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 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. 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. 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. Our results suggest that variations in the ESR2 might influence the susceptibility to hypospadias
Published Version
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