Does Testosterone Salvage PDE5i Non-Responders? A Scoping Review

Erectile physiology, in order to function normally, requires the complex coordination of endocrine, neurocognitive, neuromuscular and vascular mechanisms. Testosterone (T) influences male sexuality as well as penile erections at multiple levels, including a direct influence on the nitric oxide synthase (NOS)/cGMP/phosphodiesterase 5 pathway in the penis. However, the precise role of testosterone replacement (TRT) to “salvage” men with mixed ED failing phosphdiesterase-5 inhibitors (PDE5i) remains unclear. We conducted a scoping review identifying the rationale for TRT in ED failing PDE5i, and we critically discuss clinical trials that have examined TRT in the setting of PDE5i use. Overall, TRT replacement appears to be well tolerated and may enhance the response to PDE5i and quality of life, particularly for men with mixed ED, and particularly among men with very low levels of testosterone. However, most of the available literature examines concurrent TRT alone or simultaneous TRT + PDE5i usage, without necessarily selecting for PDE5i failure cases. The present studies are limited to heterogenous studies with small sample sizes, without an exact predominant etiologic factor causing ED. Furthermore, studies showing the most benefit are non-placebo-controlled trials; however, the correction of more profound hypogonadism may lead to an improved response to PDE5i. Stronger conclusions would require properly selected patient populations and larger placebo-controlled RCTs.