Current and future strategies for managing erectile dysfunction following nerve-sparing robot-assisted radical prostatectomy (literature review)

Erectile dysfunction (ED) is one of the most frequently developing and significantly reducing quality of life complications of radical prostatectomy (RPE). According to the number of studies, ED is diagnosed in 60-75% of patients after the RPE. The use of nerve-sparing surgical techniques has reduced the incidence of ED after RPE, but has not completely solved this problem. In addition, it is not always possible to preserve the vascular-nerve bundles for the reason of oncological radicalism. All of the above factors make the issue of restoring erectile function one of the priority areas of medical rehabilitation of patients after the radical surgery for prostate cancer (PC). The development of new strategies for the treatment of ED after NS RP, aimed at maintaining endothelial function in the cavernous arteries until the completion of remyelination and restoration of damaged cavernous nerves, is a relevant and actively developing area of modern andrology.

1. I. Bray F., Laversanne M., Sung H., Ferlay J., Siegel R.L., Soerjomataram et al. Global cancer statistics 2022: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J. Clin. 2024;74(3):229–263. https://doi.org/10.3322/caac.21834

2. Montorsi F., Briganti A., Salonia A., Rigatti P., Burnett A.L. Current and future strategies for preventing and managing erectile dysfunction following radical prostatectomy. Eur. Urol. 2004;45(2):123–33. https://doi.org/10.1016/j.eururo.2003.08.016

3. Nosov D.A., Volkova M.I., Gladkov O.A. Karabina E.V., Krylov V.V., Matveev V.B. et al. Prostate cancer. RUSSCO practical recommendations, part 1.2. Malignant tumors. 2024;14(3s2):242–269. (In Russ.). https://doi.org/10.18027/2224-5057-2024-14-3s2-1.2-10

4. Walsh P.C., Donker P.J. Impotence following radical prostatectomy: Insight into etiology and prevention. J. Urol. 2017;197(2S):S165–70. https://doi.org/10.1016/s0022-5347(17)53012-8

5. Jiang N., Wu C., Zhou X., Zhai G., Wu J. Cavernous nerve injury resulted erectile dysfunction and regeneration. J. Immunol. Res. 2021;2021:5353785. https://doi.org/10.1155/2021/5353785

6. Spirito L., Chessa F., Hagman A., Lantz A., Celentano G., Sanchez-Salas R. et al. Long-term oncological outcomes after nerve-sparing robot-assisted radical prostatectomy for high-risk localized prostate cancer: a single-center, two-arm prospective study. Diagnostics. 2024;14(8):803. https://doi.org/10.3390/diagnostics14080803

7. Haga N., Miyazaki T., Tsubouchi K., Okabe Y., Shibayama K., Emoto D et al.Comprehensive approach for preserving cavernous nerves and erectile function after radical prostatectomy in the era of robotic surgery. Int. J. Urol. Off. J. JpnUrol. Assoc. 2021;28(4):360–368. https://doi.org/10.1111/iju.14491

8. Whalen M. Preventing erectile dysfunction after radical prostatectomy: nerve-sparing techniques, penile rehabilitation, and novel regenerative therapies. Open access peer-reviewed chapter. In: Genadiev T., ed. Prostatectomy [Internet]. IntechOpen; 2019. https://doi.org/10.5772/intechopen.79398

9. Kyriazis I., Spinos T., Tsaturyan A., Kallidonis P., Stolzenburg J.U., Liatsikos E. Different Nerve-Sparing Techniques during Radical Prostatectomy and Their Impact on Functional Outcomes. Cancers. 2022;14(7):1601. https://doi.org/10.3390/cancers14071601

10. Mandel P., Preisser F., Graefen M., Steuber T., Salomon G., Haese A. et al. High chance of late recovery of urinary and erectile function beyond 12 months after radical prostatectomy. Eur. Urol. 2017;71:848–850. https://doi.org/10.1016/j.eururo.2016.09.030

11. Noldus J., Michl U., Graefen M., Haese A., Hammerer P., Huland H. Patient-reported sexual function after nerve-sparing radical retropubic prostatectomy. Eur. Urol. 2002;42(2):118–124. https://doi.org/10.1016/s0302-2838(02)00219-1

12. de Carvalho P.A., Barbosa J.A.B.A., Guglielmetti G.B., Cordeiro M.D., Rocco B., Nahas W.C. et al. Retrograde release of the neurovascular bundle with preservation of dorsal venous complex during robot-assisted radical prostatectomy: Optimizing functional outcomes. Eur. Urol. 2020;77(5):628–635. https://doi.org/10.1016/j.eururo.2018.07.003

13. Haese A., Knipper S., Isbarn H., Heinzer H., Tilki D., Salomon G. et al. A comparative study of robot-assisted and open radical prostatectomy in 10 790 men treated by highly trained surgeons for both procedures. BJU Int. 2019;123(6):1031–1040. https://doi.org/10.1111/bju.14760

14. Maruo M., Goto Y., Miyazaki K., Inoue A., Kurokawa K., Enomoto A. et al. Novel nerve-sparing robot-assisted radical prostatectomy with endopelvic fascia preservation and long-term outcomes for a single surgeon. Sci. Rep. 2024;14(1):926. https://doi.org/10.1038/s41598-024-51598-3

15. Egan J., Marhamati S., Carvalho F.L.F., Davis M., O’Neill J., Lee H. et al. Retzius-sparing Robot-assisted radical prostatectomy leads to durable improvement in urinary function and quality of life versus standard robot-assisted radical prostatectomy without compromise on oncologic efficacy: Single-surgeon series and step-by-step guide. Eur. Urol. 2021;79(6):839–857. https://doi.org/10.1016/j.eururo.2020.05.010

16. MacDonald S.M., Burnett A.L. Physiology of Erection and Pathophysiology of Erectile Dysfunction. Urol Clin. North Am. 2021;48(4):513–525. https://doi.org/10.1016/j.ucl.2021.06.009

17. Argiolas A., Argiolas F.M., Argiolas G., Melis M.R. Erectile dysfunction: treatments, advances and new therapeutic strategies. Brain Sci. 2023;13(5):802. https://doi.org/10.3390/brainsci13050802

18. Lukovic E., Emala C. Diacylglycerol kinase puts the brakes on airway smooth muscle contraction. Am. J. Respir. Cell. Mol. Biol. 2021;65(6):578–580. https://doi.org/10.1165/rcmb.2021-0325ED

19. Omirinde J.O., Azeez I.A. Neuropeptide profiles of mammalian male genital tract: distribution and functional relevance in reproduction. Front. Vet. Sci. 2022;9:842515. https://doi.org/10.3389/fvets.2022.842515

20. Kong L., Gao X., Qian Y., Sun W., You Z., Fan C. Biomechanical microenvironment in peripheral nerve regeneration: from pathophysiological understanding to tissue engineering development. Theranostics. 2022;12(11):4993–5014. https://doi.org/10.7150/thno.74571

21. De Leonardis F., Colalillo G., FinazziAgrò E., Miano R., Fuschi A., Asimakopoulos A.D. Endothelial dysfunction, erectile deficit and cardiovascular disease: an overview of the pathogenetic links. Biomedicines. 2022;10(8):1848. https://doi.org/10.3390/biomedicines10081848

22. Belenichev I., Popazova O., Bukhtiyarova N., Savchenko D., Oksenych V., Kamyshnyi O. Modulating nitric oxide: implications for cytotoxicity and cytoprotection. Antioxid. Basel Switz. 2024;13(5):504. https://doi.org/10.3390/antiox13050504

23. Musicki B., Bhunia A.K., Karakus S., Burnett A.L. S-nitrosylation of NOS pathway mediators in the penis contributes to cavernous nerve injury-induced erectile dysfunction. Int. J. Impot. Res. 2018;30(3):108–116. https://doi.org/10.1038/s41443-018-0021-y

24. Noh T.I., Shim J.S., Kang S.G., Cheon J., Lee J.G., Kang S.H. Efficacy of tadalafil in penile rehabilitation started before nerve-sparing robot-assisted radical prostatectomy: a double-blind pilot study. Sex Med. 2022;10(3):100508. https://doi.org/10.1016/j.esxm.2022.100508

25. Sari Motlagh R., Abufaraj M., Yang L., Mori K., Pradere B., Laukhtina E. et al. Penile rehabilitation strategy after nerve sparing radical prostatectomy: a systematic review and network meta-analysis of randomized trials. J. Urol. 2021;205(4):1018–1030. https://doi.org/10.1097/JU.0000000000001584

26. Goh H.J., Sung J.M., Lee K.H., Jo J.K., Kim K.N. Efficacy of phosphodiesterase type 5 inhibitors in patients with erectile dysfunction after nerve-sparing radical prostatectomy: a systematic review and meta-analysis. Transl. Androl. Urol. 2022;11(2):124–138. https://doi.org/10.21037/tau-21-881

27. Cecerska-Heryć E., Heryć R., Wiśniewska M., Michalczyk A., Dołęgowska B. Regenerative potential of platelets in patients with chronic kidney disease. Int. Urol. Nephrol. 2019;51(10):1831–1840. https://doi.org/10.1007/s11255-019-02190-6

28. Wu C.C., Wu Y.N., Ho H.O., Chen K.C., Sheu M.T., Chiang H.S. The neuroprotective effect of platelet-rich plasma on erectile function in bilateral cavernous nerve injury rat model. J. Sex Med. 2012;9(11):2838– 2848. https://doi.org/10.1111/j.1743-6109.2012.02881.x

29. 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(5):926–935. https://doi.org/10.1016/j.jsxm.2021.03.008

30. Inoue S., Hayashi T., Teishima J., Matsubara A. Effect of penile rehabilitation with low intensity extracorporeal shock wave therapy on erectile function recovery following robot-assisted laparoscopic prostatectomy. Transl. Androl. Urol. 2020;9(4):1559–1565. https://doi.org/0.21037/tau19-888

31. Kohada Y., Babasaki T., Goto K., Inoue S., Kurimura Y., TasakaR. et al. Long-term efficacy of penile rehabilitation with low-intensity extracorporeal shock wave therapy for sexual and erectile function recovery following robotic-assisted radical prostatectomy: a single-cohort pilot study. Sex Med. 2023;11(2):qfad023. https://doi.org/10.1093/sexmed/qfad023

32. Matthew A.N., Rogers D.E., Grob G., Blottner M., Kodama S., Krzastek S.C. The use of low-intensity extracorporeal shockwave therapy in management of erectile dysfunction following prostate cancer treatment: a review of the current literature. Transl. Androl. Urol. 2023;12(6):1023–1032. https://doi.org/10.21037/tau-22-791

33. Epifanova M.V. Application of regenerative medicine technologies in sexual functions and infertility disorders in men: diss. … doctor of medical sciences. Moscow, 2022:400. (In Russ.). URL: https://dissovet.rostgmu.ru (13.05.2025).

34. Kuznik B.I., Ryzhak G.A., KhavinsonV.Kh. Polypeptide vessel complex and its role in physiology function regulation in aging pathology. Advances in Gerontology. 2019;32(1–2):174–179. (In Russ). URL: https:// khavinson.info/assets/files/russ/2019-kuznik_ryzhak.pdf (13.05.2025).

35. Khochenkova Yu.A., Khochenkov D.A., KorzhovaK.V., Kazharskaya Ye.Yu., Machkova Yu.S., Sidorova T.A. Angioprotective and regenerative potential of the polypeptide drug slavinorm in endothelial dysfunction and atherosclerotic vascular lesions. Effective pharmacotherapy. 2023;19(5):24–31. (In Russ.). https://doi.org/10.33978/2307-3586-2023-19-5-24-31

36. Suchkov I.A., Kalinin R.E., Mzhavanadze N.D., Kamaev A.A., Burenin A.G., Larkov R.N. Efficacy and safety of a drug based on vascular regulatory polypeptides for the treatment of intermittent claudication (results of a multicenter, double-blind, placebo-controlled randomized trial). Angiology and Vascular Surgery. 2023;29(1):3–33. (In Russ.). https://doi.org/10.33029/1027-6661-2023-29-1-23-33

37. Jabir N.R., Firoz C.K., Zughaibi T.A., Alsaadi M.A., Abuzenadah A.M., Al-Asmari A.I. et al. A literature perspective on the pharmacological applications of yohimbine. Ann. Med. 2022;54(1):2861–2875. https://doi.org/10.1080/07853890.2022.2131330

38. Pyke R.E. Trazodone in sexual medicine: underused and overdosed? Sex Med. Rev. 2020;8(2):206–216. https://doi.org/10.1016/j.sxmr.2018.08.003

39. Melis M.R., Sanna F., Argiolas A. Dopamine, erectile function and male sexual behavior from the past to the present: a review. Brain Sci. 2022;12(7):826. https://doi.org/10.3390/brainsci12070826

40. Dorr R.T., Lines R., Levine N., Brooks C., Xiang L., Hruby V.J. et al. Evaluation of melanotan-II, a superpotent cyclic melanotropic peptide in a pilot phase-I clinical study. Life Sci. 1996;58(20):1777–1784. https://doi.org/10.1016/0024-3205(96)00160-9

41. Wessells H., Fuciarelli K., Hansen J., Hadley M.E., Hruby V.J., Dorr R. et al. Synthetic melanotropic peptide initiates erections in men with psychogenic erectile dysfunction: double-blind, placebo controlled crossover study. J. Urol. 1998;160(2):389–393. https://doi.org/10.1016/S00225347(01)62903-3

42. Kim S., Cho M.C., Cho S.Y., Chung H., Rajasekaran M.R. Novel emerging therapies for erectile dysfunction. World J. Men's Health. 2021;39(1):48–64. https://doi.org/10.5534/wjmh.200007

43. Diamond L.E., Earle D.C., Rosen R.C., Willett M.S., Molinoff P.B. Double-blind, placebo-controlled evaluation of the safety, pharmacokinetic properties and pharmacodynamic effects of intranasal PT-141, a melanocortin receptor agonist, in healthy males and patients with mild-to-moderate erectile dysfunction. Int. J. Impot. Res. 2004;16(1):51–59. https://doi.org/10.1038/sj.ijir.3901139

44. Safarinejad M.R., Hosseini S.Y. Salvage of sildenafil failures with bremelanotide: a randomized, double-blind, placebo controlled study. J. Urol. 2008;179(3):1066–1071. https://doi.org/10.1016/j.juro.2007.10.063

45. Diamond L.E., Earle D.C., Garcia W.D., Spana C. Co-administration of low doses of intranasal PT-141, a melanocortin receptor agonist, and sildenafil to men with erectile dysfunction results in an enhanced erectile response. Urology. 2005;65(4):755–759. https://doi.org/10.1016/j.urology.2004.10.060

46. Ren Y., Yuan J., Xue Y.,Zhang Y., Li S., Liu C.et al. Advanced hydrogels: New expectation for the repair of organic erectile dysfunction. Mater. Today Bio. 2023;19:100588. https://doi.org/10.1016/j.mtbio.2023.100588

47. Choe S., Kalmanek E., Bond C., Harrington D.A., Stupp S.I., McVary K.T. et al. Optimization of sonic hedgehog delivery to the penis from self-assembling nanofiber hydrogels to preserve penile morphology after cavernous nerve injury. Nanomedicine Nanotechnol. Biol. Med. 2019;20:102033. https://doi.org/10.1016/j.nano.2019.102033

48. Martin S., Harrington D.A., Ohlander S., Stupp S.I., McVary K.T., Podlasek C.A. Peptide amphiphile nanofiber hydrogel delivery of Sonic hedgehog protein to the penis and cavernous nerve suppresses intrinsic and extrinsic apoptotic signaling mechanisms, which are an underlying cause of erectile dysfunction. Nanomedicine Nanotechnol. Biol Med. 2021;37:102444. https://doi.org/10.1016/j.nano.2021.102444

49. Wang C.M., Wu B.R., Xiang P., Xiao J., Hu X.C. Management of male erectile dysfunction: From the past to the future. Front. Endocrinol. 2023;14:1148834. https://doi.org/10.3389/fendo.2023.1148834

50. Zhao W., Sun J., Yao L.Y., Hang D., Li Y.Q., Chen C.P. et al. MYPT1 reduction is a pathogenic factor of erectile dysfunction. Commun. Biol. 2022;5(1):744. https://doi.org/10.1038/s42003-022-03716-y