Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Restorative therapy clinical trials for erectile dysfunction: a scoping review of endpoint measures

Abstract

Given the lack of regulatory approval for restorative therapies for the treatment of erectile dysfunction, we hypothesized that clinical trials would vary in methodology and endpoint measurements. Our objective was to analyze methodological approaches and outcome measures of clinical trials evaluating restorative therapies for erectile dysfunction. Data was extracted from clinicaltrials.gov on trials which contained the keywords “erectile dysfunction”. We evaluated trials initiated between 2004 and 2021 which listed a restorative therapy intervention. We identified 95 trials investigating energy-based/shockwave therapies (60/95), stem cell therapies (25/95), platelet-based therapies (6/95), and others (4/95). Only 41.1% of the trials evaluated safety. The most common efficacy endpoint was International Index of Erectile Function and Sexual Health Inventory for Men, and only 29.5% utilized penile Doppler. Thirty (31.6%) trials had been completed yet only 3 (3.2%) have published results. We found substantial heterogeneity in methodological approach in the trials. Subjective measures of erectile function were commonly reported, but definitions of inclusion criteria and objective outcome measures were inconsistent. These results provide a basis for the design of future clinical trials to improve the quality of trial data and aid in the development of standardized criteria for erectile dysfunction clinical trials.

This is a preview of subscription content, access via your institution

Access options

Buy article

Get time limited or full article access on ReadCube.

$32.00

All prices are NET prices.

Fig. 1: Restorative therapies used in clinical trials.
Fig. 2: Common endpoints assessed in clinical trials.

Data availability

The data that support the findings of this study are available from www.clinicaltrials.gov.

References

  1. Consensus development conference statement. National Institutes of Health. Impotence. December 7–9, 1992. Int J Impot Res. 1993;5:181–284.

  2. Dunn KM, Croft PR, Hackett GI. Association of sexual problems with social, psychological, and physical problems in men and women: a cross sectional population survey. J Epidemiol Community Health. 1999;53:144–8.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  3. Goldstein I, Goren A, Li VW, Tang WY, Hassan TA. Epidemiology update of erectile dysfunction in eight countries with high burden. Sex Med Rev. 2020;8:48–58.

    PubMed  Article  Google Scholar 

  4. Stein MJ, Lin H, Wang R. New advances in erectile technology. Ther Adv Urol. 2014;6:15–24.

    PubMed  PubMed Central  Article  Google Scholar 

  5. McMahon CG. Current diagnosis and management of erectile dysfunction. Med J Aust. 2019;210:469–76.

    PubMed  Article  Google Scholar 

  6. Grover S, Shouan A. Assessment scales for sexual disorders—a review. J Psychosexual Health. 2020;2:121–38.

    Article  Google Scholar 

  7. Yee CH, Chan ES, Hou SS, Ng CF. Extracorporeal shockwave therapy in the treatment of erectile dysfunction: a prospective, randomized, double-blinded, placebo controlled study. Int J Urol. 2014;21:1041–5.

    PubMed  Article  Google Scholar 

  8. Poulios E, Mykoniatis I, Pyrgidis N, Zilotis F, Kapoteli P, Kotsiris D, et al. Platelet-rich plasma (PRP) improves erectile function: a double-blind, randomized, placebo-controlled clinical trial. J Sex Med. 2021;18:926–35.

    PubMed  Article  Google Scholar 

  9. Al Demour S, Jafar H, Adwan S, AlSharif A, Alhawari H, Alrabadi A, et al. Safety and potential therapeutic effect of two intracavernous autologous bone marrow derived mesenchymal stem cells injections in diabetic patients with erectile dysfunction: an open label phase I clinical trial. Urol Int. 2018;101:358–65.

    PubMed  Article  Google Scholar 

  10. Haahr MK, Harken Jensen C, Toyserkani N, Andersen DC, Damkier P, Sorensen JA, et al. A 12-month follow-up after a single intracavernous injection of autologous adipose-derived regenerative cells in patients with erectile dysfunction following radical prostatectomy: an open-label phase I clinical trial. Urology. 2018;121:203 e6–203 e13.

    Article  Google Scholar 

  11. Gollwitzer H, Saxena A, DiDomenico LA, Galli L, Bouche RT, Caminear DS, et al. Clinically relevant effectiveness of focused extracorporeal shock wave therapy in the treatment of chronic plantar fasciitis: a randomized, controlled multicenter study. J Bone Jt Surg Am. 2015;97:701–8.

    Article  Google Scholar 

  12. Liu JL, Chu KY, Gabrielson AT, Wang R, Trost L, Broderick G, et al. Restorative therapies for erectile dysfunction: position statement from the Sexual Medicine Society of North America (SMSNA). Sex Med. 2021;9:100343.

    PubMed  PubMed Central  Article  Google Scholar 

  13. Muncey W, Sellke N, Kim T, Mishra K, Thirumavalavan N, Loeb A, et al. Alternative treatment for erectile dysfunction: a growing arsenal in men’s health. Curr Urol Rep. 2021;22:11.

    PubMed  Article  Google Scholar 

  14. Lokeshwar SD, Patel P, Shah SM, Ramasamy R. A systematic review of human trials using stem cell therapy for erectile dysfunction. Sex Med Rev. 2020;8:122–30.

    PubMed  Article  Google Scholar 

  15. Pai R, Ory J, Delgado C, Ramasamy R. Energy-based therapies for erectile dysfunction: current and future directions. Urol Clin North Am. 2021;48:603–10.

    PubMed  Article  Google Scholar 

  16. Nashed A, Lokeshwar SD, Frech F, Mann U, Patel P. The efficacy of penile duplex ultrasound in erectile dysfunction management decision-making: a systematic review. Sex Med Rev. 2021;9:472–7.

    PubMed  Article  Google Scholar 

  17. Rosen RC, Cappelleri JC, Gendrano N 3rd. The International Index of Erectile Function (IIEF): a state-of-the-science review. Int J Impot Res. 2002;14:226–44.

    CAS  PubMed  Article  Google Scholar 

  18. Vroege JA. The sexual health inventory for men (IIEF-5). Int J Impot Res. 1999;11:177.

    CAS  PubMed  Article  Google Scholar 

  19. Parisot J, Yiou R, Salomon L, de la Taille A, Lingombet O, Audureau E. Erection hardness score for the evaluation of erectile dysfunction: further psychometric assessment in patients treated by intracavernous prostaglandins injections after radical prostatectomy. J Sex Med. 2014;11:2109–18.

    PubMed  Article  Google Scholar 

  20. Tamler R, Bar-Chama N. Assessment of endothelial function in the patient with erectile dysfunction: an opportunity for the urologist. Int J Impot Res. 2008;20:370–7.

    CAS  PubMed  Article  Google Scholar 

  21. Bieri M, Said E, Antonini G, Dickerson D, Tuma J, Bartlett CE, et al. Phase I and registry study of autologous bone marrow concentrate evaluated in PDE5 inhibitor refractory erectile dysfunction. J Transl Med. 2020;18:24.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  22. Hadanny A, Lang E, Copel L, Meir O, Bechor Y, Fishlev G, et al. Hyperbaric oxygen can induce angiogenesis and recover erectile function. Int J Impot Res. 2018;30:292–9.

    PubMed  Article  Google Scholar 

  23. Yiou R, Hamidou L, Birebent B, Bitari D, Le Corvoisier P, Contremoulins I, et al. Intracavernous injections of bone marrow mononucleated cells for postradical prostatectomy erectile dysfunction: final results of the INSTIN clinical trial. Eur Urol Focus. 2017;3:643–5.

    PubMed  Article  Google Scholar 

  24. Levy JA, Marchand M, Iorio L, Cassini W, Zahalsky MP. Determining the feasibility of managing erectile dysfunction in humans with placental-derived stem cells. J Am Osteopath Assoc. 2016;116:e1–5.

    PubMed  Google Scholar 

  25. Fode M, Borre M, Ohl D, Lichtbach J, Sonksen J. Penile vibratory stimulation in the recovery of urinary continence and erectile function after nerve-sparing radical prostatectomy: a randomized, controlled trial. BJU Int. 2014;114:111–7.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  26. Katz JE, Molina ML, Clavijo R, Prakash NS, Ramasamy R. A Phase 2 Randomized Trial To Evaluate Different Dose Regimens of Low-intensity Extracorporeal Shockwave Therapy for Erectile Dysfunction: Clinical Trial Update. Eur Urol. Focus. 2018;4:336–7.

    Google Scholar 

  27. You D, Jang MJ, Song G, Shin HC, Suh N, Kim YM, et al. Safety of autologous bone marrow-derived mesenchymal stem cells in erectile dysfunction: an open-label phase 1 clinical trial. Cytotherapy. 2021;23:931–8.

    CAS  PubMed  Article  Google Scholar 

  28. Rosen RC, Riley A, Wagner G, Osterloh IH, Kirkpatrick J, Mishra A. The international index of erectile function (IIEF): a multidimensional scale for assessment of erectile dysfunction. Urology. 1997;49:822–30.

    CAS  PubMed  Article  Google Scholar 

  29. Cappelleri JC, Rosen RC. The Sexual Health Inventory for Men (SHIM): a 5-year review of research and clinical experience. Int J Impot Res. 2005;17:307–19.

    CAS  PubMed  Article  Google Scholar 

  30. Kassouf W, Carrier S. A comparison of the International Index of Erectile Function and erectile dysfunction studies. BJU Int. 2003;91:667–9.

    CAS  PubMed  Article  Google Scholar 

  31. Golijanin D, Singer E, Davis R, Bhatt S, Seftel A, Dogra V. Doppler evaluation of erectile dysfunction - part 2. Int J Impot Res. 2007;19:43–8.

    CAS  PubMed  Article  Google Scholar 

  32. Golubinski AJ, Sikorski A. Usefulness of power Doppler ultrasonography in evaluating erectile dysfunction. BJU Int. 2002;89:779–82.

    CAS  PubMed  Article  Google Scholar 

  33. Nascimento B, Miranda EP, Terrier JE, Carneiro F, Mulhall JP. A critical analysis of methodology pitfalls in duplex doppler ultrasound in the evaluation of patients with erectile dysfunction: technical and interpretation deficiencies. J Sex Med. 2020;17:1416–22.

    PubMed  PubMed Central  Article  Google Scholar 

  34. Golijanin D, Singer E, Davis R, Bhatt S, Seftel A, Dogra V. Doppler evaluation of erectile dysfunction—part 1. Int J Impot Res. 2007;19:37–42.

    CAS  PubMed  Article  Google Scholar 

  35. Foresta C, Ferlin A, De Toni L, Lana A, Vinanzi C, Galan A, et al. Circulating endothelial progenitor cells in subjects with erectile dysfunction. Int J Impot Res. 2005;17:288–90.

    CAS  PubMed  Article  Google Scholar 

  36. Foresta C, Carerra N, Lana A, Cabrelle A, Palu G, Ferlin A. Circulating endothelial progenitor cells and endothelial function after chronic Tadalafil treatment in subjects with erectile dysfunction. Int J Impot Res. 2006;18:484–8.

    CAS  PubMed  Article  Google Scholar 

  37. Kaya C, Uslu Z, Karaman I. Is endothelial function impaired in erectile dysfunction patients? Int J Impot Res. 2006;18:55–60.

    CAS  PubMed  Article  Google Scholar 

  38. Andersson K, Stief C. Penile erection and cardiac risk: pathophysiologic and pharmacologic mechanisms. Am J Cardiol. 2000;86:23F–26F.

    CAS  PubMed  Article  Google Scholar 

  39. Mobley DF, Khera M, Baum N. Recent advances in the treatment of erectile dysfunction. Postgrad Med J. 2017;93:679–85.

    CAS  PubMed  Article  Google Scholar 

  40. Stein RA. Endothelial dysfunction, erectile dysfunction, and coronary heart disease: the pathophysiologic and clinical linkage. Rev Urol. 2003;5:S21–7.

    PubMed  PubMed Central  Google Scholar 

  41. Shockwave therapy and platelet rich plasma for the treatment of erectile dysfunction. https://ClinicalTrials.gov/show/NCT05048667.

  42. The effect of combination therapy using Li-ESWT and PDE-5 inhibitor in patients with erectile dysfunction. https://ClinicalTrials.gov/show/NCT05043896.

  43. Effectiveness and safety of adipose-derived regenerative cells for treatment of erectile dysfunction. https://ClinicalTrials.gov/show/NCT02472431.

  44. The value of enhanced external counterpulsation on erectile dysfunction. https://ClinicalTrials.gov/show/NCT01815593.

  45. Double blind placebo controlled study on the effect of extracorporal shock wave therapy on erectile dysfunction in PDE5i responders. https://ClinicalTrials.gov/show/NCT01274923.

  46. Double blind placebo controlled study on the effect of extracorporal shock wave therapy on erectile dysfunction. https://ClinicalTrials.gov/show/NCT01274156.

  47. The outcomes of intracavernosal umbilical cord mesenchymal stem cells implantation in patients with diabetic erectile dysfunction. https://ClinicalTrials.gov/show/NCT04972890.

  48. Alhathal N, Al-Qaoud T, Carrier S. Considerations in the design of clinical trials for erectile dysfunction. Clin Investig. 2012;2:733–45.

    CAS  Article  Google Scholar 

  49. DiBenedetti DB, Gondek K, Sagnier PP, Kubin M, Marquis P, Keininger D, et al. The treatment satisfaction scale: a multidimensional instrument for the assessment of treatment satisfaction for erectile dysfunction patients and their partners. Eur Urol. 2005;48:503–11.

    PubMed  Article  Google Scholar 

  50. Sadovsky R. The role of the primary care clinician in the management of erectile dysfunction. Rev Urol. 2002;4:S54–63.

    PubMed  PubMed Central  Google Scholar 

Download references

Funding

This work was supported by National Institutes of Health Grant R01 DK130991 and Clinician Scientist Development Grant from the American Cancer Society.

Author information

Authors and Affiliations

Authors

Contributions

RS conceived of the research question that led to the submission, acquired data, and helped draft the manuscript. RG acquired data and helped draft the manuscript. TM contributed to interpretation of the results and revised the manuscript. AS helped with interpretation of results and revised the manuscript. RR helped interpret the results and revised the manuscript. All authors approved of the final version of the manuscript and agreed to be accountable for all aspects of the work to ensure that questions related to accuracy or integrity of any part of the work are appropriately investigated and resolved.

Corresponding author

Correspondence to Ranjith Ramasamy.

Ethics declarations

Competing interests

The authors declare no competing interests.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Springer Nature or its licensor holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Saltzman, R.G., Golan, R., Masterson, T.A. et al. Restorative therapy clinical trials for erectile dysfunction: a scoping review of endpoint measures. Int J Impot Res (2022). https://doi.org/10.1038/s41443-022-00610-3

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1038/s41443-022-00610-3

Search

Quick links