Understanding Estrogen Metabolism

by | Aug 1, 2020

estrogen metabolism pathway

Estrogen is a group of hormones that plays an important role in reproductive health and fertility. Our hormones need to work together like a well-calibrated machine. While having adequate estrogen is important, too much estrogen can cause issues, such as increasing your risk for breast or endometrial cancer.1

Our total estrogen exposure is not only determined by the production of the estrogens, but also by the breakdown into their different metabolites. Estrogen is broken-down mostly in the liver, and to some extent in the gut, allowing the inactivated metabolites to be excreted.

Yet the breakdown and excretion of estrogens is complicated and influenced by multiple factors. Sometimes the detoxification process produces an excess of “strong” metabolites, which have a more pronounced estrogen effect. When investigating hormonal imbalances, and conditions that are affected by estrogen, it’s important to consider hormone metabolism as a piece of the puzzle.

Watch this summary of estrogen metabolism in the liver:


Estrogen and the Metabolites

Estrogen is produced in the adrenal glands and fat tissue, as well as the ovaries in women and the testes in men. In women and people who menstruate, there are three different types of estrogen 2:

  • Estrone (E1): Is considered to be a weak estrogen. It is produced mostly in body fat, but also in the placenta and ovaries.
  • Estradiol (E2): This is the most potent and active of the estrogens. It is made in the ovaries, and in lesser amounts from DHEA/testosterone. It binds very strongly to estrogen receptors, and is the main estrogen involved in the menstrual cycle.
  • Estriol (E3): Estradiol can be converted to estriol, predominantly in the liver. Estriol is a weak estrogen. It is the main estrogen of pregnancy, and is secreted by the placenta.


Estrogen is metabolized in the liver through three pathways into 2-hydroxyl, 4-hydroxyl and 16-hydroxyl estrogen. This is known as phase I of estrogen metabolism. The 2-hydroxyl metabolite pathway is considered the best, as it creates a weak metabolite. The other two pathways, the 4-hydroxyl and 16-hydroxyl metabolite pathway, produce more potent estrogenic metabolites. The 4-hydroxyl metabolite, in particular, is associated with a higher risk of breast and endometrial cancer. 1,3

Phase II of estrogen metabolism involves turning the estrogens into water-soluble compounds that can easily be excreted in the urine or gut. 4 It’s important that both Phase I and II are supported when addressing hormone metabolism.

In which patients do I investigate estrogen metabolism?

  • Any premenopausal patients with risk factors for breast or endometrial cancer
  • People demonstrating symptoms of elevated estrogen (i.e. endometriosis, fibroids), or what’s commonly referred to as “estrogen dominance” symptoms
  • People taking hormone replacement therapy (estrogen) and are concerned about estrogen exposure

How do we measure hormone metabolism?

The most accurate way to assess hormone metabolites is to measure them in the urine. In clinical practice I use the DUTCH test  to measure the hormones and their metabolites. This allows me to assess whether someone is producing too much of the 4-hydroxyl and 16-hydroxyl metabolites compared to the 2-hydroxyl metabolite. It gives us insight into both Phase I and Phase II of estrogen detoxification.

Having this data allow us to be specific with treatment and how we target hormone metabolism. We can help to augment or reduce certain metabolite pathways through diet, lifestyle and supplementation.

For more information regarding hormone metabolism, check out the following articles and resources:

    1. 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), 4992.1.
    2. Speroff, L., & Fritz, M. A. (Eds.). (2005). Clinical gynecologic endocrinology and infertility. lippincott Williams & wilkins.
    3. Samavat, H., & Kurzer, M. S. (2015). Estrogen metabolism and breast cancer. Cancer letters, 356(2), 231-243.
    4. Raftogianis, R., Creveling, C., Weinshilboum, R., & Weisz, J. (2000). Estrogen metabolism by conjugation. JNCI Monographs, 2000(27), 113-124.
    5. Thomson, C. A., Chow, S. H. H., Roe, D., Wertheim, B., Chalasani, P., Altbach, M., … & Maskaranic, G. (2017). Effect of Diindolylmethane on Estrogen-related Hormones, Metabolites and Tamoxifen Metabolism: Results of a Randomized, Placebo-controlled Trial. Cancer Epidemiology and Prevention Biomarkers, 26(3), 435-435.