Androgen deprivation therapy (ADT) is the main treatment strategy for men with metastatic prostate cancer (PC). However, ADT is associated with various metabolic disturbances, including impaired glucose tolerance, insulin resistance and weight gain, increasing risk of diabetes and cardiovascular death. Much remains unknown about the metabolic pathways and disturbances altered by ADT and the mechanisms. We assessed the metabolomic effects of ADT in the serum of 20 men receiving ADT. Sera collected before (baseline), 3 and 6 months after initiation of ADT was used for the metabolomics and lipidomics analyses. The ADT‐associated metabolic changes were identified by univariable and multivariable statistical analysis, ANOVA, and Pearson correlation. We found multiple key changes. First, ADT treatments reduced the steroid synthesis as reflected by the lower androgen sulfate and other steroid hormones. Greater androgen reduction was correlated with higher serum glucose levels, supporting the diabetogenic role of ADT. Second, ADT consistently decreased the 3‐hydroxybutyric acid and ketogenesis. Third, many acyl‐carnitines were reduced, indicating the effects on the fatty acid metabolism. Fourth, ADT was associated with a corresponding reduction in 3‐formyl indole (a.k.a. indole‐3‐carboxaldehyde), a microbiota‐derived metabolite from the dietary tryptophan. Indole‐3‐carboxaldehyde is an agonist for the aryl hydrocarbon receptor and regulates the mucosal reactivity and inflammation. Together, these ADT‐associated metabolomic analyses identified reduction in steroid synthesis and ketogenesis as prominent features, suggesting therapeutic potential of restricted ketogenic diets, though this requires formal testing. ADT may also impact the microbial production of indoles related to the immune pathways. Future research is needed to determine the functional impact and underlying mechanisms to prevent ADT‐linked comorbidities and diabetes risk.

中文翻译：

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雄激素剥夺治疗对前列腺癌的代谢影响。

雄激素剥夺疗法（ADT）是转移性前列腺癌（PC）男性的主要治疗策略。但是，ADT与各种代谢紊乱有关，包括葡萄糖耐量降低，胰岛素抵抗和体重增加，糖尿病和心血管死亡的风险增加。关于由ADT改变的代谢途径和紊乱及其机理，目前尚不清楚。我们评估了20名接受ADT的男性血清中ADT的代谢组学作用。在开始ADT之前（基线），3和6个月后收集的血清用于代谢组学和脂质组学分析。通过单变量和多变量统计分析，ANOVA和Pearson相关性确定了ADT相关的代谢变化。我们发现了多个关键变更。第一，ADT治疗降低了类固醇的合成，这反映在较低的硫酸雄激素和其他类固醇激素上。更高的雄激素减少与更高的血清葡萄糖水平相关，支持ADT的致糖尿病作用。其次，ADT持续降低了3-羟基丁酸和生酮能力。第三，许多酰基肉碱被还原，表明对脂肪酸代谢的影响。第四，ADT与饮食色氨酸中微生物来源的代谢物3-甲酰基吲哚（aka吲哚-3-羧甲醛）的相应减少有关。吲哚-3-羧醛是芳烃受体的激动剂，调节粘膜反应性和炎症。这些与ADT相关的代谢组学分析共同确定了类固醇合成和生酮的减少是主要特征，提示限制生酮饮食的治疗潜力，尽管这需要正式测试。ADT还可能影响与免疫途径相关的吲哚的微生物产生。需要进行进一步的研究以确定功能性影响和潜在机制，以预防与ADT相关的合并症和糖尿病风险。