| ANTI-AGEING MEDICINE | PEER-REVIEW
200 000 180 000 160 000 140 000 120 000 100 000 80 000 60 000 40 000 20 000 0
Total HRT Incidence 50-69 years oestrogen, unlike the dose-related relationship between
oestrogen and endometrial cancer. Understanding the role of oestrogen in the pathophysiology of breast cancer will ultimately lead to an understanding of why conventional HRT (where Ôone size fits allÕ) should be replaced with personalised bioidentical HRT (BHRT) supported by a close monitoring of individual oestrogen metabolites and their ratios, tailored nutrition, and lifestyle changes. The human body perceives its own oestrogen as a
toxin. The metabolism of oestrogen primarily takes place in the liver through phase I (hydroxylation) and phase II (methylation, glucuronidation and sulfation) pathways, with a final excretion in the urine and faeces. Oestrogen and its metabolites show a great variation in biological activity, oestrogen receptor affinity, and carcinogenicity;
therefore, the ultimate biologic effect
depends on how oestrogen is metabolised. This will depend on the specific polymorphism (single nucleotide polymorphism; SNPs) of the genes involved in oestrogen detoxification in each individual, their interaction with nutrition, and the environment, and the total body oestrogen burden. It is unique to every patient.
Figure 2 Relative risk (RR) of invasive breast cancer by type of hormone replacement therapy (HRT) and duration of exposure compared with HRT never-users
Compared with HRT never-use (French E3N cohort study) Oestrogen alone (95% CI; 1.02–1.65)
≥ 6 years
Oestrogen–progestogen (CI 1.50–1.91) ≥ 6 years
Oestrogen–progesterone (CI 0.83–1.22) ≥ 6 years
Weak oestrogen
Figure 1 Decline in breast cancer incidence in the Flemish region of Belgium after a decline in hormonal replacement. (Adapted from Renard et al37
)
450 400 350 300 250 200 150 100 50 0
Hydroxylation Cytochrome P450 enzymes are responsible for the hydroxylation of oestrogen, leading to a production of different metabolites, such as 2-OH, 16α-OH and 4-OH estrones. The 2-OH metabolites ® produced by SNP CYP1A1 activity ® are considered good oestrogens, with a weak receptor affinity, protective against breast cancer by inducing apoptosis, and with significant antioxidant activity6
. In contrast, the 16α-OH and 4-OH estrones
(metabolised through CYP3A4 and CYP1B1) show persistent oestrogenic activity and promote tissue proliferation7–10
genotoxic effect and carcinogenicity11
. They have been associated with direct a .
It is suggested that women who metabolise a larger
proportion of their endogenous oestrogen via the C16 α-hydroxylation pathway may be at a significant risk of breast cancer compared with women who metabolise proportionally more oestrogen via the C2 pathway12
. As
the catechol : oestrogen (Phase I) metabolite ratio is actually more important than the total oestrogen body burden, the 2-OH : 16α-OH estrone ratio is used as a predictive risk factor for hormone-sensitive breast cancers. The higher the ratio, the lower the incidence of breast cancer. However, many conditions can lower
this ratio, and physicians should be aware of these: ■ Pesticide and xenobiotic exposure
■ Hypothyroidism ■ High fat, low fibre diet ■ High omega-6 fatty acid diet ■ Oral contraceptives ■ Oestrogen dominance ■ Alcohol consumption ■ Obesity ■ Autoimmune diseases. Another carcinogenic metabolite,
1.29-fold increased relative risk 1.31 (0.76–2.28)
1.69-fold increased relative risk 1.96-fold increased relative risk
1.00 (no increased relative risk) 1.22-fold increased relative risk
0.90 (no increased relative risk)
4-0H E2, can be associated with higher risk, especially when hydroxylmethylation is poor and they can readily oxidise into DNA-damaging quinones. This can happen in cases of CYP1B1 polymorphism, which is present in the general population to varying degrees, and can be detected through genetic testing. CYP1B1 is definitely an unfavourable genetic polymorphism as it can cause a double-fold increased risk of breast cancer as a result of long-term HRT and smoking. Quinone formation can be neutralised to mercapturates by GSTT1 and GSTM1 enzyme activity. GSTM1 SNP is present in a combination of high-risk genotypes for breast cancer with CYP1A1*2A and COMT V158M (Figure 3). 4-OH E2 is a carcinogenic oestrogen metabolite with binding affinity for oestrogen receptor greater than the parent E1 and E2. Reactive quinones formed from 4-OH E2 can deplete cellular thiol levels, making cells vulnerable to oxidative damage. In addition, a high oestrogen 4-/2-OH ratio appears to be a marker for the presence of neoplasms. Further metabolism to quinone/semiquinone intermediates results in oxidative damage ® especially if they are not
prime-journal.com | January/February 2013 ❚ 51
Total sales of HRT
Incidence of breast cancer
1992 1993 1994 1995 1996 1997 1998 1999
2000 2001 2002 2003 2004 2005 2006 2007 2008
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