Polymorphisms of estrogen receptor beta gene are associated with hypospadias

Abstract

Purpose Hypospadias is regarded as a complex disorder caused by both genetic and environmental factors. The importance of androgens and the androgen receptor (AR) in male external genital development is well recognized. Recently however, the presence of estrogen receptors in the developing male external genitalia seems to indicate that there is also a finely tuned balance between male and female hormone activity during sex development. There are two isoforms of the human estrogen receptor, {ESR1} and ESR2, with distinct tissue and cell patterns of expression. We hypothesized that modifications in the estrogen receptor genes could affect the risk of hypospadias. Material and methods We have screened sixty boys with hypospadias for mutations in the coding regions of {ESR1} and {ESR2} genes. In addition, genotyping of the {CA} repeat polymorphism in {ESR2} and the {TA} repeat polymorphism in {ESR1} was analyzed and compared with a control group. Results The {CA} repeat polymorphism in {ESR2} is prolonged in hypospadias patients compared to controls (P < 0,05). Prolongation of this {CA} repeat polymorphism has previously been associated with lower levels of testosterone. Six patients presented the genetic variant 2681-4A > G in {ESR2} in heterozygous form, which was a significantly higher frequency than in the control population (P < 0,05). In ESR1, no significant gene alteration was found to be associated with hypospadias. Conclusions Our results suggest that variations in the {ESR2} might influence the susceptibility to hypospadias