EGR4 is a master gene responsible for fertility in cryptorchidism. Is gene therapy going to replace surgery?
The purpose of early medical or surgical treatment of boys with undescended testes is to prevent the development of infertility. However, early and successful surgery cannot prevent infertility in cryptorchid boys who lack type A dark (Ad) spermatogonia a stem cell for spermatozoa. Despite a successful surgery for undescended testes all males in the high risk of infertility group were oligospermic (mean: 8.9 × 10 6 sperm/ ejaculate) and 20 % were azoospermic. These patients had 25 times less sperm compared to the group with presence of Ad spermatogonia in both testes. Thus, infertility induced by cryptorchidism is an endocrine disease of impaired mini-puberty. Correlations between testicular histology and postpubertal hormone levels confirmed a relative gonadotropin deficiency in the majority of males with cryptorchidism.
The aim of present study was to compare the gene expression pattern of patients with completed transformation of gonocytes into Ad spermatogonia, associated with low infertility risk, with patients that had failed to undergo this process and had a high infertility risk. Whole-genome expression profiling showed that boys in the high infertility risk group according to testicular histology, showed decreased or lack of expression of most of the genes essential for hypothalamo-pituitary-testicular axis function relative to low or intermediate risk group as well as controls. In particular, EGR4, which is involved in regulating the secretion of luteinizing hormone, was virtually not expressed. Thus, we found multiple differences in gene expression between the high and low infertility risk groups, confirming the importance of an intact hypothalamo-pituitary testicular axis and EGR4 in fertility development. Gene therapy is a new and promising approach for treatment of different human diseases. Gene transfer to sperm and testes to obtain transgenic animals has already being utilized. In the future this technique could be implemented for EGR4 in those cryptorchid individuals risking infertility.