Regenerative Therapy in Sexual Medicine: The Hard Facts

This is the authors' abstract. We don't add key points for this paper.

You have accessJournal of UrologyJU Forum1 Jun 2023Regenerative Therapy in Sexual Medicine: The Hard Facts Gustavo M. Gryzinski, Muhammed A. Moukhtar Hammad, David W. Barham, and Faysal A. Yafi Gustavo M. GryzinskiGustavo M. Gryzinski *Correspondence:Department of Urology, University of California Irvine Medical Center, 101 The City Dr S, Orange, CA 92868 ( E-mail Address: [email protected] https://orcid.org/0000-0001-6952-8207 Department of Urology, University of California Irvine Medical Center, Orange, California , Muhammed A. Moukhtar HammadMuhammed A. Moukhtar Hammad https://orcid.org/0000-0001-5396-1364 Department of Urology, University of California Irvine Medical Center, Orange, California , David W. BarhamDavid W. Barham Department of Urology, University of California Irvine Medical Center, Orange, California , and Faysal A. YafiFaysal A. Yafi Department of Urology, University of California Irvine Medical Center, Orange, California View All Author Informationhttps://doi.org/10.1097/JU.0000000000003403AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail Erectile dysfunction (ED) is a complex medical condition defined as the inability to achieve and maintain an erection satisfactory for intercourse.1 In addition to lifestyle changes, some commonly used treatment options have been phosphodiesterase type 5 inhibitors (PDE5is), intracavernosal injections, intraurethral pellets/gel, vacuum devices, and penile prostheses. However, none of these traditional treatment options offer a permanent cure for ED. This necessitates the continuous development of regenerative therapies. Modalities that are currently being developed and analyzed include low-intensity shock wave therapy (LI-SWT), stem cell therapy (SCT), and platelet-rich plasma therapy (PRPT). These therapies have emerged as promising minimally invasive treatment options for ED that may be utilized as first-line treatments or in men who did not tolerate or improve with standard therapies. We aim to summarize the evidence supporting these therapies and current recommendations regarding their use. Regenerative Therapies LI-SWT Shock wave therapy in the field of urology is not a novel practice. Extracorporeal shock wave therapy was utilized for nephrolithiasis dating back to the 1970s and 1980s.2 However, it was not until the 2000s that shock wave therapy was proposed as a modality in the management of ED in the form of LI-SWT.3 Although the exact mechanism by which LI-SWT plays a regenerative role in ED has not been concretely defined, there is evidence that its effects are due to improved endothelial function, regeneration of nerve fibers, angiogenesis, and corporal tissue remodeling.4,5 This is a result of shock waves producing microbubbles, which induce sheer stress that activates biological pathways that cause increased expression of growth factors.4 There is an important distinction that must be made between shock waves and radial waves, which are both advertised for their use in ED. Radial waves function more similarly to sound waves and offer lower energy than shock waves; more importantly, there is insufficient evidence that radial waves have a beneficial role in treating ED.6 Schoofs et al analyzed outcomes of LI-SWT in multiple single-arm studies, randomized controlled trials (RCTs), and systematic reviews/meta-analyses.4 Single-arm studies have repeatedly shown benefit, but are, however, limited by biases and placebo effects. RCTs and systematic reviews/meta-analyses had mixed findings and their own sources of biases such as heterogeneity of outcome measures, high dropout rates, and significant methodological flaws. In light of these limitations, most of these larger studies did report a modest benefit of LI-SWT.4 In addition to aiding in achieving erections in men not taking PDE5is, LI-SWT has also been shown to improve response to these medications. More recently, there was a double-blind RCT conducted by Kalyvianakis et al that demonstrated a positive minimal clinically important difference in both the International Index of Erectile Function (IIEF) score as well as the Sexual Encounter Profile (SEP) score in men who received LI-SWT when compared to sham therapy.5 IIEF was improved by about 4 points at both 1- and 3-month follow-ups. SEP was also improved by 18 and 22 points at 1- and 3-month follow-ups, respectively. This was essentially the first RCT to analyze the efficacy of LI-SWT in men with ED using an overall homogenous sample with regard to baseline demographics and severity of ED. Nevertheless, there were some limitations—namely, this was a single-center study, utilized a relatively small sample size, and had a short follow-up period. While LI-SWT is exceptionally safe for use, there is concern that affording these treatments could be an obstacle for patients as each session could cost from $400 to $5,000.7,8 SCT Another regenerative modality that is being analyzed for its role in treating ED is intracavernosal injection of mesenchymal stem cells (MSCs). These multipotent cells are able to self-renew as well as differentiate into several different tissues.9 The literature additionally highlights that injections with stromal vascular fraction are also utilized, which is a less refined adipose extract that contains endothelial precursor cells, regulatory T-cells, macrophages, smooth muscle cells, pericytes, preadipocytes, and MSCs—although there have not been studies comparing the efficacies of isolated MSCs vs stromal vascular fraction.10 While the exact mechanism of action by which SCT improves erectile function has yet to be determined, pathways involving either paracrine signaling via secretion of cytokines and growth factors or direct local engraftment are thought to play a primary role.11 However, more recent studies favor the paracrine role as the main mechanism.9 Although there is a limited number of credible studies looking at this modality to date, a recent systematic review analyzed 9 articles that focused on the role of SCT in ED. Importantly, the selected articles were all clinical studies utilizing human subjects.9 There was significant variation in follow-up period, subtype of MSCs used, and assessment tools utilized to grade treatment response; most of the studies had a follow-up period of 9 months and most studies used the IIEF score to assess response.9 Overall, there was a positive response to SCT seen with improved IIEF and IIEF-5 scores, and a handful of the included studies also demonstrated improved peak systolic velocity. These improvements were of 3 points, 6 points, and 41 cm/s, respectively.9 However, in addition to the variability of study design, there were significant limitations in detailing the specific treatment regimen used in each study—specifically regarding the source of MSCs, preparation, dosage, and confounding/concomitant therapies.9 Additionally, the cost per treatment is quite considerable—each injection may cost up to $10,000.8 PRPT In addition to MSC injections, platelet-rich plasma (PRP) is also being studied in its regenerative role in ED. A recent systematic review by Alkandari et al analyzed 18 relevant articles pertaining to PRPT's effectiveness, 12 of which were in humans and the other 6 in rats.8 Although there was a handful of these studies that looked at use of PRPT in patients with Peyronie's disease, the studies strictly looking at nonspecific ED had positive results with regard to peak systolic velocity, IIEF score, and SEP scores. There was also evidence that combining PRPT with LI-SWT had significant benefit in a randomized, controlled, interventional study with 100 men for up to 24 weeks.8 Despite these initial positive results, a large majority of human-based studies focused on PRPT had only been accepted as abstracts, and therefore were missing significant details of study design and outcomes. Similar to the limitations of the SCT studies, there is a lack of homogeneity and a significant discrepancy of treatment protocol, follow-up periods, and how the PRP was prepared. Additionally, only a minority of contemporary studies had been randomized, and several studies also lacked a control/sham group.8 Of note, the strongest study so far was a double-blind RCT done by Poulios et al, which found that men who received PRPT had achieved a positive minimal clinically important difference in their IIEF score when compared to the control group.12 However, this study had its own limitations, including relatively small sample size, short follow-up period, and lack of generalizability due to being a single-center trial. The authors also note that while they used a constant PRP preparation method for their subjects, there is no concrete consensus regarding the ideal concentration of platelets within the PRP.12 Outside of study design flaws, another obstacle pertains to PRPT accessibility; each injection could cost between $1,500 and $3,000.8 Recommendations on Restorative Therapies AUA The AUA maintains the position that LI-SWT and SCT should be considered investigational, with Grade C evidence level. PRPT is considered experimental by expert opinion.1 European Association of Urology The European Association of Urology (EAU) determined that there is weak evidence supporting the use of LI-SWT in patients with mild ED, as a first-line therapy, or in patients with ED who had poor response to PDE5is. Despite the limited positive results seen so far, there is insufficient evidence for the EAU to recommend the use of SCT or PRPT for ED at this time.13 Sexual Medicine Society of North America SMSNA (the Sexual Medicine Society of North America) states there is an absence of robust clinical data supporting the efficacy of restorative therapies regarding ED, though technologies such as LI-SWT have established relative safety.14 Conclusion and Future Expectations In conclusion, regenerative therapies offer a promising new treatment option for patients with ED. These therapies have the potential to restore lost erectile function, with improved safety and efficacy compared to existing treatments. So far, there seems to be more substantial evidence supporting the use of LI-SWT than with SCT and PRPT, and this is echoed by recommendations provided by the AUA, EAU, and SMSNA. However, many of these studies lack consistent inclusion and exclusion criteria in addition to clear end point goals.15 Further research is needed to fully understand the effects of these therapies and to develop safe and effective protocols that can be generalized for large-scale use. Additionally, other obstacles will need to be addressed such as affordability, and accessibility to facilities that are equipped with these novel modalities. Furthermore, the paucity of clear protocols and generalizable evidence for these new therapies allows for detrimental consumerization of sexual health. There are many clinics in large metropolitan areas offering these treatments directly to consumers despite this lack of standardized protocol, which may ultimately cause more harm than good.16 REFERENCES 1. . Erectile dysfunction: AUA guideline. J Urol. 2018; 200(3):633-641. Link, Google Scholar 2. . Review of the current status of low intensity extracorporeal shockwave therapy (Li-ESWT) in erectile dysfunction (ED), Peyronie's disease (PD), and sexual rehabilitation after radical prostatectomy with special focus on technical aspects of the different marketed ESWT devices including personal experiences in 350 patients. Sex Med Rev. 2021; 9(1):93-122. Crossref, Medline, Google Scholar 3. . Can low-intensity extracorporeal shockwave therapy improve erectile function? A 6-month follow-up pilot study in patients with organic erectile dysfunction. Eur Urol. 2010; 58(2):243-248. Crossref, Medline, Google Scholar 4. . Current guideline recommendations and analysis of evidence quality on low-intensity shockwave therapy for erectile dysfunction. Int J Impot Res. 2019; 31(3):209-217. Crossref, Medline, Google Scholar 5. . The effect of low-intensity shock wave therapy on moderate erectile dysfunction: a double-blind, randomized, sham-controlled clinical trial. J Urol. 2022; 208(2):388-395. Link, Google Scholar 6. . Are radial pressure waves effective in treating erectile dysfunction? A systematic review of preclinical and clinical studies. Sex Med. 2021; 9(4):100393. Crossref, Medline, Google Scholar 7. . Low-intensity shockwave therapy for erectile dysfunction. Sex Med Rev. 2018; 6(4):624-630. Crossref, Medline, Google Scholar 8. . Platelet-rich plasma injections for erectile dysfunction and Peyronie's disease: a systematic review of evidence. Sex Med Rev. 2022; 10(2):341-352. Crossref, Medline, Google Scholar 9. . Application of stem cell in human erectile dysfunction—a systematic review. Res Rep Urol. 2022; 14:379-388. Medline, Google Scholar 10. . Stromal vascular fraction: a regenerative reality? Part 1: current concepts and review of the literature. J Plast Reconstr Aesthet Surg. 2016; 69(2):170-179. Crossref, Medline, Google Scholar 11. . Stem cell therapy for erectile dysfunction. Sex Med Rev. 2019; 7(2):321-328. Crossref, Medline, Google Scholar 12. . Platelet-rich plasma (PRP) improves erectile function: a double-blind, randomized, placebo-controlled clinical trial. J Sex Med. 2021; 18(5):926-935. Crossref, Medline, Google Scholar 13. . European Association of Urology guidelines on sexual and reproductive health-2021 update: male sexual dysfunction. Eur Urol. 2021; 80(3):333-357. Crossref, Medline, Google Scholar 14. . Restorative therapies for erectile dysfunction: position statement from the Sexual Medicine Society of North America (SMSNA). Sex Med. 2021; 9(3):100343. Crossref, Medline, Google Scholar 15. . Restorative therapy clinical trials for erectile dysfunction: a scoping review of endpoint measures. Int J Impot Res. 2022; 10.1038/s41443-022-00610-3. Crossref, Google Scholar 16. . Analysis of direct-to-consumer marketing of platelet-rich plasma for erectile dysfunction in the US. JAMA Netw Open. 2022; 5(5):e2214187. Crossref, Medline, Google Scholar Support: None. Conflict of Interest: GMG: Coloplast, Clarus Therapeutics, Antares Pharma, Acerus. The remaining Authors have no conflicts of interest to disclose. Ethics Statement: In lieu of a formal ethics committee, the principles of the Helsinki Declaration were followed. © 2023 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 209Issue 6June 2023Page: 1048-1050 Peer Review Report Advertisement Copyright & Permissions© 2023 by American Urological Association Education and Research, Inc.MetricsAuthor Information Gustavo M. Gryzinski Department of Urology, University of California Irvine Medical Center, Orange, California *Correspondence:Department of Urology, University of California Irvine Medical Center, 101 The City Dr S, Orange, CA 92868 ( E-mail Address: [email protected] More articles by this author Muhammed A. Moukhtar Hammad Department of Urology, University of California Irvine Medical Center, Orange, California More articles by this author David W. Barham Department of Urology, University of California Irvine Medical Center, Orange, California More articles by this author Faysal A. Yafi Department of Urology, University of California Irvine Medical Center, Orange, California More articles by this author Expand All Support: None. Conflict of Interest: GMG: Coloplast, Clarus Therapeutics, Antares Pharma, Acerus. The remaining Authors have no conflicts of interest to disclose. Ethics Statement: In lieu of a formal ethics committee, the principles of the Helsinki Declaration were followed. Advertisement Advertisement PDF downloadLoading ...