Proceedings of the Summit on Environmental Challenges to Reproductive Health and Fertility
Abstract
DES is but one example of how exposure to EDCs can disrupt developing organ systems and cause abnormalities, many of which only appear much later in life or in the subsequent generation.
Prenatal exposure to diethylstilbestrol (DES), a synthetic estrogen and thus EDC, provides an unfortunate example of developmental programming. DES was given to U.S. pregnant women between 1938 and 1971 under the erroneous assumption that it would prevent pregnancy complications. In fact, in utero exposure to DES alters the normal programming of gene families, such as Hox and Wnt, that play important roles in reproductive tract differentiation. As a result, female offspring exposed to DES in utero are at increased risk of clear cell adenocarcinoma of the vagina and cervix, structural reproductive tract anomalies, infertility and poor pregnancy outcomes, while male offspring have an increased incidence of genital abnormalities and a possibly increased risk of prostate and testicular cancer. These observed human effects have been confirmed in numerous animal models which have also provided information on the toxic mechanisms of DES. Animal experiments have also predicted changes later found in DES-exposed humans, such as oviductal malformations, increased incidence of uterine fibroids and second-generational effects such as increased menstrual irregularities and possibly ovarian cancer in DES-granddaughters and increased hypospadias in DES-grandsons.
DES is but one example of how exposure to EDCs can disrupt developing organ systems and cause abnormalities, many of which only appear much later in life or in the subsequent generation, such as endometriosis, fibroids and breast, cervical and uterine cancer in women; poor sperm quality and increased incidence of cryptorchidism and hypospadias in men; and subfertility and infertility in men and women.
The majority of DES-exposed women do not perform monthly breast-self examinations
DES Follow-up Study Summary
The majority of DES-exposed women do not perform monthly breast-self examinations.
The purpose of this paper was to determine if women exposed in utero to Diethylstilbestrol (DES) are more likely than unexposed women to receive recommended or additional breast cancer screening examinations.
Data from the study cohort were used to assess the degree of recommended compliance of breast cancer screenings was found in 3,140 DES exposed and 826 unexposed women. Participants were enrolled at four sites: Houston, Boston, Rochester, and Los Angeles. The data from the mailed questionnaires that included the reported frequency from 1990 through 1994 of breast-self examinations (BSEs), clinical breast examinations (CBEs), and mammograms was analyzed.
The results showed that the DES-exposed women exceeded annual recommendations for CBEs among women without a history of benign breast disease compared with unexposed women. There were no other statistically significant differences between exposed and unexposed women who reported performing BSEs, CBEs (less than 40 years of age), and mammographies, regardless of benign breast disease history.
Although this study showed that the majority of DES-exposed women receive breast cancer screenings at least at recommended intervals, it also showed that over two thirds do not perform monthly BSEs. It is recommended that Future efforts should be focused on further educating this and other at-risk populations through mailed reminders and during patient consultations on the benefits of screening examinations.
2009 Study Abstract
Purpose: To determine if women exposed in utero to diethylstilbestrol (DES) are more likely than unexposed women to receive recommended or additional breast cancer screening examinations.
Methods: 1994 Diethylstilbestrol-Adenosis (DESAD) cohort data are used to assess the degree of recommended compliance of breast cancer screenings found in 3140 DES-exposed and 826 unexposed women. Participants were enrolled at four sites: Houston, Boston, Rochester, and Los Angeles. Logistic regression modeling was used to analyze mailed questionnaire data that included reported frequency over the preceding 5 years (1990-1994) of breast-self examinations (BSEs), clinical breast examinations (CBEs), and mammograms.
Results: DES-exposed women exceeded annual recommendations for CBEs (aOR 2.20, 95% CI, 1.04-4.67) among women without a history of benign breast disease (BBD) compared with unexposed women. There were no other statistically significant differences between exposed and unexposed women who reported performing BSEs, CBEs (<40 years of age), and mammographies, regardless of BBD history.
Conclusions: The majority of DES-exposed women receive breast cancer screenings at least at recommended intervals, but over two thirds do not perform monthly BSEs. Future efforts should be focused on further educating this and other at-risk populations through mailed reminders and during patient consultations on the benefits of screening examinations.
Sources
Breast cancer screening in women exposed in utero to diethylstilbestrol,NCBI, PMID: 19361323, 2009 Apr;18(4):547-52. doi: 10.1089/jwh.2007.0580. Full text PMC2857514.
Prenatal exposure to DES increases risk of male urogenital abnormalities
DES Follow-up Study Summary
Prenatal exposure to DES increases risk of male urogenital abnormalities.
One of the most frequently asked questions from DES exposed families is whether the sons have had any adverse health effects. For that reason, our collaborative follow-up has included over 1,000 DES-exposed sons and over 1,000 other men of the same ages who were never exposed to DES. These men have been completing mailed questionnaires on the same schedule as women in the study, in 1994, 1997, 2001, and 2006. Some of the questions are the same and some are different. The men were asked whether they had ever been diagnosed with any of a list of urogenital abnormalities. These abnormalities were studied more than 20 years ago in both the offspring of mothers from the University of Chicago DES clinical trial and in a group of sons born to mothers at the Mayo Clinic. The two studies reported different findings, with the University of Chicago follow-up finding a higher prevalence of abnormalities in the DES-exposed sons and the Mayo Clinic study finding no difference between DES-exposed and unexposed sons. We thought we might be able to clarify this question with data from the entire collaborative cohort – including the Mayo sons, the Chicago sons, and additional sons from women who gave birth in Massachusetts.
We found that urogenital abnormalities were fairly rare among DES-exposed sons, as is true for the general U.S. population. However, DES-exposed sons did have a higher prevalence of both undescended testicle and epididymal cyst. They were two times as likely to have had one of those conditions as were unexposed men. For both of these conditions, the prevalence was highest if son was exposed during the first 10 weeks of gestation. In men born at the Mayo clinic, DES exposure was not significantly associated with these conditions overall, but there was a significant association with undescended testicle and epididymal cyst for sons exposed early in gestation. In the University of Chicago clinical trial, the protocol was to give DES as soon as a pregnancy was identified and for use to continue until the last weeks of pregnancy. This same protocol was typical in Boston and in some other regions of the U.S. It was not the usual protocol at the Mayo Clinic, however, where women usually began DES later in pregnancy and took it for only a few months. Differences in patterns of use may explain the conflicting findings in earlier studies of urogenital abnormalities in sons. Our conclusion is that DES-exposed sons do indeed have a higher risk of certain urogenital abnormalities particularly if they were exposed in the early months of fetal development. Fortunately, we and others have already shown that prenatal DES exposure does not affect fertility in men, even in those men with these urogenital abnormalities.
Because the sons are now adults, they were also asked if they had ever been diagnosed with infection or inflammation of the urogenital organs. Prenatal DES exposure was not associated with occurrence of infection or inflammation of the prostate, urethra, or epididymus, or with benign prostatic hypertrophy (enlarged prostate). DES-exposed sons were approximately two and a half times more likely to have had an infection or inflammation of the testes. We do not know the reasons for such an increase. It is possible that minimal structural abnormalities, such as minor obstructions, could explain the increase in infection and inflammation. We will continue to investigate these conditions, especially benign prostatic hypertrophy, as men in the study grow older.
2009 Study Abstract:
BACKGROUND: Diethylstilbestrol (DES), a synthetic estrogen widely prescribed to pregnant women during the 1940s70s, has been shown to cause reproductive problems in the daughters. Studies of prenatally-exposed males have yielded conflicting results.
METHODS: In data from a collaborative follow-up of three U.S. cohorts of DES-exposed sons, we examined the relation of prenatal DES exposure to occurrence of male urogenital abnormalities. Exposure status was determined through review of prenatal records. Mailed questionnaires (1994, 1997, 2001) asked about specified abnormalities of the urogenital tract. Risk ratios (RR) were estimated by Cox regression with constant time at risk and control for year of birth.
RESULTS: Prenatal DES exposure was not associated with varicocele, structural abnormalities of the penis, urethral stenosis, benign prostatic hypertrophy, or inflammation/infection of the prostate, urethra, or epididymus. However, RRs were 1.9 (95% confidence interval 1.13.4) for cryptorchidism, 2.5 (1.54.3) for epididymal cyst, and 2.4 (1.54.4) for testicular inflammation/infection. Stronger associations were observed for DES exposure that began before the 11th week of pregnancy: RRs were 2.9 (1.65.2) for cryptorchidism, 3.5 (2.06.0) for epididymal cyst, and 3.0 (1.75.4) for inflammation/infection of testes.
CONCLUSION: These results indicate that prenatal exposure to DES increases risk of male urogenital abnormalities and that the association is strongest for exposure that occurs early in gestation. The findings support the hypothesis that endocrine disrupting chemicals may be a cause of the increased prevalence of cryptorchidism that has been seen in recent years.
Sources:
Urogenital abnormalities in men exposed to diethylstilbestrol in utero: a cohort study,NCBI, PMID: 19689815, 2009 Aug 18;8:37. doi: 10.1186/1476-069X-8-37. Full text PMC2739506.
La situation de la médecine est très proche de celle de l’économie des années 2000
par Dominique Dupagne, janvier 2009
” … En revanche, dans l’affaire du Distilbène, des millions de femmes ont été touchées dans le monde alors que l’on savait dès 1945 que ce produit n’avait aucun intérêt pour traiter les menaces d’accouchement prématuré. La poursuite de la prescription du Distilbène aux femmes enceintes jusqu’en 1971 est inexcusable… ”
The orphan nuclear receptor small heterodimer partner mediates male infertility induced by diethylstilbestrol in mice
” The sexual function of male rodents can be impaired by in utero and/or neonatal exposure to external molecules that disrupt normal hormone functioning, giving rise to concerns that low-level exposure to such molecules might cause similar effects in humans. Examples of such molecules include the synthetic nonsteroidal estrogen DES, which was used as a treatment for various diseases until the mid 1990s, and BPA, which is found, among other places, in some plastic containers. “
2009 Study Abstract
Studies in rodents have shown that male sexual function can be disrupted by fetal or neonatal administration of compounds that alter endocrine homeostasis, such as the synthetic nonsteroidal estrogen diethylstilbestrol (DES). Although the molecular basis for this effect remains unknown, estrogen receptors likely play a critical role in mediating DES-induced infertility. Recently, we showed that the orphan nuclear receptor small heterodimer partner (Nr0b2), which is both a target gene and a transcriptional repressor of estrogen receptors, controls testicular function by regulating germ cell entry into meiosis and testosterone synthesis. We therefore hypothesized that some of the harmful effects of DES on testes could be mediated through Nr0b2. Here, we present data demonstrating that Nr0b2 deficiency protected mice against the negative effects of DES on testis development and function. During postnatal development, Nr0b2-null mice were resistant to DES-mediated inhibition of germ cell differentiation, which may be the result of interference by Nr0b2 with retinoid signals that control meiosis. Adult Nr0b2-null male mice were also protected against the effects of DES; however, we suggest that this phenomenon was due to the removal of the repressive effects of Nr0b2 on steroidogenesis. Together, these data demonstrate that Nr0b2 plays a critical role in the pathophysiological changes induced by DES in the mouse testis.
Sources and more information
Disrupting male fertility, sciencedaily, November 18, 2009.
The orphan nuclear receptor small heterodimer partner mediates male infertility induced by diethylstilbestrol in mice,American Society for Clinical Investigation, November 2, 2009.
Jusqu’en 1977, les médecins en France ont prescrit massivement du Distilbène aux femmes enceintes pour tenter d’éviter les fausses couches. Ce médicament était en fait très dangereux pour les enfants nés de ces grossesses.
Embodied Knowledge and the Transformation of Women’s Health Politics
In DES Daughters, Susan Bell recounts the experiences of this generation of DES-victims. In moving, heartfelt narratives, she presents the voices of those women who developed cancer, those who were cancer-free but have concerns about becoming pregnant, and those who suffered other medical and/or reproductive difficulties.
What Bowdoin Books says
” Susan Bell‘s book tells a story about women who attained legendary status in the annals of medicine. They were exposed prenatally to what was promoted as a benign and exciting new wonder drug prescribed to millions of American women to prevent miscarriage from the 1940s to the 1970s. This new reproductive technology—the synthetic estrogen DES— proved to be ineffective in preventing miscarriage, and in the long run it has had profound and damaging consequences for children, especially daughters of the women for whom it was prescribed (Dieckmann et al. 1953; Giusti, Iwamoto, and Hatch 1995). In 1971, medical scientists observed an association between prenatal exposure to DES and a rare form of vaginal cancer (clear cell adenocarcinoma) in women under age twenty; using available medical categories, they identified this synthetic estrogen as the first “transplacental carcinogen” (Herbst, Ulfelder, and Poskanzer 1971). “DES Daughters”, as these women are now called, are also at risk for poor reproductive outcomes, including ectopic pregnancy, miscarriage, premature birth, and stillbirth (Giusti, Iwamoto, and Hatch 1995). Almost forty years later, DES-related cancer remains rare, but reproductive tract problems—including menstrual irregularities, poor reproductive outcomes, and structural or cellular anomalies—are common among DES Daughters. ” Sources: Bowdoin Books
