Longer polyglutamine tracts in the androgen receptor are associated with moderate to severe undermasculinized genitalia in XY males

The androgen receptor (AR) is essential to the normal development of the male internal and external genitalia. Consequently, impairment of AR function can result in undermasculinized genitalia that vary from a completely female appearance to isolated hypospadias. Since in vitro studies demonstrate that AR function is reduced by expansion of the polyglutamine tract within the receptor [AR(Gln) n ]; this study examined whether longer AR(Gln) n repeats are associated with moderate to severe undermasculinization. The average AR(Gln) n length of the undermasculinized group (n = 78, median 25, interquartile range 23-26) was significantly greater than that of the control population (n = 850, median 23, interquartile range 22-26, P = 0.002). The odds ratio of having ≥23 repeats (as opposed to ≤22 repeats) in the undermasculinized group was 2.51 (95% confidence interval 1.41-4.48). The estimated increase in the OR for each additional repeat was 9.07%. Hormonal and AR binding data were used to select subgroups of patients that had a reduced likelihood of a sex steroid biosynthetic defect or an AR abnormality. A clear trend was demonstrated in which the mean AR(Gln) n length and the odds ratio increased with the rigour of the subgroup selection criteria. Undermasculinization of the male genitalia is a rare example of a non-neurodegenerative, congenital disorder that is associated with triplet repeat allele size. Furthermore, the association of both undermasculinized genitalia and isolated male factor infertility with AR(Gln) n length provides additional evidence that they may represent different degrees of severity of the same disease process.