The oestrogen paradox: an hypothesis

As shown in Figure ​Figure1,1, a wide range of epidemiologic and observational data suggest that oestrogens are associated with the development of breast cancer [1,2]. 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 [3,4]. However, when taken for more than 20 years, the risk appeared to increase [5,6]. We call this the 'oestrogen paradox' to highlight the fact that short-term oestrogen use decreases the risk for breast cancer whereas long-term use increases it. 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 [7-9]. It is paradoxical then that both oestrogens and anti-oestrogens cause tumour regressions. Figure 1 Hormonal risk factors associated with an increased risk of breast cancer and related to oestrogen exposure. For references supporting the validity of this figure, see Santen [1]. E, oestrogen; E2, oestradiol; HRT, hormone replacement therapy; OOX, oophorectomy; ... Short-term oestrogen use and breast cancer risk The initial publication of the Women's Health Initiative (WHI) [3] reported a 23% decrease in invasive breast cancer incidence in patients taking oestrogen alone compared with placebo, a finding which narrowly fell short of statistical significance (hazard ratio [HR] 0.77, 95% confidence interval [CI] 0.59 to 1.01). 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 [4]. 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 addition, a 31% lower incidence of localized breast cancer (HR 0.69, 95% CI 0.51 to 0.95) and a 29% reduction in ductal cancers (HR 0.71, 95% CI 0.52 to 0.99) were reported in oestrogen users. The decreases in breast cancer risk were limited to women who had not previously used MHT [4]. In a concurrent report from the Nurses Health Study [2], 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 [5] reported a 7% reduction in breast cancer risk at 6 years in women receiving oestrogen alone, and Lyytinen and coworkers [10] 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.