Defective Spermatogenesis in Cryptorchid Testes: Cause or Effect?

Environ Health Perspect. doi:10.1289/ehp.11489 available via http://dx.doi.org [Online 28 July 2008]

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

Martin et al. (2008) recently published their quantitative meta-analysis focusing on the estrogen hypothesis of testicular dysgenesis syndrome. I congratulate the authors on their thorough review and excellent summary of the existing literature. The study findings are in line with other articles; however, there are several concerns that need further attention.

Martin et al. (2008) pointed out that a common etiology underlies impaired spermatogenesis, male reproductive tract abnormalities such as hypospadias and cryptorchidism, and testicular cancer. I am especially interested in exploring the relationship between defective spermatogenesis and cryptorchidism.

Maldescended testes is commonly cited as an important cause for defective spermatogenesis (Tomomasa et al. 2002). In contrast, testicular ascent (acquired cryptorchidism) could also be a risk factor for spermatogenesis in infertile men without any history of maldescended testes (Mieusset et al. 1997). However, it remains controversial whether impaired testicular function and spermatogenesis imparts an increased risk—and therefore represents a common pathogenetic mechanism of both congenital and acquired cryptorchidism—or is merely associated with disease. Recently, a potential link was proposed relating spermatogenesis and testicular descent (Skandhan and Rajahariprasad 2007). Observational studies of many lower animals (rodents, bats, and insectivores) have revealed that testicular position is dependent on its functional status: It is scrotal during breeding seasons and inguinal or abdominal at other times (Bannister and Dayson 1995). Therefore, it is possible that maldescended testes or acquired testicular ascent simply report a state of defective testicular function and spermatogenesis. In animal studies, estrogen has been shown to increase the number of type A spermatogonia, together with inhibition of their differentiation into further steps (Kula et al. 1997). Furthermore, supportive evidence suggests that undifferentiated type A spermatogonia are the only germ cells present in cryptorchid testes (Nishimune et al. 1978). I believe that the results of Martin et al. (2008) would have been more convincing if the authors could have shown that high levels of estrogens suppress spermatogenesis.

The data of Martin et al. (2008) do not allow us to extrapolate whether exposure to environmental chemicals and pollutants with estrogenic or antiandrogenic effects can cause testicular "ascent" (Barthold and González 2003). There is strong experimental evidence that prenatal exposure to environmental chemicals, including phthalate esters, is associated with an increased risk of postnatal cryptorchidism (Imajima et al. 1997). The similarity in the histopathology of the ascending testis and the testis undescended since birth suggests that ascending testes are not retractile testes trapped in scar tissue (Rusnack et al. 2002). Furthermore, this finding also suggests that, as in primary undescended testes, estrogen/antiandrogen hypotheses could explain the cause of ascending testes, because a thermal effect cannot be blamed for the decreased germ cell count in the descended testis.

Overall, the systematic review and meta-analysis by Martin et al. (2008) is the most extensive attempt to date to investigate the link between estrogenic agents and testicular dysgenesis syndrome. Although some of the data from the cited studies are of limited quality, the fact that nearly all of the included studies identified an increase in the risk of hypospadias, cryptorchidism, and testicular cancer in the groups prenatally exposed to diethylstilbestrol provides strong support for that association being genuine. However, from the data of Martin et al. (2008), we cannot conclude whether exposure to environmental chemicals with estrogenic effects significantly increases the risk of developing acquired cryptorchidism. Further research to evaluate the effects of endocrine-disrupting chemicals (EDCs)—particularly those with estrogen-like effects on reproductive health—is justified and should continue.

The author declares he has no competing financial interests.

References

Bannister LH, Dayson M. 1995. Reproductive system. In: Grays Anatomy (Dussek JE, William PL, Bannister LH, Berry MM, Collin P, Dayson M, Dussek JE, et al., eds). 38th ed. London:Churchhill Livingstone, 1854.

Barthold JS, González R. 2003. The epidemiology of congenital cryptorchidism, testicular ascent and orchiopexy. J Urol 170:2396–2401.

Imajima T, Shono T, Zakaria O, Suita S. 1997. Prenatal phthalate causes cryptorchidism postnatally by inducing transabdominal ascent of the testis in fetal rats. J Pediatr Surg 32:18–21.

Kula K, Slowikowska-Hilczer J, Walczak R, Oszukowska E. 1997. Hormones and premeiotic spermatogenesis in man and rat. A possible involvement of estradiol and prolactin. Pol J Endocrinol 2:S75–S89.

Martin OV, Shialis T, Lester JN, Scrimshaw MD, Boobis AR, Voulvoulis N. 2008. Testicular dysgenesis syndrome and the estrogen hypothesis: a quantitative meta-analysis. Environ Health Perspect 116:149–157.

Mieusset R, Bujan LE, Massat G, Mansat A, Pontonnier F. 1997. Inconstant ascending testis as a potential risk factor for spermatogenesis in infertile men with no history of cryptorchism. Hum Reprod 12:974–979.

Nishimune Y, Aizawa S, Komatsu T. 1978. Testicular germ cell differentiation in vivo. Fertil Steril 29: 95–102.

Rusnack SL, Wu HY, Huff DS, Snyder HM III, Zderic SA, Carr MC, et al. 2002. The ascending testis and the testis undescended since birth share the same histopathology. J Urol 168:2590–2591

Skandhan KP, Rajahariprasad A. 2007. The process of spermatogenesis liberates significant heat and the scrotum has a role in body thermoregulation. Med Hypotheses 68: 303–307.

Tomomasa H, Adachi Y, Oshio S, Umeda T, Irie H, Ishikawa H. 2002. Germ cell apoptosis in undescended testis: the origin of its impaired spermatogenesis in the TS inbred rat. J Urol 168:343–347.

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Defective Spermatogenesis: Martin et al. Respond

Environ Health Perspect. doi:10.1289/ehp.11489R available via http://dx.doi.org [Online 28 July 2008]

In response to Prasad's constructive comments on our quantitative meta-analysis of the estrogen hypothesis and testicular dysgenesis syndrome (Martin et al. 2008), we offer the following observations regarding the scope of our study and limitations of the methodology applied.

The primary objective of a quantitative meta-analysis is to combine the results of previous studies examining a specific research question to arrive at a summary conclusion about a body of research. This statistical pooling of several studies, taking into account the size of individual studies, confers more power to detect a potential association, and quantitative meta-analyses are often put at the top of evidence hierarchies. It cannot, however, correct for potential bias and confounding of the studies included; we addressed this issue in our review (Martin et al. 2008) by rating the quality of individual studies and carrying out a sensitivity analysis by excluding studies for which the quality score was below a chosen value. The method also requires that included studies report a measure of association such as a risk ratio or odds ratio. For this reason—although we did mention impaired spermatogenesis as one of the end points encompassed by the testicular dysgenesis syndrome—it was necessary to exclude this end point from our analysis.

In previous work and a scoping study, we found that most of the research carried out in relation to impaired spermatogenesis had investigated time trends rather than association with specific risk factors (Martin et al. 2007). Further, our analysis was limited to prenatal exposure to estrogenic agents. A number of studies have found associations between sperm motility or sperm DNA damage with levels of estrogenic chemicals measured either in urine or serum (Duty et al. 2003; Spanò et al. 2005). It would not be possible however to relate such levels to prenatal exposure. This also illustrates the difficulty of selecting a suitable marker of impaired spermatotogenesis.

Our study was implicitly limited to congenital cryptorchidism because the literature search did not yield any case–control or cohort studies that addressed the question of prenatal exposure to estrogenic compounds and acquired cryptorchidism in humans. In retrospect, this should have been explicitly stated in our article (Martin et al. 2008).

We concluded that the significant association between prenatal diethylstilbestrol exposure and all three end points considered conferred weight to the hypothesis of a common etiology for these disorders, and therefore to the existence of a testicular dysgenesis syndrome (Martin et al. 2008). Separate analyses were carried out for the three end points but the methodology applied did not allow us to explore the specific nature of causal relationships between congenital cryptorchidism, hypospadias, and testicular cancer. We are therefore grateful for Prasad's insights.

The authors declare they have no competing financial interests.

References

Duty SM, Silva MJ, Barr DB, Brock JW, Ryan L, Chen ZY, et al. 2003. Phthalate exposure and human semen parameters. Epidemiology 14(3):269–277.

Martin OV, Lester JN, Voulvoulis N, Boobis AR. 2007. Human health and endocrine disruption: a simple multicriteria framework for the qualitative assessment of end point–specific risks in a context of scientific uncertainty. Toxicol Sci 98(2):332–347.

Martin OV, Shialis T, Lester JN, Scrimshaw MD, Boobis AR, Voulvoulis N. 2008. Testicular dysgenesis syndrome and the estrogen hypothesis: a quantitative meta-analysis. Environ Health Perspect 116:149–157.

Spanò M, Toft G, Hagmar L, Eleuteri P, Rescia M, Rignell-Hydbom A, et al. 2005. Exposure to PCB and p,p'-DDE in European and Inuit populations: impact on human sperm chromatin integrity. Human Reprod 20(12):3488–3499.