Role of INSL3 and LGR8 in cryptorchidism and testicular functions

Cryptorchidism is the most frequent congenital anomaly of the urogenital tract in human males. INSL3 and LGR8/GREAT proteins seem to act as ligand and receptor respectively, and to have a role in gubernaculum development involved in testicular descent. Mutations in the INSL3 gene or LGR8/GREAT were found to be associated with cryptorchidism in humans. In a cohort of 135 ex-cryptorchid patients and 100 controls, mutations were sought in INSL3 and LGR8/GREAT genes by sequencing. Six patients were found with mutations in the INSL3 gene and four patients with LGR8/GREAT mutation (10/135, 7.4%). The 10 patients show different phenotypes, ranging from normozoospermia to complete azoospermia, and from bilateral cryptorchidism to retractile testes. Furthermore, the endocrine function of the testis appeared normal in all subjects. These findings demonstrate that INSL3-LGR8/GREAT mutations are frequently associated with human cryptorchidism, and that the only clinical consequence of alterations of the INSL3-LGR8/GREAT system seems to be failure of the testis to descend normally in the scrotum during embryonic development, without affecting the spermatogenic and endocrine components of the testis itself. The first analysis in humans of INSL3 was then performed using a novel radioimmunoassay kit to measure INSL3 concentrations in serum of adults. The results show that INSL3 circulates in adult men, it is a male-specific hormone, and it is of almost exclusively testicular origin. The role of this hormonal system in adulthood is, however, to date unknown.