Testicular dysgenesis syndrome and the estrogen hypothesis: a quantitative meta-analysis

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.

Keywords: cryptorchidism; diethylstilbestrol; endocrine disruption; environment; estrogen; hypospadias; meta-analysis; oral contraceptives; testicular cancer; testicular dysgenesis.

Figure 1

Forest plot of the risk estimates and their 95% CIs from the studies included in the meta-analysis of the association between prenatal exposure to estrogenic agents and hypospadias.

Figure 2

Funnel plot of the risk estimate studies included in the meta-analysis of the association between prenatal exposure to estrogenic agents and hypospadias and their SEs.

Figure 3

Forest plot risk estimates and their 95% CIs from the studies included in the meta-analysis of the association between prenatal exposure to estrogenic agents and cryptorchidism.

Figure 4

Funnel plot of the risk estimate studies included in the meta-analysis of the association between prenatal exposure to estrogenic agents and cryptorchidism and their SEs.

Figure 5

Forest plot risk estimates and their 95% CIs from the studies included in the meta-analysis of the association between prenatal exposure to estrogenic agents and testicular cancer.

Figure 6

Funnel plot of the risk estimate studies included in the meta-analysis of the association between prenatal exposure to estrogenic agents and testicular cancer and their SEs.

Figure 7

Time trend for quality showing quality score attributed to studies included in the meta-analysis of the association between prenatal exposure to estrogenic agents and testicular cancer by year of publication. R² = 0.5711.