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The following paradox has been known for many decades, although not fully understood: estrogen therapy in postmenopausal women can either result in breast cancer cell growth or breast cancer regression. In the WHI trial, the mono-arm with conjugated estrogen caused a decrease in the incidence of breast cancer after 11.8 years median follow-up. In the Million Women Study, current users had little increase in breast cancer if estrogen-alone use was started more than 5 years after menopause (RR = 1.05), but, if it was begun straight after menopause, there was an increase in breast cancer (RR = 1.43). A similar pattern, although with higher RR was recorded for the estrogen–progestogen users (RR = 1.53, RR = 2.04, respectively). The reason for this result remains unclear. The estrogen receptor (ER) is extremely promiscuous in its desire to bind with a wide spectrum of phenolic ligands  either to switch off or to switch on the ER signal transduction pathway, which may then under certain circumstances trigger breast cancer cell apoptosis. Jordan [1] has raised an interesting hypothesis, based on experimental and clinical data, that long-term estrogen deprivation may convert breast cancer cells vulnerable to estrogen-induced apoptosis. Based on clinical and experimental data Jordan proposed that ‘A 5-year gap is necessary after menopause to permit the selection of estrogen-deprived breast cancer cell populations to cause them to become vulnerable to apoptotic cell death. Earlier treatment with estrogen around menopause encourages growth of ER-positive tumor cells, as the cells are still dependent on estrogen to maintain replication within the expanding population.’


  • Alfred O. Mueck
    University Womens Hospital of Tuebingen, Germany and Beijing OB/GYN Hospital, Capital Medical University, China
  • Harald Seeger
    University Womens Hospital of Tuebingen, Germany


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