Testicular Dysgenesis Syndrome (TDS)

An increasingly common developmental disorder with environmental aspects, 2001

Abstracts

Numerous reports have recently focused on various aspects of adverse trends in male reproductive health, such as the rising incidence of testicular cancer; low and probably declining semen quality; high and possibly increasing frequencies of undescended testis and hypospadias; and an apparently growing demand for assisted reproduction.

Due to specialization in medicine and different ages at presentation of symptoms, reproductive problems used to be analysed separately by various professional groups, e.g. paediatric endocrinologists, urologists, andrologists and oncologists.

This article summarizes existing evidence supporting a new concept that poor semen quality, testis cancer, undescended testis and hypospadias are symptoms of one underlying entity, the testicular dysgenesis syndrome (TDS), which may be increasingly common due to adverse environmental influences.

Experimental and epidemiological studies suggest that TDS is a result of disruption of embryonal programming and gonadal development during fetal life. Therefore, we recommend that future epidemiological studies on trends in male reproductive health should not focus on one symptom only, but be more comprehensive and take all aspects of TDS into account. Otherwise, important biological information may be lost.

Evidence from animal studies and wildlife

There is a wealth of data showing that male animals exposed in utero or perinatally to exogenous oestrogens (diethylstilbo-estrol, ethinyl oestradiol, bisphenol A) and anti-androgens [flutamide, vinclozolin, 1,1-dichloro-2, 2-bis(p-chlorophenyl)ethylene (DDE), 1,1,1-trichloro-2, 2-bis(4-chlorophenyl)ethane(DDT)] develop hypospadias, undescended testis, low sperm counts or, in the worst case, intersex conditions, teratomas and Leydig cell tumours. A recent report provided experimental evidence that ubiquitous phthalates, can also hamper testicular descent in rats when administered prenatally.

References

  • Testicular dysgenesis syndrome: an increasingly common developmental disorder with environmental aspects, Endocrinology, Human reproduction (Oxford, England), NCBI PubMed, PMID: 11331648, 2001 May.
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Testicular dysgenesis syndrome

Possible role of endocrine disrupters, 2006

Abstracts

The testicular dysgenesis syndrome (TDS) hypothesis proposes that the four conditions cryptorchidism, hypospadias, impaired spermatogenesis and testis cancer may all be manifestations of disturbed prenatal testicular development. The TDS hypothesis is based on epidemiological, clinical and molecular studies, all suggestive of an interrelation between the different symptoms. The aetiology of TDS is suspected to be related to genetic and/or environmental factors, including endocrine disrupters.

…Important insight into the effect of in utero exposure to compounds with oestrogenic activity in humans comes from the former widespread use of diethylstilboestrol (DES), a synthetic oestrogen. …
… The effect of DES on sperm concentration and risk of development of testis cancer is unclear, as some studies have found a reduced sperm concentration in men exposed to DES in utero, whereas others have not. For testis cancer, only a slight increase in risk has been cautiously suggested (1996), (2001). …

Few human studies have found associations/correlations between endocrine disrupters, including phthalates, and the different TDS components. However, for ethical reasons, evidence of a causal relationship between prenatal exposure and TDS is inherently difficult to establish in human studies, rendering the recently developed animal TDS model an important tool for investigating the pathogenesis of TDS. Clinically, the most common manifestation of TDS is probably a reduced sperm concentration, whereas the more severe form may include a high risk of testis cancer. Clinicians should be aware of the interconnection between the different features of TDS, and inclusion of a programme for early detection of testis cancer in the management of infertile men with poor semen quality is recommended.

References

  • Testicular dysgenesis syndrome: possible role of endocrine disrupters, Best practice & research. Clinical endocrinology & metabolism, NCBI PubMed PMID: 16522521, 2006 Mar.
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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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Testicular dysgenesis syndrome and the estrogen hypothesis: a quantitative meta-analysis

Some extreme positive risk ratios were reported after what is commonly referred to as “third-generation 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)-alpha-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, NCBI PubMed PMC2235228, 2008 Feb.
  • Featured image credit Arthur Osipyan.
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