Extensive experimental evidence suggests that endocrine-disrupting exposures contribute to hypospadias etiology. The observational epidemiologic literature, however, falls short regarding whether (or which) environmental exposures contribute. There is highly publicized concern about these and other chemicals in our environment. Nevertheless, generalizations that focus on ‘positive’ findings rather than a more comprehensive view that incorporates null findings and study limitations should be avoided. It is important that future studies are designed to produce strong internal as well as external validity, as well as measurements that cover a broader range of chemicals, in a more direct way.
Extensive evidence suggests that genetic variation contributes to hypospadias, but again the observational literature does not provide firm evidence regarding which genetic variants contribute. In the area of genetic susceptibility, important challenges for future studies will be to incorporate a more in-depth inquiry of existing candidate genes and more attention to gene discovery tools. Another critical goal is to be able to interrogate interactions among the various endogenous, exogenous and genetic factors of interest. Thus far, studies have tended to be too small and/or lacking the data to make such inquiries.
Another lingering concern is whether phenotypic heterogeneity exists. Some studies suggest that heritability is somewhat higher for more severe hypospadias cases (Bauer and others, 1981
; Opitz, 1985
; Schnack and others, 2008
; Sweet and others, 1974
), while others do not (Brouwers and others, 2010
; Fredell and others, 2002
). Studies examining candidate genes have tended to report similar findings across the range of severity (Sata and others, 2010
; Silver and Russell, 1999
; Thai and others, 2005
; van der Zanden and others, 2010a
; Watanabe and others, 2007
), as have studies examining descriptive risk factors such as age, parity and race-ethnicity(Brouwers and others, 2010
; Carmichael and others, 2003
). The association of hypospadias with low birthweight tends to be stronger, the more severe the phenotype (Brouwers and others, 2010
; Carlson and others, 2009
; Carmichael and others, 2003
), but this may simply reflect the underlying severity of the condition, rather than different etiologies. Regarding embryology, more recent studies indicate that urethral closure involves a continuous process of ventral fusion in the proximal to distal direction (Kurzrock and others, 1999
; Seifert and others, 2008
; Van Der Werff and others, 2000
). Thus, existing evidence tends to point toward similarity of etiology regardless of severity, but many studies have had sample sizes that limited the ability to detect phenotypic differences. The most prudent approach at this point is to consider phenotype-specific analyses whenever feasible.
Examining the associations of environmental and genetic factors with hypospadias remain important areas of inquiry, although our actual understanding of their contribution to hypospadias risk in humans is currently limited. A more solid understanding of their contribution to hypospadias etiology will help guide the development of appropriate messages related to public health as well as individual-level risk, and it will facilitate the elucidation of underlying mechanisms, which are all important to its eventual prevention.