GnRHa Treatment of Cryptorchid Boys Affects Genes Involved in Hormonal Control of the HPG Axis and Fertility

The gonadotropin-releasing hormone agonist (GnRHa; Buserelin) rescues fertility during adulthood in the majority of high infertility risk cryptorchid boys presenting with defective mini-puberty. However, the molecular events governing this effect are not understood. We report the outcome of an RNA profiling analysis of testicular biopsies from 4 operated patients who were treated with GnRHa for 6 months versus 3 operated controls who were not treated. GnRHa induces a significant transcriptional response, including protein-coding genes involved in pituitary development, the hypothalamic-pituitary-gonadal axis, and testosterone synthesis. Furthermore, we observed an increased abundance of long noncoding RNAs (lncRNAs) participating in epigenetic processes, including AIRN, FENDRR, XIST, and HOTAIR. These data are consistent with the hypothesis that hypogonadotropic hypogonadism in boys with altered mini-puberty is the consequence of a profoundly altered gene expression program involving protein-coding genes and lncRNAs. Our results point to molecular mechanisms that underlie the ability of GnRHa to rescue fertility.