The Role of Testosterone in Amplifying the Effect of a Phosphodiesterase Type 5 Inhibitor After Pelvic Irradiation

Background: After radiotherapy, the risk of hypogonadism increases, and the incidence of erectile dysfunction increases with time. Aim: We investigated the effect of testosterone and a phosphodiesterase type 5 inhibitor (PDE5I) on erectile tissue after radiotherapy. Methods: 12 male Wistar rats were assigned to each of 5 groups (group C: control; group R: radiation; group RPT: radiation, testosterone, and a PDE5I; group RP: radiation and a PDE5I; and group RT: radiation and testosterone). A 12.5 Gy/fraction dose was administered to the rectum in groups R, RPT, RP, and RT. Udenafil (20 mg/kg) was administered daily via nasogastric tubes in group RPT and group RP for 4 weeks starting 1 day after radiotherapy. Testosterone enanthate (25 mg/kg, IM) was administered immediately after radiotherapy in group RT and group RPT. 6 rats from each group were used to evaluate endothelial nitric oxide synthase (eNOS), neuronal nitric oxide synthase (nNOS), and NOX2, and cavernosal pressure was evaluated in the other 6 rats in each group. Outcome: Testosterone enhanced the effect of PDE5I on penile tissue after radiotherapy by amplifying the nitric oxide synthase activity. Results: eNOS mRNA expression increased in response to either testosterone replacement or PDE5I administration after radiotherapy. nNOS mRNA expression did not significantly increase in response to testosterone replacement, but testosterone significantly enhanced the effect of PDE5I on nNOS mRNA expression. Testosterone significantly amplified the effect of PDE5I on both eNOS and nNOS protein expression. Both testosterone and PDE5I reduced NOX2 protein expression. The intracavernosal pressure during electrical stimulation showed that testosterone alone did not significantly enhance erectile function. Clinical Translation: Clinicians should consider both hypoxic tissue damage and hypogonadism during and after radiation, and the combination of testosterone and PDE5I could be more beneficial for preserving erectile tissue than either individual treatment. Strengths & Limitations: This study describes the role of testosterone in amplifying the effect of a PDE5I on pelvic radiotherapy-induced hypogonadism. However, we did not show the time-dependent effects of testosterone and PDE5I. Conclusions: Despite the fact that the intracavernosal pressure during electrical stimulation did not significantly increase with testosterone replacement after radiotherapy, important changes in nitric oxide synthase activity and superoxide regulation might have amplifying effects on erectile tissue. Therefore, we recommend that physicians monitor testosterone levels and should not hesitate to combine testosterone and PDE5I in cases of radiation-induced hypogonadism if testosterone replacement is not contraindicated. Lee DS, Sohn DW. The Role of Testosterone in Amplifying the Effect of a Phosphodiesterase Type 5 Inhibitor After Pelvic Irradiation. J Sex Med 2020;17:1268–1279.