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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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Effect of oestradiol on apoptosis in wild type and long-term oestradiol-deprived cells. (a) Long-term oestradiol deprived (LTED) MCF7 cells respond to oestradiol (E2) with an increase in apoptosis, whereas (b) wild type MCF7 cells respond to the same dose of oestradiol with a reduction in apoptosis. Reproduced with permission from Oxford University Press from Song RX, Mor G, Naftolin F, McPherson RA, Song J, Zhang Z, Yue W, Wang J, Santen RJ: Effect of long-term estrogen deprivation on apoptotic responses of breast cancer cells to 17beta-estradiol. J Natl Cancer Inst 2001, 93:1714–1723.
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Figure 2: Effect of oestradiol on apoptosis in wild type and long-term oestradiol-deprived cells. (a) Long-term oestradiol deprived (LTED) MCF7 cells respond to oestradiol (E2) with an increase in apoptosis, whereas (b) wild type MCF7 cells respond to the same dose of oestradiol with a reduction in apoptosis. Reproduced with permission from Oxford University Press from Song RX, Mor G, Naftolin F, McPherson RA, Song J, Zhang Z, Yue W, Wang J, Santen RJ: Effect of long-term estrogen deprivation on apoptotic responses of breast cancer cells to 17beta-estradiol. J Natl Cancer Inst 2001, 93:1714–1723.

Mentions: Our preclinical data demonstrate that long-term deprivation of oestradiol causes this sex steroid to trigger cell death through apoptosis (Figure 2a), whereas wild-type cells with a normal oestrogen milieu exhibit reduced apoptosis (Figure 2b) [13-21]. The postmenopausal women receiving MHT with oestrogen alone may be considered to be in a state of long-term oestradiol deprivation. Extensive review of autopsy studies provides strong evidence that there is a reservoir of undiagnosed breast cancer in postmenopausal women (Table 1) [22,23]. The short-term reduction in breast cancer in the patients with undiagnosed occult breast tumours may be due to oestrogen-induced apoptosis of tumour cells. Similarly, the effect of oestrogen in inducing tumour regressions in patients with known breast cancer may reflect a similar phenomenon. 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 [24,25]: the genotoxic effects of oestradiol metabolites and the ER-mediated proliferative effects of oestradiol. The following sections of this treatise will review the evidence for each of these statements.


The oestrogen paradox: an hypothesis
Effect of oestradiol on apoptosis in wild type and long-term oestradiol-deprived cells. (a) Long-term oestradiol deprived (LTED) MCF7 cells respond to oestradiol (E2) with an increase in apoptosis, whereas (b) wild type MCF7 cells respond to the same dose of oestradiol with a reduction in apoptosis. Reproduced with permission from Oxford University Press from Song RX, Mor G, Naftolin F, McPherson RA, Song J, Zhang Z, Yue W, Wang J, Santen RJ: Effect of long-term estrogen deprivation on apoptotic responses of breast cancer cells to 17beta-estradiol. J Natl Cancer Inst 2001, 93:1714–1723.
© Copyright Policy
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC2230529&req=5

Figure 2: Effect of oestradiol on apoptosis in wild type and long-term oestradiol-deprived cells. (a) Long-term oestradiol deprived (LTED) MCF7 cells respond to oestradiol (E2) with an increase in apoptosis, whereas (b) wild type MCF7 cells respond to the same dose of oestradiol with a reduction in apoptosis. Reproduced with permission from Oxford University Press from Song RX, Mor G, Naftolin F, McPherson RA, Song J, Zhang Z, Yue W, Wang J, Santen RJ: Effect of long-term estrogen deprivation on apoptotic responses of breast cancer cells to 17beta-estradiol. J Natl Cancer Inst 2001, 93:1714–1723.
Mentions: Our preclinical data demonstrate that long-term deprivation of oestradiol causes this sex steroid to trigger cell death through apoptosis (Figure 2a), whereas wild-type cells with a normal oestrogen milieu exhibit reduced apoptosis (Figure 2b) [13-21]. The postmenopausal women receiving MHT with oestrogen alone may be considered to be in a state of long-term oestradiol deprivation. Extensive review of autopsy studies provides strong evidence that there is a reservoir of undiagnosed breast cancer in postmenopausal women (Table 1) [22,23]. The short-term reduction in breast cancer in the patients with undiagnosed occult breast tumours may be due to oestrogen-induced apoptosis of tumour cells. Similarly, the effect of oestrogen in inducing tumour regressions in patients with known breast cancer may reflect a similar phenomenon. 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 [24,25]: the genotoxic effects of oestradiol metabolites and the ER-mediated proliferative effects of oestradiol. The following sections of this treatise will review the evidence for each of these statements.

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