Significance of mutations in the androgen receptor gene in males with idiopathic infertility

Abnormal human spermatogenesis is caused by a variety of genetic and acquir ed conditions. Because spermatogenesis is dependent on androgens, some male s may have a minimal form of androgen insensitivity,that does not inhibit v irilization but impairs fertility. This has lead us to investigate the poss ibility of abnormalities in the androgen receptor (AR) gene in a large coho rt of males suffering from infertility of unknown cause. We studied 180 males with variable impairment of spermatogenesis. In all pa tients, serum levels of testosterone and gonadotropins were analyzed to def ine an androgen sensitivity index (ASI). Single-strand conformation analysi s and direct DNA sequencing of PCR-amplified blood leukocyte DNA were used to identify mutations within the whole coding region of the AR-gene. Endocr ine and molecular investigations were compared with 53 normal males with pr oven fertility. In three infertile males, mutations in the AR were identified. Two unrelate d males had the same variation within the first exon encoding for the trans activation domain of the receptor (Pro390Ser), whereas, in the third, a mut ation in the hormone-binding region was characterized (Gln798Glu). All iden tified mutation carriers had a significantly elevated ASI. A proportion of males with idiopathic infertility carry relevant variations within the AR-gene. These males may be distinguished on the basis of hormo ne levels, calculating the ASI, although this index lacks specificity.