<b>Conclusions:</b> These findings further support the role of INSL3 in human testicular descent and could prove relevant in uncovering the pathophysiology of cryptorchidism.
The abnormal development of fetal Leydig cells could lead to the reduction of androgen and insulin-like 3, thus causing the male reproductive tract anomalies in male neonates, including cryptorchidism and hypospadias.
Previous studies of undescended testis (UT) has focused on insulin-like hormone 3 (INSL3), the genitofemoral nerve, and androgens in the testicular descent.
While both the insulin-like peptide 3 (INSL3) and its receptor, relaxin family peptide receptor 2 (RXFP2), have been demonstrated to control testicular descent in mice, their link to human cryptorchidism is weak, with no clear cause-effect demonstrated.
Under this perspective, we aimed to study the presence of INSL3 allelic variations in a cohort of patients with cryptorchidism and to estimate their potential consequences.
Using a case-control design, we show that cryptorchidism and hypospadias are both significantly associated with increased amniotic concentration of INSL3 during gestational weeks 13-16, and some, though not all steroid biomarkers.
In two different patients with unilateral cryptorchidism, we found the variants rs121912556 and p.R105R of INSL3 gene in a heterozygous form associated with cryptorchidism, so we could considered them as risk factors for cryptorchidism.
Mutations in the human genes encoding insulin-like factor 3 (INSL3) and its Leu-rich repeat-containing G protein-coupled receptor 8 (LGR8), homeobox A10 (HOXA10), zinc finger 214 (ZNF214) and 215 (ZNF215) have occasionally been identified but do not seem to be a frequent cause of cryptorchidism.
A novel V39GINSL3 mutation in a patient with cryptorchidism was identified; however, the functional analysis of the mutant peptide did not reveal compromised function.
Major regulators of testicular descent are the hormones insulin-like factor 3 (INSL3) and testosterone, and disruption of these pathways might cause cryptorchidism.
The results, in conjunction with the previous data, suggest that mutations of INSL3 and LGR8/GREAT remain rare, and that the Thr/Thr genotype of Ala60Thr polymorphism in INSL3 may constitute a susceptibility factor for the development of CO.
A second Leydig cell product, insl3, is also significantly down regulated and is likely responsible for the cryptorchidism commonly seen in these phthalate-treated animals.
However, although some of mutations were found only in cryptorchid patients, it remains to be verified whether there is a causative link between the presence of mutations in INSL3 or GREAT/LGR8 and the undescended testis phenotype in men.