20a-Dihydroprogesterone

20α-Dihydroprogesterone is a less potent metabolite of progesterone, synthesized primarily by human aldo-keto reductases (AKR1C1-AKR1C4) and AKR1D1 enzymes. These enzymes are critical in steroid hormone metabolism, influencing the activity of progesterone and other steroids. 

In endometriosis, the up-regulation of AKR1C1 and AKR1C3 enzymes leads to increased conversion of progesterone into 20α-dihydroprogesterone, reducing progesterone's protective effects against the proliferative influence of estradiol on endometriotic tissue.

Testing for 20α-dihydroprogesterone, typically done through urine samples, helps assess hormone metabolism. 

Elevated levels can indicate pregnancy or estrogen dominance, while low levels may suggest menstrual irregularities or reproductive hormone imbalances. 

Understanding the role of 20α-dihydroprogesterone is crucial for diagnosing and treating conditions related to hormone metabolism and reproductive health.

What is 20a-Dihydroprogesterone?  20a-Dihydroprogesterone Biochemistry and Metabolism

20a-Dihydroprogesterone is a metabolite derived from the hormone progesterone, which plays a crucial role in the female reproductive system and pregnancy. 

20α-Dihydroprogesterone a less-potent version of progesterone, which modulates progesteronic activity.  It is synthesized primarily through the action of human aldo-keto reductases (AKR1C1-AKR1C4) and AKR1D1 enzymes.  [1., 3.]

These enzymes play critical roles in steroid hormone metabolism, neurosteroid biosynthesis, and bile acid formation. 

AKR1C1-AKR1C4 enzymes function as 3-keto, 17-keto, and 20-ketosteroid reductases, while AKR1D1 serves as the sole Δ4-3-ketosteroid-5β-reductase in humans.

These enzymes regulate the concentrations of active steroid ligands, modulating nuclear receptor activity and the effects of neurosteroids on GABAA and NMDA receptors. Mutations or altered expression of AKR1C genes are linked to several conditions, including prostate, breast, and endometrial cancers, as well as disorders of sexual development and bile acid deficiencies.  [3.] 

Location of Human Aldo-Keto Reductases (AKR1C1-AKR1C4) and AKR1D1 Enzymes  [1., 3.]

Human aldo-keto reductases (AKR1C1-AKR1C4) and AKR1D1 enzymes are distributed in various tissues throughout the body, reflecting their diverse roles in steroid metabolism, neurosteroid biosynthesis, and bile acid formation.

AKR1C Enzymes (AKR1C1-AKR1C4)

• AKR1C1: found in the liver, prostate, mammary gland, endometrium, and the central nervous system. It plays roles in steroid hormone metabolism, including the inactivation of progestins and androgens.  This enzyme is also called 20alpha-hydroxysteroid dehydrogenase.  [5.] 

• AKR1C2: predominantly expressed in the liver, prostate, and endometrium. It is involved in the metabolism of androgens and neurosteroids, as well as the inactivation of potent androgens in the prostate.

• AKR1C3: located in the liver, prostate, mammary gland, endometrium, and the central nervous system. It is crucial for the formation of active androgens and estrogens and the regulation of prostaglandins.

• AKR1C4: primarily liver-specific, where it plays a significant role in bile acid biosynthesis and the metabolism of various steroids, including glucocorticoids and androgens.

AKR1D1 Enzyme

• AKR1D1: expressed mainly in the liver, this enzyme is essential for bile acid biosynthesis and the metabolism of steroid hormones. It reduces the C4-C5 double bond in Δ4-3-ketosteroids, forming 5β-reduced steroids crucial for bile acid synthesis.

Effects of 20a-Dihydroprogesterone

Due to the lack of specific research on 20a-Dihydroprogesterone, it is difficult to determine the disorders or conditions that may be associated with altered levels of this metabolite. However, some potential areas implicated in progesteronic activity include:

Endometriosis  [1.] 

Human aldo-keto reductases 1C1 and 1C3 (AKR1C1 and AKR1C3) are key enzymes that regulate progesterone action by converting it into the less potent metabolite, 20α-hydroxyprogesterone.  AKR1C1 exhibits higher catalytic efficiency in this conversion compared to AKR1C3.

In ovarian endometriosis, an estrogen-dependent disease, there is significant up-regulation of AKR1C1 and AKR1C3. This condition is characterized by increased estradiol production which stimulates endometriotic tissue proliferation, and impaired progesterone action due to reduced progesterone receptor B (PRB) expression and increased conversion of progesterone into less active metabolites by AKR1 enzymes.

Labor Induction  [2.] 

The enzyme 20α-HSD, encoded by the AKR1C1 gene, is essential for converting progesterone to its less active form, 20α-hydroxyprogesterone. This conversion is significant because it reduces the local progesterone levels in the uterus, contributing to the onset of labor. 

Increased expression of AKR1C1 mRNA and 20α-HSD protein has been observed in the myometrium during term labor, suggesting that this enzyme's activity is a critical mechanism for initiating labor by promoting progesterone withdrawal.

Inflammation and Preterm Labor  [2.] 

In cases of spontaneous preterm labor, increased 20α-HSD activity has been linked to inflammation, particularly in preterm labor associated with clinical chorioamnionitis. This implies that inflammation can drive progesterone withdrawal through enhanced 20α-HSD activity, leading to labor onset.

20a-Dihydroprogesterone Laboratory Testing

Test Information, Sample Collection and Preparation

Samples for the analysis of 20a-Dihydroprogesterone are typically collected in urine. Testing 20a-Dihydroprogesterone in the urine as part of a more comprehensive assessment of hormone metabolites may provide important information regarding hormone detoxification and processing.  

Urine samples may be easily collected from the comfort of home.  It is important to consult with the ordering provider prior to sample collection, as certain drugs, supplements, or hormonal medications may need to be avoided or adjusted prior to sample collection.  

Interpretation of 20a-Dihydroprogesterone Results

Optimal Levels of 20a-Dihydroprogesterone

It is important to assess individual hormone levels within the context of an individual’s broader hormone profile, taking into account the metabolites of various sex hormones.  Additionally, a comprehensive assessment of hormonal health, signs and symptoms, diet and lifestyle, and time of life including early reproductive years, perimenopause or menopause, or conditions such as pregnancy must be considered.  

For reference, one company reports optimal levels of 20a-dihydroprogesterone as: 3.93-11.62 μg/g Cr Premenopausal women in the luteal phase, or women on progesterone replacement therapy  [4.] 

Clinical Significance of Elevated 20a-Dihydroprogesterone Levels

Elevated 20a-Dihydroprogesterone levels may be seen in physiological conditions such as pregnancy.  They may also be seen in conditions of relative estrogen dominance, such as endometriosis.  

A comprehensive hormone assessment is often warranted to assess for other hormonal imbalances, including adrenal hormones.  

In women supplementing with progesterone, elevated 20a-dihydroprogesterone levels may also be seen; in this case, it is important to assess for symptoms of progesterone excess, and to evaluate clinical effectiveness of her current progesterone dosage.  

Clinical Significance of Low 20a-Dihydroprogesterone Levels

Low 20a-dihydroprogesterone levels imply low levels of the progesterone hormone, which is associated with menstrual irregularities, infertility, and reproductive hormone imbalance that could manifest in various symptoms including mood swings, heavy periods, PMS, and decreased libido.  

20a-Dihydroprogesterone Related Biomarkers

The analysis of 20a-Dihydroprogesterone as a potential biomarker is often performed in conjunction with the measurement of other related biomarkers, as they can provide valuable insights into the overall metabolic pathways and physiological processes involved.

Other Steroid Hormones and Metabolites

Since 20a-Dihydroprogesterone is a metabolite of the hormone progesterone, it is essential to consider the levels of progesterone itself, as well as other related steroid hormones and their metabolites. These may include:

• Estrogens (e.g., estradiol, estrone, estriol, and their metabolites)

• Androgens (e.g., testosterone, dihydrotestosterone, DHEAS)

• Corticosteroids (e.g., cortisol, corticosterone)

The ratios and interplay between these hormones and their metabolites can provide valuable information about the overall hormonal balance and metabolic pathways involved in various physiological and pathological conditions.

Biomarkers for Related Conditions

Depending on the specific clinical context or condition being investigated, other biomarkers related to reproductive health, endocrine function, or metabolic disorders may be relevant. 

These could include:

• Gonadotropins (e.g., luteinizing hormone, follicle-stimulating hormone)

• Markers of ovarian function (e.g., anti-Müllerian hormone, inhibin)

• Markers of placental function (e.g., human chorionic gonadotropin, placental growth factor)

• Markers of metabolic disorders (e.g., insulin, glucose, lipid profiles)

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