Tryptophan metabolism and erectile dysfunction: pathophysiological insights into kynurenine pathway dysregulation

Abstract

Abstract Background ED refers to the persistent difficulty in attaining or sustaining a firm enough erection for satisfactory sexual performance. The kynurenine pathway (KP) of tryptophan metabolism is associated with reactive oxygen species production and inflammation and may be related to the pathophysiology of ED. This study aimed to analyze KP biomarker levels in ED patients and examine their potential connection to ED. Methods 110 consecutive male patients diagnosed with ED and 60 age-matched healthy male volunteers were included. Serum KP metabolite levels were analysed using the liquid chromatography tandem mass spectrometry method (LC-MS/MS). Multivariate Firth penalized logistic regression was used to assess the independence of metabolite associations, adjusted for age, BMI, total testosterone, LH, FSH, prolactin and smoking status. Results Compared to the control group, ED patients showed significantly lower TRP (6,760 vs 10,600 ng/mL, p < 0.001) and KYNA levels (1.39 vs 2.19 ng/mL, p < 0.001), while KYN, 3-HK, 3-HAA and QA levels were significantly higher (p < 0.001 for all). In Firth penalized logistic regression adjusted for age, BMI, smoking status, total testosterone, LH, FSH and prolactin, all metabolite associations remained independently significant (e.g., 3-HK OR 13.44, 95% CI 5.02–35.99; TRP OR 0.24, 95% CI 0.14–0.43; all q < 0.05). In exploratory ROC analysis, 3-HK (apparent AUC 0.902; LOOCV AUC 0.898) and TRP (AUC 0.811; LOOCV 0.801) revealed the highest performance; according to the DeLong test, the AUC of 3-HK was significantly higher than that of TRP (Z = 2.295, p = 0.021). In the subgroup analysis of severity, QA levels were similar between the control and mild ED groups, while they were significantly increased in moderate to severe cases. Conclusions These findings suggest an independent association between ED and KP metabolite imbalance, highlighting the kynurenine pathway as a potential target for future research.