Pregnanediol-3-Glucuronide

Pregnanediol-3-glucuronide (PdG) is the phase II glucuronidated excretory metabolite of pregnanediol, the primary urine metabolite of progesterone. 

Produced in the liver by UDP-glucuronosyltransferase, PdG serves as a critical urinary marker for confirming ovulation with high specificity. 

Elevated urinary PdG levels, maintained over 5 µg/mL for three consecutive days, can accurately indicate ovulation. 

PdG measurements are essential for assessing progesterone production, monitoring fertility, and managing early pregnancy, where they can identify luteal phase defects and the risk of threatened abortion. 

Understanding PdG levels provides valuable insights into hormonal changes, particularly ovulation and luteal phase health, aiding in personalized fertility management.

What is PdG?

Pregnanediol-3-glucuronide (PdG) is the phase II (glucuronidated) excretory metabolite of pregnanediol, the major urinary metabolite of progesterone. [14.]

Pregnanediol-3-glucuronide is a natural metabolite of pregnanediol produced by UDP glucuronosyltransferase in the liver [14.] 

Urinary pregnanediol-3-glucuronide levels over 5 μg/ml for three consecutive days can be used as a positive confirmation of ovulation with high sensitivity and specificity. [3., 11.] 

PdG’s Relationship to Progesterone Metabolism [7., 8., 13.] 

Progesterone metabolism is a complex process that occurs primarily in the liver, but also in other tissues like the intestines, brain, and skin.  

Pregnanediol is a terminal urinary metabolite of progesterone. Pregnanediol exists in two stereoisomeric forms, α-pregnanediol and β-pregnanediol.

Both urinary α-pregnanediol and β-pregnanediol serve as indicators of progesterone metabolism.

The initial enzymes involved in progesterone metabolism are 5-alpha-reductase and 5-beta-reductase, which determine whether the alpha- or beta-pregnanediol isomer will be formed. 

a-Pregnanediol is made by the initial step of progesterone metabolism featuring 5-alpha reductase, and b-pregnanediol is made by the initial step featuring 5-beta reductase.

Alpha-Pregnanediol Formation

First, progesterone is reduced to 5α-Dihydroprogesterone by 5-alpha reductase.

Then, 5α-Dihydroprogesterone is converted to allopregnanolone (3α-hydroxy-5α-pregnan-20-one) by 3α-HSD.

Finally, allopregnanolone is converted to α-pregnanediol (5α-Pregnan-3α,20α-diol) by 20α-HSD.

Beta-Pregnanediol Formation

First, progesterone is reduced to 5β-Dihydroprogesterone (5β-DHP) by 5-beta reductase.

Then, 5β-Dihydroprogesterone is converted to pregnanolone (3α-hydroxy-5β-pregnan-20-one) by 3α-HSD.

Finally, pregnanolone is converted to β-pregnanediol (5β-Pregnan-3α,20α-diol) by 20α-HSD.

Pregnanediol Glucuronidation [12.] 

These pregnanediol metabolites undergo glucuronidation, a process where a glucuronic acid molecule is attached to them.

The enzyme responsible for this process is typically UDP-glucuronosyltransferase (UGT).

The result is the formation of pregnanediol-3-glucuronide (PdG), which is then excreted in the urine.

PdG as a Marker for Fertility and the Menstrual Cycle

Role in Predicting Ovulation

Pregnanediol-3-glucuronide (PdG) is a urine metabolite of progesterone, which rises approximately 24-36 hours post-ovulation. 

Previous studies have shown that three consecutive days of PdG levels above 5μg/mL can confirm ovulation with 92.2% sensitivity and 100% specificity. [3., 11.]

Another study demonstrated the following specific thresholds for PdG excretion rates were established to determine ovulation and fertility: [2.]

7 µmol/24 h to indicate the end of the fertile window.

9 µmol/24 h as biochemical proof of ovulation.

13.5 µmol/24 h as sufficient for luteal phase function to support pregnancy.

Importance in Assessing Threatened Abortion

PdG measurements can also be valuable in assessing the risk of threatened abortion during early pregnancy. [6.]

As progesterone is crucial for maintaining pregnancy, monitoring PdG levels can provide insights into the health and viability of early pregnancies. 

Abnormally low PdG levels may indicate insufficient progesterone production, which could signal an increased risk of miscarriage or signal an ectopic pregnancy. [6., 10.] 

This information allows healthcare providers to intervene early and provide appropriate support and treatment when necessary.

Significance in Menstrual Cycle Maintenance and Fertility 

Progesterone is essential in regulating the menstrual cycle and supporting pregnancy. Progesterone levels rise after ovulation which leads to several physiological changes including an increase in basal body temperature (BBT), or the body's temperature at rest.

BBT is a commonly tracked metric that holds clinical significance.  However, research shows that measuring PdG levels alongside BBT can provide additional information to improve accuracy.

As a progesterone metabolite found in urine, measuring PdG levels provides an indirect but accurate reflection of progesterone levels in the body. [3., 11.]

Monitoring both BBT and PDG levels across the menstrual cycle offers valuable insights into hormonal changes, particularly ovulation and luteal phase health. [5.] 

For example, monitoring both PDG and BBT helps in identifying the fertile window for those trying to conceive. It also aids in diagnosing and managing conditions related to ovulatory dysfunction, especially when other factors are affecting BBT (for example, thyroid disorders, illness, or nighttime breastfeeding). 

Measuring both metrics may also improve accuracy of timing of intercourse or insemination for couples trying to conceive. 

Progesterone secretion, indicated by rising PDG levels, begins before ovulation.  However, BBT does not predict ovulation but confirms it retrospectively, and a drop in BBT during the luteal phase can indicate a decrease in corpus luteum activity. [5.] 

However, research indicates that at lower levels of progesterone, BBT becomes a more clinically relevant predictor of ovulation; therefore, measuring both BBT and PdG can further inform the value that BBT holds. [5.] 

What is PdG in Pregnancy?

Pregnanediol-3-glucuronide (PdG) is a key metabolite of progesterone. Progesterone has known essential roles in various physiological processes including pregnancy, embryogenesis, and maternal immune response. [4.]

Accurate measurement of PdG levels is crucial for assessing progesterone production, especially during pregnancy.

In a recent study, a highly sensitive and specific liquid chromatography-tandem mass spectrometry (LC–MS/MS) method was developed to measure PdG levels in the serum of different female groups, including pregnant women, healthy controls, and thyroid cancer patients. [4.]

The study found that serum PdG/creatinine levels were significantly higher in pregnant women compared to healthy controls, indicating increased progesterone production essential for supporting pregnancy. [4.] 

Changes in PdG Levels During Pregnancy

During pregnancy, PdG levels undergo significant changes as the body adapts to support fetal development. As the main metabolite of progesterone in urine, PdG concentrations reflect the increased production of progesterone by the placenta. [6.]

Typically, PdG levels rise steadily after conception and continue to increase throughout pregnancy. This increase is particularly notable during the first trimester when progesterone production is critical for maintaining the pregnancy. [6., 10.]

Potential Applications for Monitoring Pregnancy Health

Monitoring PdG levels is valuable in assessing the risk of threatened abortion during early pregnancy, as abnormally low PdG levels may indicate insufficient progesterone production, potentially signaling an increased risk of miscarriage or ectopic pregnancy. This information allows healthcare providers to intervene early and provide appropriate support and treatment when necessary. [6., 10.]

The PdG/E1G Ratio

The analysis of daily urinary excretion rates of estrone glucuronide (E1G) and pregnanediol glucuronide (PdG) provides detailed insights into ovarian activity, crucial for monitoring menstrual cycles and managing fertility. [1., 2.] 

Key findings from research include the following about the PdG/E1G ratio:

Reliable Indicators of Ovarian Activity

E1G levels indicate follicular growth, while PdG levels confirm ovulation and corpus luteum function, making them reliable markers for ovarian and luteal phase activities. [1., 2.] 

Complex Menstrual Cycle Profiles

About 40% of menstrual cycles exhibit complex hormonal profiles differing from textbook descriptions, reflecting variations in follicular growth, atresia, and ovulation. [1.]

Detection of Fertility and Subfertility

Monitoring E1G and PdG can identify fertile and subfertile cycles. Nearly 20% of cycles showed luteal phase defects like short luteal phases and luteinized unruptured follicles (LUFs), indicating subfertility despite normal cycle lengths. [1.] 

Daily Monitoring Benefits

Daily monitoring provides a precise picture of the menstrual cycle, identifying the start of the fertile window through the first rise in E1G and confirming ovulation with the rise in PdG, marking the end of the fertile window. [1., 2.] 

E1G and PdG Peaks and Thresholds

Specific PdG excretion rate thresholds define the end of the fertile window (7 µmol/24 h), biochemical proof of ovulation (9 µmol/24 h), and adequate luteal phase function for pregnancy maintenance (13.5 µmol/24 h). [1., 2.] 

Home Monitoring and Natural Family Planning

Point-of-care assays like the Ovarian Monitor allow accurate home monitoring of E1G and PdG, facilitating natural family planning by providing real-time fertility data without lab tests. [1., 2.]

Identifying Subfertility

The study highlighted the importance of regular monitoring to detect luteal phase deficiencies and other subfertile conditions, enabling timely medical intervention for women with consistent subfertile profiles. [1., 2.] 

Variability and Individuality

Menstrual cycle variability underscores the need for individualized monitoring. E1G and PdG levels reveal unique hormonal patterns for each woman, aiding personalized fertility management. [1., 2.] 

Laboratory Testing for PdG

Test Information, Sample Collection and Preparation

PdG levels are typically tested in the urine. Samples may be collected from the comfort of home. 

Special preparation is often not required, although it is important to consult with the ordering provider prior to sample collection, especially for individuals taking certain hormone therapies or medications. 

PdG Test Interpretation

Optimal Levels of PdG

Test results should be interpreted within the context of an individual’s symptoms, female health history, and a broader hormonal assessment. This is especially important in the context of testing PdG levels for fertility treatment or menstrual irregularities.  

One company reports the following optimal levels of PdG according to a woman’s cycle timing: [9.] 

Baseline Follicular PdG: 346-1719 ng/mg Creatinine

Luteal PdG: 3994-10860 ng/mg Creatinine 

Clinical Significance of Elevated PdG Levels

Typically, relatively higher levels are expected during the luteal phase of the menstrual cycle, and in pregnancy. 

Clinically elevated levels of PdG are very rare outside of excessive hormone supplementation. A finding of elevated levels of PdG warrants further assessment. 

Clinical Significance of Low PdG Levels

Conversely, low levels may indicate insufficient progesterone production, which can have various underlying causes such as luteal phase defects, where the luteum does not produce enough progesterone to maintain a pregnancy in the early stages, or ovarian insufficiency.  

Low PdG levels might indicate anovulation, where no egg is released, thus no corpus luteum is formed to produce progesterone.  Such conditions are critical concerns for individuals attempting to conceive, as adequate progesterone levels are essential for embryo implantation and the maintenance of early pregnancy.

Clinicians must consider these factors when interpreting test results, as they provide crucial insights into a patient’s reproductive health and can guide further diagnostic or therapeutic actions.

Related Biomarkers

Estrone-3-Glucuronide (E1G)

Estrogen, primarily as estradiol, is metabolized in the liver into various forms including estrone (E1). 

Estrone can then undergo conjugation with glucuronic acid to form estrone glucuronide (E1G), a water-soluble metabolite that is excreted in urine. 

This process involves enzymatic reactions in the liver and is crucial for the elimination of excess estrogen from the body.

Testing E1G along with PdG provides a comprehensive understanding of ovarian activity throughout the menstrual cycle. [1., 2.] 

E1G levels indicate follicular growth, while PdG levels confirm ovulation and luteal phase function, offering a reliable means to monitor both phases.  [1., 2.] 

This dual measurement helps accurately define fertile windows, detect luteal phase defects, and manage fertility more effectively by identifying subfertile conditions despite normal cycle lengths. Overall, it supports personalized fertility management and timely medical interventions.

Luteinizing Hormone (LH) [11.] 

Luteinizing hormone (LH) is a key hormone in the regulation of the menstrual cycle and ovulation. 

Secreted by the anterior pituitary gland, LH levels surge just before ovulation, triggering the release of a mature egg from the ovarian follicle. This LH surge is a critical marker for identifying the fertile window. 

While PdG levels rise after ovulation, indicating the luteal phase, LH levels provide a signal for the imminent release of the egg. 

Combining LH testing with PdG measurements can enhance the accuracy of ovulation prediction. For instance, a positive LH test followed by a subsequent rise in PdG levels confirms that ovulation has occurred, allowing for precise timing of fertility-related activities.

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