Growth Hormone and Cancer Risk: A Two-Sample Bidirectional Mendelian Randomization Study with Mediation Testing.
INTRODUCTION Growth Hormone (GH) therapy for deficiency carries potential cancer risks with unclear causality. This Mendelian randomization study investigated the relationship between genetically predicted GH levels and cancer risk across 16 types. METHODS We selected genetic variants strongly associated with serum GH levels from published GWAS as instrumental variables. The primary analysis employed inverse-variance weighted MR, supplemented by MR-Egger regression. Sensitivity analyses, including MR-PRESSO and pleiotropy tests, were conducted to evaluate robustness. Mediation analysis was performed to assess the contribution of specific metabolites. RESULTS Genetic instruments for GH were derived from genome-wide association studies. Analyses suggested GH may be a risk factor for breast cancer, prostate cancer, and malignant lymphoma, and potentially a protective factor for oral/oropharyngeal cancer and skin cancer. Sensitivity analyses partially supported robustness, though notable limitations were present for some outcomes. Mediation analysis revealed that isovalerylglycine (mediating 34.12%) and the proline/trans-4- hydroxyproline ratio (28.40%) partially explained GH's effect on breast cancer, while the histidine/ glutamine ratio mediated 36.28% of GH's effect on prostate cancer. DISCUSSION These findings demonstrate tissue-specific effects of GH on carcinogenesis, partially mediated through metabolic pathways. Results suggest careful risk-benefit assessment in GH therapy and suggest metabolite monitoring could help mitigate cancer risk in susceptible individuals. CONCLUSION This Mendelian randomization study provides genetic evidence suggesting a potential causal role of GH exposure and the development of specific cancers, partially mediated by certain metabolites. GH shows both promoting and protective effects depending on the cancer type, with important implications for clinical management. The findings highlight the potential value of exploring risk-stratified approaches in GH replacement therapy and suggest further investigation into metabolic interventions to modulate GH-related cancer risk.