Environmental endocrine modulators and human health: an assessment of the biological evidence, 1998
Several studies have investigated breast cancer risk in women given DES or other exogenous estrogens during pregnancy. In a cohort study of 1531 women exposed to DES during pregnancy, the relative risk for breast cancer was 1.5 (CI 0.88 to 2.49). Within the exposed group, there was also no evidence for a dose-response relationship with relative risks for breast cancer of 1.38, 1.46, and 1.29 for total DES doses of <1000 mg, 1000 to 4500 mg, and >4500 mg, respectively. The mean total DES dose in this study was 2100 mg. While there was a slight excess of breast cancer in the DES group (although not statistically significant), the authors note that this may have also been due to hormonally related reproductive difficulties in these women, which was why they were given DES.
In a study comparing the incidence of breast cancer in a cohort of 3033 women who had taken DES during pregnancy with an appropriate unexposed group, there was an increased relative risk of 1.46 (CI 1.1–1.9). Breast cancer mortality was slightly higher in the DES-exposed group (RR = 1.1), but this was not statistically significant. Because information on total DES doses used was not available, a dose-response relationship between DES and breast cancer could not be determined. The authors were unable to rule out whether the increased incidence of breast cancer was due solely to DES or some other characteristic of DES-exposed women (e.g., an underlying hormonal disorder that precipitated the use of DES). In a follow-up study of the same cohort, there was a modest, but statistically significant increase in breast cancer risk associated with exposure to DES during pregnancy (RR = 1.35). Because this follow-up study included 127 new breast cancer cases and 42,000 additional women-years of observation, in addition to controlling for previous miscarriage, the relative rate estimates are more precise than those in the earlier report. However, it did not appear that breast cancer risk associated with DES increased over time. Finally, in a study of 319 women who were part of a randomized clinical trial of DES, there was no difference in the incidence of breast cancer between DES exposed and unexposed. The mean total DES dose in this study was 11.5 g.
The data addressing increased breast cancer risk associated with DES exposure during pregnancy are equivocal. While the available data support a possible weak association between exposure to DES and increased risk of breast cancer, studies are limited by a lack of sufficient information on dose and duration and the inability to distinguish DES-induced effects from indicators for using DES (i.e., an underlying hormonal imbalance). Nevertheless, exposure to DES during pregnancy does not appear to appreciably increase the risk of breast cancer.
In Utero Exposure
It has also been hypothesized that increased maternal estrogen levels during pregnancy may be associated with an increased probability of breast cancer in daughters. However, there are limited empirical data to confirm this hypothesis. To date, there is no evidence of an association between in utero DES exposure and increased risk of breast cancer in adulthood because the relevant birth cohorts of DES offspring have not reached the age range at highest risk for breast cancer. Only indirect evidence has been used to suggest that intrauterine exposure to estrogens may be associated with subsequent increased risk of breast cancer. Correlations between endogenous serum estrogen levels during pregnancy in certain populations and breast cancer risk in the daughters may be useful in evaluating the potential association between in utero DES exposure and breast cancer. Significantly lower (i.e., 30%) serum estrogen levels in pregnancy have been reported in younger women (<20 years) compared with older women (20 to 29 years). These findings, together with evidence showing an association between later maternal age at birth and increased breast cancer risk in daughters have been used to suggest that in utero exposure to the potent, synthetic estrogen, DES, may be associated with increased breast cancer risk. However, this is entirely hypothetical and confirmation of this must await the results of studies now in progress, of women exposed in utero to DES as they reach the age of greatest breast cancer risk.
- Environmental endocrine modulators and human health: an assessment of the biological evidence, Critical reviews in toxicology, NCBI PubMed, PMID: 9557209, 1998.
- Featured image Samuel Zeller.