Genetic variation in sensitivity to DES and breast cancer risk

Extent of variation in responses to DES among strains of rodents

2018 Study Abstract

Breast cancer risk is intimately intertwined with exposure to estrogens. While more than 160 breast cancer risk loci have been identified in humans, genetic interactions with estrogen exposure remain to be established. Strains of rodents exhibit striking differences in their responses to endogenous ovarian estrogens (primarily 17β-estradiol). Similar genetic variation has been observed for synthetic estrogen agonists (ethinyl estradiol) and environmental chemicals that mimic the actions of estrogens (xenoestrogens).

This review of literature highlights the extent of variation in responses to estrogens among strains of rodents and compiles the genetic loci underlying pathogenic effects of excessive estrogen signaling.

Genetic linkage studies have identified a total of the 35 quantitative trait loci (QTL) affecting responses to 17β-estradiol or diethylstilbestrol in five different tissues. However, the QTL appear to act in a tissue-specific manner with 9 QTL affecting the incidence or latency of mammary tumors induced by 17β-estradiol or diethylstilbestrol.

Mammary gland development during puberty is also exquisitely sensitive to the actions of endogenous estrogens. Analysis of mammary ductal growth and branching in 43 strains of inbred mice identified 20 QTL. Regions in the human genome orthologous to the mammary development QTL harbor loci associated with breast cancer risk or mammographic density.

The data demonstrate extensive genetic variation in regulation of estrogen signaling in rodent mammary tissues that alters susceptibility to tumors. Genetic variants in these pathways may identify a subset of women who are especially sensitive to either endogenous estrogens or environmental xenoestrogens and render them at increased risk of breast cancer.

Responses to DES among strains of rodents

…”Long-term exposure to diethylstilbestrol (DES) increased ductal branching to a similar extent in wild type BALB/cJ and 129/SvEv female mice but no mammary tumors were observed in either strain.” …

…”ACI rats also developed mammary tumors with chronic exposure to 17β-estradiol or DES.”…

…”While estrogen agonists induce proliferative responses in mammary, uterine and pituitary, they cause regression in other tissues. DES induced thymic regression in both C57BL/6 and BALB/c strains. Although the strains differed in initial thymus weights, both exhibited similar ~1.5 g decreases following DES treatment. In rats, the F433 strain was most responsive in pituitary and uterine tissues, but DES-induced thymic regression was greatest in the SD strain compared to F344 and BN.”…

… “In contrast, ACI rats have a persistent proliferative response to DES in mammary epithelium without a compensatory increase in apoptosis and was associated with extensive hyperplasia. Thus, strains of rodents appear to have adopted different strategies to achieve tissue homeostasis. The ability to attenuate signaling also appears to differ among tissues. An example is the formation of neoplastic lesions in the uterus of 129/SvEv mice treated with DES, but no lesions developed in the mammary glands of these mice.”…

Genetic variants determining responses to DES

…”When pituitary weight was used as a phenotypic indicator of estrogen stimulated lactotroph proliferation, five QTL were identified upon characterization of DES treated female F2 progeny generated in an intercross between F344 and BN rats. One additional QTL was mapped during characterization of backcross progeny generated using these same strains. When ACI rats were utilized as the sensitive strain, six QTL were mapped upon characterization of DES treated male F2 progeny generated in reciprocal intercrosses between ACI and COP rats…”

…”A second QTL, Eutr2 was mapped to the same region of chromosome 5 through characterization of DES treated congenic rats in which BN alleles across proximal chromosome 5 were introgressed onto the F344 genetic background.”…

…”Treatment with DES identified QTL influencing repression on chromosome 10 (Esta1) and chromosome 2 (Esta2 and Esta3) in a study using male F2 progeny from a BN x ACI intercross. QTL associated with regression of testes induced by DES were identified on chromosomes 1 and 7 in recombinant inbred male rats.”…

Sources

  • Full study (free access) : Genetic variation in sensitivity to estrogens and breast cancer risk, Mammalian genome : official journal of the International Mammalian Genome Society, NCBI PubMed PMC5936622, 2018 Feb 29.
  • Positions of QTL regulated responses to estrogens in 5 tissues in rats featured image credit figure/F1.
DES DIETHYLSTILBESTROL RESOURCES

Third generation offspring – granddaughters and grandsons

Current perspective of diethylstilbestrol (DES) exposure in mothers and offspring

Highlights

  • Diethylstilbestrol (DES) is a synthetic, non-steroidal estrogen of the stilbestrol group acting as an endocrine disruptor.
  • Adverse pregnancy outcomes, infertility, cancer, and early menopause have been identified in women exposed to DES, their offspring, and subsequent generations.
  • DES is one of the major disasters in medicine and it is mandatory to tackle and promote programs of DES-related cancer prevention.

2017 Review Abstracts

Diethylstilbestrol (DES) was an orally active estrogen prescribed to the pregnant women to prevent miscarriages. DES is known as a ‘biological time bomb’ and long-term effects of DES have been recorded in the mothers exposed to DES and their offspring (DES-daughters and DES-sons). Adverse pregnancy outcomes, infertility, cancer, and early menopause have been discovered in women exposed to DES, and some events occur in their offspring and subsequent generations. An increased risk of breast cancer is not limited to the DES-exposed daughters.

We were told that it “could take over 50 years” to detect the effects of DES exposure in future generations, due to the length of time required for diseases to manifest. It is predicted that cross-generational responses to the exposure of DES are possible due to epigenetic changes in the DNA.

The studies on the cohort of grandchildren (grandsons and granddaughters) whose mothers were exposed to DES prenatally (i.e., grandchildren had no direct DES exposure) are limited as they have just reached the age when relevant health problems could be studied.

It seems that the DES 3rd generation has also an increased risk for cancer. The epigenetic effects of DES could be manifested in this generation. DES could affect daughters of the exposed mothers as their oocytes might be developing at the critical stage, but transgenerational effect of DES, i.e., children of sons or daughters of DES mothers, may have an epigenetic basis.

In opposition to developmental epigenetics transgenerational epigenetics implies an absence of resetting of epigenetic states between generations. In fact,the exposure to endocrine disruptor chemical compounds is associated with abnormal DNA methylation and other epigenetic modifications, as well as altered expression of genes important for development and function of reproductive tissues as recently observed by Ho et al.

In a multi-center study, an increase of congenital disabilities in the sons and daughters of the 3rd generation was observed. Currently, there are no large human studies that show adverse events of DES for granddaughters. Kaufman et al. conducted a small cohort study on 28 DES granddaughters and found neither CCA nor abnormalities of the lower genital tract. On the other hand, granddaughters may have more menstrual problems and higher infertility rate compared to non-exposed granddaughters. Direct maternal DES exposure during pregnancy can cause not only an alteration to the reproductive capacity of the woman, but also this alteration may be passed on to next generation, a phenomenon that is called ‘DES granddaughter effect’ and DES granddaughters may also harbor a higher risk of ovarian cancer rather than breast cancer. In DES grandsons, the incidence of hypospadia is 20 times higher than unexposed grandsons, but the risk of developing such anomaly seems to be low.

There is an urgent need to find ways to stop the inheritance cycle of DES and prevent adverse effects of DES in the future generations. The present article reviews the health implications of DES exposure and screening exams currently recommended to DES daughters and their offspring.

Sources

  • Current perspective of diethylstilbestrol (DES) exposure in mothers
    and offspring
    , NCBI PubMed, 28461243, August 2017.
  • Image credit gstatic.
DES DIETHYLSTILBESTROL RESOURCES

Diethylstilboestrol – A long-term legacy

Transgenerational effect of DES, i.e., children of sons or daughters of DES mothers, may have an epigenetic basis

2012 Study Abstract

Diethylstilboestrol (DES) is an endocrine disrupter which causes cancer in rodents.

It was prescribed in large amounts to treat women with gynaecological problems; some of the daughters of these women subsequently developed a rare cancer (vaginal clear cell adenocarcinoma) while genital abnormalities were found in some of the sons.

It was used for decades in livestock feed and this may have contaminated the food chain leading to the exposure of the more general population.

DES appears to cause epigenetic effects in animals and there is some evidence that this also occurs in man.

The mechanisms of carcinogenesis are complex and the effects are difficult to prove due to the background of dietary and environmental phyto- and xenooestrogens.

It has been suggested that, like other endocrine disrupters, DES may have acted as an obesogen in the human population.

Sources

DES DIETHYLSTILBESTROL RESOURCES

Reproductive and hormone-related outcomes in DES third generation women

Reproductive and hormone-related outcomes in women whose mothers were exposed in utero to diethylstilbestrol (DES): A report from the US National Cancer Institute DES Third Generation Study

2019 Study Highlights

  • Studies of mice indicate intergenerational effects of DES exposure; i.e., effects in the offspring of prenatally DES-exposed animals.
  • We assessed DES exposure in relation to outcomes in a cohort of third generation women whose mothers were prenatally DES-exposed and unexposed.
  • Results suggested DES-exposed third generation women have increased risks of menstrual aberrations, preterm birth, and possibly ectopic pregnancy.
  • The data did not indicate an increase in same-sex orientation in DES-exposed third generation women.
  • Menstrual aberration and preterm birth in the DES-exposed third generation suggest intergenerational effects of endocrine disrupting chemicals in humans.

Abstract

Background
Animal studies suggest that prenatal exposure to diethylstilbestrol (DES) causes epigenetic alterations in primordial germ cells that affect the next generation, but human studies are sparse.

Methods
We assessed hormonally mediated outcomes in third generation women whose mothers were prenatally DES-exposed and unexposed.

Results
Compared to the unexposed, DES-exposed third generation women had an increased risk of irregular menses and amenorrhea; the respective prevalence ratios and 95% confidence intervals (CI) in follow-up data were 1.32 (95% CI: 1.10, 1.60) and 1.26 (95% CI: 1.06, 1.49); associations were more apparent in third generation women whose prenatally DES-exposed mothers were affected by vaginal epithelial changes. The follow-up data also indicated an association with preterm delivery (relative risk (RR): 1.54; 95% CI: 1.35, 1.75).

Conclusion
DES third generation women may have an increased risk of irregular menstrual cycles, amenorrhea, and preterm delivery, consistent with inter-generational effects of endocrine disrupting chemical exposure in humans.

Sources

  • Reproductive and hormone-related outcomes in women whose mothers were exposed in utero to diethylstilbestrol (DES): A report from the US National Cancer Institute DES Third Generation Study, ScienceDirect doi.org/10.1016/j.reprotox.2018.12.008, Reproductive Toxicology Volume 84, March 2019, Pages 32-38.
  • Featured image credit ars.els-cdn.
DES DIETHYLSTILBESTROL RESOURCES

Breast cancer risk for women exposed in utero and their offspring

Diethylstilbestrol: Potential health risks for women exposed in utero and their offspring

2017 Study Abstract

An increased risk of breast cancer has been well documented for women who took DES during pregnancy, and is estimated to be 30% greater than in unexposed women.

Long-term US studies of women exposed in utero reveal an increased risk of breast cancer in women age 40 years and older, with a hazard ratio of 1.82 (95% CI, 1.04-3.18) when compared with unexposed women. European follow-up studies do not support the finding of an increased breast cancer risk in women exposed to DES in utero. However, this may be due to the fact that the European cohort of women studied were 10 years younger than the American cohort and thus, at the time, included many women under age 40 years.

Animal studies suggest a transgenerational risk specifically for breast cancer in female offspring of women exposed to DES in utero, but this has not been supported by current patient data from United States or European follow-up studies.

Sources

DES DIETHYLSTILBESTROL RESOURCES

DES genotoxicity causes specific mutations known to induce high risk of breast cancer

Exposure to diethylstilbestrol during sensitive life stages: a legacy of heritable health effects

2013 Abstract

The legacy of the adverse effects that stem from DES administration to pregnant women in the 1950s to 1970s has not completely formed. The male and female offspring of those women have reported significant fertility, cancer, and birth-related outcomes, but the cancer outcomes are not completely understood, with few exceptions (CCA and breast cancer in women over 40 yr old).

Information on DES mothers and daughters, in addition to substantial animal data, earned DES a place in the First Annual Report on Carcinogens, a critical review of carcinogenic compounds produced by the National Toxicology Program, in 1980 and was noted by the International Agency for Research on Cancer in their Monographs (IARC 1974). As the male and female offspring of those women age, the overall effect of DES on reproductive cancers will be better understood. Even more important to understand is the potential effect of this endocrine disruptor and carcinogen on the 3rd generation offspring who were not directly exposed, but may be affected in a heritable way through estrogen reprogramming and DNA modification.

Further research is needed to indicate the mechanisms of action on the target tissues, so that future pharmaceuticals/environmental estrogen mimics will avoid these pathways, leading to healthier future generations. Future studies should focus on common target tissue pathways affected and the health of the DES grandchildren.

Walker and Haven (1997) predicted that “if the high intensity of DES multigenerational carcinogenicity seen in mice is applicable to the human population, this is a health problem of major proportions.” They go on to say that it “could take over 50 years” to detect the effects in future generations, due to the length of time required for diseases such as cancer to manifest. It is predicted that cross-generational responses to DES exposure are possible due to epigenetic changes in the DNA and that the “germ cell pool could have become massively contaminated”. For example, early exposure to EDCs, like DES, is thought to reprogram mouse female reproductive tract development and affect how the reproductive tract responds to endogenous estrogens later in life (Ma 2009; Hilakivi-Clarke et al., 2013). They (Walker and Haven 1997) suggest that “environmental estrogens may be more potent than previously suspected, due to synergistic action from concurrent exposures.”

The studies on the cohort of men (grandsons) and women (granddaughters) whose mothers were exposed prenatally to DES (grandchildren had no direct exposure) are limited as they are just beginning to reach the age when relevant health problems can be studied (CDC 2012). Studies that have been performed contain preliminary data, as the power is low. Therefore, the main sources of information for third generation effects are rodent studies. In general, multi-generational mouse studies have shown an increased susceptibility to tumor formation in the third generation which suggests that DES grandchildren are also at an increased risk for cancer

Sources

  • Full study (free access) : Exposure to Diethylstilbestrol during Sensitive Life Stages: A legacy of heritable health effects, Birth Defects Res C Embryo Today, NCBI PubMed PMC3817964, 2013 Nov 5.
  • Mechanisms involved in breast cancer etiology featured image credit PMC3817964/figure/F2.
DES DIETHYLSTILBESTROL RESOURCES

Breast cancer epidemiology : summary and future directions

Epidemiologic reviews, 1993

Abstract

The most common cancer in US women and the 2nd leading cause of cancer death is breast cancer.

Between 1980-1987 in the US. age-adjusted incidence rates of breast cancer rose rapidly. They are also rising rapidly in several Asian countries (e.g., in Japan) which have the lowest incidence rates. These rapid increases may mean that environmental factors are responsible.

Incidence rates rise greatly with age until the late 40s. US women at highest risk of breast cancer are Jewish women, urban women, single women, and women living in the northern US. Women at lowest risk include Mormon and Seventh-Day Adventist women, Hispanic and Asian women, rural women, women living in the southern US, and married women.

Factors that have a relative risk greater than 2 are

  • mother and sister with history of breast cancer, especially if diagnoses at an early age;
  • atypical epithelial cells in nipple aspirate fluid;
  • nodular densities on the mammogram;
  • history of cancer in 1 breast;
  • mother or sister with history of breast cancer;
  • biopsy-confirmed benign proliferative breast disease;
  • hyperplastic epithelial cells without atypia in nipple aspirate fluid;
  • and radiation to chest in moderate to high doses.

Ovarian hormones appear to stimulate cell division in the breast, thus elevated levels may be risk factors.

Exogenous hormones may also increase the risk. Women are exposed to these exogenous hormones through

  • estrogen replacement therapy,
  • progestin only pills,
  • oral contraceptives,
  • long-acting injectable contraceptives,
  • and diethylstilbestrol.

Postmenopausal obesity increases the risk while premenopausal obesity decreases the risk. A high fat diet in childhood and adolescence may increase the risk. Alcohol drinking may also increase the risk.

Older, white, and nulliparous women are more likely to have estrogen receptor-positive cancers.

Breast cancer in males tends to share the same risk factors as well as its own unique factors.

Prevention of postmenopausal obesity is the only established primary prevention effort. Screening is the only secondary prevention means.

Sources

DES DIETHYLSTILBESTROL RESOURCES

Increased Breast Cancer risk in DES-Exposed Progeny

Maternal exposure to diethylstilbestrol during pregnancy and increased breast cancer risk in daughters, 2014

Study Summary

The idea that susceptibility to breast cancer is determined not only through inherited germline mutations but also by epigenetic changes induced by alterations in hormonal environment during fetal development is gaining increasing support. Using findings obtained in human and animal studies, this review addresses the mechanisms that may explain why daughters of mothers who took synthetic estrogen diethylstilbestrol (DES) during pregnancy have two times higher breast cancer risk than women who were not exposed to it. The mechanisms likely involve epigenetic alterations, such as increased DNA methylation and modifications in histones and microRNA expression.Further, these alterations may target genes that regulate stem cells and prevent differentiation of their daughter cells. Recent findings in a preclinical model suggest that not only are women exposed to DES in utero at an increased risk of developing breast cancer, but this risk may extend to their daughters and granddaughters as well. It is critical, therefore, to determine if the increased risk is driven by epigenetic alterations in genes that increase susceptibility to breast cancer and if these alterations are reversible.

Abstracts

In this review, findings related to in utero DES exposure and breast cancer are discussed for the purpose of weighing evidence as to whether fetal hormonal environment can impact breast cancer risk in women several decades later. Since causal studies can readily be performed using animal models, findings obtained in DES-exposed mouse and rat offspring also are discussed. Importantly, animal studies were done prior to any epidemiological studies addressing a possible link between maternal DES exposure and breast cancer risk among daughters could be performed. By the 1980s, exposed daughters in the cohorts began to be old enough to develop breast cancer and several human studies have been performed since to determine if maternal exposure to DES during pregnancy increases an offspring’s breast cancer risk.

…”The animal studies show that the doses of DES relevant to pregnant women increased later risk of developing mammary tumors. Specifically, female offspring of rat dams exposed to a total of 1.2 μg DES either on gestation week 2 or 3, to 0.6 μg or 4 μg DES on both gestation days 15 and 18 (all via injection), or via diet to 0.1, 1 or 10 ppm DES between gestation days 13 and 21 (week 3) exhibited increased mammary cancer risk. An increase in risk also was seen in rats exposed to a single dose of 0.1, 1 or 10 μg or less of DES at birth.” …

…”Importantly, in utero exposure to DES leads to an increase in terminal end buds (TEBs) numbers. It is thus possible that one of the mechanisms causing an increase in mammary cancer risk in DES offspring is an increase in the number of targets for malignant transformation.”…

…”Several published studies have investigated breast cancer risk in the daughters of DES mothers, the majority of which were cohort studies done in the US. As the women in the cohorts aged, their breast cancer risk grew higher, compared with matched non-exposed controls. The findings clearly indicate that after age 40 years the incidence of breast cancer is at least two-fold higher in the daughters of DES-exposed mothers. Many pregnant women in Europe and Australia also used DES, but the peak exposure occurred 10 to 20 years later than in the US, and this probably explains why a recent study done in Europe found a trend but not a significant increase in breast cancer risk among them. Once the European daughters reach the age when breast cancer is more commonly detected, they too are likely to exhibit a significant increase in breast cancer risk.”…

To summarize, animal and human studies have generated similar findings and indicate that there is a causal link between maternal exposure to DES during pregnancy and increased breast cancer risk among female offspring. According to animal studies, the increase in risk may reflect the presence of a higher number of TEBs in the mammary epithelium in the DES offspring. Baik and colleagues have proposed that the increase in mammary epithelial cells in in utero estrogen-exposed females is caused by a high number of mammary stem cells or an increase in their potential to generate daughter cells. Our unpublished data support this conclusion”

Epigenetic alterations induced by in utero diethylstilbestrol exposure

We and others have observed that the expression of DNA methyltransferases (DNMTs) is persistently altered in estrogen-regulated tissues following estrogenic exposures during early life. In utero exposure to DES is reported to increase the expression of DNMT1 in the epididymis and uterus. We found that DNMT1 expression is increased in the mammary glands of adult rat offspring of dams exposed to ethinyl estradiol during pregnancy. These changes provide a key regulatory layer to influence gene expression in the mammary gland and perhaps breast tumors of individuals exposed to DES or other estrogenic compounds in utero.

The effects of maternal diethylstilbestrol exposure are not limited to the F1 generation?

Some researchers have begun to investigate whether the effects of maternal DES exposure during pregnancy extend to the third generation in humans. Although there is no evidence that DES granddaughters have cervical and ovarian abnormalities similar to DES daughters, there is evidence that they may have more menstrual irregularities and a higher rate of infertility than non-exposed granddaughters. In addition, DES granddaughters may have a slightly higher risk of ovarian cancer. The granddaughters are still too young to assess whether they might also be at an increased risk of developing breast cancer.

Millions of women in the US, Europe and Australia have been exposed to DES in the womb, and consequently exhibit about a two times higher breast cancer risk than unexposed women. The increase in risk may not be limited to the DES-exposed daughters, but could also increase breast cancer risk in granddaughters and great granddaughters. Such outcome would be consistent with the findings we obtained in studies using a synthetic estrogen ethinyl estradiol (EE2). If DES has similar effects to ethinyl estradiol on the transgenerational increase in breast cancer risk, it is urgent to find ways to stop the cycle of inheritance, and also prevent breast cancer in DES-exposed granddaughters and great granddaughters.

To achieve this goal, we need to understand how maternal DES exposure during pregnancy increases a daughter’s breast cancer risk. A plausible model is proposed in the featured image. It is evident from studies done in animal models that in utero DES exposure induces epigenetic changes in reproductive tract tissues and the breast. DES exposure might also have induced epigenetic changes in primordial germ cells and consequently germ cells, and further be detectable in the somatic cells in granddaughters and great granddaughters. We are not aware of any study that has compared epigenetic changes in germ cells and the next generation somatic cells in individuals exposed to DES or other endocrine disruptors in utero. Second, we should investigate whether the transgenerational increase in breast cancer risk can be prevented with drugs that reverse epigenetic modifications. Our preliminary studies in mice suggest that this is achievable in daughters by using the well-tolerated and non-toxic histone deacetylase inhibitor valproic acid and DNMT inhibitor hydralazine. However, whether these compounds also prevent an increase in granddaughters and great granddaughters in experimental models remains to be investigated.

Sources

  • Full study (free access) : Maternal exposure to diethylstilbestrol during pregnancy and increased breast cancer risk in daughters, Breast cancer research : BCR, NCBI PubMed PMC4053091, 2014.
  • Featured image : Proposed model to explain an increase in breast cancer risk in daughters, and possibly granddaughters and great granddaughters, of mothers who took diethylstilbestrol during pregnancy. DES, diethylstilbestrol; TDLU, terminal ductal lobular unit; TEB, terminal end bud. PMC4053091/figure/F1.
DES DIETHYLSTILBESTROL RESOURCES

DES Implications for the Third Generation

image of Grandson

The Health Effects of Diethylstilbestrol Revisited

Abstract

“… DES has been associated with increased risk of reproductive tract tumors in third-generation mice, that is, mice whose grandmothers were exposed to DES. These tumors have included uterine adenocarcinomas and sarcomas and benign ovarian tumors in females as well as tumors in the rete testis in males.

By identifying persons with known exposure, as well as their children, potential participants for studies of the long-term effects of DES could also be identified. With appropriate samples and further research, greater knowledge of the health effects of DES on the children and grandchildren of women who took DES could be gained. Persons who may have been exposed to DES may find national websites and organizations (helpful to access current research and health information as it becomes available.”

Sources

  • The health effects of diethylstilbestrol revisited, Journal of obstetric, gynecologic, and neonatal nursing : JOGNN, NCBI PubMed, PMID: 16020417, 2005 Jul-Aug.
DES DIETHYLSTILBESTROL RESOURCES

Increased Risk of Cancer in DES Grandsons and Granddaughters

Offspring of women exposed in utero to diethylstilbestrol (DES): a preliminary report of benign and malignant pathology in the third generation, 2008

Abstract

BACKGROUND
Animal studies suggest that prenatal exposure to the synthetic estrogen diethylstilbestrol (DES) causes epigenetic changes that may be transmitted to the next generation. Specifically, these studies show an elevated incidence of reproductive tumors in the female offspring of prenatally-exposed mice.

METHODS
We assessed cancer and benign pathology diagnoses occurring in the offspring of women whose prenatal exposure to DES (or lack of exposure) was verified by medical record. Our data arose from 2 sources: the mothers’ reports of cancers occurring in 8216 sons and daughters, and pathology-confirmed cancers and benign diagnoses self-reported by a subset of 793 daughters.

RESULTS
Although statistical power is limited, our data are consistent with no overall increase of cancer in the sons or daughters of women exposed in utero to DES. Based on pathology-confirmed diagnoses reported by the daughters, we saw no association between DES and risk of benign breast disease or reproductive tract conditions. Based on 3 cases, the incidence of ovarian cancer was higher than expected in the daughters of women exposed prenatally to DES.

CONCLUSIONS
Our data do not support an overall increase of cancer risk in the sons or daughters of women exposed prenatally to DES, but the number of ovarian cancer cases was greater than expected. While preliminary, this finding supports continued monitoring of these daughters.

Third-Generation Cohort

In 2001, the NCI assembled the third-generation cohort, consisting of the adult daughters (≥18 years of age) of DES-exposed and unexposed second-generation women.37 A review of parity records at all 5 study centers identified 763 exposed and 577 unexposed mothers of 966 exposed and 815 unexposed age-eligible daughters. About half of the mothers, 414 (54%) of the exposed and 297 (52%) of the unexposed, gave permission to contact 515 (53%) exposed and 383 (47%) unexposed daughters. The questionnaires, which queried daughters for hormonal and reproductive information, screening histories, and medical events (including gynecologic biopsies, breast biopsies, and cancer diagnoses), were returned by 793 (88%) of 898 daughters, including 463 (90%) exposed and 330 (86%) unexposed. Pathology reports were obtained to verify self-reported diagnoses and biopsies. A study-related review of histology slides confirmed 1 of 2 reported cases of borderline ovarian cancer. Slides were unavailable for the second case, which involved metastatic disease.

The confirmation of cancers occurring in the subset of adult daughters participating in the third-generation study was excellent. Of the 8 self-reported cancers, 7 (5 exposed, 2 unexposed) were confirmed by pathology; consent was not obtained to confirm a melanoma reported by an unexposed woman. For other conditions, confirmation of benign biopsies was reasonably good, generally exceeding 60%.

DES Follow-up Study Summary

Studies have shown a slightly increased risk of breast cancer in women who were given Diethylstilbestrol (DES) while they were pregnant. Their daughters, who were exposed to DES prenatally (before they were born), have an elevated risk of reproductive tract conditions, including a rare vaginal cancer. A question now being studied is whether DES health effects can be passed from the prenatally exposed women to their offspring (intergenerational transmission).

Studies in mice suggest that intergenerational transmission of DES health effects may be possible. Recent evidence indicates that prenatal exposure to DES may cause changes in the behavior of genes that influence hormones and the development of the female reproductive tract. These changes in gene behavior may be passed on to the next generation. Evidence for intergenerational transmission comes from mouse studies showing a higher number of reproductive tract tumors in the daughters of prenatally exposed female mice. We used the DES Follow-up Study data to assess whether cancer was more common in the offspring of women who were prenatally exposed to DES. Cancers affecting these offspring (the third generation) were identified using two approaches. First, we asked women participating in the DES Follow-up Study to report cancers diagnosed in their 8,216 third generation sons and daughters. Second, we asked 793 third generation daughters participating in the Third Generation Study to tell us about their cancers. We also asked the third generation daughters to tell us about their reproductive tract and breast biopsies. Next we confirmed the reported biopsies and cancers by checking the medical records of these third generation daughters.

Our results did not show an overall increase of cancer in the sons or in the daughters of prenatally DES-exposed women. However, based on only three cases, the number of ovarian cancers was higher than expected in the daughters of women exposed prenatally to DES. Because of the small number of cases, this result must be considered preliminary. The association may be a chance finding or may be due to the way in which the data were reported or collected. We did not find an association between DES and benign breast disease or reproductive tract conditions, but most of the women are too young for a meaningful assessment of these outcomes. Further follow-up is needed to assess whether prenatal DES exposure can affect the third generation in humans.

Sources

  • Full study (free access) : Offspring of Women Exposed In Utero to Diethylstilbestrol (DES): A Preliminary Report of Benign and Malignant Pathology in the Third Generation, Epidemiology doi: 10.1097/EDE.0b013e318163152a, March 2008.
  • Featured image credit oaks.journals.
  • NCIDES Follow-up Study Published Papers.
DES DIETHYLSTILBESTROL RESOURCES