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The oestrogen paradox: an hypothesis

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With these data as a background, it was quite surprising that recently published data suggested that women taking postmenopausal hormone therapy (MHT) with oestrogen alone for 5 to 9 years unexpectedly experienced a decrease in the risk for breast cancer... A second component of the oestrogen paradox is that high-dose oestrogen therapy in postmenopausal women with breast cancer causes tumour regression, whereas the anti-oestrogen tamoxifen is equally effective in causing remissions in similar patient groups... A recent exploratory analysis of updated data from this study examined subgroups to determine whether oestrogens might reduce the incidence of breast cancer significantly in women falling into certain categories... Notably, this analysis reported a statistically significant 33% reduction in invasive breast cancer incidence in patients who strictly adhered to their oestrogen therapy (HR 0.67, 95% CI 0.47 to 0.97)... In a concurrent report from the Nurses Health Study, a significant 26% decrease in risk for breast cancer was observed in obese women, and a nonsignificant 10% decrease in all study participants, taking oestrogen alone for 5 to 9 years... Other observational studies reported a reduction in risk with oestrogen alone but of lesser magnitude and not statistically significant... For example, Schairer and colleagues reported a 7% reduction in breast cancer risk at 6 years in women receiving oestrogen alone, and Lyytinen and coworkers identified a similar 7% reduction... These combined results, although not conclusive, are highly suggestive of a beneficial effect of oestrogen in reducing breast cancer risk... However, this conclusion must be considered provisional until rigorous confirmation in additional studies is reported... The postmenopausal women receiving MHT with oestrogen alone may be considered to be in a state of long-term oestradiol deprivation... We suggest that the increased risk for breast cancer results from long-term use of oestrogens alone because the risk from MHT may occur via different mechanisms : the genotoxic effects of oestradiol metabolites and the ER-mediated proliferative effects of oestradiol... If our hypothesis were correct, then exposure to oestrogen therapy as MHT would induce apoptosis and shrink or even eradicate the occult tumours, which would reduce the detection of a cancer by mammography or palpation over the next several years... These combined observations suggest that directly genotoxic as well as ER-mediated mechanisms may be responsible for the long-term carcinogenic effects of oestradiol... In time, the pro-carcinogenic effects of oestradiol would outweigh the pro-apoptotic effects.

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Two pathways potentially responsible for oestradiol induced carcinogenesis. E2, oestradiol; ER, oestrogen receptor.
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Figure 3: Two pathways potentially responsible for oestradiol induced carcinogenesis. E2, oestradiol; ER, oestrogen receptor.

Mentions: Why would oestrogen increase the risk for breast cancer when it is given for more than 20 years? The commonly accepted explanation for the carcinogenic effect of oestrogen is that this sex steroid stimulates breast cancer proliferation genes, increases the rate of breast cell divisions, and thereby enhances the chances for development of mutations [25]. An additional and more controversial mechanism suggests that metabolites of oestradiol are directly genotoxic [24,25] (Figure 3). Recent studies demonstrate that oestradiol is converted to 4-OH-oestradiol in human breast tissue via the cytochrome p450 1B1 enzyme, and it is then oxidized to quinone metabolites. These metabolites are highly reactive and covalently bind to adenine and guanine on DNA, resulting in depurination, error-prone DNA repair, and point mutations [24]. Other recent studies have shown that 4-OH-oestradiol is directly mutagenic in cellular mutagenesis assays [26-29]. In addition, 4-OH-oestradiol can transform ER-negative benign breast epithelial cells into serially transplantable carcinomas in immune deficient mice [28]. Finally, an ER knockout model of breast cancer forms tumours in response to increasing doses of exogenous oestradiol in previously castrated animals [24,30]. These combined observations suggest that directly genotoxic as well as ER-mediated mechanisms may be responsible for the long-term carcinogenic effects of oestradiol [24]. In time, the pro-carcinogenic effects of oestradiol would outweigh the pro-apoptotic effects.


The oestrogen paradox: an hypothesis
Two pathways potentially responsible for oestradiol induced carcinogenesis. E2, oestradiol; ER, oestrogen receptor.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2230529&req=5

Figure 3: Two pathways potentially responsible for oestradiol induced carcinogenesis. E2, oestradiol; ER, oestrogen receptor.
Mentions: Why would oestrogen increase the risk for breast cancer when it is given for more than 20 years? The commonly accepted explanation for the carcinogenic effect of oestrogen is that this sex steroid stimulates breast cancer proliferation genes, increases the rate of breast cell divisions, and thereby enhances the chances for development of mutations [25]. An additional and more controversial mechanism suggests that metabolites of oestradiol are directly genotoxic [24,25] (Figure 3). Recent studies demonstrate that oestradiol is converted to 4-OH-oestradiol in human breast tissue via the cytochrome p450 1B1 enzyme, and it is then oxidized to quinone metabolites. These metabolites are highly reactive and covalently bind to adenine and guanine on DNA, resulting in depurination, error-prone DNA repair, and point mutations [24]. Other recent studies have shown that 4-OH-oestradiol is directly mutagenic in cellular mutagenesis assays [26-29]. In addition, 4-OH-oestradiol can transform ER-negative benign breast epithelial cells into serially transplantable carcinomas in immune deficient mice [28]. Finally, an ER knockout model of breast cancer forms tumours in response to increasing doses of exogenous oestradiol in previously castrated animals [24,30]. These combined observations suggest that directly genotoxic as well as ER-mediated mechanisms may be responsible for the long-term carcinogenic effects of oestradiol [24]. In time, the pro-carcinogenic effects of oestradiol would outweigh the pro-apoptotic effects.

View Article: PubMed Central - HTML

AUTOMATICALLY GENERATED EXCERPT
Please rate it.

With these data as a background, it was quite surprising that recently published data suggested that women taking postmenopausal hormone therapy (MHT) with oestrogen alone for 5 to 9 years unexpectedly experienced a decrease in the risk for breast cancer... A second component of the oestrogen paradox is that high-dose oestrogen therapy in postmenopausal women with breast cancer causes tumour regression, whereas the anti-oestrogen tamoxifen is equally effective in causing remissions in similar patient groups... A recent exploratory analysis of updated data from this study examined subgroups to determine whether oestrogens might reduce the incidence of breast cancer significantly in women falling into certain categories... Notably, this analysis reported a statistically significant 33% reduction in invasive breast cancer incidence in patients who strictly adhered to their oestrogen therapy (HR 0.67, 95% CI 0.47 to 0.97)... In a concurrent report from the Nurses Health Study, a significant 26% decrease in risk for breast cancer was observed in obese women, and a nonsignificant 10% decrease in all study participants, taking oestrogen alone for 5 to 9 years... Other observational studies reported a reduction in risk with oestrogen alone but of lesser magnitude and not statistically significant... For example, Schairer and colleagues reported a 7% reduction in breast cancer risk at 6 years in women receiving oestrogen alone, and Lyytinen and coworkers identified a similar 7% reduction... These combined results, although not conclusive, are highly suggestive of a beneficial effect of oestrogen in reducing breast cancer risk... However, this conclusion must be considered provisional until rigorous confirmation in additional studies is reported... The postmenopausal women receiving MHT with oestrogen alone may be considered to be in a state of long-term oestradiol deprivation... We suggest that the increased risk for breast cancer results from long-term use of oestrogens alone because the risk from MHT may occur via different mechanisms : the genotoxic effects of oestradiol metabolites and the ER-mediated proliferative effects of oestradiol... If our hypothesis were correct, then exposure to oestrogen therapy as MHT would induce apoptosis and shrink or even eradicate the occult tumours, which would reduce the detection of a cancer by mammography or palpation over the next several years... These combined observations suggest that directly genotoxic as well as ER-mediated mechanisms may be responsible for the long-term carcinogenic effects of oestradiol... In time, the pro-carcinogenic effects of oestradiol would outweigh the pro-apoptotic effects.

No MeSH data available.


Related in: MedlinePlus