PEER-REVIEW | ANTI-AGEING MEDICINE | for minimally- to moderately-increased risks where the


decision to prescribe BHRT is made on the basis of favourable oestrogen metabolism determined by genetic testing, a good 2-OH : 16α-OH ratio, absence of oestrogen dominance, and a balanced oestrogen : progesterone ratio.


Nutrigenetics to modulate oestrogen metabolism Certain nutrients can selectively alter gene expression involved in oestrogen metabolism, modifying the type and amount of oestrogen metabolites. The aim is to enhance production of protective metabolites in order to safely prescribe BHRT. Once genetic testing is complete, there is a protocol for the application of nutrigenetics. Nutritional therapy can be used to balance oestrogen in the body and to deal with excess oestrogen from all resources as following: ■ Promote a healthy ratio of phase I oestrogen metabolites (2-OH : 16α-OH estrone)


■ Protect cells from Phase I oestrogen metabolites (carcinogenic 16α-OH and 4-OH estrone)


■ Promote healthy methylation (Phase II) ■ Encourage healthy intestinal excretion ■ Balanced (endogenous and exogenous) oestrogen input.


Promote a healthy ratio of Phase I oestrogen metabolites A number of lines of evidence support the conclusion that indole-3-carbinol (I3C) induces hepatic CYP4501A1 with a resultant increase in 2-hydroxyestrogens. Cruciferous (Brassica) vegetables and their glucosinolates ® mainly I3C and DIM ® showed extensive anti-oestrogenic effects, favourably affecting the balance of oestrogen metabolites towards protective 2-OH, and even inhibiting breast cancer cell growth in vitro. In this study, 18 volunteers received 500 g of fresh


broccoli every day for 12 days, following a 6-day period of standard diet. The activity of CYP1A2, CYP2E1, E2 and 16α-hydroxylation were determined before and after the broccoli diet. The average activity of CYP1A2 and the average E2 : 16α-hydroxyestrone ratio increased by 19% (P < 0.0005) and 29.5% (P < 0.05) respectively29


. This


healthy ratio could also be promoted by adding flaxseeds on a daily basis. It has been found that as little as 25 g ground flaxseed leads to favourable shifts in oestrogen metabolites. Urinary concentrations of 2-hydroxyestrone, but not of 16α-hydroxyestrone, increased significantly in the flaxseed group. In the flaxseed group, the ratio of 2-hydroxyestrone to 16α-hydroxyestrone was positively correlated with urinary lignan excretion30


. There have been many controversies as to whether


dietary soya should be used in breast cancer. As it increases the 2-0H : 16-0H ratio, which is a favourable oestrogen metabolism protective against breast cancer, this study is pro-dietary soya. The ratio of 2-OH estrone to 16α-OH estrone was higher during the isoflavone-rich soya diet compared with during the isoflavone-free diet, which saw a 27% increase31


. One must be careful not to induce too much CYP1A1 owing to the risk of poor 54 ❚


methylation as a result of a lack of supporting nutrients for healthy methylation and the presence of the COMT genotype with decreased predictive activity, as even


ÔgoodÕ metabolites such as 2-OH need to be methylated to prevent oxidation to more dangerous semiquinones. This is even more dangerous in the presence of exogenous toxins using the same CYP1A1 for detoxification, such as polycyclic aromatic hydrocarbons from fuel exhaust or chargrilled meat, and tobacco smoking for example. In practice, this means obtaining a fine balance between prescribed BHRT, supportive supplements and necessary lifestyle changes for safer hormone supplementation.


Protect cells from phase I oestrogen metabolites Protecting cells from phase I dangerous oestrogen metabolites is very important as they are directly involved in DNA adduct


Key points


■ Genetic testing is an additional and powerful tool that will help the physician to identify the risk of breast cancer risk genotypes in order to modulate them and create a more favourable oestrogen metabolism


formation and breast


carcinogenesis. These are Resveratrol, N-acetylcysteine and berries. There is much data to support the role of Resveratrol in


protecting against 4-OH E2. To summarise, the protective properties of Resveratrol are three-fold32


:


■ The inhibition of CYP1B1 expression, which decreases the formation of 4-OH E2 that should be further methylated


■ The induction of NQO1 enzyme, that provides a decrease in oestrogen quinones and an increase in catechol oestrogen


■ The antioxidant properties of Resveratrol reduce oestrogen semiquinones to catechol oestrogens, as indirectly determined in vitro.


One must make sure that Resveratrol is prescribed


while methylation is supported. Therefore, all patients with CYP1B1 increase predictive activity should receive Resveratrol with supported methylation. If COMT is present and unhealthy methylation is suspected, it is important to promoted healthy levels of glutathione S-transverase (GST). GST SNP results in decreased detoxifying capacity of dangerous oestrogen quinones. Nutritional support could be achieved with alpha-lipoic acid, whey protein, vitamin C, Sylimarin and cruciferous vegetables (I3C). N-acetylcysteine blocks the formation of


cancer-initiating oestrogenÐ DNA adducts in cells, and could be used as a potential chemopreventive agent to block the initial step in the genotoxicity caused by catechol oestrogen quinones33, 34


.


Promote healthy methylation Supporting healthy methylation is vital during HRT for the prevention of breast cancer and endometrial cancer. The COMT enzyme is involved in the detoxification of dangerous catechol oestrogen metabolites and biotransformation into neutral and protective methoxylated metabolites. In fact, it is not recommended to prescribe any hormonal substitution in cases of homozygous genetic variants of COMT SNP, where there is a total decreased enzyme activity. In heterozygous


January/February 2013 | prime-journal.com


■ Bioidentical hormone replacement therapy (BHRT) (customised dose and strength) with nutrigenetics for oestrogen modulation should be prescribed as a personalised treatment according to the calculated risk of each case


■ In cases in which the danger of developing breast cancer outweighs the protective benefit of HRT, the prescription of BHRT will not be implemented


■ This treatment methodology allows the physician to increase the safety of HRT


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