Estrogen as a new option for prevention and treatment of breast cancer – does this need a 'time gap'?

Due to experimental and clinical data, the hypothesis has been raised that a 'time gap' is necessary to achieve 'carcinoprotection' by estrogen therapy in postmenopausal women, possibly also in combination with certain ('neutral') progestogens. As the mechanism, apoptotic effects are discussed, which, however, would only work after long-term estrogen deprivation. Based on this hypothesis, in general, an early initiation of menopausal hormone therapy would increase the risk of breast cancer, in sharp contrast to the beneficial cardiovascular effects, only protective within the 'window of opportunity' directly after menopause. However, other mechanisms are possible which could work without a time gap, leading to a decreased risk of breast cancer or even being carcinoprotective compared with no treatment. For example, within estradiol metabolism, carcinoprotective enzymes can be upregulated and protective estradiol metabolites can be produced, as shown, for example, especially in women with balanced nutrition and physical activity. In addition, it has to be considered that a long time is needed to see any clinical effects based on the biological mechanisms which may start early after estrogen exposure. Thus, more research and studies are needed to prove the 'gap hypothesis', and it may be that estrogen is beneficial for a woman at any time of her life.