Introduction. This prospective study investigated the efficacy of a gonadotropin-releasing hormone agonist (LH-RHa) in restoring defective mini-puberty. Materials and Methods. Boys with isolated bilateral cryptorchidism and defective mini-puberty were randomly divided into two groups. The “surgery only” group underwent a second orchidopexy without hormonal treatment (control). The “LH-RHa” group received LH-RHa therapy followed by a second orchidopexy. The number of Ad spermatogonia and the total germ cell count per tubule (S/T) were analyzed. Results. Five boys were included in each arm. In the LH-RHa group, the median S/T increased from 0.11 to 0.42, p=0.04. In the surgery only group, the median S/T did not change. In the surgery only group, none of the testes had Ad spermatogonia. In contrast, in the LH-RHa group, all testes completed the transition from gonocytes to Ad spermatogonia (p=0.008). Conclusions. Treatment with LH-RHa was effective in rescuing defective mini-puberty in boys with bilateral cryptorchidism.

Background: Cryptorchidism is a frequent endocrinopathy in boys that has been associated with an increased risk of developing testicular cancer and infertility. The condition is curable by combined surgery and hormonal treatment during early pre-pubertal stages using gonadotropin releasing hormone agonist (GnRHa). However, whether the treatment also alters the expression of testicular long non-coding RNAs (lncRNAs) is unknown. To gain insight into the effect of GnRHa on testicular lncRNA levels, we re-analyzed an expression dataset generated from testicular biopsies obtained during orchidopexy for bilateral cryptorchidism. Results: We identified EGFR-AS1, Linc-ROR, LINC00221, LINC00261, LINC00282, LINC00293, LINC00303, LINC00898, LINC00994, LINC01121, LINC01553, and MTOR-AS1 as potentially relevant for the stimulation of cell proliferation mediated by GnRHa based on their direct or indirect association with rapidly dividing cells in normal and pathological tissues. Surgery alone failed to alter the expression of these transcripts. Conclusion: Given that lncRNAs can cooperate with chromatin-modifying enzymes to promote epigenetic regulation of genes, GnRHa treatment may act as a surrogate for mini-puberty by triggering the differentiation of Ad spermatogonia via lncRNA-mediated epigenetic effects. Our work provides additional molecular evidence that infertility and azoospermia in cryptorchidism, resulting from defective mini-puberty cannot be cured with successful orchidopexy alone.

Correlation between Histology and Gene Expression in Cryptorchidism