Safe Estrogen Metabolism by Jim Paoletti, RPh

In my opinion we often overlook the best ways, both physiologically and economically, of ensuring safe metabolism of estrogens to decrease the risk of cancer. The majority of a woman's estrogens are normally conjugated in the liver and eliminated in the stool. To ensure that this natural method of safely metabolizing estrogens is optimized, the first thing I strongly suggest before initiation of any estrogen therapy is liver detoxification. Make sure the bowels are moving regularly before detoxifying. In addition, if the normal flora in the lower intestine has been disrupted, the result can be an increase in the enzyme activity of beta-glucuronidase. This enzyme cleaves the conjugated estrogen and re-circulates the estrogen that was conjugated and meant to be eliminated from the body. Therefore, I also strongly recommend at least a month or two of good probiotic therapy supporting Bifobacterium bifidium to restore the normal flora of the lower intestine.

Any form of estrogen other than estriol increases the amount of estrogen that is metabolized down the pathway to form catechol quinones, the metabolites that form DNA adjuncts that cause DNA mutations which can lead to cancer. Any estrogen therapy other than E3 in any amount increases dangerous metabolites. Therefore, I recommend to never give women more estrogen than absolutely needed. This can only be accomplished by addressing progesterone deficiencies, as well as insulin resistance, adrenal, and thyroid issues to eliminate their participation as a possible cause of supposed "estrogen deficiency" symptoms, as well as by measuring estrogen levels, the only true way to determine if estrogen itself is actually needed. Symptoms alone can never guarantee the need for estrogen.

Metabolism to the unsafe 4-OH metabolites can be inhibited by reducing lipid peroxidase activity. This is best accomplished by avoiding trans-fats and taking an antioxidant combination. Avoidance of pesticides also decreases the amount of unsafe metabolites produced.

Of the estrogen that is not conjugated, the vast majority should be normally methylated, producing safe estrogen metabolites. Methylation is dependent on the COMT enzyme, which is dependent on Vitamins B1, B6, B12 and folic acid. I strongly recommend these vitamins and a methyl donor such as MSM or TMG. At this point over 99% of any estrogens produced by the body or given (as long as not excessive) should be going down the normal pathways to safe metabolites. That leaves very little going down the remaining pathways, forming cancer causing depurinating adducts.

Additional safe metabolites can be encouraged by glutathione activity, which can be increased by NAC, Cysteine, aged garlic or MSM (to provide sulfur) or by administration of glutathione itself. Sulforaphane, an organosulfur compound found in cruciferous vegetables, can convert the estrogen glutathione conjugate metabolite formed just prior to the formation of the dangerous depurinating adducts back to the 4-OH metabolite, where it can then be acted on by COMT or glutathione. In other words, it takes the metabolite about to form the dangerous structure back to one where you have at least 3 more shots at metabolizing it safely.

With so many natural ways to ensure normal safe metabolism, concentrating on the ratio of the 2-OH and 16-OH ratios seems an inefficient way to address safe estrogen metabolism. Although many believe the 16-OH metabolite to be carcinogenic, I am not convinced of it. In vivo work by Cavalieri and associates has concluded that the 16-OH metabolites cause no further damage. This work also shows that the dangerous catechol quinones are formed from both estradiol and estrone, so both have the potential for forming the metabolites which initiate cancer. Although I do suggest the use of I3C or DIM in patients of either sex to increase the overall metabolism of estrogens and help reduce the burden of excess estrogens, I do not feel that increasing the proportion of 2-OH metabolites compared to 16-OH metabolites necessarily reduces the risk of breast cancer.

In my opinion, those that push for testing of these substances are not using patient's money most efficiently and are concentrating on a controversial downstream effect, instead of optimizing the system that is already in place to protect against dangerous estrogen metabolites.

To summarize, here is how I approach safe estrogen metabolism:
• Ensure proper liver and bowel function to conjugate and eliminate the conjugated estrogens
o Liver Detox
o Fiber to help optimize bowel movements, increase SHBG, and eliminate bile toxins
o Probiotic therapy
• Balance estrogen with progesterone which has been shown to reduce the estradiol-induced proliferation of breast tissue and cause natural cell death
• Avoid pesticides and trans-fats
• Never give any more estrogen than absolutely necessary. Address need for progesterone first, as well as any adrenal, insulin resistance, or thyroid issues. Always dose estrogen low initially and increase dose slowly
• Ensure proper methylation with active B1, B6, B12, folic acid and a methyl donor
• Support immune function, including restoring DHEAs levels to normal
• Take an antioxidant combination of at least Vitamin C and Vitamin E

Optional additional considerations:
• Glutathione support
• Sulforaphane
• I3C or DIM to increase estrogen metabolism
• Calcium-D-Glucorate to inhibit beta-glucuronidase

Two excellent references I would recommend are:
"What Your Doctor May Not Tell You About Breast Cancer" by John Lee, MD and David Zava, PHD
And
E.L. Cavalieri, E.G. Rogan and D. Chakravarti. Initiation of cancer and other diseases by catechol ortho-quinones: A unifying mechanism. CMLS 59 (2002), 665-681.
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