Stem cell therapy for erectile dysfunction: a systematic review and meta-analysis

Introduction

Erectile dysfunction (ED) is a prevalent condition worldwide, significantly affecting the quality of life for men and their partners (1,2). Recent research estimates that most men between 40 and 70 years old, experience some degree of ED, with around 10% facing severe or complete ED (3). However, ED is not limited to older men; studies indicate that younger men also experience ED, often due to psychogenic factors. For instance, in a study from Türkiye, 85.2% of men under 40 years were reported to have psychogenic ED, while 14.8% had organic ED (4). ED is commonly linked to comorbidities such as hypertension, diabetes, atherosclerosis, hyperlipidemia, and metabolic syndrome, which typically increase with age (5). Additionally, ED is a frequent complication following radical prostatectomy, a treatment for clinically localized prostate cancer (6,7).

Penile erection is a neurovascular response mediated primarily through a nitric oxide synthase (NOS)-nitric oxide (NO) signaling pathway. NO, the main neurotransmitter involved in erection, is released by endothelial cells and nerve terminals in the penile cavernosal tissue. This release relaxes the cavernosal smooth muscle by reducing intracellular calcium through cyclic guanosine monophosphate (cGMP) and when the lacunar spaces fill with blood, erection occurs by compressing the subtunical venules. Phosphodiesterase type 5 enzyme (PDE5) subsequently breaks down cGMP (8) to terminate smooth muscle relaxation and penile erection.

ED treatment often involves first-line monotherapy with phosphodiesterase type 5 inhibitors (PDE5Is). Currently used PDE5Is include sildenafil, vardenafil, and tadalafil, with newer options like avanafil, udenafil, and mirodenafil also available in certain regions (9,10). Another medication for ED, alprostadil (a prostaglandin E1 analog), induces penile erection by raising cyclic adenosine monophosphate (cAMP) levels in the corpus cavernosum smooth muscle cells after the intracavernosal injection (2). Androgen replacement therapy has been critical in ED treatment via normalizing serum testosterone levels and enhancing sexual desire (11,12). While physical treatments for ED include vacuum devices and low-intensity extracorporeal shock wave therapy (Li-ESWT) (13,14), several surgical options, including penile prosthesis implantation, penile augmentation surgery, penile revascularization, and penile reinnervation procedures have been applied to patients with ED (15). However, many patients discontinue the treatment due to cost, insufficient efficacy, and adverse events such as priapism, pain, ecchymosis, and hematoma that can occur with intracavernosal injections (16-18).

The new innovative therapies for ED have been under intense investigation. In that regard, recent studies have focused on cell-based therapies, specifically stem cells (SCs), to halt the progression of ED and potentially reverse the various pathophysiological processes involved in ED development (19,20). SCs are a unique type of cell that possess the ability to self-renew and differentiate (21). The types of SCs currently being tested for ED treatment, both in preclinical animal models and in clinical studies, include embryonic stem cells (ESCs), endothelial progenitor stem cells (EPSCs), bone marrow-derived stem cells (BMSCs), skeletal muscle-derived stem cells (SKMSCs), neural crest SCs, adipose tissue-derived stem cells (ADSCs), testicular SCs, and human urine stem cells (USCs) (8,22,23). SCs exert their therapeutic effects predominantly through paracrine signaling by releasing growth factors and cytokines such as vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF), and insulin-like growth factor (IGF-1), which promote angiogenesis, enhance penile blood flow, and support neural regeneration. These paracrine effects also contribute to anti-inflammatory and anti-fibrotic processes. In addition, SCs may directly differentiate into endothelial and smooth muscle cells, facilitating vascular repair and improving cavernosal smooth muscle content (Figure 1). However, the mechanisms of action underlying these therapies and their clinical effectiveness have not yet been fully clarified (24).

Figure 1 Potential mechanisms of stem cell therapy for erectile dysfunction. Created in BioRender. Helvacı G (2026). BDNF, brain-derived neurotrophic factor; bFGF, basic fibroblast growth factor; GDNF, glial cell line-derived neurotrophic factor; IGF-1, insulin-like growth factor; NGF, nerve growth factor; VEGF, vascular endothelial growth factor.

This meta-analysis aims to investigate the overall effect of stem cell therapy (SCT) on ED by consolidating findings from clinical studies. While recent systematic reviews and meta-analyses have considered the efficacy of SCT for ED, gaps remain in appraising the most current evidence and applying advanced statistical interrogation to address trial heterogeneity and potential bias (25). To our knowledge, only a limited number of studies have attempted to address these limitations. In this context, our study provides a comprehensive appraisal of SC clinical studies in ED treatment, incorporating a wide range of parameters and presenting an updated analysis including data up to July 2024. Furthermore, we utilize meta-regression and sensitivity analyses as a critical part of our risk-of-bias framework to rigorously enhance the robustness and clinical applicability of the pooled findings. The results of this study will potentially serve as a guide for critical assessment of future SC therapies for ED. We present this article in accordance with the PRISMA reporting checklist (available at https://tau.amegroups.com/article/view/10.21037/tau-2026-0348/rc).

Methods

Study design

The study was pre-registered in the International Prospective Register of Systematic Reviews (PROSPERO Identifier: CRD420251005006). The five-dimensional PICOS framework was effectively utilized in the meta-analysis to refine search terms, encompassing the key components of research: participants (P), intervention (I), control (C), outcome (O), and study design (S). The participants (P) in this meta-analysis consisted of patients with any diagnosis causing ED. The intervention (I) involved SC therapies. The included studies were single-group studies with no control group (C). The outcome variables (O) assessed in this study were the International Index of Erectile Function (IIEF), peak systolic velocity (PSV), end-diastolic velocity (EDV), resistive index (RI), and erection hardness score (EHS). Lastly, ClinicalTrials.gov were selected as the study design (S) for inclusion in the meta-analysis. Based on the PICOS framework, the research question was formulated as follows: “What is the overall effect of SCT on ED?”.

Search strategy

A search in online databases of PubMed, Web of Science, MEDLINE, and ClinicalTrials.gov was carried out and was concluded on July 26, 2024. A study search was performed using combinations of the following keywords/terms:

• “Stem cell” OR “Progenitor cell” OR “Mother cell”
• “Erectile dysfunction” OR “Impotence” OR “Intracavernosal pressure”
• 1 AND 2

In the first phase, two independent investigators searched the databases using identical keywords, without assistance from others. All studies retrieved from the search were transferred to Endnote X20 (Clarivate Analytics, Philadelphia, PA, USA) for reference management by the authors.

Inclusion and exclusion criteria

This meta-analysis study included clinical studies (I) involving patients with ED due to any diagnosis, (II) applying SCT, (III) evaluating ED, and (IV) published in English language. Animal studies, reviews, descriptive studies, and studies that did not report the mean and standard deviation necessary for conducting analysis were excluded from the study. To avoid confusion and ensure clarity and consistency in the presentation of pooled results, we included only studies eligible for quantitative analysis in the meta-analysis section. Furthermore, grey literature, including articles in non-peer-reviewed journals without oversight from commercial publishers, as well as theses, expert opinions, letters, and conference presentations, was also omitted from the study.

Selection process

The related articles were accessed via keywords. Two investigators separately selected the articles according to their titles and abstracts. In the next step, the full texts of the articles were examined according to the inclusion and exclusion criteria. In case of divergence, a third investigator, in a blinded manner, determined whether the article was to be included in the study.

Data extraction

All studies gathered in Endnote X20 reference management software (Clarivate Analytics, Philadelphia, PA, USA) were examined by the authors. After removing duplicates, the titles and abstracts of the remaining studies were screened by two investigators per the inclusion criteria. The full texts of the eligible studies were evaluated per the inclusion and exclusion criteria. In case of discrepancies during the data extraction process, the other blinded investigators were consulted to reach a consensus.

A standardized data collection form was developed by the investigators to assess the studies thoroughly and consistently. The form included the following headings: study (years), country, study design, diagnosis of the patients, total number of patients, inclusion criteria, exclusion criteria, age, IIEF score, other ED evaluations, assessment intervals, cell types, cell source, single injection or multiple injection, route of injection, and adverse effect.

Outcomes

IIEF is a commonly used questionnaire tool for assessing ED. IIEF-15 consists of 15 items under 5 domains, including erectile function, orgasmic function, sexual desire, intercourse satisfaction, and overall satisfaction. Its shortened version, IIEF-5, consisting of five questions, is used to measure men’s sexual function and quality of life. The IIEF-5 evaluates various factors such as erection quality, frequency of sexual activity, and overall sexual satisfaction. The IIEF-5 questionnaire requires respondents to answer each question on a 5-point scale. The responses are scored on a specific scale and the scores are interpreted as follows: 21–25 points, normal sexual function; 17–20 points, mild ED; 11–16 points, moderate ED; 6–10 points, severe ED; 0–5 points, very severe ED. This index is considered as a the most common index that can discriminate patients with ED (26).

PSV, EDV, and RI are important hemodynamic parameters commonly measured using Doppler ultrasound to assess blood vessels and blood flow. These parameters are often used in the diagnosis and evaluation of ED. High PSV, low EDV, and RI indicate good blood flow (27).

EHS is a simple and widely used measure for evaluating ED. EHS assesses the degree of erection hardness and allows for an objective evaluation of sexual function. This measurement is commonly used to monitor the effectiveness of treatment processes and assess men’s sexual health. An increase in the score indicates good erectile hardness (28).

Risk of bias

The Risk of Bias in Non-randomized Studies-of Interventions (ROBINS-I) tool is designed to evaluate the risk of bias in non-randomized studies that investigate the effects of interventions. This tool assesses bias across seven key domains: bias due to confounding, bias in the selection of participants into the study, bias in the classification of interventions, bias due to deviations from intended interventions, bias due to missing data, bias in the measurement of outcomes, bias in the selection of the reported result and overall bias. Each domain is rated to reflect the risk of bias, typically categorized as “low risk of bias”, “moderate risk of bias”, or “high risk of bias”. ROBINS-I is widely used to ensure a systematic and transparent approach to evaluating study reliability and the validity of evidence from non-randomized intervention studies (29). In this study, two independent investigators assessed the risk of bias; in case of any disagreements, the other blinded investigators were consulted to reach a consensus.

Statistical analysis

The outcomes were analyzed using the Comprehensive Meta-Analysis software version 3.0 (Biostat, Englewood, New Jersey). The Q statistic and I2 statistics were used to evaluate heterogeneity. The I2 statistics values were categorized into no (0–25%), low (25–50%), moderate (50–75%), and high (75–100%) heterogeneity. A fixed-effects model was used to present the studies in the case of I²≤50% and P>0.1; otherwise, a random-effects model was applied (30). In addition, the Q value statistic was used to complement the assessment of heterogeneity and reveal the variance among the studies. For continuous outcomes, pooled analyses were conducted using post-intervention (final) values. The pooled effect size was expressed as standardized mean differences with 95% confidence intervals (CIs). Cohen’s d was adopted as the effect size measure for each study and weighted according to the sample size of the respective study. These d values were then averaged to calculate the overall effect size. The d value was converted to a z value. Moreover, Forest plots were generated to provide a visual representation of the effect sizes across studies. Publication bias was examined visually using funnel plots. An asymmetrical funnel plot represents a potential publication bias. The Begg’s regression test was performed to statistically evaluate funnel plot asymmetry (31). Subgroup analysis and meta-regression were performed to assess any potential moderating variables. The subgroup analysis and meta-regression were performed according to the diagnosis of the patients, age, baseline IIEF, cell types, and the number of injections.

Results

Study selection

The initial search of the databases identified a total of 3,361 records. After removing 2,681 duplicates, a total of 655 records with animal studies (n=169), no SCT (n=239), and no evaluation of ED (n=247) were excluded in the abstract and title review. Following the examination of full texts of the remaining 25 records, 11 were excluded as they were descriptive studies (n=2) or did not apply SCT (n=9). Of the remaining 14 records, 3 records did not report mean and standard deviation, therefore, a total of 11 articles were selected for inclusion in the meta-analysis (Figure 2). Selected studies were conducted in Jordan (n=2), Florida (n=2), Egypt (n=1), Japan (n=1), Iran (n=1), Vietnam (n=1), Greece (n=1), France (n=1), Korea (n=1).

Figure 2 PRISMA flowchart of studies in the meta-analysis. PRISMA, preferred reporting items for systematic reviews and meta-analyses.

Characteristics of patients

Clinical characteristics of the ED patients from 11 studies included 4 studies which had only diabetes (23,24,32,33), 3 studies which had chronic organic ED (34-36), 2 studies which had only post prostatectomy ED (37,38), 1 study which had Peyronie’s disease (39) and 1 study which had reduced sexual activity (40). The mean age of the patients ranged between 48.4±7.5 years (40) and 65.6±5.1 years (24). The baseline IIEF scores of the patients ranged between 5.09±1.79 (37) and 47.60±19.591 (39) (Table S1).

Type of SCT

SCs were supplied from different tissues, including BM-MSCs (n=3), ADSCs (n=2), placental matrix-derived mesenchymal stem cells (PM-MSCs) (n=2), Wharton’s Jelly derived mesenchymal SCs (n=1), SCs derived from human exfoliated deciduous teeth (n=1), oral mucosa derived mesenchymal SCs (n=1), and bone marrow mononuclear cells (BM-MNCs) (n=1). The number of administration of SC injections was variable in the studies: in five studies the administration was two injections, in three studies there was a single administration, in two studies the administration was eight injections, and one study administered six injections. As for the source of SCs, the source was donors (allogeneic) in 4 studies, patients themselves (autologous) in 6 studies, and were not reported in 1 study. Side effects were not mentioned in 3 studies. In the studies that reported side effects, patients experienced mild to moderate pain during the procedure. Other reported side effects included elevated liver enzymes, hyperglycemia, bacterial growth, fever, back pain, and viral upper respiratory tract infections (Table 1).

Risk of bias

The included studies were assessed using the ROBINS-I tool across seven domains (D1–D7) and for overall risk of bias. In the overall assessment, the majority of studies carried a moderate risk of bias. In particular, the risk was moderate in most studies in the confounding (D1) domain; however, a serious risk of bias was identified in the studies by Levy et al. [2015] and Levy et al. [2016]. Whilst a moderate risk was generally observed in the participant selection (D2) domain, a low risk was predominantly identified in the classification of the intervention (D3) and deviations from the intended intervention (D4) domains. In the missing data (D5) and measurement of outcomes (D6) domains, a moderate risk of bias was predominantly identified. In terms of selective reporting (D7), the majority of studies were assessed as having a low risk. Overall, whilst two studies showed a serious risk of bias, most of the other studies carried a moderate risk of methodological bias (Figure 3).

Figure 3 Risk-of-bias summary of the studies.

The Begg regression test revealed no publication bias in the included studies (intercept =0.273, P=0.283). However, the funnel plot presented a slight asymmetry among these studies (Figure S1). Various factors might have caused this asymmetry, including heterogeneity, sample size, age, gender, and duration of intervention.

Overall effect

There were a total of 11 studies evaluating the IIEF level, with a combined sample size of 140 across these studies. An examination of heterogeneity between studies revealed a Q-value of 135.104 (P<0.001) and an I² value of 92.59%, indicating high heterogeneity among the studies. Therefore, a random effects model was used to determine the overall effect. The pooled mean effect was 16.872 (95% CI: 13.311–20.432). The overall effect of the studies was statistically significant (Z-value =9.288, P<0.001) (Figure 4A).

Figure 4 Forest plot for (A) IIEF results; (B) PSV results. IIEF, international index of erectile dysfunction; PSV, peak systolic velocity.

There were a total of 8 studies evaluating the PSV level, with a combined sample size of 77 across these studies. An examination of heterogeneity between studies revealed a Q-value of 331.112 (P<0.001) and an I² value of 97.88%, indicating high heterogeneity among the studies. Therefore, a random effects model was used to determine the overall effect. The random-effects model estimated a mean effect of 37.387 (95% CI: 23.776–50.999). The overall effect of the studies was statistically significant (Z-value =5.384, P<0.001) (Figure 4B).

There were a total of 8 studies evaluating the EDV level, with a combined sample size of 77 across these studies. An examination of heterogeneity between studies revealed a Q-value of 138.888 (P<0.001) and an I² value of 94.96%, indicating high heterogeneity among the studies. Therefore, a random effects model was used to determine the overall effect. The mean effect was 5.847 (95% CI: 3.358–8.336; Z=4.604, P<0.001) (Figure 5A).

Figure 5 Forest plot for (A) EDV results; (B) EHS results; (C) RI results. EDV, end-diastolic velocity; EHS, erection hardness score; RI, resistive index.

There were a total of 3 studies evaluating the EHS level, with a combined sample size of 42 across these studies. An examination of heterogeneity between studies revealed a Q-value of 20.879 (P<0.001) and an I² value of 90.421%, indicating high heterogeneity among the studies. Therefore, a random effects model was used to determine the overall effect. The mean effect was 1.706 (95% CI: 0.936–2.476; Z=4.341, P<0.001) (Figure 5B).

There were a total of 4 studies evaluating the RI level, with a combined sample size of 52 across these studies. An examination of heterogeneity between studies revealed a Q-value of 15.758 (P=0.001) and an I² value of 80.962%, indicating high heterogeneity among the studies. Therefore, a random effects model was used to determine the overall effect. According to the random effects model, the mean overall effect was 0.788 (95% CI: 0.719–0.857; Z=22.302, P<0.001) (Figure 5C).

Meta-regression

Statistically significant subgroup differences were observed according to patient diagnosis (z=3.29, P=0.017), baseline IIEF values (z=−3.64, P=0.003), and type of SC applied (z=−2.38, P=0.019). Improvements in IIEF scores appeared to be more pronounced in patients with organic ED compared with those with post-radical prostatectomy or diabetic ED. Similarly, greater increases were observed in patients with baseline IIEF scores ≥11 compared with those scoring <11. In addition, patients receiving placental-derived SCs showed relatively higher improvements than those receiving other SC types (Table 2).

Sensitivity analysis

Leave-one-out sensitivity analyses showed that excluding individual studies did not materially change the pooled estimates or statistical significance of the results. For the IIEF outcomes, pooled effect sizes ranged from 15.26 to 17.85, with heterogeneity remaining high (I²=89.0–93.3%). Exclusion of Koga and Horiguchi [2021] produced the greatest reduction in heterogeneity. For the PSV outcomes, pooled effect sizes ranged from 4.44 to 6.41, while heterogeneity remained considerable (I²=88.7–95.5%). Exclusion of Protogerou et al. [2020] resulted in the largest decrease in heterogeneity (Table S2). For EDV outcomes, pooled effect sizes ranged from 4.44 to 6.41, with heterogeneity remaining high (I²=88.7–95.5%). Exclusion of Protogerou et al. [2020] resulted in the greatest reduction in heterogeneity. For EHS outcomes, pooled effect sizes ranged from 1.38 to 1.98. Removal of Al Demour et al. [2021] reduced heterogeneity from 90.4% to 74.2%, indicating its notable contribution to between-study variability. For RI outcomes, pooled effect sizes remained stable between 0.77 and 0.82. Exclusion of Al Demour et al. [2024] markedly reduced heterogeneity from 81.0% to 42.1% (Table S3). Overall, no single study materially changed the direction or significance of the pooled results, supporting the robustness of the meta-analytic findings.

Discussion

SCs are a special type of cell with the potential for indefinite division and the ability to differentiate into different cell types (8). In preclinical studies, SCs obtained from different tissues have been investigated in animal models of ED (20,41,42). Similarly, some clinical studies have also demonstrated the positive impact of SCT on ED, although a concrete therapeutic conclusion as to the SC type, quantity, preparation and route of administration for clinical use have been lacking and requires further research (24,38).

This systematic review and meta-analysis evaluated the effects of BM-MSCs and ADSC, SCs of bone marrow and adipose tissue, respectively. ADSCs can be isolated in large quantities due to the abundance of adipose tissue and its rich vascularization, thus, making them a feasible alternative for clinical applications (43). ADSCs also possess neurotrophic properties and the ability to differentiate into multiple cell lineages (44). Similarly, BM-MSCs offer a proven safety profile and ease of accessibility as a SC source, providing an advantage in clinical settings (45). As within the most practised SCs in clinical studies, ADSCs and BM-MSCs are also commonly used and appear to be clinically effective in ED treatment. In this review, it was observed that great extent of the SCs administered were autologous cells. Autologous SCs are derived from the patient’s own body and have several advantages including easier extraction and reduced risk of immune reaction after injection (46), although allogeneic SC use requires a preparation step and potential discomfort for the patient before the treatment. It should be noted that despite the risk of immunogenicity, allogeneic SCs also have advantages such as the flexibility of donor selection and preparation from donor cells in advance without creating discomfort to the patient (46,47). In addition, other emerging regenerative approaches for ED include Li-ESWT, PRP, and extracellular vesicle-based therapies. While these modalities show varying degrees of preclinical and early clinical promise, evidence remains heterogeneous and no direct comparative studies exist. SCT represents a broader regenerative strategy, but its clinical superiority has not been established (48).

Several preclinical animal studies have shown that SCs are effective in treating various forms of ED, namely Peyronie’s disease, diabetes-related ED, and chronic ED (41,49). As for the clinical effect, the majority of the studies included in this systematic review and meta-analysis involved ED patients with diabetes. In these studies, regardless of the underlying cause of ED or the type of SC administered, this treatment approach improved erectile function, indicating a strong therapeutic potential of SCs in clinical settings. Emerging evidence suggests that the therapeutic effects of SCT are predominantly mediated through paracrine mechanisms rather than direct cell engraftment or differentiation. SCs are known to secrete a variety of bioactive factors, including cytokines, growth factors, and extracellular vesicles, which contribute to angiogenesis, neuroprotection, anti-apoptotic signaling, and modulation of inflammation. This paracrine activity is now considered a key driver of tissue repair and functional recovery in ED. Therefore, the beneficial effects observed in clinical studies may largely reflect these indirect regenerative processes rather than the long-term survival or integration of transplanted cells (50-52).

The route of administration is critical for maintaining effective clinical treatment. In this analysis, it has been reported that SCs were given directly to the penis via intracavernous injection, except in one study where SCs were injected intravenously. The intravenous drug administration is a well-practiced and well-established minimally invasive route compared with other routes of drug administration; thus it is commonly preferred for a systemic effect in clinical studies (53). However, this approach is invasive and may be associated with procedure-related discomfort or complications. In contrast, systemic administration routes, such as intravenous delivery, offer a less invasive alternative and may allow broader distribution; however, they are limited by pulmonary first-pass effects, reduced homing efficiency to penile tissue, and potential off-target distribution. However, in ED treatment, in addition to intracavernosal use of conventional therapies, SCs were also injected intracavernosally, whereas systemic intravenous administration has not been widely used. Both preclinical and clinical studies indicate that intracavernosal injection is the preferred method (23,54). This analysis confirms that due to its proven efficacy and relative ease of application, the intracavernosal administration remains the most commonly used direct route for conventional and cellular treatment of ED (8). One of the most significant clinical limitations of intracavernosal SCT is the low survival and retention rates of the transplanted cells within penile tissue. To overcome these limitations, various strategies have been proposed to enhance cell persistence and survival, including the use of hydrogels, biomaterial scaffolds, and delivery systems developed through tissue engineering. In addition, SC-derived extracellular vesicles/exosomes have recently emerged as a potential cell-free therapeutic approach for ED. Preclinical studies suggest that these vesicles may mediate many of the paracrine effects attributed to SCs, including pro-angiogenic, anti-apoptotic, and anti-fibrotic actions. Moreover, a number of approaches have been developed to enhance the effectiveness of SCT for ED. Studies have shown that growth factors can enhance the efficacy of SC applications and promote SC proliferation (55). These approaches include the use of hydrogels coated with growth factors and the physical application of biodegradable membranes (56,57). However, these strategies remain largely in the preclinical experimental stage and require further validation in clinical settings.

The clinical studies in this meta-analysis evaluated SCT effectiveness using IIEF and EHS scores and hemodynamic parameters (PSV, EDV, RI). The IIEF score is a widely used, multidimensional self-report tool for assessing male sexual function (58). SC treatment significantly improved IIEF scores regardless of SC type or administration route. Preclinical animal studies comparing different SCs showed similar outcomes. A network meta-analysis by Wani et al. [2022] on rats with cavernous nerve injury and post-radical prostatectomy patients found improved IIEF scores with SCT, without significant differences among cell sources (59). Likewise, in an experimental necrotizing enterocolitis model, four SC types reduced disease incidence and severity (60). Consistent with preclinical findings, no substantial difference was observed among SC types in our review. PSV, EDV, and RI key Doppler parameters assessing penile blood flow also significantly improved after SCT. Across eight PSV, eight EDV, three EHS, and four RI studies, SCT enhanced hemodynamic function. In systemic sclerosis, IIEF correlated positively with PSV and RI and negatively with EDV (61). Similarly, our results showed increased PSV and RI but decreased EDV, independent of SC type or route.

It has been essential to explore and understand SC-mediated mechanisms underlying therapeutic action in ED. Some studies suggest that the effects of SCs primarily occur through paracrine mechanisms, including immunomodulation and the secretion of cytokines and growth factors (62). A meta-analysis study demonstrated that SCT might improve erectile function in diabetic rats via upregulating NOS and eNOS expression, increasing VEGF secretion, and reducing fibrosis and apoptosis (63). Similarly, in rats with aging-induced ED, it has been shown that SCs can improve erectile capacity partially through secretion of several growth factors such as IGF-1, bFGF and VEGF (64). Detailed elucidation of the signalling pathways and cellular mechanisms that mediate beneficial effects of SCs is crucial both for a deeper understanding and for development of desirable SC based drugs for ED.

At present, SCT for ED remains largely experimental and has not been established as a standard treatment in routine clinical practice. Although early-phase clinical studies have reported promising results, the evidence is still limited by small sample sizes, heterogeneity, and short follow-up durations. Importantly, SCT for ED has not yet received regulatory approval from major authorities such as the U.S. Food and Drug Administration (FDA) or the European Medicines Agency (EMA). Therefore, its clinical use should be considered investigational, and further large-scale, well-designed randomized controlled trials are required before its widespread adoption (65,66).

Importantly, SCT for ED should still be considered experimental. Major professional societies, including the International Society for Sexual Medicine (ISSM), the Sexual Medicine Society of North America (SMSNA), the European Society for Sexual Medicine (ESSM), the American Urological Association (AUA), and the European Association of Urology (EAU), generally do not recommend its routine clinical use outside of well-designed clinical trials. Therefore, while the findings of this meta-analysis are encouraging, they should be interpreted as hypothesis-generating, and further large-scale, well-controlled studies are required before SCT can be considered an established treatment option (65,67).

This study is the pooling of IIEF outcomes across studies involving heterogeneous etiologies of ED. The included populations comprise patients with diabetic ED, post-radical prostatectomy ED, chronic organic ED, Peyronie’s disease, and broader sexual dysfunction conditions. These entities differ substantially in their underlying pathophysiological mechanisms, including vascular impairment, neurogenic injury, fibrotic remodeling, and structural penile alterations. Therefore, the pooled effect estimates should be interpreted with caution, as they may not fully reflect condition-specific therapeutic responses. ED should not be considered a biologically uniform disease entity in this context, and future studies with more homogeneous populations are warranted to better elucidate treatment effects.

It suggests that there is potential for improvement following SCT; however, it should be noted that the level of certainty is low due to study designs lacking a control group, small sample sizes, heterogeneous populations, and short follow-up periods. Therefore, the estimate of the pooled effects should be interpreted with caution, as it may not fully reflect condition-specific therapeutic responses, and future studies with more homogeneous populations are warranted to better elucidate treatment effects.

Our meta-analysis provided the most up-to-date overview of SCT outcomes by including the latest evidence available through July 2024. Unlike previous reviews limited by restricted data, we were able to perform detailed subgroup analyses based on patient diagnosis, age, baseline IIEF, cell types, and number of injections, which provided a deeper understanding of the reasons for clinical heterogeneity. One of the important strengths of our study is the inclusion of a sensitivity analysis that confirmed the robustness and stability of our main pooled effect estimates when low-quality studies were excluded. The application of meta-regression also allowed us to investigate potential correlations between treatment response and patient diagnosis, age, baseline IIEF, cell types, and number of injections, thus, enabling us to gain the new mechanistic insights.

Limitations

This meta-analysis has several important limitations that should be considered when interpreting the findings. First, most of the included studies lacked control groups and were designed as single-arm or uncontrolled trials. Therefore, the observed improvements in IIEF scores cannot be definitively attributed to SCT itself and may have been influenced by placebo effects, regression to the mean, natural disease fluctuations, concurrent treatments, behavioral modifications, or expectation bias. Consequently, the present meta-analysis summarizes changes observed after SC administration rather than providing conclusive evidence regarding treatment efficacy or causality.

Second, substantial clinical and methodological heterogeneity was present across the included studies. The pooled analyses combined studies involving different etiologies of ED, including diabetic ED, post-radical prostatectomy ED, chronic organic ED, Peyronie’s disease, and broader sexual dysfunction conditions. These conditions differ considerably in their underlying pathophysiological mechanisms, such as vascular impairment, neurogenic injury, fibrotic remodeling, and structural penile alterations, which may limit the comparability of pooled estimates. In addition, variations in SC derivatives, administration protocols, cell doses, and follow-up durations may have further contributed to heterogeneity. Although subgroup analyses, meta-regression analyses, and sensitivity analyses were performed, the high heterogeneity observed across several outcomes may still reduce the robustness of the pooled estimates.

Third, publication bias could not be reliably assessed because of the limited number of included studies. Furthermore, the certainty of evidence remains low due to small sample sizes, heterogeneous populations, short follow-up periods, and the predominance of uncontrolled study designs.

Conclusions

The findings of this systematic review and meta-analysis suggest that SCT may be associated with improvements in erectile function among patients with ED. However, these findings should be interpreted with caution due to methodological limitations of the included studies, including small sample sizes, heterogeneity in study design, short follow-up periods, and the predominance of single-arm or early-phase clinical investigations with limited placebo-controlled evidence. Therefore, the observed functional improvements cannot be attributed solely to SCT, as potential placebo effects, regression to the mean, natural fluctuations, and patient selection bias may also have contributed to the reported outcomes.

To our knowledge, this is the first study comprehensively evaluating clinical studies of SCT for ED across a broad range of treatment-related parameters and outcome measures. We employed advanced statistical approaches, including meta-regression and sensitivity analyses within a risk-of-bias framework, to explore the robustness and clinical applicability of the pooled findings and to provide an updated synthesis of the evidence available up to July 2024. Although improvements were observed in outcomes such as IIEF, PSV, EDV, RI, and EHS across different cell sources and administration routes, the heterogeneity of interventions and study designs limits definitive conclusions regarding therapeutic efficacy.

Consequently, SCT may represent a promising regenerative approach for ED treatment; however, the current evidence remains preliminary and insufficient to support definitive conclusions regarding efficacy or broad clinical implementation. Additional prospective, multicenter, large-scale randomized placebo-controlled trials with standardized protocols for SC type, dosing, preparation, and administration are needed to better establish both efficacy and safety. Furthermore, long-term follow-up studies are essential to determine the durability of treatment effects and identify potential adverse outcomes.

Acknowledgments

None.

Footnote

Reporting Checklist: The authors have completed the PRISMA reporting checklist. Available at https://tau.amegroups.com/article/view/10.21037/tau-2026-0348/rc

Peer Review File: Available at https://tau.amegroups.com/article/view/10.21037/tau-2026-0348/prf

Funding: None.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tau.amegroups.com/article/view/10.21037/tau-2026-0348/coif). A.L.B. reports fellowship support from Boston Scientific and Coloplast; serves in an unpaid role in the International Society for Sexual Medicine; and holds stock in Comphya. The other authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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