Estrogen Metabolism Pathway And The 3 Primary Estrogen Metabolites

Estrogen Metabolism Pathway

Estrogen metabolism pathway: there are three pathways and I label them as the good, bad, and ugly.

Previously, I mentioned the 3 primary estrogens: estradiol, estrone, and estriol. That is the simple. The complex is that there are many more estrogens that are actually produced by the body through the process of estrogen metabolism—estrogen metabolites.

Estrogen metabolites have been shown to have different effects on cancer risk. This difference in risk is the result of an interplay between an individuals genetics and their environment. The vast majority of the research on estrogen metabolism is with cancer. The majority of the research on estrogen metabolism with cancer is with breast cancer.

When it comes to estrogen metabolism and cancer there are 3 primary estrogen metabolism pathways to highlight.  I call them the good, the bad and the ugly. There are 3 primary estrogen metabolites from these 3 pathways: 2-hydroxy estrone (2OH-estrone), 4-hydroxy estrone (4OH-estrone), and 16alpha-hydroxy estrone (16alphaOH-estrone).

The origin estrogens for these 3 metabolites are primarily Estradiol (the most potent estrogen) and Estrone (the second most potent estrogen). Estriol, the weakest estrogen, can be converted to the 16alpha-OH-estrone metabolite, but not to the 2OH-estrone or 4OH-estrone metabolites. Additional estrogen metabolites include:

  • 2-OH Estradiol
  • 4-OH Estradiol
  • 16alpha-OH Estradiol
  • 2-methoxy Estrone
  • 2-methoxy Estradiol
  • 16-epi Estriol
  • 17-epi Estriol
  • 16-keto Estradiol

For the purpose of the brevity of this blog post, I will stick to a brief discussion of these 3 primary estrogen metabolites.

Dr. Nathan Goodyear Explains The 3 Primary Estrogen Metabolism Pathways

2OH-Estrone Metabolite

The 2OH-estrone metabolite is the safest estrogen metabolite.  The better descriptive term to describe the 2OH-estrone metabolite is “safest” or “lowest risk” and that may too be overly simplistic. The 2OH-estrone metabolite is the most prevalent estrogen metabolite circulating in the blood [63].

Research points to the 2OH-estrone metabolite as the byproduct of the CYP1A1, CYP1A2, and CYP1B1 detoxification enzymes [64] [65] though studies do suggest that CYP1A1 is the primary enzyme involved in the production of the 2OH-estrone metabolite [66] [67] [68]. This “good” term for the 2OH-estrone metabolite is also an oversimplification of the scientific evidence on this estrogen metabolite as some more recent evidence points to an increased breast cancer risk with the 2-hydroxyestrone metabolite.

There are several mechanisms that support 2OH-estrone metabolite as the safest estrogen metabolite.  First, all of the estrogen metabolites are particularly unstable compounds.  The 2OH-estrone metabolite is the most stable of the 3 estrogen metabolites discussed [69] which translates to less potential DNA damage.

It is DNA damage that is critical in carcinogenesis. Second, the 2OH-estrone metabolite elicits a very weak, almost anti-estrogenic activity [70] [71].  Low binding affinity for the estrogen receptor and increased removal from the estrogen receptor are the primary reasons for the weak estrogenic activity of the 2OH-estrone metabolite. This estrogenic activity is the weakest of the 3 estrogen metabolites.

Third, though weak as indicated above, the 2OH-estrone metabolite is easily methylated and thus inactivated. Last, the 2OH-estrone metabolite lacks significant anti-apoptosis activity [72] which maintains a strong anti-growth potential check through the active process of apoptosis (programmed cell death).

4OH-Estrone Metabolite

The bad estrogen or what I call the “ugly” estrogen metabolite is the 4OH-estrone metabolite.  The overwhelming evidence points to the 4OH-estrone metabolite as pro-carcinogenic and pro-growth.

There are several reasons why the 4OH-estrone metabolite is the most dangerous estrogen metabolite. First, the 4OH-estrone metabolite is the most unstable of the estrogen metabolites and it is this instability that can lead to DNA damage which is important in carcinogenesis. Second, of the 3 metabolites, the 4OH-estrone metabolite elicits the strongest estrogenic activity via its high affinity and tight binding to the estrogen receptor and lower disassociation rate from the estrogen receptor.

Third, in contrast to the 2OH-estrone metabolite, the 4OH-estrone metabolite is not easily deactivated through methylation. Last, the 4OH-estrone metabolite has a significant anti-apoptotic effect which favors such cancer cell survival.   All this at an estimated 15-25% less circulating volume than the 2OH-estrone metabolite.

16alphaOH-Estrone Metabolite

The 16alphaOH-estrone metabolite has been historically labeled as a “bad” estrogen. This pathway of estrogen metabolism, as a whole, is the dominant pathway of estrogen metabolism 16.  The proposed high cancer risk of the 16alphaOH-estrone metabolite is due to its increased estrogen signaling and growth capacity through its tight binding to the estrogen receptor.  In addition, it is not easily removed leaving the metabolite tightly bound to the estrogen receptor resulting in a prolonged growth signal.

In addition, the 16alphaOH-estrone metabolite does not down-regulate the estrogen receptor, which is a key mechanism by which cells can turn down the potential signal. Finally, 16alphaOH-estrone metabolite has a strong anti-apoptotic effect [73]. The jury is out on the “bad” label for this metabolite. The 16alpha-OH-estrone metabolite has a strong positive link to breast cancer in post-menopause women [74] yet, other studies have found no link between 16alpha-OH-estrone and cancer risk [75] [76].

The implication is that it may not only be the estrogen levels or the estrogen receptors that are involved in cancer risk, but it is, in fact, what the body is doing with the estrogens through estrogen metabolism that also poises the cancer risk.

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[73] Seeger H et al.  Comparison of possible carcinogenic estradiol metabolites: effects on proliferation, apoptosis, and metastasis of human breast cancer cells. Maturitas. 2006 Apr;54(1):72-7.

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[76] Arslan AA et al. Circulating estrogen metabolites and risk for breast cancer in premenopausal women. Cancer Epidemiol Biomarkers Prev. 2009 Aug;18(8):2273-9.

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