Quistini A. et al., 2025: Comparative efficacy of combination therapy including regenerative therapies versus monotherapy for erectile dysfunction: A systematic review and meta-analysis.
Alberto Quistini 1, Giuseppe Fallara 2, Marco Tozzi 2, Massimiliano Depalma 3, Rocco Damiano 4, Alessandro Palmieri 5, Fabio Castiglione 6, Andrea Salonia 7 8, Roberto Bianchi 2, Matteo Ferro 2, Asif Muneer 9 10, Hussain M Alnajjar 9 10, Karl H Pang 9 10 11
1Department of Urology, ASST Grande Ospedale Metropolitano Niguarda, University of Milan, Milan, Italy.
2Department of Urology, ASST Santi Paolo e Carlo, University of Milan, Milan, Italy.
3Division of Urology, IRCCS European Institute of Oncology, University of Milan, Milan, Italy.
4Urology Unit, Magna Graecia University of Catanzaro, Catanzaro, Italy.
5Department of Neurosciences, Reproductive Sciences and Odontostomatology, Urology Unit, University of Naples "Federico II", Naples, Italy.
6Department of Urology, King's College Hospital NHS Foundation Trust, London, UK.
7Vita-Salute San Raffaele University, Milan, Italy.
8Division of Experimental Oncology/Unit of Urology, URI, IRCCS Ospedale San Raffaele, Milan, Italy.
9Division of Surgery and Interventional Science, University College London, London, UK.
10Department of Urology, University College London Hospitals NHS Trust, London, UK.
11Department of Urology, Chelsea and Westminster Hospital NHS Foundation Trust, London, UK.
Abstract
Background and objective: The Current European Association of Urology guidelines do not provide recommendation for combination of regenerative therapies with standard therapies for erectile dysfunction. The aim of this study was to compare the efficacy of combined regenerative therapy with monotherapy for erectile dysfunction.
Methods: A systematic review and meta-analysis were conducted following the 2020 Preferred Reporting Items for Systematic Reviews and Meta Analyses guidelines. The protocol was registered on PROSPERO (CRD42024522307). Randomized controlled trials and prospective/retrospective studies comparing combination therapies (low-intensity external shockwave therapy, platelet-rich plasma, stem cell therapy with phosphodiesterase-5 inhibitors, or other treatments) with monotherapy were included. Erectile function was assessed using the International Index of Erectile Function-5 and Erection Hardness Scale. Groups were compared using standardized mean difference. Subgroup analyses based on treatment type, erectile dysfunction cause, and follow-up duration were also conducted. Risk of bias was assessed using risk of bias 2 and Robins-I tools.
Key findings and limitations: Of 1416 articles screened, eight studies involving 553 patients met the inclusion criteria. All studies included phosphodiesterase-5 inhibitors and low-intensity external shockwave therapy as regenerative treatment, with no studies on stem cell therapy or platelet-rich plasma. After treatment, no significant difference in International Index of Erectile Function scores was found between combination and monotherapy groups. However, subgroup analysis revealed that combination therapy showed a statistically significant improvement compared to low-intensity external shockwave therapy alone (standardized mean difference: 0.61; 95% confidence interval: 0.13‒1.09; p = 0.013). A statistically significant improvement was found in vasculogenic (standardized mean difference: 0.65; p < 0.001) and diabetic cases (standardized mean difference: 1.05; p < 0.001).
Conclusions and clinical implications: Combination of phosphodiesterase-5 inhibitors and intensity external shockwave therapy resulted in significant improvement of International Index of Erectile Function compared to intensity external shockwave therapy alone. However, the risk of bias was high because of the low quality of the studies.
Patient summary: Combination of phosphodiesterase-5 inhibitor with intensity external shockwave therapy significantly improved erectile function, especially in patients with vasculogenic erectile dysfunction or diabetes.
Andrology. 2025 Aug 12. doi: 10.1111/andr.70108. Epub ahead of print. PMID: 40797370
Comments 1
Background and Objective
Current guidelines from the European Association of Urology do not recommend combining regenerative therapies with standard treatments for erectile dysfunction (ED). This study aimed to evaluate the efficacy of combination therapies, specifically low-intensity external shockwave therapy (Li-ESWT) and phosphodiesterase-5 inhibitors (PDE5i), compared to monotherapy for treating ED.
Methods
A systematic review and meta-analysis were conducted according to the 2020 PRISMA guidelines. The review included randomized controlled trials and prospective/retrospective studies comparing combination therapies (including Li-ESWT and PDE5i) with monotherapy. Effectiveness was measured using the International Index of Erectile Function-5 (IIEF-5) and Erection Hardness Scale (EHS). Subgroup analyses were performed based on treatment type, ED cause, and follow-up duration. Risk of bias was assessed using established tools.
Key Findings
Study Inclusion: Out of 1,416 articles screened, eight studies involving 553 patients met the criteria. All studies included PDE5i and Li-ESWT, but none included platelet-rich plasma (PRP) or stem cell therapy.
Efficacy: No significant difference in IIEF scores was observed overall between combination and monotherapy groups. However, combination therapy showed statistically significant improvements over Li-ESWT alone (SMD: 0.61; p=0.013) and was particularly effective for patients with vasculogenic (SMD: 0.65; p less 0.001) and diabetic ED (SMD: 1.05; p less 0.001).
Limitations: The studies had a high risk of bias and varied significantly in treatment protocols, patient populations, and follow-up durations. Many studies lacked detailed information on prior treatments, which could influence outcomes.
Conclusions and Clinical Implications
The combination of PDE5 inhibitors and Li-ESWT significantly improved erectile function relative to Li-ESWT alone, especially in patients with vasculogenic or diabetic ED. However, the high risk of bias and low quality of the available studies warrant caution. Further research is necessary to explore long-term benefits and identify which patient subgroups may benefit most from these combination therapies. The absence of studies on PRP and stem cell therapy in combination with standard treatments highlights a gap in current research that needs to be addressed.
Patient Summary
Combining PDE5 inhibitors with Li-ESWT can lead to better erectile function, particularly in patients with specific types of ED like vasculogenic or diabetes-related ED, compared to using Li-ESWT alone. More studies are needed to confirm these findings and optimize treatment strategies.
Jens Rassweiler