In close collaboration with the DES Centre (an association of DES victims) a careful procedure was followed before this settlement was realised. The Dutch Expert Committee on DES-related Health Effects first reviewed the literature for evidence and established a list of disorders with a causal association with DES. For each DES-related disorder covered by the settlement, the appropriate compensation was determined by the attributive risk and the severity of the disease. The Dutch collective settlement is the result of close collaboration between all parties involved.
Contrary to the opinion expressed by ‘t Hoen and Dukes, we, as well as the Dutch DES Centre, strongly believe that the recently agreed collective settlement of diethylstilbestrol claims in the Netherlands is unique and highly beneficial for Dutch diethylstilbestrol victims. Our opinion is based on the large number of diethylstilbestrol-related disorders covered and the fact that individual women do not have to start an expensive and emotionally difficult legal procedure with uncertain outcome, which could last several years. Individual women can now be compensated on the basis of medical evidence of diethylstilbestrol exposure and the presence of a diethylstilbestrol-related disorder covered by the settlement.
A unique aspect of the Dutch collective settlement is that it also allows compensation for diseases with a weak but established association with diethylstilbestrol. DES mothers (those who took diethylstilbestrol during pregnancy) have a 1·35-fold increased risk of breast cancer. This implies that the attributable risk is 26%—ie, among DES mothers with breast cancer, one in four cases can be attributed to diethylstilbestrol. Since there is no way to identify the one woman whose breast cancer was indeed caused by diethylstilbestrol, it was agreed that all (living) DES mothers who developed (or will develop) breast cancer should be compensated, taking into account the attributable risk.
The proposed collective settlement was widely publicised among those exposed to diethylstilbestrol, and, of more than 100 000 affected, the Amsterdam court received only four objections. The court validated the diethylstilbestrol agreement and ruled against the four defendants. We regret that this information was not included the Comment.
We declare that we have no conflict of interest. ”
Flora E van Leeuwen, Elisabeth J M van Erp, Theo J M Helmerhorst, Peter A M Heintz,
Department of Epidemiology, Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, Netherland.
Necessity of close extended follow-up in the DES-exposed
2007 Study Abstract
Primary vaginal clear cell adenocarcinoma (CCA) is a rare gynecological malignancy occurring predominantly in young females with a history of diethylstilbestrol exposure in utero. Vaginal CCA commonly metastasizes to the lungs and the supraclavicular lymph nodes; however we present a rare case of diethylstilbestrol-induced vaginal CCA with cerebral metastases.
A 43-year-old woman with prenatal diethylstilbestrol exposure and history of vaginal CCA treatment 8 years prior to current presentation noted new onset headache and dizziness. MRI showed an enhancing mass in the right frontal lobe. Histopathology was consistent with CCA.
This case report highlights the necessity of close extended follow-up in patients with a history of vaginal CCA and demonstrates the potential for spread of primary vaginal CCA to the brain.
Sources and more information
Diethylstilbestrol (DES)-induced clear cell adenocarcinoma of the vagina metastasizing to the brain, Gynecologic oncology, NCBI pubmed 17292458, 105(1):273-6. Epub 2007 Feb 8.
Environmental chemicals are contributing to overweight and obesity
2007 Study Abstract
Xenobiotic and dietary compounds with hormone-like activity can disrupt endocrine signaling pathways that play important roles during perinatal differentiation and result in alterations that are not apparent until later in life. Evidence implicates developmental exposure to environmental hormone-mimics with a growing list of health problems. Obesity is currently receiving needed attention since it has potential to overwhelm health systems worldwide with associated illnesses such as diabetes and cardiovascular disease. Here, we review the literature that proposes an association of exposure to environmental endocrine disrupting chemicals with the development of obesity. We describe an animal model of developmental exposure to diethylstilbestrol (DES), a potent perinatal endocrine disruptor with estrogenic activity, to study mechanisms involved in programming an organism for obesity. This experimental animal model provides an example of the growing scientific field termed “the developmental origins of adult disease” and suggests new targets of abnormal programming by endocrine disrupting chemicals.
Summary and Conclusions
Taken together, our data supports the idea that brief exposure early in life to environmental endocrine disrupting chemicals, especially those with estrogenic activity like DES, increases body weight as the mice age. These data also suggest that these chemicals may contribute to overweight and obesity and other obesity-associated diseases such as type 2 diabetes and cardiovascular disease. Whether our results can be extrapolated to humans as the reproductive abnormalities from the DES mouse model did, remain to be determined but it provides a fruitful area of further research. In addition, the use of this animal model to study “obesogens” and mechanisms involved in altered weight homeostasis (direct and/or endocrine feedback loops, i.e., ghrelin, leptin, etc.) by environmental endocrine disrupting chemicals is an important basic research area that may be addressed by using this model. No longer can we assume than overweight and obesity are simply personal choices, but we have to consider that complex events including environmental chemicals are contributing to this mounting human health problem.
Developmental Exposure to Endocrine Disruptors and the Obesity Epidemic,Retha R. Newbold, Elizabeth Padilla-Banks, Ryan J. Snyder,1 Terry M. Phillips and Wendy N. Jefferson, Reprod Toxicol doi: 10.1016/j.reprotox.2006.12.010, NCBI PMCID: PMC1931509, 2007 Jan 17.
DiEthylStilbestrol DES, environmental estrogens and obesity
2007 Study Abstract
Dietary substances and xenobiotic compounds with hormone-like activity can disrupt the programming of endocrine signaling pathways that are established during perinatal differentiation. The consequences of this disruption may not be apparent until later in life but increasing evidence implicates developmental exposure to environmental hormone-mimics with a growing list of adverse health effects including reproductive problems and increased cancer risks. Obesity has recently been proposed to be yet another adverse health consequence of exposure to endocrine disrupting substances during development. There is a renewed focus on identifying contributions of environmental factors to the development of obesity since it is reaching worldwide epidemic proportions, and this disease has the potential to overwhelm healthcare systems with associated illnesses such as diabetes and cardiovascular disease. Here, we review the literature that proposes an association of perinatal exposure to endocrine disrupting chemicals, in particular those with estrogenic activity, with the development of obesity later in life. We further describe an animal model of developmental exposure to diethylstilbestrol (DES) to study mechanisms involved in programming for obesity. Our experimental data support the idea that adipocytes and the mechanisms involved in weight homeostasis are novel targets of abnormal programming of environmental estrogens, some of which are found in our foods as naturally occurring substances or inadvertently as contaminants.
Perinatal exposure to environmental estrogens and the development of obesity,Newbold RR1, Padilla-Banks E, Snyder RJ, Jefferson WN, Mol Nutr Food Res. 2007 Jul;51(7):912-7. NCBI PMID: 17604389.
DES mothers exposed early to high doses of DES had more sons than daughters
2007 Study Abstract
BACKGROUND: Diethylstilbestrol (DES), a synthetic estrogen widely prescribed to pregnant women during the mid-1900s, is a potent endocrine disruptor. Previous studies have suggested an association between endocrine-disrupting compounds and secondary sex ratio.
Data were provided by women participating in the National Cancer Institute (NCI) DES Combined Cohort Study. We used generalized estimating equations to estimate odds ratios (ORs) and 95% confidence intervals (CIs) for the relation of in utero DES exposure to sex ratio (proportion of male births). Models were adjusted for maternal age, child’s birth year, parity, and cohort, and accounted for clustering among women with multiple pregnancies.
The OR for having a male birth comparing DES-exposed to unexposed women was 1.05 (95% CI, 0.95-1.17). For exposed women with complete data on cumulative DES dose and timing (33%), those first exposed to DES earlier in gestation and to higher doses had the highest odds of having a male birth. The ORs were 0.91 (95% C, 0.65-1.27) for first exposure at > or = 13 weeks gestation to < 5 g DES; 0.95 (95% CI, 0.71-1.27) for first exposure at > or = 13 weeks to > or = 5 g; 1.16 (95% CI, 0.96-1.41) for first exposure at < 13 weeks to < 5 g; and 1.24 (95% CI, 1.04-1.48) for first exposure at < 13 weeks to > or = 5 g compared with no exposure. Results did not vary appreciably by maternal age, parity, cohort, or infertility history.
Overall, no association was observed between in utero DES exposure and secondary sex ratio, but a significant increase in the proportion of male births was found among women first exposed to DES earlier in gestation and to a higher cumulative dose.
Secondary sex ratio among women exposed to diethylstilbestrol in utero, NCBI, PMID: 17805421, 2007 Sep;115(9):1314-9. PMC1964903. Full text link.
In this 2007 research, prenatal DES exposure was not associated with a significant decrease in either fecundability or secondary sex ratio
Little is known about the influence of prenatal Diethylstilbestrol (DES) exposure on time to pregnancy or secondary sex ratio in men.
The authors evaluated these associations among men participating in the DES Combined Cohort Follow-up Study for whom exposure status was confirmed by medical record. In 2001, men provided data on their reproductive histories. Demographic, behavioral, and medical data were collected in 1994, 1997, and 2001.
Cox’s proportional hazards models with frailty were used to estimate fecundability ratios for time to pregnancy in relation to DES. Generalized estimating equations were used to estimate odds ratios for fathering a male birth in relation to DES. Models included potential confounders and accounted for multiple pregnancies contributed by each man.
Overall, DES was not associated with a delay in time to pregnancy (fecundability ratio = 0.95, 95% confidence interval: 0.86, 1.06). The odds ratio for fathering a male birth was 0.92 (95% confidence interval: 0.80, 1.04) comparing the exposed with the unexposed.
In conclusion, prenatal DES exposure was not associated with a significant decrease in either fecundability or secondary sex ratio.
Time to pregnancy and secondary sex ratio in men exposed prenatally to diethylstilbestrol, NCBI, PMID: 17596265, 2007 Oct 1;166(7):765-74. Epub 2007 Jun 27. Full text link.
A total of 143 exposed women and 49 unexposed women in the DES Combined Cohort Follow-up Study were diagnosed with cancer as of 2001.
Compared with breast cancer rates in the general US population, there was no overall higher risk among DES exposed women. Comparing exposed with unexposed women within the study, there was about a 30% increase in cancer risk but this finding could be due to chance. As reported in a previous article (Palmer 2006), breast cancer risk was elevated but only among women over 40 years of age. Exposed women had a risk of CCA that was nearly 40% higher than the general population, however; the incidence of CCA decreased substantially after age 25 compared with women 20 to 24 years old. Excluding CCA and breast cancer, the higher risk of cancer among the DES exposed women was about 20%, a result that could be due to chance. DES was not associated with higher risks of either endometrial or ovarian cancer. These data suggest that the DES associated increase in CCA rates remains elevated through the reproductive years. There was no consistent evidence of a higher risk for cancers other than CCA, and breast in older women.
Given that the population is still young, continued follow-up is necessary to assess the overall cancer risk associated with prenatal DES exposure.
Cancer risk in women prenatally exposed to diethylstilbestrol,NCBI, PMID: 17390375, 2007 Jul 15;121(2):356-60.
In utero exposure to DES is associated with a 50 % higher risk of preeclampsia
DES Follow-up Study Summary
Women exposed to Diethylstilbestrol (DES) in utero experience a greater risk of adverse reproductive events including infertility, ectopic pregnancies, spontaneous pregnancy losses and premature births. These complications may in part be due to prenatal effects of DES on the structure of the uterus or cervix. Preeclampsia, a common pregnancy complication characterized by maternal hypertension, and high levels of uric acid and protein, frequently involves the placenta not entirely attaching to the mother’s endometrium (implantation). DES-associated uterine abnormalities and possible alterations in immune function may adversely affect successful implantation.
The hypothesis that prenatal DES exposure is associated with preeclampsia risk was previously addressed in a small case-control study that reported a greater than two-fold risk in women who reported a history of DES exposure compared with those who did not. We used data from the National Cancer Institute DES Combined Cohorts Follow-up Study to readdress this issue. A total of 285 preeclampsia cases (210 exposed and 75 unexposed) occurred in 7313 live births (4759 DES exposed and 2554 unexposed). Prenatal DES exposure was associated with nearly a 50% elevation in preeclampsia risk in the daughters’ pregnancies. Taking into account differences in DES exposed and unexposed women in preeclampsia risk factors including age at the pregnancy, number of pregnancies, education, smoking, a measure of body fatness, and year of preeclampsia diagnosis, the risk was slightly lower, about 40%. The increased risk of preeclampsia associated with prenatal DES exposure was concentrated among women who developed preeclampsia in their first pregnancy (80% higher risk), those who were exposed to DES before 15 weeks of pregnancy (57% higher risk) and those who were treated with magnesium sulfate (over two times the risk). Among DES-exposed women who had a prior hysterosalpingogram (a procedure that allows physicians to view the reproductive organs), preeclampsia prevalence was higher in those with uterine abnormalities (12.4%) than in those without (7.7%). Our data suggest that prenatal DES exposure is associated with a slightly elevated risk of preeclampsia that is possibly due to a higher prevalence of uterine abnormalities in DES daughters.
Women exposed to diethylstilbestrol (DES) in utero experience a greater risk of adverse reproductive events including infertility, ectopic gestations, spontaneous pregnancy losses and premature births. These complications may in part be mediated through teratogenic effects, namely the structural uterine and cervical abnormalities that have been associated with in utero DES exposure. Preeclampsia, a common pregnancy complication characterized by maternal hypertension, hyperuricemia, and proteinuria frequently involves shallow placentation. Placental establishment requires cytotrophoblast invasion of the underlying stroma and blood vessels of the maternal endometrium, a process involving immune and angiogenic mechanisms. DES-associated uterine abnormalities and possible alterations in immune function (4-7) may adversely affect successful implantation.
The hypothesis that prenatal DES exposure is associated with preeclampsia risk was previously addressed in a small case-control study that reported a greater than two-fold risk in women who reported a history of DES exposure compared with those who did not.
2007 Study Abstract
To assess whether preeclampsia risk is elevated in pregnancies of diethylstilbestrol (DES)-exposed daughters.
This study used data from the National Cancer Institute DES Combined Cohorts Follow-up Study. A total of 285 preeclampsia cases (210 exposed and 75 unexposed) occurred in 7,313 live births (4,759 DES exposed and 2,554 unexposed). Poisson regression analysis estimated relative risks and 95% confidence intervals (CI) for preeclampsia adjusted for age at the index pregnancy, parity, education, smoking, body mass index, year of diagnosis, and cohort.
In utero DES exposure was associated with nearly a 50% elevation in preeclampsia risk. Adjustment for preeclampsia risk factors attenuated the relative risk slightly (1.42, 95% CI 1.04-1.94). The excess risk with DES was concentrated among women who developed preeclampsia in their first pregnancies (relative risk 1.81, 95% CI 1.17-2.79), who were exposed before 15 weeks of gestation (relative risk 1.57, 95% CI 1.11-2.23), and who were treated with magnesium sulfate (relative risk 2.10, 95% CI 0.82-5.42). Among DES-exposed women who had a prior hysterosalpingogram, preeclampsia prevalence was higher in those with uterine abnormalities (12.4%) than in those without (7.7%).
These data suggest that in utero exposure to DES is associated with a slightly elevated risk of preeclampsia, and that one possible biological mechanism involves uterine abnormalities.
Preeclampsia risk in women exposed in utero to diethylstilbestrol,NCBI, PMID: 17601905, 2007 Jul;110(1):113-20.