Abstract Introduction Refractory Erectile Dysfunction (ED) remains a significant clinical challenge, driving the search for regenerative interventions focused on restoring cavernous tissue and neurovascular function. The main modalities under clinical investigation include: Low-Intensity Extracorporeal Shock Wave Therapy (Li-ESWT), Cell Therapy (MSCs/ADSCs), Platelet-Rich Plasma (PRP), and Gene Therapy. Objective This Systematic Review aimed to consolidate and critically evaluate the safety, clinical efficacy (primarily measured by the change in the IIEF-EF score), and methodological level of evidence for the most advanced regenerative therapies. Methods A comprehensive search was conducted on PubMed/MEDLINE, LILACS, and Google Scholar databases, following PRISMA 2020 guidelines. Twenty-three highly relevant clinical articles were identified for synthesis. The entire screening, eligibility, and data extraction process was conducted by a single reviewer, which is noted as a methodological limitation. The Risk of Bias (RoB) of the studies was assessed. Results Li-ESWT demonstrated established efficacy (NE 1), showing a consistent Delta IIEF-EF of +5.5 points. PRP efficacy was robustly confirmed in aggregated data (Delta IIEF-EF +7.0). However, the highest-level evidence for ADSC Therapy did not demonstrate superiority over placebo in severe ED. Combined therapy (PRP + Li-ESWT) showed the most significant synergistic effect, reaching a maximum Delta IIEF-EF of +8.5. All evaluated modalities exhibited an excellent safety profile. Conclusions Li-ESWT remains an established treatment (Level A Evidence). Although Cell Therapy is the most promising curative frontier, methodological limitations and the failure in Low RoB RCTs to demonstrate superior efficacy over placebo in severe ED justify the positioning of medical societies. The greatest clinical benefit (Delta IIEF-EF of +8.5) is achieved by combined therapies, suggesting that tissue pre-conditioning is essential for regenerative success. Disclosure No
Sarnoski et al. (Mon,) studied this question.
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