Growth Hormone Deficiency and Subsequent Replacement Therapy Trigger Differential Expression of Specific MicroRNAs in Males and Females: Not Just a Matter of Height

Introduction: Sex differences influence various physiological processes, including growth, body composition, and hormonal regulation, underscoring the importance of sex-specific therapeutic strategies. Growth hormone (GH) plays a pivotal role in growth and metabolism. While sex differences in response to GH therapy (GHT) are already documented in adults, data on pediatric patients remain sparse and often conflicting. Additionally, the role of epigenetic regulators, such as microRNAs (miRNAs), in mediating sex-specific responses to GHT has been largely unexplored. Methods: We investigated gender-specific changes in the miRNA profile that occur before and after 3 months on GHT in a cohort of prepubertal children with GH deficiency (GHD) re-analyzing a previously published miRNA profiling (GSE193450) dataset using statistical and pathway enrichment analysis. Results: We found that 3 miRNAs (hsa-miR-185-5p, hsa-miR-380-3p, hsa-miR-486-5p) in females and 9 miRNAs (hsa-miR-30b-5p, hsa-miR-30c-5p, hsa-miR-132-3p, hsa-miR-139-5p, hsa-miR-142-5p, hsa-miR-195-5p, hsa-miR-197-3p, hsa-miR-200c-3p, hsa-miR-340-5p) in males were significantly upregulated before the start of GHT. After 3 months, 3 miRNAs (hsa-miR-124-3p, hsa-miR-215-5p, hsa-miR-525-3p) in females and 4 (hsa-miR-30c-5p, hsa-miR-30e-5p, hsa-miR-551b-3p, hsa-miR-671-3p) in males were significantly upregulated. Performing pathway enrichment analyses, we found that the most affected pathways, among others, were Wnt, TGFβ, Jak-STAT, and p53 signaling pathways. Conclusions: Overall, in addition to the shared changes previously documented by our group, this study shows that prepubertal males and females with isolated idiopathic GHD have distinct miRNA profiles before and after 3 months on GHT, suggesting gender effects that are not currently taken into consideration while treating pediatric patients.