2-Methoxyestrone/2-Hydroxyestrone Ratio

The 2-MeO-E1/2-OH-E1 ratio is the ratio between 2-methoxyestrone (2-MeO-E1) and 2-hydroxyestrone (2-OH-E1), two metabolites derived from a primary type of estrogen hormone, estrone.

This ratio is a marker of estrogen metabolism and has been implicated in various physiological processes and disease states.  Increasingly the hydroxylation pathway is implicated in disease processes including cancer and endometriosis, while the methylation pathway seems to demonstrate protective effects.  [5., 8.]

In recent years, researchers have focused on the 2-MeO-E1/2-OH-E1 ratio due to its potential role in understanding estrogen metabolism, hormone balance, and disease pathophysiology. 

The ratio offers insights into the relative proportions of different estrogen metabolites and their impact on estrogenic activity and health outcomes.

What is the 2-MeO-E1/2-OH-E1 Ratio

Explanation of 2-MeO-E1 and 2-OH-E1

2-MeO-E1 and 2-OH-E1 are metabolites of estrone, a major estrogen hormone produced primarily in the ovaries and adrenal glands.  2-MeO-E1, or 2-methoxyestrone, is formed through the methylation of estrone, while 2-OH-E1, or 2-hydroxyestrone, is produced via hydroxylation of estrone. 

These metabolites play crucial roles in estrogen metabolism and exert diverse effects on various physiological processes.

2-MeO-E1  [11., 17.]

2-Methoxyestrone is a metabolically significant 17-oxo steroid characterized by the addition of a methoxy (-OCH3) group at the 2-position of the estrone molecule. This chemical modification alters the structure and properties of estrone, resulting in a metabolite with distinct biochemical activity and characteristics.

Produced through the catechol-O-methyltransferase (COMT) enzyme on 2-hydroxyestrone, 2-methoxyestrone can further undergo transformations to form sulfated or glucuronidated derivatives via enzyme-mediated reactions. 

2-MeO-E1 exhibits low affinity for estrogen receptors, indicating minimal estrogenic activity compared to other related compounds.  However, it may have other roles in non-receptor mediated pathways.

2-OH-E1 

2-Hydroxyestrone is a metabolite of estrone.

Estrone (E1) is processed to 2-hydroxyestrone, 4-hydroxyestrone, or 16-hydroxyestrone via the CYP family of enzymes.  Each of these forms of estrone have different health implications.  

2-Hydroxyestrone is a hydroxylated form of estrone that is converted from estrone via the CYP1A1 enzyme.  It is produced via hydroxylation at the 2nd carbon position.

2-OH-E1 as a Catechol Estrogen

2-hydroxyestrone is a catechol estrogen.  Catechol estrogens undergo processes known as redox cycling, producing reactive oxygen species (ROS) such as hydrogen peroxide and hydroxyl radicals.  [10.] 

Catechol estrogens are implicated in the development of breast cancer due to their mutagenic properties and ability to cause DNA damage. 

Unlike their parent compounds (estradiol, estrone, estriol), these catechol estrogens actively participate in redox cycling, significantly contributing to oxidative stress within breast epithelial cells.  [10., 24.] 

Additionally, catechol estrogens exhibit varied binding affinities to estrogen receptors, which can influence their roles as neurotransmitters in neuronal cells and as hormones in other tissues.  [24.]

Relative to estradiol-17β (considered as a baseline with a relative binding affinity of 100), 2-hydroxyestradiol and 4-hydroxyestradiol show high affinities (100–150) when assessed using human estrogen receptors in cell-free setups.  However, their affinity varies significantly with the receptor source.

Conversely, methoxylated derivatives like 4-methoxyestradiol and 2-methoxyestradiol demonstrate minimal affinity (less than 0.1 to 1).  

Notably, catechol estrogens also interact with membrane-associated receptors, showing potential competitive inhibition against catecholaminergic agonists and antagonists in the brain, and bind with sex-hormone binding globulin with varying efficacies, suggesting a broad spectrum of physiological roles.

Biological Significance of 2-MeO-E1/2-OH-E1 Ratio

The ratio between 2-MeO-E1 and 2-OH-E1 reflects the relative activity of two major estrogen metabolic pathways: methylation and hydroxylation.  Methylation of estrone results in the formation of 2-MeO-E1, which is considered a weak estrogen with minimal estrogenic activity. 

On the other hand, hydroxylation of estrone leads to the production of 2-OH-E1, a catechol estrogen which exhibits stronger estrogenic effects and has been implicated in estrogen-mediated carcinogenesis and other estrogen-related diseases.

The balance between 2-MeO-E1 and 2-OH-E1 is influenced by various factors including genetic polymorphisms, hormonal status, dietary factors, and environmental exposures.  

Changes in the 2-MeO-E1/2-OH-E1 ratio may indicate alterations in estrogen metabolism, hormonal imbalances, or disease states, making it a potential biomarker for estrogen-related disorders.

‍

2-MeO-E1/2-OH-E1 Ratio and Diet  [3.]

Dietary factors, particularly the balance of fat and fiber intake, have been shown to affect the 2-MeO-E1/2-OH-E1 ratio.  A study involving postmenopausal women, including vegetarians and omnivores with and without breast cancer, found that a lower fat/fiber ratio was associated with a significantly higher 2-MeO-E1/2-OH-E1 ratio. 

Vegetarians, who typically consume a diet richer in fiber and lower in fat, exhibited higher levels of this ratio compared to their omnivore counterparts. 

This suggests that dietary fiber may positively impact estrogen metabolism, potentially influencing breast cancer risk by altering the balance of estrogen metabolites.

An additional dietary intervention may come from flaxseed.  The dietary phytoestrogens, such as lignans from flaxseed, may modify the risk of hormone-related diseases by altering the levels of active estrogen metabolites in the body.  [15.]

2-MeO-E1/2-OH-E1 Ratio and Environmental Toxins  [1.]

Environmental toxins are increasingly recognized as major health hazards, in large part because of their extensive effects on the endocrine system.  Their escalating concentrations in ecosystems, posing risks to soil, water resources, and human health. 

These toxins, entering the human food chain through plant uptake, disrupt normal estrogen metabolism pathways by mimicking or blocking natural hormones and altering metabolic enzyme activities. 

The presence of these toxins is linked to various health issues, such as breast and prostate cancers and reproductive disorders in wildlife and humans.

Their persistence in the environment, facilitated by industrial agricultural practices and waste disposal systems, highlights the urgent need for more comprehensive research to fully understand their ecological and health impacts.

2-MeO-E1/2-OH-E1 Ratio and Genetics  [5., 13.]

Genetics play a significant role in the metabolism of sex hormones, such as 2-methoxyestrone (2-MeO-E1).  An important genetic factor is the rs165599 variant in the COMT gene, which is involved in the metabolic pathways of these hormones. [13.]

Research shows that individuals with certain alleles of rs165599 have altered enzyme activity affecting hormone metabolism, impacting the levels of 2-MeO-E1. This genetic variation has been linked to an increased risk of colorectal cancer, suggesting that both the levels of specific metabolites like 2-MeO-E1 and genetic variations in their metabolic pathways contribute to disease risk.

Specific SNPs (single nucleotide polymorphisms) in the genes COMT (catechol-O-methyltransferase) and CYP1B1 (cytochrome P450 1B1) have also been shown to influence the metabolism of 2-OH-E1 and 2-MeO-E1.  [16.]

The COMT Val158Met and CYP1B1 Leu432Val genotypes affect how estrogen metabolites are processed in the body.

COMT is involved in the methylation of catechols, including estrogen metabolites. The Val158Met SNP in COMT affects the enzyme's activity, with the Met allele resulting in a significant reduction in COMT activity, leading to less methylation and consequently higher levels of catechol estrogens like 2-OH-E1 that may not have been converted to less active forms such as 2-MeO-E1.  [16.]

CYP1B1 plays a role in the 4-hydroxylation of estrogens, but it can also affect the production of 2-OH-E1. The Leu432Val SNP in CYP1B1 is associated with variations in enzyme activity. Individuals with the Val allele typically show higher enzyme activity, which can lead to increased conversion of estrogen to its 2-hydroxylated forms.

Role of 2-MeO-E1/2-OH-E1 Ratio in Health and Disease

The 2-MeO-E1/2-OH-E1 ratio has implications for various aspects of health and disease. An imbalance in the ratio has been associated with conditions such as hormone-related cancers, cardiovascular disease, and osteoporosis. 

Understanding the role of the 2-MeO-E1/2-OH-E1 ratio in these diseases provides insights into disease pathogenesis, risk assessment, and therapeutic strategies.

2-MEO-E1/2-OH-E1 Ratio and Endometrial Cancer  [5., 8.]

Endometrial cancer is the most common gynecologic malignancy in developed countries, with early detection crucial for effective treatment. 

Current diagnostic methods like transvaginal ultrasonography and endometrial biopsy, although commonly used, have limitations in sensitivity and specificity.  This has sparked interest in identifying non-invasive biomarkers, particularly those related to hormonal imbalances.  

Specifically, those hormone imbalances caused by unopposed estrogen are known to influence cell proliferation and apoptosis, leading to cancer.

Additionally, the catechol estrogens which include 2-OH-E1, are converted into reactive quinones that cause oxidative DNA damage, a key process in carcinogenesis.  

2-MEO-E1/2-OH-E1 Ratio and Breast Cancer  [19.]

Various factors can affect estrogen levels within breast glandular and adipose tissues, specifically estrogens like 17β-estradiol, estrone, and their metabolites such as estrone-3-sulfate and 2-methoxy-estrone.  

Key influencers include metabolic precursors, lifestyle factors such as body mass index, smoking, and intake of estrogen-active drugs, as well as specific tissue characteristics.  These may increase or decrease various levels of estrogen and alter its metabolism, tilting the balance toward a pro-inflammatory and possibly carcinogenic state within the breast tissue.

Research underscores the influence of both systemic factors, like menopausal status, and local tissue activities, such as enzyme actions, on intramammary estrogen levels.  

Enzymes like aromatase, hydroxysteroid-17 beta-dehydrogenase 2, and beta-glucuronidase play significant roles in modifying intratissue estrogen levels, demonstrating the complex interaction between extramammary production and intramammary metabolism.  

Ongoing research continues to identify potential pathways linking lifestyle and systemic factors with breast cancer risks through modulation of estrogen metabolism within the breast.

2-MeO-E1/2-OH-E1 Ratio and Cardiovascular Health and Disease  [6.]

Studies suggest that a higher ratio of 2-MeOE1 to 2-OHE1 is associated with protective effects against cardiovascular diseases.  [6.]

This is due to the anti-inflammatory and vasoprotective properties of 2-MeOE1, which help mitigate vascular damage and inflammation, key factors in cardiovascular disease development. 

Conversely, lower ratios may indicate a greater risk of developing cardiovascular issues, underscoring the importance of these metabolites in disease pathophysiology and potential therapeutic targeting.

2-MeO-E1/2-OH-E1 Ratio and Osteoporosis  [20.]

Higher levels of inactive metabolites like 2-OH-E1 and 2-MeO-E1 may have an increased risk of osteoporosis, particularly with higher levels of 2-MeO-E1.  The findings of one study indicate that higher levels of 2-MeOE1 are associated with lower BMD at various skeletal sites, including the vertebrae and proximal femur. 

Additionally, women with lower ratios of urinary 2-OHE1 to 16α-hydroxyestrone (16αOHE1) experienced no bone loss over a year, suggesting a protective effect against osteoporosis. 

These results support the hypothesis that the rate of estrogen inactivation through 2-hydroxylation may be a crucial factor influencing postmenopausal bone health.

Lab Testing for 2-MeO-E1/2-OH-E1 Ratio

Overview of Testing, Sample Collection and Preparation

Urine samples are commonly used for testing 2-MeO-E1/2-OH-E1 ratio.  

Estrogen metabolites can be excreted in the urine, making it a reliable method for testing estrogen detoxification and comparing ratios of estrogen metabolites.  Urine testing specifically assesses phase I estrogen detoxification, and it can also be used to assess phase II methylation detoxification.    

Urine collection can be easier and less stressful for patients compared to blood draws, as samples can be collected at home without the need for a clinical setting.  

Additionally, urinary levels can reflect longer-term hormone exposure rather than the transient levels often seen in blood, as it reflects detoxification patterns (rather than providing snapshots of levels in the bloodstream).

Interpretation of 2-MeO-E1/2-OH-E1 Ratio Test Results

Reference Range for 2-MeO-E1/2-OH-E1 Ratio

It is important to consult with the lab company providing testing for 2-MeO-E1/2-OH-E1 ratio.  

For reference, one lab provides the following reference range for urine 2-MeO-E1/2-OH-E1 ratio: 0.1-0.36  [9.]

Optimal Levels of 2-MeO-E1/2-OH-E1 Ratio

Hormones never act alone, and their effects are nuanced.  An optimal 2-MeO-E1/2-OH-E1 Ratio in urine tests varies depending on individual health conditions, gender, and age, although a higher ratio is typically preferred.   

One recommendation is that 60-80% of a woman's circulating estrogen utilize the 2-OH pathway; that 13-30% utilizes the 16-OH pathway; and that the remaining 7.5-11% utilizes the 4-OH pathway.  [9.]

Health professionals often recommend that women remain within the reference range of 0.1-0.36 in urine samples.  However, a professional's recommendation will be affected by many factors including the patient’s overall health, detoxification capacity, personal and family health history, time of life, diet and lifestyle, medications, and other factors.  

Regular monitoring through urinary tests is essential to ensure that the metabolite levels are within a safe range, thereby reducing the potential for DNA damage and promoting better hormonal balance and overall health.

Clinical Significance of a High 2-MeO-E1/2-OH-E1 Ratio

A higher 2-MeO-E1/2-OH-E1 ratio is preferred because it indicates an appropriate amount of methylation activity, metabolizing estrogen to its less potent and more anti-inflammatory metabolite, 2-MeO-E1.  

See below for more information on natural methods to promote hormone balance.   

Clinical Significance of Low 2-MeO-E1/2-OH-E1 Ratio

A lower 2-MeO-E1/2-OH-E1 ratio indicates a relatively higher amount of 2-OH-E1, which can signify inadequate methylation.  Relative to 2-MeO-E1, the effects of 2-OH-E1 are considered less beneficial to health and may signify that a more comprehensive assessment of estrogens and their metabolites is warranted.  

2-MeO-E1/2-OH-E1 Ratio-Related Biomarkers to Consider

Several other biomarkers are associated with estrogen metabolism and activity.  Other estrogen metabolites including 16-hydroxyestrone (16-OH-E1) and 4-hydroxyestrone (4-OH-E1), as well as estrone (E1), estradiol (E2), and estriol (E3) levels should be considered.  

16-Hydroxyestrone (16-OH estrone)

16-Hydroxyestrone (16-OH E1) is a metabolite of estrone, one of the three main naturally occurring estrogens in the human body.  

Unlike some other estrogen metabolites, 16-OH E1 exhibits relatively strong estrogenic activities. It binds to estrogen receptors, potentially influencing estrogen-responsive gene expression and cellular functions.

 This metabolite has been associated with various physiological effects and is implicated in different health conditions, including increased risks for certain types of cancers due to its potent estrogenic properties.

4-Hydroxyestrone (4-OH estrone)

4-OH estrone is another metabolite of estrone with strong estrogenic properties and potential carcinogenic effects. 

 Specifically, 4-OH estrone is known for its potential to form quinones that can directly damage DNA and generate reactive oxygen species, increasing the risk of mutagenesis.

Measuring 4-OH estrone alongside 16-OH estrone and 2-OH estrone can help assess the overall estrogenic and carcinogenic potential within the body.

Estrone (E1)

Estrone is a weaker estrogen compared to estradiol but is prevalent in postmenopausal women and can be converted back to estradiol. 

Testing for estrone is important for understanding the overall estrogenic activity, especially in postmenopausal women who are at increased risk for estrogen-sensitive cancers.

Estradiol (E2)

Estradiol is the most potent estrogen and has significant implications for bone density, reproductive health, and cardiovascular health.  Monitoring estradiol levels is essential for assessing reproductive health and menopausal status, and for managing hormone replacement therapy effectively.

Estriol (E3)

Estriol is a weak estrogen predominantly produced during pregnancy. Outside of pregnancy, its levels are very low, but it has been suggested to have protective effects against breast cancer. 

Testing for estriol, especially in non-pregnant states, might provide additional insights into estrogenic activity and potential protective mechanisms against estrogen-related pathologies.

Natural Ways to Promote Hormone Balance

It is always essential to work with a qualified healthcare professional in any case of hormone imbalance.  The following diet and lifestyle measures have been shown to naturally promote healthy hormone balance:

Dietary Fiber Increase: consuming more fiber helps bind estrogen in the digestive tract, promoting its excretion and reducing reabsorption.  [11.]  

Interestingly, one study of 240 women also showed a correlation between increased fiber intake and anovulation, possibly due to lower estrogen levels.  [11 .]

Cruciferous Vegetables: foods like broccoli, cauliflower, and Brussels sprouts contain indole-3-carbinol, which aids in detoxifying excessive estrogen and optimizing hormone balance.  [4.] 

Regular Exercise: physical activity can help balance hormones by improving metabolism and reducing fat, which is significant since body fat can produce and store estrogen.  [22.]

Probiotics and Gut Health: a healthy gut flora supports proper digestion and detoxification processes, including the breakdown, elimination and balance of hormones like estrogen.  [14.]

Limit Alcohol and Caffeine: reducing intake of substances that can impair liver function helps ensure the liver effectively processes and removes excess hormones.  [7., 21.]

Stress Management: stress may have an impact on estrogen levels and metabolism; techniques such as yoga, meditation, or even simple breathing exercises can reduce cortisol levels and help maintain a healthy hormonal balance.  [2.]

Order 2-MeO-E1/2-OH-E1 Ratio Testing

Click here to explore testing options and order testing for 2-MeO-E1/2-OH-E1 Ratio.