Linkage between cryptorchidism, hypospadias, and GGN repeat length in the androgen receptor gene

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. (J Clin Endocrinol Metab 89: 5105–5109, 2004)