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

Abstract

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.

DMRTC2, PAX7, BRACHYURY/T and TERT Are Implicated in Male Germ Cell Development Following Curative Hormone Treatment for Cryptorchidism-Induced Infertility

“…Patients were age and ethnicity matched. RNA sequencing data from manually selected germ cell marker genes from our two previous studies [ 22 , 23 ] were analyzed.…”

“…The workflow from RNA isolation, through to purification, library preparation, sequencing, data analyses, and expression level analyses, has been described previously [ 22 , 23 ].…”

Genes Involved in Long-Term Memory Are Expressed in Testis of Cryptorchid Boys and Respond to GnRHa Treatment

“…Treatment with GnRHa stimulates LH secretion and the development of juvenile Leydig cells [Hadziselimovic et al, 1984]. This therapy increased, as expected, the abundance of several genes that regulate testosterone synthesis ( HSD3B1 , HSD17B2 , CYP19A1 , CYP11B2 , and CYP11B1 ) [Hadziselimovic et al, 2017]. The LH increase observed after 6 months of therapy suggests that LH secretion results from an alternate pathway stimulation via EGR2 and EGR3 , indicating that both genes compensate for EGR1 and EGR4 .…”

“…Approximately 90% (5,823/6,469) showed increased expression following GnRHa treatment [Hadziselimovic et al, 2017]. In the present analysis, we re-interpreted the data with emphasis on selected genes known to be relevant for learning and memory or directly implicated in memory formation ( Table 1 ).…”

“…The workflow from RNA isolation, purification, library preparation, sequencing, and data analysis was described previously in a HIR patient RNA profiling study [Hadziselimovic et al, 2017].…”