenal crisis include severe weakness, low blood pressure, low blood glucose, vomiting, diarrhea, confusion, darkening of the skin, shock and coma.  [3.]  Fertility issues can also be seen.  

Low Pregnanetriol levels may also be seen with decreased endogenous progesterone production.  

Lab Testing for Pregnanetriol

Testing Methods, Sample Collection and Preparation

Pregnanetriol levels are most commonly assessed in urine, typically over a 24 hour period.  Serum tests may also be done.  Urine sample collection is typically done at home, although it may be done in some clinical settings.  

Blood samples require a venipuncture.

Newborn screening for 21-hydroxylase deficiency is typically done by assessing 17-OH-progesterone levels in blood.  

It is important to consult with the ordering physician prior to sample collection, as certain medications or supplements may need to be avoided during collection.  

Interpreting Pregnanetriol Test Results

Optimal Levels of Pregnanetriol 

Interpreting the results of Pregnanetriol tests should be done within the broader context of an individual’s health history, symptoms, and a complete hormone panel.  Normal Pregnanetriol levels can vary based on age, sex, and physiological conditions. 

One laboratory company reports an optimal range of Pregnanetriol levels as: 0.6-2.5 micromol/24 hour.  [4.]

Clinical Significance of Elevated Pregnanetriol

Elevated Pregnanetriol is most often seen in conditions like congenital adrenal hyperplasia due to 21-hydroxylase deficiency; elevated levels of 17-OH progesterone are also seen in this setting.  

In patients supplementing with progesterone who have elevated Pregnanetriol levels, levels of other progesterone metabolites should be assessed, as well as progesterone levels in saliva and/or serum, to determine whether the individual is receiving excessive amounts of the hormone.    

Clinical Significance of Decreased Pregnanetriol

Low urinary Pregnanetriol may indicate adrenal insufficiency or low progesterone production.

Related Biomarkers to Test Alongside Pregnanetriol

Steroid Metabolites

Measurement of steroid hormone metabolites can provide valuable insights into the body's metabolic processes. 

Testing for progesterone metabolites such as 17-hydroxyprogesterone as well as alpha- and beta-pregnanediol may provide additional insight.  Other hormones to consider include estrogen and its main metabolites such as 2-hydroxy and 4-hydroxy metabolites and 16-hydroxyestrone.  

Testosterone may be assessed in conjunction with other androgens including 5-dihydrotestosterone, DHEA-S, etiocholanolone, androsterone and androstanedione in order to understand the balance of sex hormones.  

Cortisol and its metabolites are adrenal steroid hormones, and these hormones may be assessed by testing cortisol and cortisone and their metabolites including 5-alpha-tetrahydrocortisol, 5-beta-tetrahydrocortisol, 5-alpha-tetrahydrocorticosterone and 5-beta-tetrahydrocorticosterone.   

By evaluating these metabolites together, clinicians can identify specific enzyme defects, understand hormonal imbalances, and tailor treatment strategies more effectively.

Frequently Asked Questions (FAQs) About Pregnanetriol

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

What Is Pregnanetriol?

Pregnanetriol is a metabolite of progesterone, a hormone produced in the adrenal glands and gonads. It can be measured to assess adrenal function and certain hormonal disorders.

Why Is Pregnanetriol Important?

Pregnanetriol is important because its levels can indicate abnormalities in steroid hormone metabolism.  Elevated or decreased levels of Pregnanetriol can be associated with various health conditions, including congenital adrenal hyperplasia (CAH) and other hormonal imbalances.

What Is the Pregnanetriol Test?

The Pregnanetriol test measures the levels of this metabolite in the urine or blood.  This test is used primarily to diagnose and monitor conditions related to abnormal steroid hormone production, such as congenital adrenal hyperplasia (CAH).

How Is the Pregnanetriol Test Performed?

The Pregnanetriol test typically involves collecting a urine sample over a 24-hour period or a single blood sample. The sample is then analyzed in a laboratory to determine the concentration of Pregnanetriol.

What Are Normal Levels of Pregnanetriol?

Normal levels of Pregnanetriol can vary depending on factors such as age, sex, and health status.  Reference ranges are established by individual laboratories, and results should be interpreted by a healthcare provider in the context of the patient’s overall health and medical history.

What Can Cause Elevated Levels of Pregnanetriol?

Elevated levels of Pregnanetriol are often associated with congenital adrenal hyperplasia (CAH), a genetic disorder affecting adrenal gland function.  Other possible causes include excessive production or supplementation of progesterone.

What Can Cause Low Levels of Pregnanetriol?

Low levels of Pregnanetriol may indicate adrenal insufficiency.  It may also be associated with  decreased progesterone levels, although further testing of progesterone as well as its metabolites should be done as part of further assessment.

What Are the Symptoms of Abnormal Pregnanetriol Levels?

Symptoms of abnormal Pregnanetriol levels can vary depending on the underlying condition. 

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High levels may be associated with symptoms of CAH, such as ambiguous genitalia in newborns, early onset of puberty, and excessive hair growth.  

Low levels may lead to symptoms of adrenal insufficiency such as fatigue, muscle weakness, and low blood pressure.

How Are Abnormal Pregnanetriol Levels Treated?

Treatment for abnormal Pregnanetriol levels depends on the underlying cause. 

For conditions like congenital adrenal hyperplasia (CAH), treatment may include hormone replacement therapy to balance steroid hormone levels. 

Managing adrenal insufficiency typically involves glucocorticoid and mineralocorticoid replacement.

Is the Pregnanetriol Test Safe?

Yes, the Pregnanetriol test is safe. The most common risk is slight discomfort or bruising at the site where blood is drawn if a blood sample is taken.  Urine collection is non-invasive and generally risk-free.

Why Might a Doctor Order a Pregnanetriol Test?

A doctor might order a Pregnanetriol test if there are symptoms suggestive of congenital adrenal hyperplasia (CAH) or other adrenal gland disorders. 

It can also be part of a diagnostic workup for unexplained symptoms related to hormone imbalance.

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