Family History is Underestimated in Children with Isolated Hypospadias

A French Multicenter Report of 88 Families, 2018

In humans massive exposure to strong EDCs (DES) has effects through several generations and may contribute to some familial expression of hypospadias.

Abstract

Purpose
While familial forms of complex disorders/differences of sex development have been widely reported, data regarding isolated hypospadias are sparse and a family history is thought to be less frequent. We aimed to determine the frequency of hypospadias in families of boys with hypospadias, to establish whether these familial forms exhibit a particular phenotype and to evaluate the prevalence of genetic defects of the main candidate genes.

Materials and methods
A total of 395 boys with hypospadias were prospectively screened for a family history with a standardized questionnaire, extensive clinical description, family tree and sequencing of AR, SF1, SRD5A2 and MAMLD1.

Results
Family history of hypospadias was more frequent than expected (88 patients, 22.3%). In 17 instances (19.3%) familial hypospadias cases were multiple. Familial hypospadias was related to the paternal side in 59.1% of cases, consisting of the father himself (30.7%) as well as paternal uncles and cousins. Premature birth, assisted reproductive techniques, other congenital abnormalities and growth retardation were not more frequent in familial hypospadias than in sporadic cases. The severity of phenotype was similar in both groups. The results of genetic analysis combined with previous data on androgen receptor sequencing revealed that familial cases more frequently tend to demonstrate genetic defects than sporadic cases (5.68% vs 1.63%, p = 0.048).

Conclusions
Familial forms of hypospadias are far more frequent than previously reported. Even minor and isolated forms justify a full clinical investigation of the family history. Detecting these hereditary forms may help to determine the underlying genetic defects, and may improve followup and counseling of these patients.

References

DES DIETHYLSTILBESTROL RESOURCES

Harms to the third generation

Diethylstilbestrol (DES): also harms the third generation,
Prescrire international, 2016 Dec

Abstract

Diethylstilbestrol(DES) is a synthet- ic nonsteroidal oestrogen and endo- crine disruptor that was used in the 1950s-1970s to prevent spontaneous abortion, despite its lack of proven efficacy.

Millions of women worldwide took DES during pregnancy. In France, between 1951 and 1981, about 160 000 children were exposed to DES during the first trimester of their intrauterine life, and in some cases almost throughout the entire pregnancy. They are referred to as “DES daughters” and “DES sons“. In 2010, in France, about 25 000 DES daughters were aged 33 to 40 years: pregnancies among these women are foreseeable until about 2020.

In utero exposure to DES can have harmful effects. In particular, DES daughters have an increased risk of cancer and structural abnormalities of the uterus that can adversely affect their pregnancies.

What are the consequences of taking DES during pregnancy for the third generation, i.e. the children of DES children? To answer this question, we reviewed the available data in mid- 2016 using the standard Prescrire methodology.

According to a retrospective study conducted in France by Réseau DES France, published in 2016, which included 4409 DES grandchildren (2228 girls and 2181 boys) and about 6000 controls, about one-quarter of DES grandchildren are born prematurely. Preterm delivery exposes neonates to serious neonatal complications, including

  • neurosensory disorders,
  • disabilities
  • and increased neonatal mortality.

The more premature the baby, the greater the risk of complications. In the Réseau DES France study, cerebral palsy was more frequent in the DES grandchildren group: 59/10 000, versus 6/10 000 in the control group.

A study conducted in the United States in about 4500 DES daughters found that preterm delivery occurred at a frequency of about 26%, much higher than that reported in controls. Neonatal mortality was 8 times higher among DES grandchildren, and the risk of stillbirth was twice as high. Other smaller studies have also shown an increased risk of preterm birth.

A cohort study conducted in about 5000 DES grandchildren found that the risk of malformations of any type was higher than in the unexposed control group.

Epidemiological studies, conducted in several countries, found an increased frequency of hypospadias in DES grandsons. The relative risk was about 5 in the largest study. Other, less robust studies found no statistically significant difference.

Several studies in several countries have shown a twofold increase in the risk of oesophageal atresia or tracheo- oesophageal fistula in DES grandchildren.

The data on congenital heart defects or musculoskeletal malformations are limited and uninformative.

Epidemiological studies have not identified a significant increase in the risk of gynaecological anomalies or cancers in DES granddaughters.

Limited data are available on the risk of malformations in the children of DES sons. The data obtained in rodents exposed to DES (and other endocrine disruptors) make it entirely plausible that in utero exposure to DES, in humans too, provokes epigenetic effects that are passed on to future generations not directly exposed to DES.

In practice, these data should be discussed with DES daughters, their partners and healthcare teams so that appropriate monitoring, clinical management and follow-up can be arranged for both mother and baby. The harms of taking DES during pregnancy last for decades and affect future generations.

Sources

  • Diethylstilbestrol (DES): also harms the third generation, Prescrire international, NCBI PubMed PMID: 30758926, 2016 Dec 25.
  • Image credit Rod Long.
DES DIETHYLSTILBESTROL RESOURCES

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