Friday, July 17, 2009

Natural Compounds for Estrogen Metabolism Support

Recall from the last post that we looked at how the liver plays a vital role in metabolizing estrogens. I left you with the thought that those important pathways which so often go awry can be modified with specific compounds from nature. “Although the estrogen receptor is required for a cell to respond to an estrogenic stimulus, the nature and extent of that response are determined by the proteins, pathways, and processes with which the receptor interacts.” Connections and Regulation of the Human Estrogen Receptor, Dean McDonnell and John D. Norris

This means that factors other than the presence or absence of estrogen influence the response of the estrogen receptor and the cell. These factors are what make up the chemical environment in and around the cell, and can be impacted by nutritional factors. The way estrogen receptors create chemical messengers that relate to other receptors is called “cross-talk,” and it would make sense that this “cross-talk” is influenced by nutrient status.

We’ll look at a few of the natural compounds in this post that positively affect estrogen metabolism.

Indole-3-CarbinolIt has been demonstrated convincingly that Indole-3-Carbinol (I3C) from cruciferous vegetables increases the healthful 2-OHE estrogen pathway and decreases the harmful 4-/16-OHE estrogens.

“Indole-3-carbinol (I3C), a compound occuring naturally in cruciferous vegetables, exhibits a potent antitumor activity via its regulation of estrogen activity and metabolism... These results further suggest that antitumor activities of I3C are associated not only with its regulation of estrogen activity and metabolism, but also its modulation of ER transcription activity.” J Nutri 130:2927-2931(2000)

“It has been shown that it induces CyP450 1A1, increasing 2-hydroxylation of estrogens, leading to the protective 2-OHE1, and also decreases CyP 1B1 sharply, inhibiting 4-hydroxylation of estradiol, thereby decreasing the formation of the carcinogenic 4-OHE1. …it has also been shown to be effective against HPV-mediated tumors in human patients.” Ann Ny Acad Sci889:204-213(1999)

“These results indicate that anti-invasion and antimigration activities of I3C occur via estrogen-independent and estrogen-dependent pathways. …current finding is the first demonstration that I3C can activate the function of invasion suppressor molecules associated with the suppression of invasion and migration in breast cancer cells. Thus, clinical application of I3C may contribute to the potential benefit for suppression of breast cancer invasion and metastasis.” J Mol Med78:155-165(2000)

Supplementation with I3C has shown promise in the literature:

  • Supplementation with concentrate (400 mg/d) promotes 2-Hydroxylation and improves 2-OH:16-OH ratio. Michnovicz JJ, et al, J Natl Cancer Inst, 89(10):718-20, 1997.
  • May also reduce 4-Hydroxylation. Bradlow HL, et al, Ann NY Acad Sci, 889:204-13, 1999.
  • 300-400mg/d promises to be a chemopreventive agent. Wong et al., J Cell Biochem Suppl 1997;28-29:111

I3C has also shown to positively influence gene expression! Recall that estrogen metabolism occurs in specific liver pathways. The CYP450 1A1 pathway forms 2-OH, and the single nucleotide polymorphism (SNP) Msp 1 impairs 1A1 function. I3C, however, improves estrogen metabolism even in the presence of the polymorphism! Bartsch et al., Carcinogenesis 1999;20(12):2209, Taioli et al., Cancer Detection and Prev1999;23(3):232

The CYP450 1B1 pathway, however, forms the 16-OH hormone, and the SNP V432L increases the function of the 1B1 pathway. I3C inhibits 1B1 even in the presence of the SNP! Bradlow et al., Ann NY Acad Sci 1999;889:204

We’ll look at more natural compounds for healthy estrogen metabolism in the posts following.


Related Formula: Meta I3C

Wednesday, July 1, 2009

When Estrogen Metabolism Goes Awry (And How to Fix it)

I’ve heard so many positive reports on the power of the Metagenics formula for estrogen metabolism, I thought that it would be time well spent to talk about estrogen in the next few posts.

How Estrogen is Metabolized
The majority of estrogens are detoxified in the cytochrome (CYP) P-450 1A1 phase 1 liver process known as hydroxylation. Fifty percent of all estrogen is metabolized through the catechol-2 (C2) position, creating the weaker 2-hydroxyestrone catechol, whereas the rest is metabolized through much stronger estrogenic pathways known as the C4 and the C16 positions (via the cytochrome 1B1 pathways), which create the 4-OH and 16-OH hormones.

Data is piling up that the 2-OH hormone is protective, whereas overproduction of the 4 and 16-OH estrogens heighten the risk of cancer.

“The expanding data indicates that 2-OH estrone is anticarcinogenic. In every experimental model in which 2-OH was increased, protection against tumors was achieved. Correspondingly, when 2-OH was decreased, an increase in cancer was observed.” J Endocrinology 130:S239-S265 (1996)

“4-OH-E1 and 16-OH-E2 are considered carcinogenic.” Gruber et al., NEJM Jan 31,2002; 346(5):340

“In a study of 10,786 women it was found that the ratio of 2-OH to 16-OH estrone was a very sensitive indicator of breast cancer risk. The higher the ratio of 2:16 OH, the lower the incidence of breast cancer.” Epidemiology 11:635-640 (2000)

The question then, how does the body shift its load of hormone metabolism toward the unfavorable 4 and 16-OH pathways and away from the healthier 2-OH pathway?

“…environmental factors enhancing aromatase activity might result in high tissue concentrations of E2 that would likely be sufficient to serve as substrates for CYP1B1… for formation of catechol metabolites that are estrogenic and which, upon further oxidative metabolism, form genotoxic species at levels that may contribute to estrogen carcinogenesis.” J Nat’l Can Inst Monographs #27:95-112 (2000)

In short and simple terms, environmental factors including toxic pollution and chemically-altered food can enhance the enzyme aromatase, which serves as a precursor to various hormones, including testosterone. This jacked-up aromatase activity shifts estrogen metabolism in the liver toward the cytochrome 1B1 pathway, which is the one that makes more of the 4 and 16-OH estrogens.

Phase 2
After the phase 1 processes in the liver are complete, the phase 2 pathways complete the process of hormone metabolism via the methylation, glucaronidation, and conjugation pathways. Methylation, for example, is protective because once the hormones are hydroxylated in phase 1, they are then either methylated and excreted, or in the case of faulty methylation, they are oxidized to quinones.

“Methylation (of 2-OHE2 and 4-OHE2) by catechol-O-methyltransferase (COMT) is the principal means of catechol estrogen deactivation in the liver and other tissues.” Toxicol Appl Pharmacol 162, 115-123 (2000)

“Catechol-O-methyltransferase (COMT) is a phase II enzyme that deactivates catechol estrogens into non-genotoxic methyl ethers that can be easily excreted by the body.” Carcinogenesis vol.24 no.4 pp.681±687, 2003

There is a Reason for all this Biochemistry
The reason for all this biochemistry is to drive home some important take-aways: The favorable metabolic pathways can be influenced by diet and supplements! CYP 450 and COMT activity can be influenced by diet and supplements! The favorable metabolic pathways can be influenced by diet and supplements!

Where diet is concerned, the damaging effects of upregulated aromatase activity can be improved by eating less sugar, as insulin will tend to produce more adipose tissue, and fat cells contain more aromatase which in turn will produce more estrogen from testosterone. Losing weight and improving the diet can positively influence estrogen metabolism!
Xenoestrogens from the environment, likewise, contribute to the estrogen pool and inhibit normal estrogen metabolism. Thus, a detoxification program might be in order.

Where specific supplements are concerned, pathogenic gut bacteria deconjugate detoxified estrogens, allowing for their reabsorption. So probiotic bacteria can help to complete the process of estrogen conjugation and elimination in the gut. But it goes way beyond that. There are specific macro and micronutrients that can greatly influence estrogen detoxification for the better and improve hydroxylation, methylation, etc in the liver.

That is the subject of the next post. Stay tuned.