The molecular basis of cryptorchidism

Abstract

Cryptorchidism is the commonest malady to affect newborn male infants. Until recently, the molecular aetiology of this syndrome was unclear. Cryptorchidism may be part of a broader testicular dysgenesis syndrome, wherein a disturbance in steroid hormone metabolism, possibly through a perturbed hypothalamic-pituitary-gonadal axis could be involved. Disturbance may be genetic, or extrinsic through endocrine disruptors. Recently, the role of insulin-like factor-3 (INSL3; alternatively called relaxin-like factor) has been highlighted through the cryptorchid phenotype of mice where genes for either INSL3 or its receptor have been ablated. INSL3 is produced by Leydig cells of the fetal testis and acts upon the gubernacular ligament to retain the gonad in the inguinal region, from which it later passes into the scrotum. INSL3 expression in fetal testis is inhibited by maternal exposure to estrogens. Although to date no mutations have been found in the human INSL3 gene responsible for cryptorchidism, one causative mutation in the INSL3 receptor (LGR8 or GREAT) has been reported. Studies on developmental transcription factors, such as Hoxa-10 in mice, suggest that other specific molecular cascades could also lead to a cryptorchid phenotype. Considering its frequency in newborn children, and the severity of the untreated condition (infertility and often testicular cancer) these new findings should generate new information on possible causes and treatments.