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.

Superior androgen receptor (AR) function in subjects carrying a GGN repeat length of 23 (GGN23) has been indicated in vivo. Therefore, the activity of the AR carrying GGN23 combined with CAG22 was compared to the AR with GGN10, 24 and 27, respectively, in the presence of 0.1-100 nM testosterone or DHT. At 100 nM DHT, GGN24 showed 35% lower transactivating activity (95% [CI]: 20-50%) than GGN23. GGN10 and GGN27 also showed significantly less AR activity than GGN23 (mean differences [95% CI]: 54% [40-68%] and 58% [39-78%], respectively). The same trend was also observed at lower DHT concentrations. In response to R1881, GGN23 activity was significantly higher than for other lengths. ARs with other glutamine numbers than 23 have lower transactivating capacity in response to both testosterone and DHT. Congenital malformations and other signs of hypoandrogenism in subjects with AR gene GGN lengths other than 23 could, hence, be related to a lower AR activity.

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The < 21 CAG and GGN = 23 combination of repeats may confer a lower risk of infertility to the carriers. Androgen sensitivity may be higher among carriers of the GGN = 23 allele compared to the GGN = 24 allele.