Estrogens are in the list of carcinogenic chemicals from the World Health Organization (WHO). However, estrogens require additional factors such as stromal factors or progestogens to increase the ratio of proliferation/apoptosis for initiation of replication errors and consequent mutations to occur. These mutations require at least 5-10 years to develop into clinically detectable cancer, whereby this review is focused on breast cancer. The US National Cancer Institute highlighted a second mechanism of carcinogenicity: certain estrogen metabolites are capable of inducing DNA damage, even in low concentration. They can be assessed in the tissue and circulation. However, those deleterious reactions require excessive unrestricted oxidative cell stress, for example in industrial areas with heavy pollution. We have shown that this can be avoided using transdermal instead of oral estradiol treatment, especially important in smokers. The spectrum of metabolites is also influenced by other exogenous factors such as nutrition, physical activity and certain diseases. Reduction of breast cancer risk as demonstrated in the Women's Health Initiative (WHI) was explained by pro-apoptotic estrogen effects working after a certain 'time gap'. In addition, certain estrogen metabolites are carcinoprotective, if no genetic polymorphisms would impair their beneficial activities. Thus, since additional factors are required for both main pathways of carcinogenicity and because estrogens can even have carcinoprotective effects, we cannot agree with the statement from the WHO.
Keywords: World Health Organization; apoptosis; breast cancer; carcinogenicity; estrogen metabolism; estrogens; proliferation.