Vol 58, No 3 (2007)
Review paper
Published online: 2007-09-19
The oestrogen paradox: a hypothesis
Endokrynol Pol 2007;58(3):222-227.
Abstract
Epidemiological and observational studies suggest that oestrogens, when used as hormonal therapy in post-menopausal
women, can increase the risk of breast cancer if used long term. However, more recent data suggest that short-term use in
sub-groups of post-menopausal women significantly decreases the risk of breast cancer. This beneficial effect is also observed
when high-dose oestrogen is administered to post-menopausal women with breast cancer to cause tumour regression,
a phenomenon which commonly occurs. We consider these divergent responses to oestrogen to represent a "paradox".
Data from our own and other investigative groups suggest a hypothesis to explain this paradox. Deprivation of oestradiol
in model systems causes cells to adapt and to undergo apoptosis in response to oestrogen. This occurs through the Fas/Fas
ligand death receptor pathway and through alterations in apoptotic mechanisms mediated by mitochondria. This process
of programmed cell death may explain the regression of established breast cancer with oestrogen administration and the
diminution in the rate of new breast cancer diagnoses recently reported. Our hypothesis is based upon pathological data
indicating the presence of a "reservoir" of undiagnosed breast cancer in the population of women who would be starting
on oestrogens as menopausal hormonal therapy. The long-term increased risk of breast cancer may then reflect different
mechanisms. Oestrogens can cause mutations through enhancement of the rate of cell division and concomitantly the
error rate in DNA replication. In addition, oestrogens can be metabolised to directly genotoxic compounds. These carcinogenic
processes take much longer, since a number of mutations must accumulate before resulting in breast cancer. These
hypotheses regarding oestrogen-induced apoptosis in the short term and carcinogenesis in the long term now require
rigorous verification but would serve to explain the "oestrogen paradox".
(Pol J Endocrinol 2007; 58 (3): 222-227)
Keywords: oestrogensbreast cancer riskmenopausal hormonal therapy
![](https://journals.viamedica.pl/plugins/generic/popups/images/icons/close.png)