Tag: hypospadias

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Pharmacologic and Environmental Endocrine Disruptors in the Pathogenesis of Hypospadias

a Review – Current environmental health reports, 2018

Abstract

PURPOSE OF REVIEW

Endocrine disrupting chemicals (EDCs) potentially have a role in causing hypospadias malformation through modifiable in-utero exposure. Considering the emerging literature on the role of potential endocrine disrupting substances on the occurrence of hypospadias and the potential to inform public health efforts to prevent the occurrence of these malformations, we have summarized the current literature, identified areas of consensus, and highlighted areas that warrant further investigation.

RECENT FINDINGS

Pharmaceuticals, such as diethylstilbestrol, progestin fertility treatments, corticosteroids, and valproic acid, have all been associated with hypospadias risk. Data on exposure to dichlorodiphenyltrichloroethane and hexachlorobenzene pesticides, as well as non-persistent pollutants, particularly phthalates, is less consistent but still compelling. Improving exposure assessment, standardizing sample timing to relevant developmental windows, using clear case identification and classification schemes, and elucidating dose-response relationships with EDCs will help to provide clearer evidence. Promising directions for future research include identification of subgroups with genetic hypospadias risk factors, measurement of intermediate outcomes, and study of EDC mixtures that will more accurately represent the total fetal environment.

Exogenous Sex Steroids

Estrogens were the first chemicals to be studied in the context of maternal exposure and hypospadias. The synthetic nonsteroidal estrogen, diethylstilbestrol (DES), is a known carcinogen formerly administered to pregnant women to prevent miscarriage prior to evidence of adverse health effects and a lack of efficacy for that indication.

An early cohort study conducted in the Netherlands identified four cases of hypospadias among 205 sons of women exposed to DES in utero (~ 2% prevalence) versus 8 cases out of 8729 sons of mothers without DES exposure (0.09% prevalence). This study observed a strong association (prevalence odds ratio (pOR) 21.3; 95% CI 6.5–70.1) between maternal in utero DES exposure and hypospadiac son.

In a US cohort study, maternal DES exposure was related to a higher but not statistically significant increase in risk of offspring hypospadias with ten cases per 2552 live births from exposed mothers and three cases per 1336 live births from unexposed mothers (pOR 1.7; 95% CI 0.4–6.8).

A case-control study surveying 834 mothers with 251 hypospadiac children observed that women exposed to DES in utero were nearly five times more likely to have infants with hypospadias (OR 4.9; 95% CI 1.1–22.3).

A French, multigenerational cohort study also observed a relation between maternal DES exposure during pregnancy and increased prevalence of hypospadias for the next two generations, suggesting that the underlying biological mechanism may be epigenetic

Thus, studies on DES raise the possibility of an association with hypospadias. While no longer prescribed, DES is similar in chemical structure with other xenobiotic compounds and thus, the epidemiologic findings are still of relevance. It is important to note, however, that the studies of DES exposure all suggest a possible epigenetic effect on the development of hypospadias in later generations. While DES is historically important and chemically relevant to this discussion, its effect may derive from interaction with the maternal oocyte rather than the developing male penis itself.

References

  • Pharmacologic and Environmental Endocrine Disruptors in the Pathogenesis of Hypospadias: a Review, Current environmental health reports, NCBI PubMed PMID: 30578470, 2018 Dec.
  • Featured image springer.
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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
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In utero exposure to both high and low dose diethylstilbestrol disrupts mouse genital tubercle development

image of female-mice

The resulting hypospadias phenotypes in male and female mice prenatally exposed to DES

2018 Study Abstract

Exposure to estrogenic endocrine disrupting chemicals (EDCs) during in utero development has been linked to the increasing incidence of disorders of sexual development (DSDs).

Hypospadias, the ectopic placement of the urethra on the ventral aspect of the penis, is one of the most common DSDs affecting men, and can also affect women by resulting in the misplacement of the urethra.

This study aimed to comprehensively assess the resulting hypospadias phenotypes in male and female mice exposed in utero from embryonic day 9.5 to 19.5 to the potent estrogenic endocrine disruptor, diethylstilbestrol (DES), at a high, clinically relevant dose, and a low, previously untested dose, administered via water.

  • The anogenital distance of male pups was significantly reduced and hypospadias was observed in males at a high frequency.
  • Females exhibited hypospadias and urethral-vaginal fistula.

These results demonstrate the ability of an estrogen receptor agonist to disrupt sexual development in both male and female mice, even at a low dose, administered via drinking water.

Sources

  • In utero exposure to both high and low dose diethylstilbestrol disrupts mouse genital tubercle development, NCBI PubMed PMID: 29931162, 2018 Jun 21.
  • Featured image credit Steph Hillier.
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Mouse hypospadias: A critical examination and definition

The current study describes the types of adult penile malformations induced developmentally by DES (hypospadias) in cohorts of mice treated with DES over the age range of E12 to P20, but examined in adulthood when enduring malformations are present

2016 Study Abstract

Hypospadias is a common malformation whose etiology is based upon perturbation of normal penile development. The mouse has been previously used as a model of hypospadias, despite an unacceptably wide range of definitions for this malformation.

The current paper presents objective criteria and a definition of mouse hypospadias. Accordingly, diethylstilbestrol (DES) induced penile malformations were examined at 60 days postnatal (P60) in mice treated with DES over the age range of 12 days embryonic to 20 days postnatal (E12 to P20). DES-induced hypospadias involves malformation of the urethral meatus, which is most severe in DES E12-P10, DES P0-P10 and DES P5-P15 groups and less so or absent in the other treatment groups. A frenulum-like ventral tether between the penis and the prepuce was seen in the most severely affected DES-treated mice. Internal penile morphology was also altered in the DES E12-P10, DES P0-P10 and DES P5-P15 groups (with little effect in the other DES treatment groups). Thus, adverse effects of DES are a function of the period of DES treatment and most severe in the P0 to P10 period. In “estrogen mutant mice” (NERKI, βERKO, αERKO and AROM+) hypospadias was only seen in AROM+ male mice having genetically-engineered elevation is serum estrogen. Significantly, mouse hypospadias was only seen distally at and near the urethral meatus where epithelial fusion events are known to take place and never in the penile midshaft, where urethral formation occurs via an entirely different morphogenetic process.

Sources

  • Full text (free access) : Mouse hypospadias: A critical examination and definition, NCBI PubMed PMC5052099, 2016 Apr 5.
  • Featured image credit Aaron Logan.
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Hypospadias can be transmitted to the DES-exposed third-generation

Prenatal diethylstilbestrol induces malformation of the external genitalia of male and female mice and persistent second-generation developmental abnormalities of the external genitalia in two mouse strains

2014 Study Abstract

Potential trans-generational influence of diethylstilbestrol (DES) exposure emerged with reports of effects in grandchildren of DES-treated pregnant women and of reproductive tract tumors in offspring of mice exposed in utero to DES.

Accordingly, we examined the trans-generational influence of DES on development of external genitalia (ExG) and compared effects of in utero DES exposure in CD-1 and C57BL/6 mice injected with oil or DES every other day from gestational days 12 to 18. Mice were examined at birth, and on 5-120 days postnatal to evaluate ExG malformations. Of 23 adult (>60 days) prenatally DES-exposed males, features indicative of urethral meatal hypospadias (see text for definitions) ranged from 18% to 100% in prenatally DES-exposed CD-1 males and 31% to 100% in prenatally DES-exposed C57BL/6 males. Thus, the strains differed only slightly in the incidence of male urethral hypospadias. Ninety-one percent of DES-exposed CD-1 females and 100% of DES-exposed C57BL/6 females had urethral-vaginal fistula. All DES-exposed CD-1 and C57BL/6 females lacked an os clitoris. None of the prenatally oil-treated CD-1 and C57BL/6 male and female mice had ExG malformations. For the second-generation study, 10 adult CD-1 males and females, from oil- and DES-exposed groups, respectively, were paired with untreated CD-1 mice for 30 days, and their offspring evaluated for ExG malformations. None of the F1 DES-treated females were fertile. Nine of 10 prenatally DES-exposed CD-1 males sired offspring with untreated females, producing 55 male and 42 female pups. Of the F2 DES-lineage adult males, 20% had exposed urethral flaps, a criterion of urethral meatal hypospadias. Five of 42 (11.9%) F2 DES lineage females had urethral-vaginal fistula. In contrast, all F2 oil-lineage males and all oil-lineage females were normal.

Thus, prenatal DES exposure induces malformations of ExG in both sexes and strains of mice, and certain malformations are transmitted to the second-generation.

Sources

  • Full text (free access) : Prenatal diethylstilbestrol induces malformation of the external genitalia of male and female mice and persistent second-generation developmental abnormalities of the external genitalia in two mouse strains, NCBI PubMed PMC4254634, 2014 Oct.
  • Featured image credit figure/F1.
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Hypospadias in sons of women exposed to Diethylstilbestrol in utero

Increased risk of hypospadias in the DES grandsons, 2005

Abstract

BACKGROUND
Diethylstilbestrol (DES) is a synthetic estrogen that was widely prescribed to pregnant women before 1971. DES increases the risk of breast cancer in women who took the drug and the risk of reproductive tract abnormalities in their offspring. Dutch investigators have reported a 20-fold increase in risk of hypospadias among sons of women who were exposed to DES in utero. We assessed this relation in data from an ongoing study of DES-exposed persons.

METHODS
Several U.S. cohorts of women with documented exposure in utero to DES have been followed by mailed questionnaires since the 1970s. Comparison subjects are unexposed women of the same ages. In 1997, participants were asked about congenital abnormalities in their children. We calculated prevalence odds ratios for the risk of hypospadias in sons of exposed mothers relative to sons of unexposed mothers using generalized estimating equations to adjust for multiple sons per mother and controlling for maternal age at the son’s birth.

RESULTS
We obtained data from 3916 exposed and 1746 unexposed women. These women reported a total of 13 liveborn sons with hypospadias (10 exposed, 3 unexposed). The prevalence odds ratio for risk of hypospadias among the exposed was 1.7 (95% confidence interval = 0.4-6.8).

CONCLUSIONS
Our findings do not support a greatly increased risk of hypospadias among the sons of women exposed to DES in utero, as has been previously reported.

Sources

  • Hypospadias in sons of women exposed to diethylstilbestrol in utero, NCBI PubMed PMID: 15951681, 2005 Jul.
  • Featured image credit Bridget Coila.
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Hypospadias in sons of women exposed to DES in utero

These 2005 findings confirm an increased risk of hypospadias in the sons of women exposed in utero to DES and the transgenerational effect of DES

Abstract

Transgenerational effects of diethylstilbestrol (DES) have been reported in animals and humans. Alerted by two case reports, Klip H et al conducted a cohort study of all sons of a Dutch cohort of 16 284 women with a diagnosis of fertility problems and obtained a 67% response rate; their findings suggest an increased risk of hypospadias in the sons of women exposed in utero to DES. The mothers of 205 boys reported DES exposure in utero, and four of these boys were reported to have hypospadias. This defect was reported in only 8 of the remaining 8729 sons (prevalence ratio 21.3 (95% confidence interval (CI) 6.5–70.1)).

In a retrospective study, we analysed 32 406 computerized obstetrical and pediatric files at Port-Royal Maternity Center, covering births from 1 January 1993 to 31 December 2002. We compared the prevalence rate of hypospadias among 17 633 boys of mothers with and without in utero DES exposure.

The mothers of 240 boys had reported DES exposure in utero. Three (1.23%) were reported to have hypospadias. Obstetric records of the remaining 17 393 children reported hypospadias for only 44(0.5%◦) (prevalence ratio 4.99 (95% CI 1.2–16.8, p = 0.02)). All cases of hypospadias were medically confirmed by the pediatric files.

Our findings confirm an increased risk of hypospadias in the sons of women exposed in utero to DES and the transgenerational effect of DES.

The lower prevalence ratio in our study (4.99) than in the Dutch cohort (21.3) is probably due to the difference in the underlying populations: the Dutch cohort was selected for the criteria of infertility and is thus necessarily different from our general population.

Klip’s data came from questionnaires addressed to women who had consulted for infertility and been previously enrolled in a cohort. The analysis was based on a 67% response rate. We note that the 95% CI of the relative risk (RR) in the Klip study (6.5–70.1) is compatible with the RR in the present study. On the basis of both the studies, the true RR may range between 6.5 (lower range of Dutch study) and 16.8 (upper range of our study) and, given the possible bias of the Dutch study, the true RR may well be lower than 16.8.

Our study examined a large continuous series of woman who gave birth at Port Royal. During the study period, women were systematically asked about their own in utero exposure to DES. All of the obstetrical and pediatric records of our population were analysed.

The prevalence of hypospadias in our control series was 2.5 per 1000, which corresponds to the prevalence in the general French population −2.89 per 1000 male newborns. The prevalence in the control series for Klip’s population was only 0.9 per 1000.

The importance of understanding the mechanism of hypospadias warrants additional studies. Van Tongeren et al. point out that, especially in urban areas, mothers’ occupations (such as hairdressing and working in beauty salons) can increase exposure to potential endocrinedisrupting chemicals Van Tongeren et al (2002). Our study does not enable us to determine whether the mothers of sons with hypospadias were exposed to higher levels of or at higher rates to such chemicals.

Sources

  • Hypospadias in sons of women exposed to diethylstilbestrol in utero, NCBI PubMed PMID: 15906411, 2005 May.
  • Featured image credit Piron Guillaume.
DES DIETHYLSTILBESTROL RESOURCES
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DES-induced persistent second-generation developmental abnormalities of the external genitalia

Prenatal diethylstilbestrol induces malformation of the external genitalia of male and female mice and persistent second-generation developmental abnormalities of the external genitalia in two mouse strains

2014 Study Abstract

Potential trans-generational influence of diethylstilbestrol (DES) exposure emerged with reports of effects in grandchildren of DES-treated pregnant women and of reproductive tract tumors in offspring of mice exposed in utero to DES.

Accordingly, we examined the trans-generational influence of DES on development of external genitalia (ExG) and compared effects of in utero DES exposure in CD-1 and C57BL/6 mice injected with oil or DES every other day from gestational days 12 to 18. Mice were examined at birth, and on 5-120 days postnatal to evaluate ExG malformations. Of 23 adult (>60 days) prenatally DES-exposed males, features indicative of urethral meatal hypospadias (see text for definitions) ranged from 18% to 100% in prenatally DES-exposed CD-1 males and 31% to 100% in prenatally DES-exposed C57BL/6 males. Thus, the strains differed only slightly in the incidence of male urethral hypospadias. Ninety-one percent of DES-exposed CD-1 females and 100% of DES-exposed C57BL/6 females had urethral-vaginal fistula. All DES-exposed CD-1 and C57BL/6 females lacked an os clitoris. None of the prenatally oil-treated CD-1 and C57BL/6 male and female mice had ExG malformations. For the second-generation study, 10 adult CD-1 males and females, from oil- and DES-exposed groups, respectively, were paired with untreated CD-1 mice for 30 days, and their offspring evaluated for ExG malformations. None of the F1 DES-treated females were fertile. Nine of 10 prenatally DES-exposed CD-1 males sired offspring with untreated females, producing 55 male and 42 female pups. Of the F2 DES-lineage adult males, 20% had exposed urethral flaps, a criterion of urethral meatal hypospadias. Five of 42 (11.9%) F2 DES lineage females had urethral-vaginal fistula. In contrast, all F2 oil-lineage males and all oil-lineage females were normal.

Thus, prenatal DES exposure induces malformations of ExG in both sexes and strains of mice, and certain malformations are transmitted to the second-generation.

Sources

  • Full study (free access) : Prenatal diethylstilbestrol induces malformation of the external genitalia of male and female mice and persistent second-generation developmental abnormalities of the external genitalia in two mouse strains, Chemosphere, NCBI PubMed PMC4254634, 2005 Nov.
  • A scanning electron micrograph (A) and a photo (B) of the penis of an adult prenatally oil-treated (A) mouse and a prenatally DES-treated mouse (B) featured image credit PMC4254634/figure/F1.
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DES Grandsons Hypospadias ; True Transgenerational Effect ?

image of Grandson

Hypospadias in sons of women exposed to diethylstilbestrol: a true trans-generational effect?

2005 Study Abstract

In May 2005, Pons et al. reported on an increased risk of hypospadias in male children of women exposed to diethylstilbestrol (DES) in utero. The authors have retrospectively reviewed the electronic files from 17 633 deliveries of male neonates in a 10-year period. The mothers of 240 male neonates had reported in utero DES exposure, three of whom (1.23%) presented with hypospadias vs 44/17 393 (0.5%) in the remaining male neonates (from non-DES-exposed mothers). The authors conclude that there is an increased risk of hypospadias in the male children of women exposed in utero to DES due to the transgenerational effects of DES. Although these results apparently compare favourably with the initial Dutch cohort, we would like to address the authors with our concerns regarding the interpretation of these additional data.

In utero DES exposure has been associated not only with an increased risk of preterm labour but also with an increased risk of intra-uterine growth retardation (IUGR). In turn, an increased risk of cryptorchidism and hypospadias has been associated with decreased birth weight. One might expect a higher rate of IUGR in the subgroup of neonates of women exposed in utero to DES compared with the control group in the Parisian cohort, as previously observed in the Dutch one. This information, essential to the interpretation of the data, may avoid causing the patients undue concern about hypothetical transgenerational adverse effects of DES (i.e. genetic or epigenetic changes in either germ or somatic cells).

Sources

  • Hypospadias in sons of women exposed to ditheylstilbestrol: a true trans-generational effect?, Prenatal diagnosis, NCBI PubMed PMID: 16302166, 2005 Nov.
  • Featured image credit Johan Mouchet.
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Birth Defects in DES Grandsons

Birth defects in children of men exposed in utero to diethylstilbestrol (DES)

2018 Study Abstract

OBJECTIVE
Prenatal exposure to diethylstilbestrol (DES) is associated with adverse effects, including genital anomalies and cancers in men and women. Animal studies showed birth defects and tumors in the offspring of mice prenatally exposed to DES. In humans, birth defects, such as hypospadias were observed in children of prenatally exposed women. The aim of this research was to assess the birth defects in children of prenatally exposed men.

METHODS
In a retrospective study conceived by a patients’ association (Réseau DES France), the reports of men prenatally exposed to DES on adverse health effects in their children were compared with those of unexposed controls and general population.

RESULTS
An increased incidence of two genital anomalies,

  1. cryptorchidism (OR=5.72; 95% CI 1.51-21.71),
  2. and hypoplasia of the penis (OR=22.92; 95% CI 3.81-137.90),

was observed in the 209 sons of prenatally exposed men compared with controls, but hypospadias incidence was not increased in comparison with either the controls or the general population. No increase of genital anomalies was observed in daughters.

CONCLUSION
With caution due to the methods and to the small numbers of defects observed, this work suggests an increased incidence of two male genital tract defects in sons of men prenatally exposed to DES. This transgenerational effect, already observed in animals and in the offspring of women prenatally exposed to DES, could be the result of epigenetic changes transmitted to the subsequent generation through men.

Sources

  • Birth defects in children of men exposed in utero to diethylstilbestrol (DES), Therapie, NCBI PubMed PMID: 29609831, 2018 Mar 3.
  • Featured image credit Danielle MacInnes.
DES DIETHYLSTILBESTROL RESOURCES