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

Erectile dysfunction (ED) is defined as the inability to attain or maintain erections sufficient for satisfactory sexual performance [1]. There has been a significant global increase in the prevalence of ED, partly due to the rapidly aging population [2]. ED is an important health concern that can affect men's psychosocial well-being as well as the interpersonal relationships of couples [3]. Furthermore, it is an independent risk factor for impending cardiovascular disease [4].

Phosphodiesterase 5 inhibitors (PDE5i) remain the first-line treatment for ED due to their efficacy and safety but are often not effective or have adverse side effects [5]. Intracavernosal injection of alprostadil, alone or in combination with phentolamine and papaverine, was approved by the FDA in 1996 and has good efficacy, but may cause prolonged erections or pain at the injection site, and occasionally fibrosis after long-term use [6]. Alternatively, intraurethral alprostadil has also been used but is less efficacious despite having fewer adverse effects [7]. ED patients can also use vacuum erection devices, but the erection is often unsatisfactory, and compliance is generally low [8]. Finally, refractory patients who do not respond to the aforementioned treatment modalities may be considered for penile prosthesis surgery which demonstrates superior efficacy with high satisfaction rates. However, patients should be carefully selected and counseled before this irreversible surgical treatment, and its complications, though few, include corporal perforation, cross-over displacement, urethral/bladder/bowel injury, soft glans syndrome, infection, mechanical malfunction, and erosion [9, 10]. While all these treatments provide symptomatic relief, there is a need to develop new and efficacious treatment options that alter the progression of the disease and even restore normal physiologic erections.

Regenerative therapy (RT) has been suggested to aid in the repair and recovery of damaged tissues and local cell lines of dysfunctional organs [11]. Thus, RT aims to restore normal erections by attempting to regenerate erectile tissue, rather than merely relieve symptoms [12]. Emerging RT advances for ED include platelet-rich plasma (PRP), stem cells (SCs) therapy, and low-intensity shock wave therapy (LISWT).

PRP is an autologous centrifuged plasma that has more platelets than normal plasma and contains platelet-related growth components, tissue factors, plasmaderived fibrinogen, and several biologically active cytokines. Several studies have been carried out utilizing intracavernosal PRP infusion for ED, particularly for diabetic patients non-responsive to oral PDE5i [13], but more studies are needed that consider the quality and efficacy of PRP preparations and provide long-term outcomes [14].

SCs are undifferentiated cells that can divide into particular types of cell lines and tissues. Hence, SCs can replace worn-out or damaged tissues to obtain tissue- or organ-specific cells with specialized capacities [15]. Several sources of SCs have been identified, each with unique characteristics and potential applications. A limited number of studies have provided proof of their possible utility in treating ED. A meta-analysis study [16] suggested the efficacy of SC therapy for ED due to diabetic mellitus and the possible superiority of adipose tissue-derived SCs over bone marrow mesenchymal stromal cells in erection restoration and structure renovation. In addition, laboratory studies on rat models have shown the useful role of SCs and stromal vascular fraction in restoring erectile function and preventing penile fibrosis in various animal models of Peyronie’s disease and ED [17]. However, solid evidence is still lacking in clinical settings, and there is insufficient data on suitable dosage, cell heredity, or its component of activity.

LISWT has been applied for treating vasculogenic ED in PDE5i non-responders, with few adverse effects. Animal studies have shown that LISWT significantly improves penile hemodynamics and might reverse some penile pathological changes in an animal model of induced diabetes [18]. It was proposed that LISWT repairs erectile tissues by stimulating vascular endothelial growth factor (VEGF) and different chemokine proteins, such as stromal cell-derived factor 1 (SDF-1), which can partially reverse pathological changes in the corpus cavernosum, endothelial dysfunction, and peripheral neuropathy [19, 20, 21]. According to a meta-analysis of seven randomized controlled trials (RCTs) involving men who received LISWT for ED, the International Index of Erectile Function (IIEF) and Erection Hardness Score (EHS) scores increased significantly in the treatment groups [22]. Patients with moderate and/or severe ED reported better improvements in IIEF scores. The lack of penile deformation at 5-year follow-up supports the long-term safety of LISWT in men with ED [23].

However, the selection criteria, techniques, and protocols for these various RT modalities in clinical practice lack evidence-based recommendations for the best clinical practice. Therefore, the aims of this study are, 1) to explore the current global practices of the use of RT in ED, and 2) to develop expert recommendations on various clinical aspects of this treatment modality using the Delphi method.

A cross-sectional, worldwide, online survey for the global perception and practice of RT in ED was developed and distributed in accordance with the CHERRIES checklist (Supplement File 1) [24]. The initial survey questions were submitted by the senior members of Global Andrology Forum (GAF) and underwent several rounds of review to ensure that the questions and answers were unambiguous. The final list of questions was comprehensive and covered all clinical aspects of RT within the context of ED. The overall survey strategy is presented in Fig. 1.

Fig. 1
A flow diagram of the research process. GAF: Global Andrology Forum.

• Click for larger image

The completed 39-item questionnaire comprised three sections: The first section (Q1–5) gathered demographic information such as age, years of experience, country, setting of practice, and specialty of the respondents. The questions in the second section (Q6–11) were about the workload of ED patients, patient assessment, and the present and future intentions regarding the overall utilization of RT. Section three of the questionnaire (Q12–39) focused on the different facets of RT utilization, including frequently employed modalities, prevalent indications, patient feedback, as well as the effectiveness and safety of treatments.

The complete survey with the invitation letter are provided in Supplement File 2. The respondents were given the option to skip questions about specific RT modalities if they did not have experience with that specific modality, thus avoiding potential answer bias. The survey was created and globally distributed using the secure Google Forms platform to ensure the confidentiality of the submitted responses. The survey was made accessible from May 27, 2023, to August 8, 2023. Clinicians worldwide treating ED were invited to participate in this study. They were informed about the nature and objective of the survey and requested to complete the online survey. The survey questions were provided in the English language and used standard medical terms. This survey was approved by the Ethics committee (approval number: IR-02-23-103).

The answers to the questionnaire were described as numbers and percentages of each choice. For questions where the participant might choose more than one answer, each response frequency was calculated from the total number of participants. The R version 4.1.2 programming language (www.r-project.org) was used to create the bar charts (Supplement File 3).

A set of expert recommendations was created through a collaborative process between senior GAF members with substantial academic expertise and clinical experience in the treatment of ED by RT. These statements comprised the critical facets of RT in ED treatment and were circulated among the experts to achieve consensus through the Delphi method [25] (Supplement File 4).

This is the first global survey aimed at identifying the global practices and attitudes of sexual medicine practitioners toward the use of RT for ED treatment.

All the respondents to this survey were actively involved in the management of ED but the majority of respondents reported that ED represented less than 25% of their clinical work. Several studies have reported that the percentage of ED patients in outpatient clinics ranges from 21.1% to 81.5% [34, 35, 36]. A study by [37] grouped the patients who declared ED as their primary or secondary symptom as 'very early treatment seekers' (VETS) and 'early treatment seekers' (ETS) respectively. The patients who hid their ED until directly questioned and the patients whose ED was diagnosed with an IIEF-5 questionnaire were grouped as'late treatment seekers' (LTS) and 'very late treatment seekers' (VLTS) respectively. The rate of severe ED was significantly higher in the VETS group, whereas the rate of mild ED was significantly higher in the VLTS group. These authors concluded that most of the patients would not seek help for their ED until the clinician directly or indirectly questioned them.

The causes of ED are multifactorial and include both psychogenic factors and organic factors. In this survey, most participants reported that multiple factors were the primary cause of ED, with isolated vasculogenic factors being the second most common. Although previously believed to be predominantly psychogenic in origin, ED in young men is now acknowledged to involve several organic risk factors. Vasculogenic and structural alterations, such as focal arterial occlusive disease, subclinical endothelial dysfunction, and Peyronie's disease (PD), can obstruct arterial flow or induce veno-occlusive dysfunction, thus contributing to ED [38]. Desvaux et al [39] (2004) reported a mix of organic and psychogenic ED in 67.1% of men with ED constituting a vicious cycle. Additionally, Huang et al [40] (2012) reported that 73.1% of patients with psychogenic ED could have endothelial dysfunction, confirming the high rate of ED with multiple etiologies or somehow erroneous diagnosis.

In the current survey, 43.0% of the participants utilized a combination of medical history, examination, and hormonal testing in the diagnostic work-up of ED etiology, and 44.0% of them also used penile Doppler ultrasound. This is following the EAU Guidelines of Sexual and Reproductive Health established in 2023 [1]. The objectives of the assessment are to conduct a thorough evaluation of erectile function, utilizing RigiScan to monitor Nocturnal Penile Tumescence and Rigidity (NPTR), which serves as a valuable diagnostic instrument for psychogenic ED. Meanwhile, penile Doppler ultrasound facilitates an initial assessment of the functional anatomy and offers real-time evaluation of the dynamic alterations essential to differentiating between the vascular and nonvascular causes of ED and therefore determining appropriate management of the patient [41, 42].

The current survey revealed that the majority of the respondents (66.6%) are not using RT for ED in their practice. However, approximately one-third of physicians who treat patients with ED worldwide employ RT as a treatment modality, with more than half (54.6%) preferring LISWT. Our results surpass those of Fode et al [43] (2017) whose survey of 2017, found that only 14.1% of participants had utilized LISWT. This result suggests that RT has gained in popularity in recent years.

Established treatments for ED include oral medications, intracavernosal injections, vacuum erectile devices, and penile prostheses [8]. However, these conventional treatments cannot reverse the pathophysiological issues of ED. This point might be the cause of observing that young practitioners, in the current survey, were more interested in the novel lines of ED treatment, such as RT, than older practitioners.

According to the EAU Guidelines, in 2024, most of the studies have suggested that LISWT can significantly increase IIEF and EHS scores in patients with mild vasculogenic ED, although this improvement appears modest, and the rates of patients reporting a satisfactory improvement range between 40%–80% [1]. A recent RCT reported that 3 months after treatment with LISWT, 79% of the treatment group of patients with moderate ED attained a minimal clinically important difference (MCID) in IIEF-EF score vs. 0% in the sham group [44]. Likewise, previous study [20] pointed out that penile LISWT may improve erectile function, to a modest extent, in patients who do not respond to PDE5i, making it an alternative for vascular ED patients that reject more invasive therapies. 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 [45]. However, more prospective RCTs with longer follow-ups are required to provide clinicians with more confidence regarding the effectiveness of LISWT for ED. This point has been emphasized by many society guidelines as well as the GAF expert opinion.

After LISWT, the respondent’s second choice was intracavernosal PRP (24.5%), followed by a combination of both therapies (14.7%), and a minority reported using intracavernosal SCs (3.68%). In this context, intracavernosal PRP has been investigated lately in several trials [13, 46]. Available findings suggest favorable outcomes of PRP injections in terms of IIEF-5 and Sexual Encounter Profile (SEP) scores and peak systolic velocity on penile-duplex ultrasound. In a prospective interventional study, 41% of men with diabetes non-responders to oral PDE5i showed improved EHS response with daily oral tadalafil 5 mg plus on-demand vardenafil 20 mg tablets and 3 doses of intracavernosal PRP [47]. However, most of the current studies are limited by the low number of patients including the lack of placebo comparison and heterogeneity in terms of the modality of PRP preparation. Besides, the concentration of platelets and growth factors vary according to the different preparation protocols. Therefore, all society guidelines as well as our expert recommendations state that intracavernosal PRP for the treatment of ED should be used only in a clinical trial setting.

The survey presented limited data on the use of SC therapy as only 3.68% of the participants were using it, probably due to its unavailability, high cost, and possible need for certain regulations. A recently published systemic review of 18 studies involving 373 patients with organic ED suggested that SC therapy shows promise as an innovative and safe treatment for organic ED. However, the lack of standardized protocols and controlled groups in many studies hampers the ability to evaluate and compare these studies [48]. The recent European Society for Sexual Medicine guidelines stated that SC therapy for ED should be considered a treatment under investigation and not offered outside of approved clinical trials and the patients should be informed regarding the limited evidence on its efficacy and safety [33].

The current survey revealed three major factors limiting the utilization of RT in the management of ED including; lack of experience, non-coverage by insurance, and non-availability. Based on these findings, respondents indicated a willingness to use RT in the future if subsequent studies demonstrated increased efficacy, RT was endorsed by professional guidelines, and adequate training in the use of RT was available. The results of the current survey strongly highlight the need for further studies and RCTs to validate these initial promising findings and qualify RT for inclusion in international guidelines. Additionally, training and coverage by insurance could also assist in the broader use of RT in ED treatment.

This study has some limitations. Some of the responses of the survey participants were based on subjective criteria rather than objective measures, whether in the initial evaluation of ED patients (like history, examination and hormonal testing rather than basline penile Doppler ultrasound) or for the evaluation of the efficacy of RT in ED (like the use of overall patient satisfaction rather than IEEF or Doppler ultrasound). Also, the limited number respondents who are using penile SCs therapy, most propably, due to its high cost, the need for institutional approval, or the unavailability of this modality of RT.

This is the first global survey aimed at identifying the clinical practice patterns and attitudes of sexual medicine practitioners toward the use of RT for ED treatment. The current results revealed that one-third of respondents utilized different modalities of RT, and LISWT was the most commonly used, followed by PRP and a combination of both. Most of these techniques are used for non-responders or patients with adverse effects in combination with other ED treatment modalities, and they are commonly used with PDE5i.

The majority of respondents indicated that the best responses to RT were seen in middle-aged patients and those with mild-to-moderate ED severity, and almost all of them confirmed the overall safety of RT. Moreover, the respondents were diverse and uncertain about the currently available evidence and recommendations for the best clinical practice and protocols for different RT modalities.

GAF experts’ recommendations for RT in ED provide practitioners with clearer guidance in areas where clinical guidelines are lacking. However, robust conclusions can only be made based on future randomized clinical trials.

Overall, RT has the potential for treating ED in the future, but it is important to acknowledge the limitations and ongoing research efforts before it becomes a basic tool in the armamentarium of ED treatment.

Supplementary materials can be found via https://doi.org/10.5534/wjmh.240086.

Supplement File 1

Checklist for Reporting Results of Internet E-Surveys (CHERRIES)

Supplement File 2

Global Survey on The Use of Regenerative Therapies in The Treatment of Male Erectile Dysfunction

Supplement File 3

Supplement File 4

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

Supplement File 5

Demographics of survey participants include age, years of practice, professional practice setting, and nature of professional practice