Question: Please Explain Detoxification of Estrogen Hormones.

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Question: Please Explain Detoxification of Estrogen Hormones.

Answer

We are all very aware of the huge impact sex hormones have on our physiology, anatomy and emotional function. However, few of us think about what happens to the hormones once they have done their job. There are several different pathways by which hormones are detoxified - some are quick, safe and effective while others create metabolites with significant negative effects on health. The speed and detoxification pathway the hormones take is determined by genetics, lifestyle, diet and nutritional status.

Excessive Estrogen Can Be a Problem

Excessively elevated levels of estrogen throughout the menstrual cycle have been linked to many of the common symptoms of dysfunction in women's health, including PMS¹, breast tenderness², and excessive and/or irregular menstrual flow.³ Higher levels of circulating estrogens have also been correlated with increased risk of breast cancer.⁴ One of the ways women can help manage or balance excessive estrogen levels is through supporting the ability to detoxify and eliminate estrogen rapidly and efficiently.

Elimination of Estrogens: A Two-Stage Process

Detoxification of circulating estrogens happens primarily in the liver and is a two-stage process. The first stage, called Phase I detoxification, involves an enzyme family called the cytochrome p450 enzymes. Phase I creates three potential intermediate estrogen metabolites: 2-hydroxyestrone, 4-hydroxyestrone and 16-alpha-hydroxyestrone. Of these three, 2-hydroxyestrone is the safest form and believed to offer protection against cancer and other estrogen excess-related conditions.⁵ Both the 4- and 16-hydroxyestrone molecules, however, can cause estrogen-related problems in the body.⁶

In Phase II, the second stage of estrogen detoxification, the enzymes COMT (catechol O-methyltransferase) and GST (glutathione S-transferase) add a compound to the hydroxyestrone molecule (COMT adds a methyl group and GST adds glutathione). These added compounds make hydroxyestrone water-soluble, so they can be more easily removed from the body.⁷ Estrogen can also skip Phase I and be directly processed in Phase II by two other pathways, called glucuronidation and sulfation. Phase II detoxification binds estrogen to compounds that allow it to be swept out of the liver in the bile or excreted in the urine.

Nutritional Support for Each Phase

The goal for supporting Phase I metabolism is primarily to promote the production of more of the safer 2-hydroxyestrone and less of the more toxic 4- and 16-hydroxyestrone metabolites. Several foods can aid in this process, including broccoli⁸, soy⁹ and flaxseed.¹⁰ Indole-3-carbinol (I3C), a phytonutrient found in broccoli and other cruciferous vegetables, can also be taken as a nutritional supplement and has been found to increase 2-hydroxyestrone production.¹¹ Surprisingly, coffee¹² and smoking¹³ also each increase 2-hydroxyestrone production, findings that potentially explain why these appear to reduce the risk of breast cancer.

Nutritional support for Phase II detoxification of estrogens is not as well defined. Preliminary evidence suggests that, for some people, increasing folic acid and vitamin B6 could help improve COMT activity.¹⁴ N-acetylcysteine¹⁵ increases glutathione production and thus GST activity. Garlic ^16,17 supports both sulfation and glutathione conjugation.

The bile acids that sweep conjugated estrogen out of the liver require a large amount of the amino acid taurine. For most people, the amounts of taurine we get in the diet or synthesize from other amino acids appear to be sufficient. However, a number of animal studies have shown that exposure to high amounts of estrogen can tax this path, leading to a condition called cholestasis.^18,19 Whether taurine supplements would help with the cholestasis seen in pregnant women or women taking birth control pills hasn't yet been evaluated in humans, but should probably be a research priority.

This concentration of estrogen metabolites in the bile is one reason dietary fiber is so important for women as it helps bind to the bile once it is excreted from the liver and thus remove it from the body before it can be reabsorbed.

I3C Versus DIM: Which Is Superior?

Brassica family foods - broccoli, cauliflower, Brussels sprouts, cabbage - contain a chemical called glucobrassican. This chemical is broken down into the stomach into a number of metabolites, including indole-3-carbinol (I3C). I3C then induces liver metabolism of estrogen into its less toxic 2-hydroxyestrone form.

Most of the research available on this process has used either the Brassica family foods or I3C in supplement form. Extensive dose ranging studies and safety analysis have been performed on I3C.

There is another product available called diindolymethane (DIM). This molecule is made up of two I3C molecules joined together. The manufacturers of this product claim that DIM is a more potent and stable form of the nutrient, and is safer, as well. While these claims may eventually bear out, at this time, there is comparatively little research on DIM, and that which exists suggests that its effects are not as good as those of I3C.¹⁸

The Anti-Estrogen Diet

Natural medicine practitioners have traditionally used an intervention called the anti-estrogen diet to treat women having trouble with excessive estrogen or sub-optimal estrogen detoxification. There are different variations of this diet, but all tend to have the following characteristics:

• Low animal fat
• Low sugar
• Low or no alcohol
• High fiber

Modern research methods have shown that rather than reducing total estrogen levels, this diet increases a protein called sex hormone binding globulin (SHBG).¹⁹ SHBG acts to keep circulating estrogens bound up in the blood stream, reducing their ability to activate the estrogen receptors on cells.

An intriguing new research study has also suggested that diets low in fat help to prevent the reabsorption of conjugated estrogens from the intestine back into the bloodstream.²⁰ If this finding is accurate, it is another strong reason to focus on low-fat diets as a way to help reduce estrogen problems.

Can Detoxification Pathways Be Tested?

Commercial tests are available that can test several of these pathways. For example, urine tests that check 2/16-hydroxyestrone ratios are run by several labs. These can be very useful for women with breast cancer to determine if this is a contributing factor.

There are also functional tests that attempt to quantify the different Phase II systems. For example, a dose of acetaminophen can be given to a woman and then her urine collected for measurement of acetaminophen's detoxification products. Their amounts and ratios provide guidance on how well her sulfation, glucuronidation and glutathione conjugation detoxification pathways are working.

Be Patient

A consistent finding across the research studies cited here is that the therapeutic effects of these detoxification facilitation treatments can take several months to reach their full effect. Expect to see some change during the first month, but it will probably require at least two cycles to see a full effect emerge.

Bottom line: a diet rich in fiber and cabbage family vegetables supplemented, as needed, with natural health products such as N-acetyl cysteine (NAC), garlic capsules and I3C will optimize estrogen detoxification and help prevent the effects of estrogen excess and toxic estrogen metabolites.

This monograph was written with the assistance of Dr. Matt Brignall, head of the science team at SaluGenecists, Inc.

References

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⁴ The Endogenous Hormones and Breast Cancer Collaborative Group. Endogenous sex hormones and breast cancer in postmenopausal women: Reanalysis of nine prospective studies. J Natl Cancer Inst. 2002;94:606–16.

⁵ Bradlow HL, Telang NT, Sepkovic DW, Osborne MP. 2-hydroxyestrone: the ‘good' estrogen. J Endocrinol. 1996 Sep;150 Suppl:S259-65.

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¹⁰ Brooks JD, Ward WE, Lewis JE, et al. Supplementation with flaxseed alters estrogen metabolism in postmenopausal women to a greater extent than does supplementation with an equal amount of soy. Am J Clin Nutr. 2004 Feb;79(2):318-25.

¹¹ Reed GA, Peterson KS, Smith HJ, et al. A phase I study of indole-3-carbinol in women: tolerability and effects. Cancer Epidemiol Biomarkers Prev. 2005 Aug;14(8):1953-60.

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¹⁵ Manov I, Hirsh M, Iancu TC. Acetaminophen hepatotoxicity and mechanisms of its protection by N-acetylcysteine: a study of Hep3B cells. Exp Toxicol Pathol. 2002 Feb;53(6):489-500

¹⁶ Khanum F, Anilakumar KR, Viswanathan KR. Anticarcinogenic properties of garlic: a review. Crit Rev Food Sci Nutr. 2004;44(6):479-88

¹⁷ Kalantari H, Salehi M. The protective effect of garlic oil on hepatotoxicity induced by acetaminophen in mice and comparison with N-acetylcysteine. Saudi Med J. 2001 Dec;22(12):1080-4.

¹⁸ Dalessandri KM, Firestone GL, Fitch MD, et al. Pilot study: effect of 3,3'-diindolylmethane supplements on urinary hormone metabolites in postmenopausal women with a history of early-stage breast cancer. Nutr Cancer. 2004;50(2):161-7.

¹⁹ Tymchuk CN, Tessler SB, Barnard RJ. Changes in sex hormone-binding globulin, insulin, and serum lipids in postmenopausal women on a low-fat, high-fiber diet combined with exercise. Nutr Cancer. 2000;38(2):158-62

²⁰ Aubertin-Leheudre M, Gorbach S, Woods M, et al. Fat/fiber intakes and sex hormones in healthy premenopausal women in USA. J Steroid Biochem Mol Biol. 2008 Nov;112(1-3):32-9.