Platelet-rich plasma for the treatment of erectile dysfunction: a systematic review of preclinical and clinical studies

Abstract

Introduction

There has been tremendous growth in regenerative medicine during the last decade. For erectile dysfunction (ED), after the inclusion of low-intensity shockwave therapy as a treatment modality for ED management by the European Association of Urology sexual health guidelines, intracavernosal injection of platelet-rich plasma (PRP) has gained popularity between urologists and patients as a novel ED therapeutic modality with initial promising results. However, limited clinical data exist regarding efficacy and safety in patients with ED. Furthermore, despite numerous preclinical studies in other tissues and organs, the mechanism of action for restoring erectile function remains undetermined.

Objectives

This systematic review aims to present the current status of preclinical and clinical evidence regarding the use of PRP as treatment option for ED.

Methods

A systematic literature search was conducted using PubMed, Cochrane, and ScienceDirect databases, until February 2023 for studies exploring the effect of PRP on ED.

Results

We identified 517 articles, 23 of which were included in this review. These were 7 preclinical (of which 1 was a comparative trial and 6 were placebo-controlled randomized controlled trials) and 16 clinical studies (of which 1 was a comparative trial, 5 were randomized trials, and 2 were placebo-controlled randomized controlled trials). Preclinical data support the regenerative role of PRP in erectile tissue, in accordance with existing evidence in other tissues. Randomized clinical studies, as well as the first 2 available randomized, placebo-controlled clinical trials, showed promising efficacy and a lack of any adverse events.

Conclusion

As PRP for ED is widely used worldwide, there is an urgent need for high-quality studies with long-term follow-up. Standardization of research protocols, especially on the quality of PRP preparation, is also needed.

erectile dysfunction, platelet-rich plasma, PRP

Introduction

In the post–PDE5 inhibitor era, and especially after the latest adaptation of low-intensity shockwave therapy (LI-SWT) as a treatment modality for erectile dysfunction (ED) management by the European Association of Urology sexual health guidelines, there is a rapidly emerging scientific interest regarding so-called regenerative treatment options for ED.^1,2 In this scope, intracavernosal injections (ICIs) with stem cells (stem cell therapy) or platelet-rich plasma (PRP) are under investigation either as monotherapies or as part of multimodal treatment approaches for ED.^3-5 ICI with PRP—trademarked as Priapus Shot—has been marketed aggressively and is increasingly used by urologists worldwide as a novel ED therapeutic modality. However, limited publications exist regarding efficacy and safety, while the mechanism of action is under investigation.^4-6 Thus, according to the Sexual Medicine Society of North America and American Urological Association statement, PRP should only be used as treatment for ED in the context of clinical trials.⁸ This review aims to present the current status of preclinical and clinical evidence regarding the use of PRP as treatment option for ED and identify needs for standardization of this novel treatment modality.

Methods

Search strategy and selection criteria

The present study is based on the Cochrane Handbook for Systematic Reviews of Interventions and the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) statement.⁹ A systematic literature search was conducted using PubMed, Cochrane, and ScienceDirect databases until February 2023 for studies exploring the effect of PRP on ED. The applied search string was (PRP OR platelet rich plasma) AND (ED OR erectile dysfunction OR erectile function), modified accordingly based on each database. We performed a targeted search of the gray literature, including relevant websites, conference abstracts published in major urology journals, and clinical trial registries (EudraCT and ClinicalTrials.gov). The references of the eligible studies and relevant reviews were also hand-searched. We included any human or animal study assessing the effect of PRP on erectile function (EF). All PRP preparation and administration methods were considered eligible. On the contrary, we excluded reviews and non-English publications.

Data extraction, quality assessment, and statistical analysis

Two authors (E.P., I.M.) performed a 3-step parallel screening of title, abstract, and full text of all identified records based on our prespecified selection criteria. Data regarding study characteristics, PRP application details, and PRP outcomes were retrieved from all included studies and tabulated in a Microsoft Excel spreadsheet. We provided a descriptive synthesis of the main results extracted from the included full-text articles, figures, and relevant tables regarding the role of PRP in patients and animal models with ED.

Results

The literature search identified 517 articles, and after screening titles, abstracts, and full texts, 23 of them were included in the present systematic review. Of them, 7 were preclinical studies and 16 were clinical studies.

Preclinical studies

Ding et al¹⁰ in 2009 found that the application of PRP on injured cavernous nerves (CNs) had a positive impact in terms of EF and neuroprotection compared with the non-PRP group, but parameters were inferior compared with the sham group. Wu et al in 2012¹¹ and 2013¹² found that ICI of PRP had a significantly positive impact on EF and neuroprotection in rats with injured CNs compared with the sham group. In the 2013 trial, an optimized form of PRP rich in platelet-derived growth factor AB was also proposed. Diabetic rats with ED and rats with hyperlipidemia-associated ED had significantly improved EF after receiving ICI of PRP.^13,14 Another study suggested that CXCL5 and CXCR2 cytokines play a significant role as mediators of PRP effects in the preservation of EF after CN injury,¹⁵ and finally, ICI of chitosan-activated PRP was beneficial in restoring EF via neuroprotective and tissue-protective effects at an early stage in rats after CN injury.¹⁶ In all but one of the preclinical trials, the PRP preparation method is described, but there is heterogeneity among them. The characteristics of all included preclinical trials are presented in Table 1.

Table 1

Preclinical trials.

Study	N (age [y])	Animal (weight)	Protocol	PRP preparation description	Outcome	P value	Comments
Ding et al (2009)10 Prospective randomized controlled trial	24 (12)	Male Sprague-Dawley rats (250-300 g)	3 groups (8 rats each group): A. Sham surgery group B. CN dissection+2 min crushing injury with hemostatic clamp and nothing else C. CN dissection+2 min crushing injury with hemostatic clamp and nothing else+ PRP gel at the site of injury Follow-up at 3 mo	Available	CN electrostimulation (erectile response) Toluidine blue staining of myelinated axons NADPH diaphorase staining of penile nerve fibers	<.05	PRP-treated group had higher maximal ICP and ICP/MAP ratio than injured control group but lower ICP/MAP ratio than sham group. PRP-treated group had significantly more myelinated axons than injured control group but less than sham control group. PRP-treated group had significantly more NADPH diaphorase–positive nerve fibers in the dorsal nerves than injured control group but less than sham control group.
Wu et al (2012)11 Prospective randomized controlled trial	24 (12)	Sprague-Dawley rats (450-600 g)	3 groups (8 rats each): A. Sham surgery group B. Normal saline IC injection C. PRP ICI group In groups B and C, BCNC injury was performed Follow-up at 1 mo	Available	ICP Number of myelinated axons in CN and dorsal penile nerve Collagen type change Number of apoptotic cells Caspase-3 and TGF-β1	<.05	PRP resulted in significant recovery of EF as compared with the normal saline group, successful nerve regeneration, significant preservation of CNs myelinated axons, and a lower apoptotic index.
Wu et al (2013)12 Prospective randomized controlled trial	24 (12)	Sprague-Dawley rats (450-600 g)	4 groups (6 rats each): A. Sham surgery group B. Normal saline ICI C. General PRP group D. Optimized PRP ICI group In groups B, C, and D, BCNC injury was performed Follow-up at 1 mo	Available	CN electrostimulation (erectile response) Histology of penile tissue	<.05	Optimized PRP had the largest amount of PDGF-AB and showed a synergic effect on release of growth factors. Functional improvement after bilateral CN injury when the optimized PRP was applied. Optimized PRP was more stable, and its injection in CC facilitated recovery of EF.
Liao et al (2018) Prospective comparative trial	23 (6)	Male Sprague-Dawley rats (N/A)	3 groups A. Control group (no STZ injection or diabetic rat with no ED) (n = 8) B. Normal saline ICI in diabetic rats with ED (n = 7) C. PRP ICI in diabetic rats with ED (n = 8) Follow-up at 1 mo	Not available	ICP Undisclosed EF parameters	Not available	Increase in all EF parameters at day 28 in group C. PRP showed tissue-protective effects of corpus cavernosum.

(Continued)

Table 1

Continued.

Study	N (age [y])	Animal (weight)	Protocol	PRP preparation description	Outcome	P value	Comments
Huang et al (2021)14 RCT	30 (2)	Male Sprague-Dawley (320-370 g)	3 groups: A. Group N (control). Rats were fed normal diet for 5 mo and then received 1 ICI of supernatant weekly for 4 wk (n = 10) B. Group H. High-fat diet for 5 mo and the 1 ICI of supernatant weekly for 4 wk (n = 10) C. Group H + PRP. Same as group H but received ICI of PRP (n = 10) Follow-up 7 d after the last ICI	Available	ICP IGF-1 BNF CNNOS ENOS ECs Intracorporal oxidative stress Apoptotic index	<.05	ICP/MAP significantly higher in control and PRP groups than group H. IGF-1, BNF, and VEGF significantly higher in PRP group than in control group and group H. CNNOS, ENOS, and ECs weakly expressed in group H compared with the other groups. Intracorporal oxidative stress and apoptotic index were significantly higher in group H than in the control and PRP groups.
Wu et al (2021)16 RCT	54 (n/a)	Rats (n/a)	2 equal groups: ICI injection of saline after BCNC (group 1) and ICI of cPRP after BCNC (group 2) 5 animals in each group were euthanized at 3, 7, and 14 d postinjection, and the tissues were harvested to conduct transmission electron microscopy and histological assays 6 animals in each group were used to determine the recovery of EF at 14 and 28 d postinjury.	Available	ICP Neuronal NOS–positive neurons and nerve fibers in the MPG and CN	<.05	EF parameters significantly improved 14 and 28 d postinjury. cPRP injections simultaneously prevented the loss of neuronal NOS–positive neurons and nerve fibers in the MPG and CN, respectively, compared with saline injections.
Wu et al (2021)15 RCT	N = 56 (10)	Male Sprague-Dawley (350-400 g)	6 rats were used to obtain blood for PRP and whole plasma Samples were probed using a cytokine antibody array and ELISA was performed Expression patterns of CXCL5 and receptors in the MPG and corpus cavernosum were determined via immunostaining 32 rats were divided into 4 groups based on the type of injection received: (1) sham, (2) vehicle, (3) 400 mL of PRP, and (4) 30 ng/kg of CXCL5 Groups 2, 3, and 4 were subjected to BCNC injury 4 wk later, EF was assessed by CN electrostimulation, and CNs and penile tissue were collected for histological analysis	Available	Cytokine antibody array ELISA Erectile response Immunofluorescence staining readings	<.05	PRP ICI stabilized CXCR2 and increased CXCL5 expression in the MPG after BCNC, thus enhancing neuroprotection. CXCL5 injection improved BCNC-induced ED by preventing smooth muscle atrophy.

Abbreviations: BCNC, bilateral cavernous nerve crush; BNF, brain-derived neurotrophic factor; CN, cavernous nerve; CNNOS, corporal neuronal NOS; cPRP, chitosan-activated platelet-rich plasma; EC, endothelial cell; ED, erectile dysfunction; EF, erectile function; ELISA, enzyme-linked immunosorbent assay; ENOS, endothelial nitric oxide synthase; ICI, intracavernosal injection; ICP, intracavernosal pressure; IGF-1, insulin-like growth factor-1 MAP, mean arterial pressure; MPG, major pelvic ganglion; NOS, nitric oxide synthase; PDGF-AB, platelet-derived growth factor AB; STZ, streptozotocin; TGF-β1, transforming growth factor β1; VEGF, vascular endothelial growth factor; GAQ, Global Assesment Question; EDITS, Erectile Dysfunction Inventory of Treatment Satisfaction; IELT, Intravaginal ejaculation latency time; N/A, not available. RI, resistive index.

Clinical studies

Of the 16 clinical trials available, only 6 are in full article form, while the rest are only available as abstracts. Almost all of them are retro- and prospective cohort trials, while the randomized ones do not have a sham group. There are 2 double-blind randomized controlled trials (RCTs) with a sham control group. The first clinical trial by Chalyj et al¹⁷ is available only in Russian, but we were able to retrieve information from a later review in English by one of the authors.¹⁸ In this trial, PRP had a significantly positive impact on ED (increase in Sexual Encounter Profile [SEP] 2 and 3 positive answers, 5-item International Index of Erectile Function [IIEF-5], and peak systolic velocity [PSV]). In another study,¹⁹ platelet-rich fibrin matrix injections instead of PRP were used, resulting in an increase in IIEF-5 score. Combination treatments for ED with PRP, PDE5 inhibitors, and vacuum devices²⁰ as well as PRP and LI-SWT^21-25 have also been proposed. All the previously mentioned trials found a positive effect on EF. In the Ruffo et al²² study, PRP seemed to prolong the positive effect of the LI-SWT for ED. Other studies with different PRP application protocols found a significant increase in the IIEF-5 score in patients with ED.^26-28 However, it was mentioned that larger placebo-controlled RCTs are needed to confirm the results.²⁸ Interestingly, Zaghloul et al²⁹ found that smoking and the baseline IIEF score before PRP injections were significant independent variables regarding PRP responsiveness. The first sham-controlled, double-blind RCT³⁰ investigated the role of PRP ICI in patients with mild and moderate ED. Poulios et al³⁰ used an Food and Drug Administration–approved closed system for PRP preparation and found a statistically significant difference in the number of patients attaining a minimal clinically important difference (MCID) in the IIEF-EF score at 1-, 3-, and 6-month follow-up. MCID was considered as an improvement in the IIEF-EF of 2 or more points in patients with mild or mild-to-moderate ED (IIEF-EF score: 17-25) or 5 or more points in patients with moderate ED (IIEF-EF score: 11-16) after treatment.³¹ The mean IIEF-EF score in the PRP group was 20.4 ± 2.9 at baseline and 21.8 ± 4.8 at the end of the follow-up period, while it was 19.4 ± 3.7 and 19.4 ± 4.3 in the placebo group, respectively. The P value was <.001. SEP 3 positive answers reached statistical significance in the PRP group compared with placebo during follow-up. Moreover, patients in the PRP group were more satisfied regarding the treatment. Another pilot study was conducted recently, showing increased efficacy of PRP in the treatment of patients with ED not responding to any oral or ICI therapy.³² Zaghloul et al³³ found that in patients with ED not responding to on-demand PDE5 inhibitor, PRP treatment in combination with daily tadalafil and on-demand vardenafil led to significant improvement in the IIEF-5 score, improved Erection Hardness Scale score, and penile duplex readings. Recently, a double-blind, sham-controlled RCT by Khalef et al³⁴ was published, but was not included in this review due to insufficient results presentation and a very small sham group (17 vs 42 patients). The recently published second sham controlled RCT by Shaher et al³⁵ was included. PRP was produced with double centrifugation at different speeds with an open system. All parameters (IIEF, MCID, duplex parameters, SEP 2 and 3) were significantly improved in the PRP group compared with the sham group. The mean IIEF-EF score in the PRP group was 18 (range, 17–22) at baseline and 22 (range, 19.7–24.2) at the end of the follow-up period, while the scores in the placebo group were 19 (range, 17–22) and 19 (range, 17–22) respectively. The P value was <.001. There was no difference in the therapy-induced pain between groups. In most of the studies, the PRP preparation and administration method is described. The characteristics of all included clinical trials are depicted in Table 2.

Table 2

Clinical trials.

Study	N (age [y])	Protocol	PRP preparation description	Mean follow-up (range) (mo)	IIEF-5 baseline (median [range] or mean ± SD)	IIEF-5 end of follow-up (median [range] or mean ± SD)	P value	Other outcomes	Complications	Comments
Chalyj et al (2015)17 Prospective RCT	75 (—)	3 injections at weekly intervals Group A (n = 30) activated PRP with CaCl2 10% solution Group B (n = 30) activated PRP as group A + PDE5 inhibitor Group C (n = 15) Not activated PRP	N/A	24	—	—	<.05	SEP PSV RI Endothelial function	None	SEP, PSV, and IIEF-5 significant increase in all groups. RI significant increase in groups A and C. Endothelial function significant increase in all groups after 6 mo. Results available in Epifanova et al review.
Banno et al (2017)17 Prospective cohort study	9 (56)	1 PRP injection+medication and vacuum device	N/A	4	15.6	19.9	.157	—	No	Only abstract available.
Matz et al (2018)19 Retrospective study	17 (46), but only 5 with ED	1-8 (mean 2.1) injections per patient with PRFM (PRP+CaCl2 10% solution)	available	62	—	—	—	Safety	Only in patients with Peyronie’s disease (4 mild pain and 1 bruising)	Patients with ED, PD, and female urinary incontinence took part in this study. IIEF-5 improvement by 9.1% (4.14 points) for patients with ED and PD.
Ruffo et al (2018)21 Prospective RCT	60 (—)	Group A: 6 weekly sessions of LI-SWT (1500 shocks/session) Group B: 6 weekly sessions of LI-SWT +6 injections of PRP (1 injection every 2 wk)	N/A	24	Group A 11 Group B 10	Group A 18 Group B 22	—	SEP 2 SEP 3	No	SEP 2 and SEP 3 increase in Yes response % in both groups. Only abstract available.
Epifanova et al (2019)23 Prospective	10 (44.25)	6 injections with activated PRP (PRP+ CaCl2 10%) and 12 LI-ESWT (2000 waves) for 6 wk	N/A	8.57	12.4 (9-18)	18.6 (15-23)	—	SEP, CAG PSV RI	No	PSV and RI improvement. SEP yes responses % increased. All patients noted positive treatment effect according to CAG. Only abstract available. Study still in progress at the time of publication.
Raaia et al (2019)26 Prospective cohort study	30 (55.1)	PRP injection once per week for 2 mo	N/A	12	N/A	N/A	N/A	PSV EDV	No major side effects reported.	Significant improvement in IIEF-5 score at 1, 2, and 3 mo as well as improvement in PSV and EDV. Data available in study’s abstract. Could not retrieve full article.

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Table 2

Continued

Study	N (age [y])	Protocol	PRP preparation description	Mean follow-up (range) (mo)	IIEF-5 baseline (median [range] or mean ± SD)	IIEF-5 end of follow-up (median [range] or mean ± SD)	P value	Other outcomes	Complications	Comments
Ruffo et al (2019)22 Prospective RCT	100 (N/A)	Group 1 LI-ESWT twice/week for 6 wk (n = 58) Group 2 LI-ESWT twice weekly + PRP injections once weekly for 6 wk (n = 55)	Yes	24	Group 1 14.6 (10-16) Group 2 13.7 (9-16)	Group 1 17.7 (15-21) Group 2 21.6 (18-23)	Group 1: N/A Group 2: <.001	PSV	N/A	At 12 wk, significant improvement in IIEF-5 and PSV in both groups. At 24 wk, significant improvement in the combination group while stable in group 1. Only abstract available.
Alkhayal et al (2019)27 Prospective trial	267, but full data obtained for 61 (43)	PRP injections according to American Cellular Medicine Association protocol	N/A	11 (4-59)	12.5 (5-20)	17 (5-24)	<.001	GAQ 88.5% SEP3 Yes response 78%	None	Only abstract available. Results 3-4 weeks after treatment.
Zasieda et al (2020)24 Prospective randomized trial	64 (—)	Main group 1 PRP injection per week (6 focuses by 1 mL) + 2 sessions of LIPUS (the first at the same time with the PRP injection) per week for 6 wk (n = 32) Control group + 2 sessions of LIPUS per week for 6 wk (n = 32)	N/A	12	N/A	N/A	.047	VAS, EHS	No significant side effects	Only abstract available. Improvement in IIEF-5. Improvement in EHS by 1 point. VAS 2.64 ± 0.84.
Geyik (2021)25 Retrospective control trial	184 (group 1: 51.23; group 2: 46.9)	Group 1 LI-SWT for 1 course consisting of 5 implementations about 7 ± 2 d apart (n = 93) Group 2 LI-SWT as group 1+ PRP injection 10-14 d apart	Available	24	Group 1 14.33 ± 4.39 Group 2 17.82 ± 3.44	Group 1 23.8 ± 4.37 Group 2 26.3 ± 2.55	.001	IELT	Pain at the site of the injection and bruising at the same site in 24 patients in group 2.	IIEF improved significantly in both groups with no difference between them, but IELT was improved only in group 2. All patients continued using 5 mg tadalafil daily during the study.
Zaghloul et al (2021)29 Prospective pilot study	34 (50.18)	PRP injections were received once every week for 8 wk and then all patients were prescribed tadalafil 5 mg daily with vardenafil 20 mg on demand for 1 mo	Available	12	7.70 ± 2.73	13.2 ± 6.77	<.001	PSV EDV RI Mean artery diameter	No reported side effects.	No improvement in the Ultra-sound parameters. Smoking and baseline IIEF before PRP injections were significant independent variables regarding PRP responsiveness.
Tas et al (2021)28 Prospective cohort study	31 (54.41)	PRP injections 3 times with an interval of 15 d	Available	24	18	20	<.001	Orgasmic function Sexual desire Sexual satisfaction General satisfaction	Slight subcutaneous bruising (8 of 93) and 4-mm-diameter fibrotic plaque was observed on the ventral side in the middle of the penis shaft, which did not cause any symptoms or curvature.	Except for the IIEF, no significant improvement in other outcomes. Larger placebo-controlled RCTs are needed.

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Table 2

Continued

Study	N (age [y])	Protocol	PRP preparation description	Mean follow-up (range) (mo)	IIEF-5 baseline (median [range] or mean ± SD)	IIEF-5 end of follow-up (median [range] or mean ± SD)	P value	Other outcomes	Complications	Comments
Poulios et al (2021)30 Randomized placebo-controlled double blind clinical trial	60 (58.5)	Active group 10 mL PRP injections with a 1-mo difference Placebo group 10 mL normal saline injections with a 1-mo difference	Available	24	Active group 20.4 ± 2.9 Placebo group 19.4 ± 3.7	Active group 21.8 ± 4.8 Placebo group 19.4 ± 4.3	<.001	MCID, SEP 3, EDITS, VAS	No side effects reported.	A statistically significant difference of the number of participants attaining a MCID was observed at 1.3 and 6 mo follow-up at the PRP group. SEP 3 positive answers were statistically significant more in the PRP group during the follow-up. Patients in the PRP group were more satisfied regarding the treatment and had less pain.
Schirmann et al. (2022)32 Pilot prospective study	15	Patients with vascular ED unresponsive to PDE5 inhibitor and/or prostaglandin E ICI received 3 ICI of PRP 15 d apart	N/A	24	—	IIEF-EF improved 5 points at 1 mo P = .001, 4 points at 3 mo P = .003 and 3 points at 6 mo P = .022	<.05	EHS, SEP, sexual discomfort score	?	Except for the IIEF-EF, there was no other statistically significant change, although 20% of patients considered that the erection lasted long enough to have a sexual intercourse (SEP score) before P-shot vs 26.7% after the treatment (P = 1).
Zaghloul et al (2022)23 Prospective study	48	All patients with ED not responding to on-demand PDE5 inhibitor were given a daily dose of 5 mg tadalafil plus vardenafil 20 mg on demand during the study besides being subjected to 3 doses of ICI of PRP, 4 wk apart Group A 24 diabetic patients Group B 24 nondiabetic patients	N/A	N/A	Group A IIEF-5 = 8.04 Group B IIEF-5 = 10.2	Group A IIEF-5 = 12.1 Group B IIEF-5 = 14.8	<.05	EHS, pharmacodynamic duplex studies	?	After PRP injections, 33% and 50% of cases were satisfied with on-demand PDE5 inhibitors, whereas 41% and 66% of them showed improved EHS response. The significant improvement included the IIEF-5 score increase, improved EHS score, and improved penile duplex readings.
Shaher et al (2023)35 Randomized placebo-controlled double blind clinical trial	109 (55 y)	Active group (n = 54) 6 mL PRP injections 3 sessions with 2 wk interval Placebo group (n = 54) 6 mL normal saline injections 3 sessions with 2-wk interval	Available	24	PRP group 18 (17-22) Placebo group 19 (17-22)	PRP group 22 (19.7-24.2) Placebo group 19 (1-22)	<.001	MCID, IIEF, SEP 2 and 3, VAS, duplex parameters	No side effects reported.	All parameters significantly improved in the PRP group compared with the saline group. There was no difference in the treatment-induced pain between the groups.

Abbreviations: CAG, global assesment question; ED, erectile dysfunction; EDITS, erectile dysfunction inventory of treatment satisfaction; EF, erectile function; EHS, Erection Hardness Scale; IELT, intravaginal ejaculation latency time; IIEF-5, 5-item International Index of Erectile Function; LI-SWT, low-intensity shockwave therapy; LI-ESWT, low-intensity extracorporeal; shockwave therapy; LIPUS, low-intensity pulsed ultrasound; MCID, minimal clinically important difference; N/A, not available; PRFM, platelet-rich fibrin matrix; PRP, platelet-rich plasma; PSV, peak systolic velocity; RCT, randomized controlled trial; RI, resistive index; SEP, Sexual Encounter Profile; VAS, visual analog scale.

Adverse events

None of the trials reported any major adverse events. In some cases, pain and bruising at the site of the injection were reported, and in 1 case, a 4-mm-diameter fibrotic plaque was observed on the ventral side in the middle of the penis shaft, which did not cause any symptoms or curvature.

Figure 1

Platelet-rich plasma: proposed mechanism of action.

Discussion

There is an emerging investigational interest for the use of PRP as a promising regenerative therapeutic approach for ED,³⁶ which reflects the constantly increasing commercial availability and use of this treatment modality. The theoretical base for this concept was fueled by animal studies reporting that PRP may ameliorate key elements of the pathophysiologic pathways leading to ED through vasculogenic, neuroprotective, neurotrophic, reparative, and anti-inflammatory effects (Figure 1).³⁷ According to this, PRP could be a promising modality for the treatment of CN injury–induced ED.³⁸ Still, based on the relevant available preclinical studies, these mechanisms are yet neither adequately analyzed nor completely understood, even though PRP definitely augments growth factor resources. Interestingly, the results of the available human studies are encouraging in terms of effectiveness and safety, but most of the studies have a small number of participants and most of them lack a placebo arm.

Furthermore, there is no consensus of the best PRP preparation method. Despite the fact that the use of fully automated PRP preparation devices could lead to standardization of the whole procedure, unfortunately most studies do not use them. Most studies use centrifugation at different speeds, leading inevitably to the production of PRP material of dubious quality and high heterogeneity in the whole process.

Another critical issue is the use of high-quality PRP (truPRP). There are no consensus for the criteria that the produced PRP should meet to be the most appropriate preparation for the treatment of ED (volume, number of platelets, growth factor concentrations). Closed systems clearly offer several benefits for standardized preparation of PRP.³⁹ Standardization of the qualitative or quantitative composition of growth factors, cytokines, or other molecules with regenerative properties included in the PRP product is urgently needed. At the moment, the use of closed systems in the clinical setting with documented qualitative or quantitative composition of PRP is strongly recommended.

Moreover, the administration method is an issue of high clinical significance characterized by many murky points still to be resolved. The ideal number of sessions, the time interval between the treatment sessions, the ideal dosage per session, and if there is a minimum number of punctures per session are questions that currently lack a definitive answer. In clinical trials, 2 to 6 PRP injections, once per week to once per month, using 1 or 2 punctures (one in each corpora), may be reasonable to use.

Finally, the profile of the patient (age, ED severity, comorbidities) that could get the most benefit from PRP treatment should be defined, and the potential synergistic effect of combinations with other treatment modalities for ED should be further explored.^40,41 The most interesting combination treatment seems to be PRP and LI-SWT. Multiple publications from basic science demonstrated that both LI-SWT and PRP may affect the healing process and promote growth factor release. Initial results demonstrated increased efficacy of such a combination.²² Research for such combination therapy is urgently needed. Typical LI-SWT includes 12 sessions. Positive results were also shown with 2 PRP sessions in the placebo-controlled trial by Poulios et al.³⁰ A trial of 12 LI-SWT sessions, with 2 PRP sessions (the first and seventh LI-SWT sessions) could be a qualified protocol for a clinical trial. Table 3 summarizes important issues in PRP clinical protocols.

Table 3

Critical issues on PRP protocols and a proposal.

PRP protocol issues	Proposal for clinical trials
PRP preparation system	Closed systems
PRP system calibration	Platelet number should be increased more than 5 times after centrifuging
Number of sessions	2-6
Interval between sessions	1-4 wk
Number of punctures	1-4 (reaching both corpora)
Combination therapies (especially for moderate and severe ED)	LI-SWT + PDE5 inhibitor daily

Abbreviations: ED, erectile dysfunction; LI-SWT, low-intensity shockwave therapy; PRP, platelet-rich plasma.

Despite the aforementioned knowledge gaps regarding PRP ICI for ED treatment that certainly have to be filled, the promising results of the limited available preclinical and clinical literature, as well as the 2 double-blind, placebo-controlled randomized trials, are certainly a springboard for further high-quality research.³⁰

Conclusion

Although the use of PRP as a treatment option for ED is widely used, there is a need for further high-quality studies with long-term follow-up outcomes. Scientific societies should propose standardized research protocols in terms of population, PRP preparation, and administration methods, as well as PRP quality evaluation in an attempt to obtain high-quality and reproducible data, which will aid evidence-based protocols. Importantly, translational research is also mandatory, in order to provide further evidence on the mechanism of PRP action in erectile tissue as well as in EF.

Funding

This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

Conflict of interest

No conflict of interest reported.