Polymorphisms of the luteinizing hormone/chorionic gonadotropin receptor gene: association with maldescended testes and male infertility.

OBJECTIVE: Maldescended testes are the most common genital anomaly in newborns and are associated with testicular malignancy and infertility. As the inguinoscrotal phase of testis descent is androgen-dependent and requires integrity of the luteinizing hormone/chorionic gonadotropin receptor (LHCGR), we investigated whether nonsynonymous polymorphisms of the LHCGR gene are associated with maldescended testes.

METHODS: This was a retrospective case-control study including 278 patients with maldescended testes, 277 infertile men without maldescensus and 271 controls with normal sperm concentrations. Clinical and endocrinological workup of the patients was performed. Single nucleotide polymorphism (SNP) analysis was performed by GeneScan and TaqMan technology.

RESULTS: Men with maldescended testes had significantly lower testis volumes, higher serum luteinizing hormone (LH) and follicle-stimulating hormone (FSH) but similar testosterone levels compared with both the control groups. The insLQ polymorphism in exon 1 (rs4539842) and the N291S SNP in exon 10 (rs12470652), showing increased receptor sensitivity in vitro, were not differently distributed between patients and controls. The S312N SNP in exon 10 (rs2293275) was significantly less frequent in men with maldescended testes than in controls. This difference was confirmed when infertile men with and without maldescensus were considered together.

CONCLUSIONS: In men with maldescensus, a high LH drive maintains normal testosterone levels but this LH resistance is not associated with any particular LHCGR genotype. A significant association with the S312N polymorphism in exon 10 of the LHCGR is correlated to the spermatogenetic damage rather than to the maldescensus itself. Either the LHCGR itself or another genomic region linked to this SNP, possibly the germ cell-specific TFIIA-alpha/beta-like factor gene transcribed from the same genomic region in the opposite direction, is a risk factor for male infertility.