Regenerative Therapy in Erectile Dysfunction: A Survey on Current Global Practice Trends and GAF Expert Recommendations

Commentary:

One of the major achievements in the treatment of erectile dysfunction (ED) over the past few decades has been the introduction of phosphodiesterase type 5 inhibitors (PDE5i) into clinical practice in 1998. Their high efficacy, combined with accessibility and safety, has allowed PDE5i to take a leading position in the arsenal of ED treatment methods. There is perhaps nothing more convenient than taking a pill before sexual intercourse (or a daily dose) to achieve a quality erection. However, this therapy does not help all patients and has its drawbacks. Many patients do not wish to be tied to taking pills and aim to restore normal physiological erection. Great hopes in this direction are placed on the rapidly developing methods of regenerative therapy (RT) for the treatment of erectile dysfunction, which include the use of platelet-rich plasma (PRP), stem cell therapy (SC), and low-intensity shockwave therapy (LiSWT).

In this innovative study, for the first time, the real clinical experience of practicing specialists in applying regenerative medicine methods for treating ED is analyzed based on a survey. The results of a survey involving 479 practicing urologists and andrologists from 62 countries revealed that only 34% of them use regenerative therapy methods in treating ED. The most commonly used method was LiSWT, applied by 74.8% of respondents, followed by intracavernosal PRP injections (18.4%) and SC injections (3.7%). Interestingly, only 38.7% of respondents use RT methods as a first-line therapy  for ED; most consider it appropriate to employ RT only when standard therapeutic approaches are unsatisfactory (61.3%). RT methods are rarely used as monotherapy for ED (17.8%); they are more often combined with other therapeutic options (82.2%), predominantly with PDE5i.

Patient satisfaction with the use of RT for ED treatment was rated as moderate by most respondents (50.3%). Only 24.5% of surveyed specialists noted that over 50% of patients achieved objective improvement and were fully satisfied with the treatment. The clinical effect of RT application develops in 93.3% of cases within six months after treatment and lasts from 3 to 12 months for more than half of patients (56.5%). An assessment of the influence of age and severity of ED on RT outcomes showed that better results are observed in middle-aged patients with moderate erectile dysfunction.

An analysis of clinical guidelines from professional societies revealed that many of them (including Russian clinical guidelines for erectile dysfunction) indicate the possibility of routine LiSWT application for ED treatment with certain limitations. At the same time, most societies oppose the use of cell therapy methods (PRP and SC) outside clinical trials.

Based on the results of this study, an analysis of recommendations from professional societies, available literature data, and clinical experience from GAF experts, nine recommendations for the application of RT in ED treatment have been formulated.

1. RT should not be considered the standard of care for treating ED and should be offered to patients with informed consent according to its current limitations.
2. RT appears to be more effective in patients with vasculogenic ED compared to other types of ED.
3. RT appears to be most effective in men with mild-to-moderate ED.
4. Young and middle-aged males appear to derive the most benefits from RT for the treatment of ED.
5. RT can be used in combination with other ED treatment modalities or as a solo treatment in males for whom standard treatments have failed, or who wish to try and regain natural erections.
6. A limited proportion of patients treated with RT for ED report satisfaction with treatment.
7. Current evidence is unclear as to the duration of significant improvement in erectile function after RT.
8. Although RT is associated with high short-term safety and minimum adverse effects, the long-term safety of RT is still unidentified.
9. Currently, there is more evidence to support the efficacy of low-intensity shock wave therapy compared to other modalities of RT.

The application of regenerative therapy (RT) has opened a new chapter in the treatment of erectile dysfunction (ED), offering pathogenesis-directed therapeutic approaches for this condition. Low-intensity shockwave Therapy (LiSWT), being the most well-studied method of RT, has demonstrated its efficacy and safety in several large-scale studies and has already found widespread use in clinical practice. Subsequent analysis of the accumulated clinical experience will help refine and standardize LiSWT protocols and identify patient categories for whom this therapeutic modality is most justified.

In contrast, the efficacy and safety of cell-based therapy methods (Platelet-Rich Plasma (PRP) and Stem Cells (SCs)) have not been sufficiently studied, limiting their application outside clinical research settings. High-quality studies with extended follow-up periods are necessary to establish the role of PRP and SCs in the treatment of ED.

Q1. What are the most common types of regenerative therapies currently used for erectile dysfunction (ED)?

Dr. Ryzhkov: The primary types of regenerative therapy in the treatment of erectile dysfunction include intracavernosal injection of platelet-rich plasma (PRP), intracavernosal stem cell (SC) therapy, and low-intensity shockwave therapy (LISWT). Among these, LISWT has gained the most traction in clinical practice. Numerous studies and meta-analyses have confirmed its effectiveness and safety. In contrast, the safety and clinical efficacy of intracavernosal injections of PRP and SCs have not been thoroughly studied; therefore, these methods should only be employed within the framework of clinical trials.

Q2. How does low-intensity shock wave therapy (LISWT) work in the context of treating ED?

Dr. Ryzhkov: LISWT is believed to induce microtrauma to cavernous tissue, promoting the release of vascular endothelial growth factor (VEGF), stromal cell-derived factor 1 (SDF-1), and various other chemokine proteins. These factors act on the endothelium, stimulating neovascularization and improving penile hemodynamics. Enhanced blood flow in the cavernous bodies positively impacts erection quality. Studies conducted on animal models have shown significant improvements in penile hemodynamics and even a reversal of pathological changes in the cavernous bodies induced by diabetes following LISWT treatment.

Q3. What are the primary indications for the use of regenerative therapies in ED?

Dr. Ryzhkov: Regenerative therapy is suitable for men who prefer not to pursue symptomatic treatment and wish to restore natural erections. It is also advisable for men for whom standard therapy with phosphodiesterase type 5 (PDE5) inhibitors has been ineffective. In such cases, regenerative therapy can be combined with PDE5 inhibitors to enhance outcomes.

Q4. How effective is platelet-rich plasma (PRP) therapy in treating ED compared to traditional methods like PDE5 inhibitors?

Dr. Ryzhkov: Currently, no direct studies are comparing the effectiveness of PDE5 inhibitors with PRP therapy. However, a recent meta-analysis by Haotian Huang (2024) indicated that after 1, 3, and 6 months of PRP treatment, the International Index of Erectile Function (IIEF-5) scores increased by 4.05, 3.73, and 3.92 points, respectively. In contrast, a metaanalysis by JinQiu Yuan (2013) found that IIEF scores improved by 5.92 to 8.07 points with PDE5 inhibitors, depending on the specific agent used. This suggests that PDE5 inhibitors may be more effective for treating erectile dysfunction.

Q5. What are the safety concerns associated with the use of stem cell (SC) therapy for ED?

Dr. Ryzhkov: The primary concerns regarding stem cell therapy involve the potential transformation of stem cells into malignant cells, which could lead to tumor development.

The proangiogenic, anti-apoptotic, and immunomodulatory properties of stem cells may act as tumor promoters in this context. However, published research findings on human applications do not support these concerns and demonstrate an excellent safety profile for this therapy (Mohamad Abou Chakra, 2024). Conversely, evidence shows that after one month of cultivation, 45.8% of mesenchymal stem cells can spontaneously transform into malignant cells (Røsland, G.V., 2009). Thus, the safety of this therapy remains a topic of debate, underscoring the need for further in vivo and in vitro studies to resolve this contradiction.

Q6. What patient populations are most likely to benefit from regenerative therapies for ED?

Dr. Ryzhkov: Current research findings indicate that regenerative therapy is more effective in young and middle-aged men with mild to moderate vasculogenic erectile dysfunction. In my practice, I always initiate treatment with regenerative therapy (LISWT) for young and middle-aged men experiencing mild erectile dysfunction. This approach has allowed over half of my patients to regain erectile function and avoid the need for PDE5 inhibitors.

Aleksei Ryzhkov, MD, PhD: Short Biography

Q1. How do patient outcomes with regenerative therapies compare to outcomes with conventional ED treatments?

Dr. Gamidov: It is impossible to compare those modalities as they are essentially different. Most PDE5 inhibitors and prostaglandin injections are better suited for situational use and offer no long-term benefits. A daily tadalafil regimen provides some sense of independence to the patient, as the drug intake is not required to be chronologically tied to sexual intercourse, but organic ED persists once the patient stops this therapy. Penile implants are effective, but the patient forgoes any hope of natural erections following this treatment. Regenerative therapy is unique as it provides a potential long-term solution for organic ED.

Q2. What are the current limitations in the clinical application of stem cell therapy for ED?

Dr. Gamidov: I think that the clinical use of stem cell therapy is limited primarily by its cost. Of course, there are other issues, such as safety and ethics, but they seem secondary. If stem cell therapy was more affordable, robust clinical trials providing safety outcomes could have already been performed. As for the ethical problems, a reliable source of autologous stem cells would be a good solution for most of them.

Q3. How does the combination of PRP and LISWT compare to the use of either therapy alone in treating ED?

Dr. Gamidov: A combination of different regenerative therapies looks promising, considering that their modes of action complement each other. A hypothesis behind shockwave therapy states that it induces microtrauma leading to a release of growth factors.
Resulting reparation and angiogenesis could be greatly augmented by an addition of signal molecules from an «external» source. However, I am convinced that PRP is a lesser form of regenerative therapy when compared to stem cell therapy. 

Q4. What is the role of regenerative therapy in managing patients with refractory ED who do not respond to PDE5 inhibitors?

Dr. Gamidov: Non-responders to PDE5 inhibitors are a complex group of patients. Regenerative therapy works well for refractory arteriogenic ED, but with neurogenic ED one should be somewhat less optimistic. Existing regenerative modalities are useless, however, in veno-occlusive ED and for extensive corporal fibrosis.

Q5. What are the long-term outcomes of patients treated with regenerative therapies for ED?

Dr. Gamidov: We are far from being able to completely cure ED with regenerative therapies, but they provide a response that may last up to 12 months after treatment, according to some sources. However, their relative safety means that therapy may be repeated with a schedule tailored to the patient’s needs.

Q6. How does regenerative therapy address the underlying pathophysiology of ED rather than just the symptoms?

Dr. Gamidov: Release of cellular growth factors induced by regenerative therapy stimulates tissue repair, vascular growth, and, probably, nerve fiber remyelination. This leads to a general improvement in erectile response rather than a short-term symptomatic response. However, it is well known that regenerative modalities and symptomatic treatment complement each other.

Q7. What are the most promising sources of stem cells for ED treatment?

Dr. Gamidov: Embryonic cells are truly pluripotent and thus most promising from a purely scientific point of view, but their use is associated with numerous ethical issues. Perinatal stem cells would be acceptable if a hypothetical patient had them collected and preserved in a cryobank soon after birth. But it would be wiser to use those cells in case of a lifethreatening condition rather than ED. So, all things considered, autologous induced pluripotent stem cells remain the best option, though their reprogramming techniques require further refinement.

Q8. How does the efficacy of adipose-derived stem cells compare to bone marrowderived stem cells in the treatment of ED?

Dr. Gamidov: We don’t have robust data to answer this question yet. Adipose-derived stem cells are easier to obtain. They can be harvested in larger volumes. However, bone marrow stem cells may provide more growth factors necessary to induce tissue repair and improve corpora cavernosa vascularity. We need more clinical data on this issue.

Safar Gamidov, M.D., Ph.D: Short Biography

Q1. What are the potential risks of using unregulated or non-standardized PRP preparations in clinical practice?

Dr. Petrishchev: PRP is not considered a standard treatment, and the method used to prepare it is a significant source of variability. While clinical studies so far have not reported major complications, PRP is biologic but not subject to the same regulatory scrutiny as most other biologic products. Additionally, the vast majority of PRP treatments are offered off-label.

Q2. How do animal model studies inform the potential clinical utility of stem cell therapy for ED?

Dr. Petrishchev: Existing clinical trials suggest that stem cell therapy for ED has the potential to improve erectile function and may be a safe and effective treatment option. The primary mechanism behind SCT’s ability to improve erectile function is likely due to paracrine effects, with engraftment and cellular differentiation playing an ancillary role.
Larger and more rigorous clinical trials are needed to confirm these findings and to determine the optimal dosage, timing, and delivery methods of stem cell therapy for ED.

Q3. What are the current challenges in standardizing LISWT protocols for ED treatment?

Dr. Petrishchev: Shockwave devices vary in manufacturer, energy capacity, and shockwave delivery. Shockwaves may be delivered in a pinpoint manner, linear manner, or in a linear tissue-coverage manner. Data is limited due to a lack of long-term results and a small sample size. Future studies with larger cohorts and standardized protocols are needed to better delineate the long-term efficacy and feasibility of LISWT as a recommended treatment option for patients with mild to moderate ED.

Q4. What are the expert recommendations for patient selection when considering regenerative therapies for ED?

Dr. Petrishchev:

a) RT appears to be more effective in patients with vasculogenic ED compared to other types of ED,

b) RT appears to be most effective in men with mild-tomoderate ED, and

c) young and middle-aged males appears to derive the most benefits from RT for the treatment of ED.

Q5. How does the combination of regenerative therapies with traditional ED treatment influence patient satisfaction?

Dr. Petrishchev: According to the survey, RT is quite often used in combination with other ED treatments. Most commonly used are inhibitors, vacuum erection devices, intracavernosal alprostadil, or others. Approximately half of the respondents from the group utilizing RT (82 out of 163, 50.3%) indicated that their patients exhibited moderate satisfaction with the effectiveness of RT. Combination treatment with LISWT and once daily tadalafil led to a 20% higher rate of patients achieving MCID three months after treatment compared to LISWT alone. “RT can be used in combination with other ED treatment modalities or as a solo treatment in males for whom standard treatments have failed, or who wish to try and regain natural erections”.

Q6. What are the potential benefits of using regenerative therapies in patients with ED secondary to diabetes?

Dr. Petrishchev: Diabetic peripheral neuropathy and ED is a common complication of diabetes, affecting approximately 50% of diabetic individuals. By stimulating nerve regeneration, addressing the underlying causes of the disorder, and alleviating symptoms, RT and stem cell therapy for diabetic peripheral neuropathy have the potential to alter the management of this debilitating illness. One of its most significant advantages is its ability to regenerate damaged nerves. The intracavernous injection of SC to treat ED appears straightforward and logical with the proposed regenerative effect is achieved by either secreting growth factors locally via a paracrine mechanism or by migration to the major pelvic ganglia, to promote the propagation and differentiation of resident progenitor cells and encouraging the recovery of injured tissue.

Q7. What regulatory challenges exist in bringing regenerative therapies for ED to mainstream clinical practice?

Dr. Petrishchev: Regulatory and political practices vary across Europe and globally. Currently, the existing guidelines from relevant societies lack precise instructions for practitioners regarding RT in ED, primarily due to limited research and its classification as low evidence. The majority of professional societies' guidelines advise against using SC or PRP therapies outside of clinical trials.

Vlad Petrishchev, MD, MD: Short Biography

Q1. How important is patient education in managing expectations regarding the outcomes of regenerative therapies for ED?

Dr. Shatylko: Patient education is crucial. Patient-targeted sources of information on regenerative therapies may be commercially driven and unreliable, shaping unrealistic expectations. Even evidence-based articles require proper interpretation, which requires medical education and probably some experience in research. It is up to the physician to describe the possible benefits and risks of regenerative therapy to the patient to avoid disappointment. Integrity is the key here.

Q2. What are the ethical considerations surrounding the use of experimental regenerative therapies in ED?

Dr. Shatylko: First of all, ED is not a life-threatening condition. Second, there are reliable non-experimental methods to improve patients’ quality of life, such as PDE5 inhibitors and penile implants. That is why the ethical «window of opportunity» for regenerative therapies is so narrow. Moreover, even though most regenerative modalities are experimental, those experiments are rarely sponsored by investors or industry, and treatments are usually paid for by patients themselves out of pocket or, sometimes, through insurance. I think it’s also an important ethical problem.

3. How does the global adoption of regenerative therapies for ED vary by region and healthcare infrastructure?

Dr. Shatylko: Region and healthcare infrastructure do not seem to be the defining factors here. Most respondents in the survey were not aware of any specific regulations regarding regenerative therapies in their countries. Until the ambiguous status of regenerative therapies is resolved through clinical research, we can’t expect these treatments to be fully adopted regardless of region or country.

Q4. What is the current status of clinical trials investigating regenerative therapies for ED?

Dr. Shatylko: There are ongoing clinical trials on regenerative therapies for ED, but one could expect more research activity on such an intriguing topic. Shockwave and PRP therapies are more widely studied because there are fewer ethical limitations. Unfortunately,some published clinical trials provide disappointing results.

Q5.How does the cost-effectiveness of regenerative therapies compare to traditional treatments for ED?

Dr. Shatylko: Cost-effectiveness is not a strong point of regenerative therapies. Symptomatic treatment is relatively cheap with many generic formulations available. Penile implantation is costly (though semi-rigid devices are less expensive), but provides a radical lifelong solution for ED. Regenerative therapies, offering no guaranteed results and sometimes requiring repeated sessions, have no discernible benefit over traditional modalities.

Q6. What is the role of growth factors and cytokines in the efficacy of PRP therapy for ED?

Dr. Shatylko: Growth factors, cytokines, and other biologically active molecules are essential in mediating the effect of PRP on penile tissues. The composition of PRP defines its efficacy. However, currently, it’s hard to standardize it. Probably, stem cells would be a better source of growth factors for the treatment of ED and other conditions.

Q7. How does regenerative therapy potentially influence the natural course of erectile dysfunction?

Dr. Shatylko: We hope that regenerative therapy can reverse some functional and histological changes in cavernous tissues that lead to ED, thus affecting the natural course of this condition. It is obvious, however, that existing modalities can do so only in mild and moderate cases of ED. For example, corporal fibrosis is unlikely to be ameliorated by shockwave therapy, PRP, or stem cells.

Q8. What are the expert consensus guidelines on the use of regenerative therapies for ED based on current evidence?

Dr. Shatylko: Global Andrology Forum offers expert consensus guidelines which are separated into 9 statements. GAF states that regenerative therapy should not be considered the standard of care for patients with erectile dysfunction, though young men with mild-tomoderate vasculogenic ED may benefit from it. Understandably, GAF recommendations state that we need more evidence yet for many aspects of the clinical use of regenerative therapies.

Q9. What are the future directions for research and development in regenerative therapies for ED?

Dr. Shatylko: The most important future direction for regenerative therapy is the refinement of extracting reprogrammed pluripotent stem cells. We need reliable non-embryonic sources of stem cells to shake off the associated ethical limitations, and then we need to make basic research and clinical trials more affordable. PRP and stem cell products provide a powerful
cocktail of cytokines and growth factors. The next step would be to identify the exact molecules that define their efficacy, isolate them, and study them as separate drug candidates.

Taras Shatylko, MD, PhD: Short Biography