4-OH-E1, or 4-hydroxyestrone, is one of three routes your body can take when it breaks estrone down in the first phase of estrogen detoxification. It is the route you want the smallest share of your estrogen travelling down, because 4-OH-E1 can damage DNA and drive inflammation.
If your results came back high, that is common and it responds well to the right support. Your practitioner can shift more of your estrogen onto the safer 2-OH-E1 pathway through diet and targeted supplements.
If you have not tested yet, 4-OH-E1 is measured in all three FUTURE WOMAN tests.
Let’s take a closer look at what 4-OH-E1 is, why elevated levels matter, and how they can impact your health.
What is 4-OH-E1?
4-OH-E1, or 4-hydroxyestrone, is a metabolite of estrogen. Estrogen is converted into three primary forms: estrone (E1), estradiol (E2), and estriol (E3), through the action of CYP enzymes. During Phase 1 estrogen detoxification, estrone (E1) is metabolised into 2-hydroxyestrone (2-OH-E1), 4-hydroxyestrone (4-OH-E1), or 16- hydroxyestrone (16-OH-E1) via distinct biochemical pathways.
- 2-OH-E1: Generally recognised as the safer metabolite. It weakly stimulates cell proliferation and may even inhibit it.
- 4-OH-E1: This metabolite can damage DNA and is linked to increased inflammation.
- 16-OH-E1: Binds to estrogen receptors with greater strength than other metabolites, making it more proliferative, pro-inflammatory, and angiogenic (encouraging new blood vessel growth).
4-OH-E1 metabolites can be formed in the liver, breasts and uterus. They have the strongest bond to the estrogen receptor and it takes a lot more energy to break off the 4-OH-E1 metabolites for detoxification than the other metabolites. Measuring 4-OH-E1 alongside 16-OH-E1 and 2-OH-E1 can help assess the overall estrogenic and carcinogenic potential within the body.
Why Are High Levels of 4-OH-E1 Significant?
4-OH-E1 is unstable and known for its potential to form quinones that can bind to DNA, causing DNA damage and generating reactive oxygen species, increasing the risk of mutations, potentially contributing to carcinogenesis.
Elevated levels of 4-OH-E1 have been linked to several health concerns, including:
- Increased circulating inflammation linked to increased hormonal symptoms, brain fog, and development of disease.
- Lung cancer: Higher 4-OH-E1 metabolites have been seen in patients with lung cancer.
- Breast cancer: 4-OH-E1 metabolites have been shown to be increased in women with breast cancer. In one study, the 4-OH-E1 metabolite was found to be significantly increased in the urine samples of patients with breast cancer compared with the normal healthy controls and was shown to be the most important risk factor for breast cancer.
4-OH-E1 metabolites should never be assessed in isolation. Understanding your 4-OH-E1 metabolites alongside other markers for inflammation and oxidative stress is key to determine the impact this has been having inside the body.
Which pathway your body favours matters more when there is more estrogen to clear, so if you are in perimenopause, when estrogen fluctuates up and down, our guide to the perimenopause hormone test covers what to test and when.
Symptoms of High and Low 4-OH-E1 Levels
The luteal phase range for 4-OH-E1 is 0-1.8 ng/mg and the post menopausal range is 0-1.3 ng/mg.
4-OH-E1 are also reported as a percentage of all 3 Phase I metabolites. The expected and preferred percentages in women are;
- 2-OH-E1 60-80%
- 4-OH-E1 7.5-11%
- 16-OH-E1 13-30%
High 4-OH-E1 Levels :
Elevated 4-OH-E1 can lead to symptoms of high estrogen, including:
- Breast tenderness
- Bloating
- Mood swings
- Heavy periods
- Weight gain
In postmenopausal women receiving HRT, elevated levels of 4-OH E1 may indicate an excessive amount of hormone therapy, which is then increasing production of 4-OH-E1 which can worsen symptoms such as:
- Breast pain
- Heavy bleeding
- Night sweats
- Hot flushes
The good news is that your practitioner through diet and supplementation can support 4-OH-E1 moving over to the preferred 2-OH-E1 pathway.
Low 4-OH-E1 Levels:
While low levels of 4-OH-E1 are optimal, they can result in symptoms of low estrogen, if total estrogen levels are low. Symptoms include:
- Vaginal dryness
- Hot flashes
- Decreased libido
Low estrogen levels may also negatively affect bone health so a comprehensive interpretation of 4-OH-E1 levels requires evaluating them alongside other estrogen metabolites and detoxification pathways.
Which tests measure 4-OH-E1?
4-OH-E1 is measured in all three of our tests: the Classic Hormone Test, the Advanced Hormone Test and the Advanced+ Hormone Test with Cycle Mapping.
If you are not sure which test you need, our comparison guide walks through the differences.
Next steps
If your results suggest high 4-OH-E1 levels, this will be addressed in your personalised health plan by one of our experienced nutritionists. If you would like to learn more about your test results, remember you can purchase a 45 minute Hormone Health Consultation with your practitioner to discuss your results in more detail.
References:
Miao, S., Yang, F., Wang, Y., Shao, C., Zava, D. T., Ding, Q., & Shi, Y. E. (2019). 4-Hydroxy estrogen metabolite, causing genomic instability by attenuating the function of spindle-assembly checkpoint, can serve as a biomarker for breast cancer. American journal of translational research, 11(8), 4992–5007.
Parl, F. F., Dawling, S., Roodi, N., & Crooke, P. S. (2009). Estrogen metabolism and breast cancer: a risk model. Annals of the New York Academy of Sciences, 1155, 68–75. https://doi.org/10.1111/j.1749-6632.2008.03676.x
Peng, J., Meireles, S. I., Xu, X., Smith, W. E., Slifker, M. J., Riel, S. L., Zhai, S., Zhang, G., Ma, X., Kurzer, M. S., Ma, G. X., & Clapper, M. L. (2017). Estrogen metabolism in the human lung: impact of tumorigenesis, smoke, sex and race/ethnicity. Oncotarget, 8(63), 106778–106789. https://doi.org/10.18632/oncotarget.22269
Zhu, B. T., Han, G. Z., Shim, J. Y., Wen, Y., & Jiang, X. R. (2006). Quantitative structure-activity relationship of various endogenous estrogen metabolites for human estrogen receptor alpha and beta subtypes: Insights into the structural determinants favoring a differential subtype binding. Endocrinology, 147(9), 4132–4150. https://doi.org/10.1210/en.2006-0113
Ziegler, R. G., Fuhrman, B. J., Moore, S. C., & Matthews, C. E. (2015). Epidemiologic studies of estrogen metabolism and breast cancer. Steroids, 99(Pt A), 67–75.
