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.
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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.
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Testicular Dysgenesis Syndrome and the Estrogen Hypothesis: A Quantitative Meta-Analysis

It is clear that hypospadias, cryptorchidism, and testicular cancer are all positively associated with prenatal exposure to DES

2008 Study Abstract

Background
Male reproductive tract abnormalities such as hypospadias and cryptorchidism, and testicular cancer have been proposed to comprise a common syndrome together with impaired spermatogenesis with a common etiology resulting from the disruption of gonadal development during fetal life, the testicular dysgenesis syndrome (TDS). The hypothesis that in utero exposure to estrogenic agents could induce these disorders was first proposed in 1993. The only quantitative summary estimate of the association between prenatal exposure to estrogenic agents and testicular cancer was published over 10 years ago, and other systematic reviews of the association between estrogenic compounds, other than the potent pharmaceutical estrogen diethylstilbestrol (DES), and TDS end points have remained inconclusive.

Objectives
We conducted a quantitative meta-analysis of the association between the end points related to TDS and prenatal exposure to estrogenic agents. Inclusion in this analysis was based on mechanistic criteria, and the plausibility of an estrogen receptor (ER)-α–mediated mode of action was specifically explored.

Results
We included in this meta-analysis eight studies investigating the etiology of hypospadias and/or cryptorchidism that had not been identified in previous systematic reviews. Four additional studies of pharmaceutical estrogens yielded a statistically significant updated summary estimate for testicular cancer.

Conclusions
The doubling of the risk ratios for all three end points investigated after DES exposure is consistent with a shared etiology and the TDS hypothesis but does not constitute evidence of an estrogenic mode of action. Results of the subset analyses point to the existence of unidentified sources of heterogeneity between studies or within the study population.

Sources

  • Full study (free access) : Testicular Dysgenesis Syndrome and the Estrogen Hypothesis: A Quantitative Meta-Analysis, Environmental Health Perspectives, PMC2235228, 2008 Feb.
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Endocrine disruptor compounds and their role in the developmental programming of the reproductive axis

DES is the best documented compound

2007 Study Abstract

Different perturbations during fetal and postnatal development unleash endocrine adaptations that permanently alter metabolism, increasing the susceptibility to develop later disease, process known as “developmental programming.”

Endocrine disruptor compounds (EDC) are widely spread in the environment and display estrogenic, anti-estrogenic or anti-androgenic activity; they are lipophilic and stored for long periods in the adipose tissue. Maternal exposure to EDC during pregnancy and lactation produces the exposure of the fetus and neonate through placenta and breast milk. Epidemiological and experimental studies have demonstrated reproductive alterations as a consequence of intrauterine and/or neonatal exposure to EDC.

Diethystilbestrol (DES) is the best documented compound, this synthetic estrogen was administered to pregnant women in the 1950s and 1960s to prevent miscarriage. It was implicated in urogenital abnormalities in children exposed in utero and was withdrawn from the market.

The “DES daughters” are women with high incidence of vaginal hypoplasia, spontaneous abortion, premature delivery, uterine malformation, menstrual abnormalities and low fertility.

The “DES sons” show testicular dysgenesis syndrome, which is characterized by hypospadias, cryptorchidism and low semen quality.

This entity is also associated wtih fetal exposure to anti-androgens as flutamide.

The effects on the reproductive axis depend on the stage of development and the window of exposure, as well as the dose and the compound.

The wide distribution of EDC into the environment affects both human health and ecosystems in general, the study of their mechanisms of action is extremely important currently.

Sources

  • Endocrine disruptor compounds and their role in the developmental programming of the reproductive axis, Revista de investigacion clinica; organo del Hospital de Enfermedades de la Nutricion, NCBI PubMed, PMID: 17569302, 2007 Jan-Feb.
  • Featured image Jamie Street.
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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.
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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.
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DES responsibility in the testicular feminization syndrome

Ingestion of diethylstilbestrol during pregnancy, 1990 Report

Abstract

We report the cases of two women who had testicular feminization with remnants of Müllerian ducts and whose mothers had received diethylstilbestrol (DES) during the first trimester of pregnancy.

At laparotomy, masses were removed which had the microscopic appearances of testes and Fallopian tubes, and were confirmed as such at histology.

There were three possible explanations for these genetic abnormalities:

  1. deficient antimüllerian hormone (AMH) secretion (or lack of sensitivity of Müllerian ducts to AMH);
  2. early testicular descent with regression of Müllerian ducts beyond the efficacy margin of AMH;
  3. exposure to DES in utero during the first trimester of pregnancy.

In these two women, the most likely explanation seems to be the last one.

Sources

  • Ingestion of diethylstilbestrol during pregnancy. Its responsibility in the testicular feminization syndrome, Presse medicale (Paris, France : 1983), NCBI PubMed, PMID: 2146621, 1990 Sep.
  • Featured image credit Anna Sullivan.
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From malformations to molecular mechanisms in the male

Three decades of research on endocrine disrupters

2001 Study Abstract

For three decades, we have known that estrogens alter the development of the mammalian reproductive system in predictable ways.

In mice exposed prenatally to diethylstilbestrol (DES) or other estrogens, the male offspring exhibit structural malformations including cryptorchidism, epididymal cysts and retained Mullerian ducts.

The estrogen-associated alterations in the genital tract phenotype can be usefully considered as a model called Developmental Estrogenization Syndrome. While estrogen treatment during critical periods of morphogenesis of the male reproductive system has been associated with these changes, the mechanisms at the molecular level are still being discovered. Parallel findings on the hormones involved in Mullerian duct regression and testicular descent have helped guide research on the mechanisms of developmental estrogenization of the male.

Cellular localization of molecular signals associated with key steps in genital tract development, use of mice with gene disruption, and knowledge of the mechanisms underlying persistent changes in gene expression are beginning to provide a blue print for both the physiological role and pathological effects of estrogens in reproductive tract development.

Since many of the same biological principles underlie genital tract morphogenesis in mammals, one may expect some of the same changes in males of other species exposed to estrogen during the appropriate developmental periods.

Sources

  • From malformations to molecular mechanisms in the male: three decades of research on endocrine disrupters, APMIS : acta pathologica, microbiologica, et immunologica Scandinavica, NCBI PubMed, PMID: 11469497, 2001 Apr.
  • Featured image credit Jaredd Craig.
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Involvement of insulin-like factor 3 (Insl3) in DES-induced cryptorchidism

DES may interfere with gubernaculum development by altering Insl3 mRNA expression, leading to cryptorchidism

2000 Study Abstract

Recently, it has been shown that targeted inactivation of the Insl3 gene in male mice results in cryptorchidism. The Insl3 gene encodes insulin-like factor 3 (Insl3), which is expressed in fetal Leydig cells. The testicular factor Insl3 appears to play an important role in the transabdominal phase of testis descent, which involves development of the gubernaculum.

Other studies have demonstrated that in utero exposure to diethylstilbestrol (DES), a synthetic estrogen, can lead to cryptorchidism both in humans and in animal models.

The present study was undertaken to investigate whether prenatal DES-exposure might interfere with testicular Insl3 mRNA expression. Furthermore, the effect of DES on steroidogenic factor 1 (SF-1) mRNA expression level was determined, since it has been shown that SF-1 plays an essential role in transcriptional activation of the Insl3 gene promoter.

Timed pregnant mice were treated with DES (100 microg/kg body weight) or vehicle alone on days E9 (gestational day 9) through E17. Control and DES-exposed mouse fetuses were collected at E16, E17 and E18, when transabdominal testis descent is taking place. Lack of gubernaculum development in DES-exposed animals was confirmed by histological analyses at E17. Expression of Insl3 and SF-1 mRNAs was studied in testes of control and DES-exposed fetuses at E16 and E18 by RNase protection assay. Prenatal DES-exposure resulted in a three-fold decrease in Insl3 mRNA expression level (P<0.005), at both E16 and E18. In contrast, DES treatment had no effect on the expression of SF-1 mRNA.

These results support our hypothesis that DES may interfere with gubernaculum development by altering Insl3 mRNA expression, providing a possible mechanism by which DES may cause cryptorchidism.

Sources

  • Involvement of insulin-like factor 3 (Insl3) in diethylstilbestrol-induced cryptorchidism, Endocrinology, NCBI PubMed, PMID: 10650968, 2000 Feb.
  • Featured image credit Jaron Nix.
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Do environmental estrogens contribute to the decline in male reproductive health ?

About DES Sons, European Beckman Conference, Clinical chemistry, 1995

Abstract

Several observations suggest that male reproductive health has been declining since World War II in many countries. The incidence of testicular cancer, hypospadias, and cryptorchidism has been increasing and semen quality has been decreasing, and these may have a common etiology.

Treatment of several million pregnant women with the synthetic estrogen diethylstilbestrol led to an increase in these conditions among the sons of these women.

The structural abnormalities of the reproductive organs more frequently reported in males exposed to DES than in controls include meatal stenosis, hypospadias, epididymal cysts, and testicular abnormalities. McLachlan reported similar abnormalities in the male offspring of mice exposed to DES. Dieckmann et al. performed a double-blind placebo-controlled study in the 1950s. DES was given to 840 women between the 7th and 35th gestation week. Of the offspring of these mothers, 308 men were exposed to DES and 307 men were exposed to placebo; 31.5% and 7.8%, respectively, had abnormal reproductive tracts. Whitehead and Leiter reported genital abnormalities in 29 of 48 DES-exposed men. These data are convincing and cannot be explained by differences in confounding factors.

Gill et al. studied semen samples from 88 men exposed to DES and 85 men exposed to placebo who were offspring of the Dieckmann cohort. Sperm concentration was much lower among men exposed to DES. There was no difference in semen volume, whereas the total sperm count, the sperm motility grade, the total number of motile sperm, the percentage of sperm with normal morphology, and the quality score were all statistically lower in men exposed to DES. In a later study of the same men, only semen concentration differed in the two groups. Similar findings were reported in another study including 17 men exposed to DES and 12 controlsubjects.

These abnormalities probably arise during fetal development. The similarity between these effects and the adverse change in male reproductive development and function raised the question of whether the adverse changes are attributable to altered exposures to estrogenic and other endocrine-disrupting agents during fetal development. We speculate that alteration in exposure to estrogen in the past half-century may have caused the changes in male reproductive health.

Sources

  • Read the full text (free access) : Do environmental estrogens contribute to the decline in male reproductive health?, Clinical chemistry, NCBI PubMed, PMID: 7497651, 1995.
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