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.