Linkage between Cryptorchidism, Hypospadias, and GGN Repeat Length in the Androgen Receptor Gene

Abstract

Although sufficient androgen receptor (AR) function is crucial for normal male sexual differentiation, single-point mutations in the AR gene are infrequent in the two most common male congenital malformations, hypospadias and cryptorchidism. Because polymorphic CAG and GGN segments regulate AR function, we investigated whether there was any association between these polymorphisms and mentioned malformations. Genotyping was performed by direct sequencing of DNA from patients diagnosed with hypospadias (n = 51) and cryptorchidism (n = 23) and controls (n = 210). The subjects with hypospadias were divided into subgroups of glanular, penile, and penoscrotal hypospadias. Median GGN lengths were significantly higher (24 vs. 23) among both subjects with cryptorchidism, compared with controls (P = 0.001), and those with penile hypospadias, compared with either controls (P = 0.003) or glanular and penoscrotal hypospadias combined (P = 0.018). The frequency of cases with GGN 24 or more vs. GGN = 23, differed significantly among those with cryptorchidism (65/35%), compared with controls (31/54%) (P = 0.012), and among subjects with penile hypospadias (69/31%), compared with either controls (P = 0.035) or glanular or penoscrotal hypospadias combined (32/55%) (P = 0.056). There were no significant differences in CAG lengths between the cases and controls. Our findings indicate an association between GGN length and the risk of cryptorchidism and penile hypospadias, both conditions considered consequences of low androgenicity.

Could androgen receptor gene CAG tract polymorphism affect spermatogenesis in men with idiopathic infertility?

“…Moreover, the number of AR-CAG repeat stretch was statistically higher in comparison with those assessed in FM (Table 1). Our data are in agreement with most results published until now [47][48][49][50][51] except for those of a more recent study [18]. These conflicting evidence, though, can be explained by the following factors: 1) the choice of selection criteria for the patients enrolment, taken the complexity of the syndrome characterized by several clinical aspects such as idiopathic (mono or bilateral) cryptorchidism with or without comorbidity (inguinal hernia, micropenis, hypospadia etc.,) and secondary cryptorchidism (hypogonadotropic hypogonadism, Klinefelter S.) [25]; 2) the close partnership with other genes and/or hormones in testicular descent process [25]; 3) the complexity of androgen action (genomomic and/or nongenomic action) in different target tissues [19,51].…”

Hypospadias: Interactions between environment and genetics

“…An increased GGN trinucleotide repeat in the AR gene has been found to reduce its transcriptional activity in hypospadiac patients [111,112]. The role of amplification of the CAG repeats remains to be determined [113] and may be associated with undermasculinized genitalia, including hypospadias [114].…”

Factors controlling testis descent

“…Conversely, longer CAG repeats have been associated with idiopathic hypospadias, undescended testes and decreased sperm counts (36)(37)(38). The association with cryptorchidism is stronger when combined analysis of CAG and GGC repeat lengths is performed (39).…”