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2-OH-E2
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2-Hydroxyestradiol

2-Hydroxyestradiol (2-OH estradiol) is an estrogen metabolite with a multifaceted role in human health.  2-OH estradiol has significant biological activities and its implications in various physiological processes and disease states.

While 2-OH estradiol is considered a less active estrogen than its parent compound, estradiol, it is still important in the overall balance of estrogenic effects in the body.

Assessing 2-OH estradiol levels can illustrate how the body processes and detoxifies estrogens.  Such testing can aid understanding of conditions linked to estrogen metabolism such as certain cancers, estrogen dominance, and other hormonal imbalances.

This article explores the production, metabolic pathways, and the clinical significance of levels of 2-OH estradiol, alongside discussing natural approaches to maintaining hormonal balance effectively.

What is 2-OH-E2 (2-Hydroxyestradiol)?  [8., 12., 18., 19.]

2-Hydroxyestradiol (2-OH-E2 or 2-OH estradiol) is a metabolite of the hormone estradiol, and belongs to the class of compounds known as catechol estrogens. 

This metabolite arises from the hydroxylation of estradiol at the 2nd carbon of the A-ring, a transformation catalyzed by enzymes such as CYP1A2 and CYP3A4. This conversion occurs in several body tissues, including the liver, uterus, breast, and brain. 

Structurally, 2-OH estradiol retains a similar framework to its parent hormone but includes an additional hydroxyl group which modifies its activity at estrogen receptors. This modification significantly diminishes its affinity compared to estradiol, impacting its estrogenic potency and interaction with cellular pathways.

Metabolically, 2-OH estradiol is less active than estradiol, interacting weakly with estrogen receptors and showing a limited ability to stimulate estrogen-dependent processes. However, it plays a critical role in the body's handling of estrogens, influencing various physiological responses and potentially contributing to disease mechanisms when its metabolism is altered.

2-OH estradiol also interacts with catecholamine systems, influencing enzymes like catechol-O-methyltransferase and tyrosine hydroxylase, which are involved in the metabolism of catecholamines. 

Furthermore, 2-OH estradiol can be further metabolized to 2-methoxyestradiol, a molecule with significant antiproliferative properties in vascular and renal tissues, suggesting a role in cardiorenal protection.  [19.]

2-OH Estradiol: Functions and Physiological Roles

Overview of Functions of Estrogens  [6., 17.]

Estrogens play critical roles in various physiological processes including regulating reproductive function and the menstrual cycle, bone health, cardiovascular function, and cognitive function and mood.  

Additionally, estrogen signaling influences lipid metabolism, glucose homeostasis, and immune function.  

Estrogen also affects skin elasticity, hair growth, body weight, and fat distribution, while contributing to sexual health by enhancing vaginal wall thickness and lubrication. Additionally, estrogen is crucial for breast development during puberty and preparing for lactation.

Overview of Estradiol

Estradiol, a primary form of estrogen, is predominantly synthesized in the ovaries' granulosa cells during the follicular phase of the menstrual cycle, mainly through the conversion of androgens like testosterone via the enzyme aromatase. The enzyme 17-beta-hydroxysteroid dehydrogenase, which converts estrone to estradiol, also participates in estradiol production. 

Estradiol is also produced in peripheral tissues such as adipose tissue, adrenal glands, and in the placenta during pregnancy.  In men, smaller amounts of estradiol are synthesized in the testes and adrenal glands through the conversion of testosterone.

As the primary active form of estrogen in the human body, estradiol serves numerous vital physiological roles. It stimulates the development and maintenance of female reproductive tissues such as the uterus, fallopian tubes, and vagina, and also promotes the growth and maturation of ovarian follicles. 

Estradiol is crucial in regulating the menstrual cycle, influencing both the proliferation and shedding of the endometrial lining. 

It supports bone health by inhibiting bone resorption and promoting bone formation, and maintains cardiovascular health by regulating lipid metabolism and vascular function. 

Additionally, estradiol affects mood and cognition, with its receptors found in brain regions linked to emotion and memory. 

It contributes to the health of skin and hair by promoting collagen production and regulating sebum production. Estradiol also plays a role in the integrity of pelvic floor muscles, thereby supporting urinary tract function and preventing incontinence. 

It influences metabolism and body composition, with receptors present in adipose tissue and skeletal muscle, and impacts immune function by modulating inflammatory responses and interacting with immune cells.

Health Risks of Excessive Estradiol Exposure  [7.]

Excessive estradiol exposure is considered dangerous due to its stimulating and proliferative nature.  

Excessive exposure to estradiol, particularly through hormone replacement therapy (HRT), can lead to several negative health consequences. 

These include an increased risk of cardiovascular issues such as edema, hypertension, and thrombophlebitis. It can also lead to serious conditions like retinal thrombosis, cerebrovascular events, coronary artery disease, and venous thromboembolism. 

Furthermore, estradiol therapy has been linked to an elevated risk of certain cancers including breast cancer, and endometrial cancer.

Other potential adverse effects include liver issues and a variety of allergic reactions like anaphylaxis and angioedema. Additionally, estradiol can exacerbate conditions like asthma and cause various skin and gastrointestinal issues. 

Given these risks, estradiol therapy is contraindicated for women with a history of certain cancers, blood clotting disorders, cardiovascular diseases, and those who are overweight due to higher baseline estrogen levels in adipose tissue.

Estrogens and Their Interactions with Receptors  [6.]

The actions of estrogens in the body are influenced by the specific structure of each estrogen molecule, the type of estrogen receptor it binds to, and the cell to which the receptor is attached. 

Estrogens exert their effects by binding to estrogen receptors, which are part of the nuclear hormone receptor superfamily. These receptors exist mainly in two forms, estrogen receptor alpha (ERα) and estrogen receptor beta (ERβ), each encoded by different genes and varying structurally, particularly in their ligand-binding domains. 

This difference in structure affects their affinity for various ligands; for instance, some estrogens and phytoestrogens preferentially bind ERβ, whereas others have a higher affinity for ERα.

Once bound to an estrogen, the receptor undergoes a conformational change, allowing it to dissociate from chaperone proteins and move into the nucleus where it binds to DNA at sites known as estrogen-response elements.  

This binding can either activate or repress the transcription of target genes depending on the presence of coactivators or corepressors in the complex. 

The distribution of estrogen receptors varies across different tissues, which partly explains the tissue-specific effects of estrogen. For example, ERα is predominantly found in reproductive tissues like the endometrium, while ERβ is more common in non-reproductive tissues such as bone and brain. 

This selective expression and the unique interaction of estrogens with their receptors underpin the diverse physiological roles of estrogens, from reproductive functions to their roles in bone density and cardiovascular health.

2-Hydroxyestradiol’s Role in the Human Body

LIke 2-hydroxyestrone, 2-hydroxyestradiol is typically considered a safer estrogen metabolite than the 4-hydroxy metabolites.  

2-OH-E2 and Brain Health  [16.]

2-Hydroxy-estradiol (2-OH-E2), a catechol estrogen, has been identified for its significant neuroprotective effects compared to 17-β-estradiol (E2), particularly after exposure to oxidative stressors like hydrogen peroxide in neural cell models. 

It offers enhanced protection by effectively reducing lipid peroxidation, a key factor in cell damage, through mechanisms that do not solely rely on classical estrogen receptors.

This metabolite of estradiol suggests a broader physiological role, especially in the context of neurological and psychiatric disorders where oxidative stress plays a critical role in disease pathogenesis.

2-OH-E2 and Breast Cancer

In contrast to other estrogen metabolites that might promote tumorigenesis, 2-OH E2 is generally considered to have protective effects against breast cancer.  [9.]

By binding weakly to estrogen receptors, 2-OH-E2 may reduce estrogen's proliferative effects on breast tissue. Moreover, 2-OH E2 is involved in the inhibition of rapid cell proliferation and may facilitate the induction of apoptosis in malignant cells. 

One study of Chinese women found that postmenopausal breast cancer patients had lower levels of certain estrogen metabolites such as 2-hydroxyestradiol (2-OHE2) compared to controls.  [9.] 

For premenopausal women, 2-OHE2 levels differed significantly between those with breast cancer and benign conditions, suggesting a potential role of 2-OHE2 as a predictive biomarker for breast cancer.   [9.] 

Additionally, higher levels of 2-OHE2 were associated with hormone receptor-positive status in premenopausal breast cancer patients.  [9.] 

While this study is relatively small (84 breast cancer patients and 47 controls), it may point to an association between 2-OH levels and breast cancer, highlighting a new potential risk factor. 

2-OH-E2 and Endometrial Cancer

Endometrial cancer, the most common gynecological malignancy in developed countries, highlights the necessity of early detection for effective treatment and the potential to avoid radical therapies. 

Estradiol metabolites, particularly those involved in oxidative stress pathways, such as 2-hydroxyestradiol (2-OH-E2), play dual roles in both promoting and preventing carcinogenesis. [3.]

These metabolites can cause oxidative DNA damage leading to cancerous changes but also have potential anticarcinogenic effects by inducing cancer cell cycle arrest or death through nitro-oxidative stress.  [3.]

2-OH-E2 and Cardiovascular Health  [11.]

2-OH-E2 may have a protective effect on cardiovascular health.  

Its action includes promoting endothelial function by enhancing the release of nitric oxide (NO), which induces vasodilation and improves blood flow.  2-OH E2 also inhibits vascular smooth muscle cell proliferation, reducing the risk of atherosclerosis. 

Furthermore, this metabolite acts as an antioxidant, helping to mitigate oxidative stress within vascular cells, which is crucial in preventing the progression of cardiovascular diseases.  

These mechanisms highlight 2-OH E2's potential as a beneficial factor in cardiovascular health, emphasizing its importance in the metabolism of estrogens and their impact on vascular function.

Laboratory Testing for 2-Hydroxyestradiol

Overview of Testing, Sample Collection and Preparation

Urine samples are commonly used for 2-Hydroxyestradiol testing.  

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-OH-E2 Test Results

Reference Range for 2-OH-E2

It is important to consult with the lab company providing testing for 2-OH estradiol levels.  For reference, one lab provides the following reference range for urine 2-OH estradiol levels:  [13.]

For cycling women in the luteal phase: 0-1.2 ng/mg

For postmenopausal women not supplementing with hormones: 0-0.3 ng/mg

Optimal Levels of 2-Hydroxyestradiol

Hormones never act alone, and their effects are nuanced.  Optimal levels of 2-hydroxyestradiol in urine tests vary depending on individual health conditions, gender, and age.   The 2-hydroxy detoxification pathway is generally considered the preferred estrogen detoxification pathway.

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% utilize the 4-OH pathway.  [13.]

Health professionals often recommend that women remain within the reference range of 0-1.2 ng/mg in urine samples for cycling women, or 0-0.3 ng/mg in urine samples for postmenopausal women.  

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.

2-OH-E2 Related Biomarkers to Test

In addition to 2-OH-E2, several related biomarkers play crucial roles in estrogen metabolism and hormonal balance.  Understanding these biomarkers and their interactions can provide a more comprehensive assessment of hormonal health and metabolic status.

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 (E2), often referred to as the primary estrogen, is the precursor for 2-OH-E2 and other estrogen metabolites. It plays essential roles in reproductive health, bone metabolism, and cardiovascular function. 

Measuring estradiol levels provides insights into overall estrogen production and ovarian function. In combination with 2-OH-E2, estradiol levels can help assess estrogen metabolism and balance.

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.

16α-Hydroxyestrone (16α-OH-E1)

16α-Hydroxyestrone (16α-OH-E1) is another estrogen metabolite formed through hydroxylation at the 16α position of estrone.  Higher levels of 16α-OH-E1 have been associated with increased estrogenic activity and cancer risk, particularly in hormone-sensitive tissues such as the breast and uterus.  

4-Hydroxyestrone (4-OH-E1)

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.

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.  [5.]  

Interestingly, one study of 240 women also showed a correlation between increased fiber intake and anovulation, possibly due to lower estrogen levels.  [5.]

Cruciferous Vegetables: foods like broccoli, cauliflower, and Brussels sprouts contain indole-3-carbinol, which aids in detoxifying excessive estrogen and optimizing hormone balance.  [2.] 

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.  [15.]

Probiotics and Gut Health: a healthy gut flora supports proper digestion and detoxification processes, including the breakdown, elimination and balance of hormones like estrogen.  [10.]

Limit Alcohol and Caffeine: reducing intake of substances that can impair liver function helps ensure the liver effectively processes and removes excess hormones.  [4., 14.]

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.  [1.]

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What's 
2-OH-E2
?
2-Hydroxyestradiol, often abbreviated as 2-OH-E2, is a naturally occurring hormone in your body. It's a type of estrogen, which is a group of hormones that play a vital role in the development and regulation of the female reproductive system. But don't be fooled, 2-OH-E2 isn't just for women - men have it too, just in smaller amounts. What makes 2-OH-E2 special is that it's a 'metabolite' of estradiol, the most potent form of estrogen. This means that your body creates 2-OH-E2 when it breaks down estradiol. This process happens in your liver, and it's part of your body's way of managing and balancing your hormone levels. 2-OH-E2 is also a bit of a superhero when it comes to protecting your body. It has antioxidant properties, which means it helps to protect your cells from damage. It's like a tiny, invisible shield that helps keep your body healthy and functioning properly.
If Your Levels Are High
High levels of 2-Hydroxyestradiol, or 2-OH-E2, could indicate that your body is metabolizing estradiol at an increased rate. This could be due to a variety of factors, such as genetic predispositions, lifestyle choices, or even certain medications. For instance, medications like oral contraceptives or hormone replacement therapies, which contain synthetic forms of estrogen, could potentially increase the levels of 2-OH-E2 in your body. Additionally, certain health conditions, such as liver disease, could also affect the rate at which your body metabolizes estradiol, leading to elevated levels of 2-OH-E2. It's important to note that while 2-OH-E2 has protective antioxidant properties, an imbalance in hormone levels could potentially disrupt normal bodily functions.
Symptoms of High Levels
Symptoms of high levels of 2-Hydroxyestradiol could potentially include hormonal imbalances, which may manifest as irregular menstrual cycles in women, mood swings, or unexplained weight gain. However, it's also possible to have elevated levels of 2-OH-E2 without experiencing any noticeable symptoms.
If Your Levels are Low
Low levels of 2-Hydroxyestradiol, or 2-OH-E2, could mean that your body isn't breaking down estradiol, a powerful estrogen hormone, as effectively as it should be. This can happen for a variety of reasons, such as liver problems, since that's where this process takes place. Certain medications, like those for high blood pressure or cholesterol, can also interfere with how well your body metabolizes hormones. Additionally, conditions like obesity or metabolic syndrome can affect hormone balance. Low 2-OH-E2 levels might also mean your body's natural defenses are weaker, since this hormone has antioxidant properties that help protect your cells from damage.
Symptoms of Low Levels
Symptoms of low levels of 2-Hydroxyestradiol may not be easily noticeable, as they can be quite subtle and vary greatly from person to person. However, some individuals might experience hormonal imbalance symptoms such as fatigue, mood swings, or irregular menstrual cycles in women.

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See References

[1.] Assad S, Khan HH, Ghazanfar H, Khan ZH, Mansoor S, Rahman MA, Khan GH, Zafar B, Tariq U, Malik SA. Role of Sex Hormone Levels and Psychological Stress in the Pathogenesis of Autoimmune Diseases. Cureus. 2017 Jun 5;9(6):e1315. doi: 10.7759/cureus.1315. PMID: 28690949; PMCID: PMC5498122. 

[2.] Auborn KJ, Fan S, Rosen EM, et al. Indole-3-Carbinol Is a Negative Regulator of Estrogen. The Journal of Nutrition. 2003;133(7):2470S2475S. doi:https://doi.org/10.1093/jn/133.7.2470s 

[3.] Bukato, K., Kostrzewa, T., Gammazza, A.M. et al. Endogenous estrogen metabolites as oxidative stress mediators and endometrial cancer biomarkers. Cell Commun Signal 22, 205 (2024). https://doi.org/10.1186/s12964-024-01583-0 

[4.] Emanuele MA, Wezeman F, Emanuele NV. Alcohol's effects on female reproductive function. Alcohol Res Health. 2002;26(4):274-81. PMID: 12875037; PMCID: PMC6676690. 

[5.] Gaskins AJ, Mumford SL, Zhang C, et al. Effect of daily fiber intake on reproductive function: the BioCycle Study. The American Journal of Clinical Nutrition. 2009;90(4):1061-1069. doi:https://doi.org/10.3945/ajcn.2009.27990 

[6.] Gruber CJ, Tschugguel W, Schneeberger C, Huber JC. Production and Actions of Estrogens. New England Journal of Medicine. 2002;346(5):340-352. doi:https://doi.org/10.1056/nejmra000471 

[7.] Hariri L, Rehman A. Estradiol. [Updated 2023 Jun 28]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2024 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK549797/ 

[8.] Human Metabolome Database: Showing metabocard for 2-Hydroxyestradiol (HMDB0000338). hmdb.ca. Accessed April 29, 2024. https://hmdb.ca/metabolites/HMDB0000338 

[9.] Li X, Fang L, Li H, Yang X. Urinary estrogen metabolites and breast cancer risk in Chinese population. Endocr Connect. 2021 Dec 14;10(12):1615-1622. doi: 10.1530/EC-21-0226. PMID: 34812737; PMCID: PMC8679875. 

[10.] Maeng LY, Beumer A. Never fear, the gut bacteria are here: Estrogen and gut microbiome-brain axis interactions in fear extinction. International Journal of Psychophysiology. 2023;189:66-75. doi:https://doi.org/10.1016/j.ijpsycho.2023.05.350 

[11.] Masood DE, Roach EC, Beauregard KG, Khalil RA. Impact of sex hormone metabolism on the vascular effects of menopausal hormone therapy in cardiovascular disease. Curr Drug Metab. 2010 Oct;11(8):693-714. doi: 10.2174/138920010794233477. PMID: 21189141; PMCID: PMC3063102. 

[12.] PubChem. 2-Hydroxyestradiol. pubchem.ncbi.nlm.nih.gov. Accessed April 29, 2024. https://pubchem.ncbi.nlm.nih.gov/compound/2-Hydroxyestradiol

[13.] RUPA DUTCH Complete M+F Sample Report.pdf. Google Docs. Accessed April 27, 2024. https://drive.google.com/file/d/1-qmxwjo6B2TVYlgCS-FlcyF8FuqRdZEe/view 

[14.] Sisti JS, Hankinson SE, Caporaso NE, Gu F, Tamimi RM, Rosner B, Xu X, Ziegler R, Eliassen AH. Caffeine, coffee, and tea intake and urinary estrogens and estrogen metabolites in premenopausal women. Cancer Epidemiol Biomarkers Prev. 2015 Aug;24(8):1174-83. doi: 10.1158/1055-9965.EPI-15-0246. Epub 2015 Jun 10. PMID: 26063478; PMCID: PMC4526325. 

[15.] Smith AJ, Phipps WR, Thomas W, Schmitz KH, Kurzer MS. The effects of aerobic exercise on estrogen metabolism in healthy premenopausal women. Cancer Epidemiol Biomarkers Prev. 2013 May;22(5):756-64. doi: 10.1158/1055-9965.EPI-12-1325. PMID: 23652373; PMCID: PMC3648856.

[16.] Teepker M, Anthes N, Krieg JC, Vedder H. 2-OH-estradiol, an endogenous hormone with neuroprotective functions. Journal of Psychiatric Research. 2003;37(6):517-523. doi:https://doi.org/10.1016/s0022-3956(03)00068-2

[17.] The Journal of Clinical Endocrinology & Metabolism. What Does Estrogen Do? The Journal of Clinical Endocrinology & Metabolism. 2014;99(4):31A32A. doi:https://doi.org/10.1210/jc.2014-v99i4-31a 

[18.] Wittliff JL, Andres SA. Estrogens II. Elsevier eBooks. Published online January 1, 2014:467-470. doi:https://doi.org/10.1016/b978-0-12-386454-3.01015-0

[19.] Zacharia LC, Dubey RK, Mi Z, Jackson EK. Methylation of 2-Hydroxyestradiol in Isolated Organs. Hypertension. 2003;42(1):82-87. doi:https://doi.org/10.1161/01.hyp.0000074702.06466.27 

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