Cryptorchidism and endocrine disrupting chemicals

In utero DES exposure increases the risk of testicular dysgenesis syndrome ; linked to cryptorchidism, hypospadias, poor semen quality and testicular cancer

2012 Study Abstract

Prospective clinical studies have suggested that the rate of congenital cryptorchidism has increased since the 1950s. It has been hypothesized that this may be related to environmental factors.

Testicular descent occurs in two phases controlled by Leydig cell-derived hormones insulin-like peptide 3 (INSL3) and testosterone. Disorders in fetal androgen production/action or suppression of Insl3 are mechanisms causing cryptorchidism in rodents.

In humans, prenatal exposure to potent estrogen diethylstilbestrol (DES) has been associated with increased risk of cryptorchidism.

In addition, epidemiological studies have suggested that exposure to pesticides may also be associated with cryptorchidism.

Some case-control studies analyzing environmental chemical levels in maternal breast milk samples have reported associations between cryptorchidism and chemical levels.

Furthermore, it has been suggested that exposure levels of some chemicals may be associated with infant reproductive hormone levels.

Sources

  • Cryptorchidism and endocrine disrupting chemicals, Molecular and cellular endocrinology, NCBI PubMed, PMID: 22127307, 2012 May.
  • Featured image credit Ivan Bandura.
DES DIETHYLSTILBESTROL RESOURCES

DES Sons Urogenital Abnormalities, 2009

Urogenital abnormalities in men exposed to diethylstilbestrol in utero: a cohort 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

  • Full study (free access) : Urogenital abnormalities in men exposed to diethylstilbestrol in utero: a cohort study, Environmental health : a global access science source, NCBI PubMed, PMC2739506, 2009 Aug.
  • Featured image credit Kyle Loftus.
DES DIETHYLSTILBESTROL RESOURCES

DES-induced abdominal cryptorchidism

The effect of diethylstilbestrol on inducing abdominal cryptorchidism and relevant genetic expression in rats

2009 Study Abstract

OBJECTIVE
To study the effect of diethylstilbestrol (DES) at different doses on transabdominal testicular descent in rats and the expression of INSL3 in the testis and HOXA10 in the gubernaculum.

METHOD
Fifty E13.5 (embryonic day 13.5) pregnant female SD rats were randomly divided into five groups that received a subcutaneous injection of DMSO, 2.5, 5.0, 10.0 and 20.0 mg/kg DES (group A, B, C, D and E), respectively. Male offspring were killed at E19.5, and then fetal mortality, the degree of transabdominal testicular ascent (DTA) was determined by a stereomicroscope. The mRNA expressions of INSL3 in the testis and HOXA10 in the gubernaculum were determined by RT-PCR. The expression of INSL3 protein was determined by Western blotting.

RESULTS
Male fetal mortality in group A, B, C, D, and E were 3.57%, 6.90%, 12.00%, 19.23% and 36.36%, respectively, which showed a dose-effect relationship between DES and the male fatal mortality (r=0.999, P<0.01). DTA in group B, C, D and E were (23.7+/-1.7) U, (38.8+/-1.9) U, (49.3+/-1.8) U and (58.6+/-2.1) U that were significantly larger than that in group A [(8.5+/-1.3) U] (q=46.12, 88.53, 120.44 and 141.37, respectively, P<0.01). There was also a dose-effect relationship between DES and DTA. In group B, C, D, and E, the expression of INSL3 mRNA were 0.9570+/-0.1490, 0.6760+/-0.1380, 0.0170+/-0.0040 and 0.0013+/-0.0003, respectively; the expressions of INSL3 protein were 0.8360+/-0.1520, 0.5310+/-0.1070, 0.0140+/-0.0020 and 0.0011+/-0.0003, respectively, which were significantly larger than the expression of INSL3 mRNA (1.801+/-0.126) and INSL3 protein (1.612+/-0.134) in group A (qmRNA=40.4840, 52.4402, 83.1585 and 82.0582, respectively, and qprotein=38.6151, 52.2747, 77.2756 and 76.1983, respectively, P<0.01). The expression of HOXA10 mRNA in group A, B, C, D, and E were 0.945+/-0.125, 0.940+/-0.119, 0.656+/-0.115, 0.544+/-0.118 and 0.463+/-0.114, respectively. Compared with the expression of HOXA10 mRNA in group A, the expression of group B was not significantly different (q=0.2213, P>0.05), those in other groups were down-regulated significantly (q=12.4304, 17.2477 and 20.2789, respectively, P<0.01).

CONCLUSION
DES inhibited transabdominal testicular descent dose-dependently via down-regulating the expression of INSL3. HOXA10 may play no role in low-dosage DES induced intra-abdominal cryptorchidism, but down-regulated HOXA10 mRNA was involved in high-dosage DES induced ones.

Sources

  • The effect of diethylstilbestrol on inducing abdominal cryptorchidism and relevant genetic expression in rats, Chinese medical journal, NCBI PubMed, PMID: 19534997, 2009 May.
  • Featured image credit pexels.
DES DIETHYLSTILBESTROL RESOURCES

Male reproductive disorders in humans and prenatal indicators of estrogen exposure

A review of published epidemiological studies

2006 Study Abstract

Male reproductive disorders in humans and prenatal indicators of estrogen exposure. A review of published epidemiological studies. Reports of an increase in male reproductive disorders in several countries led to the hypothesis that estrogens during fetal life may cause reduced sperm counts, cryptorchidism, hypospadias and testicular cancer. So far the hypothesis is based on animal studies and reports from the wild life.

We systematically searched the epidemiological literature for evidence linking indicators of prenatal serum levels of maternal estrogens with sperm density, hypospadias, cryptorchidism and testicular cancer in humans. Indicators of fetal estrogen exposure included direct measurements, recorded intake of hormones (diethylstilbestrol (DES), oral contraceptives (OCs) and estrogens), pregnancy conditions with known deviant estrogen level as for instance twin pregnancies and some environmental exposures.

Cryptorchidism

We identified four studies focussing on estrogens given prenatally, mainly DES studies.

  1. Physical examination of men from Dieckman’s cohort revealed a higher number of men with hypoplastic testes among exposed [OR = 4.36 (1.9–11.4) calculated by the author] and cryptorchidism was more prevalent among exposed men with hypoplastic testes, but data on the occurrence of cryptorchidism among all men are not given.
  2. Vessey et al. found an equal frequency of cryptorchidism in the DES and the placebo group among offspring from Sweyer and Law’s DES cohort from 1954. Selection bias in this study is less likely since information was obtained from GP’s, blinded for exposure status. The time of entry and the total dose of DES were similar in these two DES studies (11.6 and 11.5 g, respectively).
  3. Two case-referent studies using data on estrogen prescription from medical records found increased risk of cryptorchidism [RR 1.9 (95%CI: 0.5–6.6) [52] and 2.8 (95% CI: 0.9–8.8)…

Sources

  • Male reproductive disorders in humans and prenatal indicators of estrogen exposure. A review of published epidemiological studies, Reproductive toxicology, NCBI PubMed, PMID: 16005180, 2006 Jan.
  • Featured image Nik Shuliahin.
DES DIETHYLSTILBESTROL RESOURCES

Update on cryptorchidism: endocrine, environmental and therapeutic aspects

Summary

Cryptorchidism is the most frequent developmental abnormality in boys, present in more than 1% of infants above three months of age. It is associated with an increased risk of infertility and testicular cancer. The etiological quest is often disappointing, except in bilateral cases or associated malformations. Recent focus is on genetic and environmental aspects. Animal models have revealed the role of genes encoding for proteins implicated in testicular migration (InsI3, Hoxa 10), but in humans results are less convincing. While some degree of endogenous hormonal abnormality is suspeeted in some patients, the endocrine disruptor hypothesis is also tested. It is unclear whether the incidence of cryptorchidism has really increased, or whether there is only a better screening for this condition. However, other male reproductive problems, such as subfertility, hypospadias and testicular cancer seem on the rise. This secular trend suggests the possible in utero impact of hormonally active environmental factors, such as pesticides with estrogenic or antiandrogenic effect, and is consistent with the increased risk of cryptorchidism observed in the sons of mothers exposed to diethylstilbestrol during pregnancy. From a therapeutic point of view, there is an agreement that the correction of cryptorchidism is needed, but there is controversy on the best medical and/or surgical approach and on the optimal timing. There is a recent trend in proposing early therapeutic intervention, before 1 yr of age, in the hope of improving fertility; however, there is no proof that such a strategy can reduce the risk of testicular cancer.

2003 Study Abstract

” …Prenatal exposure to diethylstilbestrol (DES) is a well known factor causing cryptorchidism in different animal models and in man. In addition, 100 g/kg/day of DES given to pregnant mice from day 9 to 17 prevent normal gubernaculum development and is associated with a three-fold decrease in Insl3 mRNA expression, with no change in steroidogenic factor 1 (SF1) expression. These results are similar to those obtained with β-estradiol, α-estradiol and DES also in mice. …

… In an American case-control study, the relative risk of cryptorchidism was 2.8 in boys whose mothers were treated with estrogens (DES, estradiol, or a contraceptive pill) during pregnancy. Regarding the risk linked to DES, results vary from one study to another; Gill reports a frequency of 8% compared to 1% in controls. …”

Sources

  • Update on cryptorchidism: endocrine, environmental and therapeutic aspects, Journal of endocrinological investigation, NCBI PubMed, PMID: 12952375, 2003 Jun.
DES DIETHYLSTILBESTROL RESOURCES

Physician advisory : health effects of the pregnancy use of diethylstilbestrol

Clinical toxicology, 1979

Abstract

A DES (diethylstilbestrol) Task Force formed in February by the Office of the Assistant Secretary for Health, examined the health effects of DES in pregnancy. This report is an outline of the Task Force’s recommendations.

Physicians should advise women to whom they prescribe the drugs of their exposure and of the need for follow-up medical care for themselves and their offspring. Physicians are also to provide patients inquiring of possible past DES exposure, complete and accurate information whenever possible, and such information should be provided free of charge.

The incidence of clear cell adenocarcinoma for DES-exposed daughters is between 1.4/100 to 1.4/10,000. Periodic examination, rather than active therapeutic intervention (e.g., surgery) is recommended for patients with adenosis. For asymptomatic DES daughters, periodic screening examinations should start at age 14 or at menarche; vaginal bleeding/discharge should be promptly evaluated. Hystersosalpingography should not be used as a routine screening procedure in DES daughters but should be reserved for cases of repeated pregnancy loss or infertility.

Asymptomatic DES mothers should have routine screening (e.g., annual pelvic exam including bimanual palpation and Pap smear; breast exam) appropriate for women with no prior estrogen exposure.

DES exposed males have been known to have:

  1. history of cryptochirdism;
  2. hypoplastic testes;
  3. epididymal cysts;
  4. and sperm abnormalities (low sperm counts, decreased motility).
    DES males should have physical examination, appropriate medical follow-up or corrective measures, as the case may be.

Use of DES postcoital contraception should be limited to situations where the fully informed patient or her physician deems that there is no alternative.

Sources

  • Induction of urogenital anomalies and some tumors in the progeny of mice receiving diethylstilbestrol during pregnancy, Clinical toxicology, NCBI PubMed, PMID: 37020, 1979 Mar.
  • Features image Michael Marusin
DES DIETHYLSTILBESTROL RESOURCES

Update on cryptorchidism : endocrine, environmental and therapeutic aspects

Journal of Endocrinological Investigation, June 2003

Abstract

Cryptorchidism is the most frequent developmental abnormality in boys, present in more than 1% of infants above three months of age. It is associated with an increased risk of infertility and testicular cancer. The etiological quest is often disappointing, except in bilateral cases or associated malformations. Recent focus is on genetic and environmental aspects.

Animal models have revealed the role of genes encoding for proteins implicated in testicular migration (InsI3, Hoxa 10), but in humans results are less convincing. While some degree of endogenous hormonal abnormality is suspected in some patients, the endocrine disruptor hypothesis is also tested. It is unclear whether the incidence of cryptorchidism has really increased, or whether there is only a better screening for this condition. However, other male reproductive problems, such as subfertility, hypospadias and testicular cancer seem on the rise. This secular trend suggests the possible in utero impact of hormonally active environmental factors, such as pesticides with estrogenic or antiandrogenic effect, and is consistent with the increased risk of cryptorchidism observed in the sons of mothers exposed to diethylstilbestrol during pregnancy.

From a therapeutic point of view, there is an agreement that the correction of cryptorchidism is needed, but there is controversy on the best medical and/or surgical approach and on the optimal timing. There is a recent trend in proposing early therapeutic intervention, before 1 yr of age, in the hope of improving fertility; however, there is no proof that such a strategy can reduce the risk of testicular cancer.

Sources

  • Update on cryptorchidism: endocrine, environmental and therapeutic aspects NCBI PubMed PMID: 12952375, 2003 Jun.
  • Featured image credit Ehowcdn.com.
  • DES DIETHYLSTILBESTROL RESOURCES

    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

    A molecular basis for estrogen-induced cryptorchidism

    image of insl3-expression

    In rodents, administration of DES during the second half of gestation resulted in a drastic reduction of Insl3 gene expression and testosterone levels, even though the expression of Sf-1 was unaltered

    2000 Study Abstract

    Male sexual differentiation relies upon testicular secretion of the hormones testosterone, Mullerian inhibiting substance, and insulin-3 (Insl3).

    Insl3 is responsible for testicular descent through virilization and outgrowth of the embryonic gubernaculum.

    In mouse, prenatal exposure to 17beta-estradiol and the nonsteroidal synthetic estrogen diethylstilbestrol (DES) disturbs the endocrine balance, causing demasculinizing and feminizing effects in the male embryo, including impaired testicular descent (cryptorchidism).

    In the current study, we show that maternal exposure to estrogens, including 17alpha- and beta-estradiol, as well as DES, specifically down regulates Insl3 expression in embryonic Leydig cells, thereby providing a mechanism for cryptorchidism.

    These experiments may have implications for the widespread use of estrogenic substances in agriculture and the environment.

    Sources and more information
    • A molecular basis for estrogen-induced cryptorchidism, Developmental biology, NCBI PubMed PMID: 10926772, 2000 Aug.
    • Cryptorchidism in mice mutant for Insl3 featured image credit media.nature.
    DES DIETHYLSTILBESTROL RESOURCES

    DES drastically reduces Insl3 gene expression

    image of Protein_INSL3

    DES exerts its anti-androgen effects mainly through classical ER signaling, particularly via ERα

    2007 Study Abstract

    Failure of the testes to descend into the scrotum (cryptorchidism) is one of the most common birth defects in humans.

    In utero exposure to estrogens, such as 17beta-estradiol (E2) or the synthetic estrogen diethylstilbestrol (DES), down-regulates insulin-like 3 (Insl3) expression in embryonic Leydig cells, which in turn results in cryptorchidism in mice.

    In humans, the offspring of pregnant women treated with diethylstilbestrol (DES),  exhibited an increased incidence of cryptorchidism and hypoplastic testes. In rodents, we and others have shown that administration of DES or E2 during the second half of gestation resulted in a drastic reduction of Insl3 gene expression and testosterone levels, even though the expression of Sf-1 was unaltered.

    To identify the molecular mechanism whereby xenoestrogens block Insl3 gene transcription, we performed a microarray analysis of wild-type or estrogen receptor (ER) alpha-mutant testes exposed in utero to pharmacological doses of E2 or DES.

    Six and 31 genes were respectively down-regulated and up-regulated by estrogen exposure (> or =4-fold). All six genes down-regulated by estrogen exposure, including Insl3 and the steroidogenic genes steroidogenic acute regulatory protein and cytochrome P450 17alpha-hydroxylase/17,20-lyase, were done so by an ERalpha-dependent mechanism. In contrast, up-regulation was mediated either by ERalpha for 12 genes or by an independent mechanism for the 19 remaining genes. Finally, we show that Insl3 gene expression and testicular descent were not affected by in utero exposure to E2 or DES in ERalpha mutant mice, whereas absence of ERbeta did not influence the effect of these estrogens.

    Collectively, these data demonstrate that xenoestrogens inhibit the endocrine functions of fetal Leydig cells through an ERalpha-dependent mechanism.

    Sources and more information
    • Full text (free access) : Estrogen receptor alpha is a major contributor to estrogen-mediated fetal testis dysgenesis and cryptorchidism, Endocrinology, NCBI PubMed PMID: 17673513, 2007 Nov.
    • Protein INSL3 featured image credit wikipedia.
    DES DIETHYLSTILBESTROL RESOURCES