“The whole is greater than the sum of its parts.”
The good, the bad, the ugly. Estrogen metabolites are the Clint Eastwood of hormone metabolites. That is the way Hollywood would market estrogen metabolites if they were slated for a prime time Hollywood production. Unfortunately, that is also the way most medical press presents it. Estrogen is the beginning and the end of the story. Estrogen alone is active. Estrogen metabolites are inactive compounds targeted for elimination only. This is the story line followed by most in the medical community. Is this sound science? Is this simply a Hollywood mirage repeated over and over by physicians in hopes that truth will present itself through repetition or does the real science of estrogen metabolites tell a different story?
No opinion, just science.
The first estrogen metabolite to discuss is the 2OH-estrone metabolite. The 2OH-estrone metabolite is the product of the CYP1A1, CYP1A2, and CYP1B1 detoxification enzymes. Studies suggest that CYP1A1 is the primary enzyme involved in the production of the 2OH-estrone metabolite . The cytochrome P450 (CYP450) enzymes play a prominent role in phase 1 of detoxification. Contrary to marketing fluff and “detox in a box” kits, detoxification pathways are real, can be evaluated, and can provide real benefit or danger in an individual’s Wellness or Disease journey. Historical evidence points to the 2OH-estrone metabolite as perhaps, the safest estrogen metabolite. Recent evidence does nothing to change this label.
How? By what mechanism is the 2OH-estrone metabolite the safest estrogen metabolite?
There are 6 proposed mechanisms, supported by science, through which the 2OH-estrone has earned the title–the “good” estrogen.
- the 2OH-estrone metabolite, compared to the other estrogen metabolites, causes the least DNA damage
- The 2OH-estrone metabolite has the weakest estrogenic effect; some studies show no estrogenic effect
- The 2OH-estrone metabolite, compared to the other estrogen metabolites, has the lowest affinity for the estrogen receptors
- The 2OH-estrone metabolite is easily removed from the estrogen receptor; removal from the receptor leads to the potential end of estrogen signaling
- The 2OH-estrone metabolite is deactivated by methylation
- The 2OH-estrone metabolite does not inhibit programed cell death of abnormal cells
This “good” term for the 2OH-estrone metabolite is an old and over simplification of the scientific evidence on the estrogen metabolite. Despite the fact that the majority of research points to a reduction in risk associated with the 2OH-estrone metabolite, the issue is not black and white. Recent evidence points to an some potential association between an increase in the 2-hydroxyestrone metabolite in postmenopausal women with an increase in breast cancer risk. The better descriptive term is to describe the 2OH-estrone metabolite as the “safest” or “lowest risk” estrogen metabolite and that may too be overly simplistic.
The second estrogen metabolite to discuss is the 4-hydroxyestrone metabolite. The 4OH-estrone metabolite is predominantly the result of the CYP1B1, CYP1A2, and CYP1A1 detoxification enzymes. Studies suggest that CYP1B1 is the primary enzyme involved in the production of the 4OH-estrone metabolite. Historically, the evidence on 4OH-estrone is consistent. According to the majority of research, the 4OH-estrone metabolite is associated with an increase in cancer risk. The 4OH-estrone is associated with an increased risk of cancer initiation and cancer growth.
How? By what mechanism is the 4OH-estrone metabolite the most dangerous estrogen metabolite?
There are 7 proposed mechanisms, supported by science, through which the 4OH-estrone has earned the title–the “ugly” estrogen.
- the 4OH-estrone metabolite, compared to the other estrogen metabolites, causes the most DNA damage
- The 4OH-estrone metabolite has the strongest estrogenic effect
- The 4OH-estrone metabolite, compared to the other estrogen metabolites, has the strongest affinity for the estrogen receptors
- The 4OH-estrone metabolite is not easily removed from the estrogen receptor; non-removal from the receptor leads to potential continuous estrogen signaling
- The 4OH-estrone metabolite is not completely deactivated by methylation
- The 4OH-estrone metabolite does inhibit programed cell death of abnormal cells, leading to potential continuous growth
- The 4OH-estrone metabolite can stimulate estrogen signal through nuclear estrogen receptors, through membrane estrogen receptors, and through non-estrogen receptor pathways
Historically, the 4OH-estrone is the “ugly” estrogen metabolite and recent research makes it hard to argue with that label.
The third estrogen metabolite to discuss is the 16alpha-hydroxyestrone (16alpha-OH-estrone) metabolite. The 16alpha-OH-estrone metabolite is predominantly the result of the CYP2C19, CYP1A1, and CYP3A5 detoxification enzymes. Studies suggest that CYP2C19, CYP3A4, and CYP3A5 are the primary enzymes involved in the production of the 16alpha-OH-estrone metabolite. Historically, the 16alpha-OH-estrone metabolite is the “bad” estrogen metabolite in “the good, the bad, the ugly” hierarchy.
How? By what mechanism is the 16alpha-OH-estrone metabolite a potentially dangerous estrogen metabolite?
There are 6 proposed mechanisms, supported by science, through which the 16alpha-OH-estrone has earned the title–the “ugly” estrogen.
- The 16alpha-OH-estrone metabolite stimulates a strong estrogen signal through the estrogen receptor
- The 16alpha-OH-estone metabolite has a strong binding affinity for the estrogen receptor
- The 16alpha-OH-estrone metabolite-estrogen receptor complex is very stable
- The 16alpha-OH-estrone metabolite causes DNA damage
- The 16alpha-OH-estrone metabolite does not down regulate the estrogen receptor
- Like the 4OH-estrone metabolite, the 16alpha-OH-estrone metabolite does inhibit programed cell death of abnormal cells, leading to potential continuous growth
Historical dogma points to the 16alpha-OH-estrone metabolite alone and as a part of the 2:16OH-estrone ratio as associated with increased cancer risk . The potential risk of the 16alpha-OH-estrone metabolite alone is real. However, more recent evidence has called into question the “bad” label as a component of the 2:16OH-estrone ratio. According to more current research, the 2:16alpha-OH-estrone ratio is no longer a valid assessment of risk. This will be covered in a future post.
Out of sight and/or out of mind knowledge of new relevant research is not a sound scientific principle. Just as there is no such thing as a good or bad cholesterol, there is no such thing as the good, the bad, and the ugly estrogen metabolites. There is only an increased risk or decreased risk associated with the dominant estrogen metabolite produced as a product of estrogen metabolism in the context of the individuals overall metabolism.
- Dogma versus Science – DHT metabolites (seasonswellness.com)
- Hormone metabolism (seasonswellness.com)
- Thyroid and Thyroid metabolism: follow the science or follow opinion? (seasonswellness.com)
- Chicken or the Egg? (seasonswellness.com)