Introduction

Our appreciation that erectile dysfunction (ED) is largely organic and not psychological is a relatively recent concept in medicine. The term ED was first recommended by the National Institutes of Health Consensus Conference in 1992. Prior to that time, “impotence” was the accepted medical terminology and bore with it the stigma of a largely psychological malady. Treatment of ED and our understanding of its pathology and etiologies were revolutionized with the discovery of the nitric oxide (NO) pathway and subsequent clinical trials of the first phosphodiesterase type 5 (PDE5) inhibitor in 1998. Impotence had largely been managed by counseling, and the only effective intervention for ED was the penile prosthetic. While PDE5 inhibitors and vasoactive penile injections can enhance or directly generate erectile responses, neither targets the pathology nor restores erection. Restorative therapies, including shock wave therapy, platelet rich plasma (PRP) injections and stem cell therapy (SCT), have emerged as possible cures for ED.

Shock Wave Therapy

Shock wave therapy has been used for many years in orthopedic (plantar fasciitis and Achilles tendinitis) and cardiovascular (myocardial revascularization) conditions. Recent studies found low-intensity (LI) extracorporeal shock wave therapy (ESWT) can safely treat ED. The theory of how LI-ESWT can benefit corporal tissues is based on the physiology literature suggesting that a cascade of biological effects follows microtrauma of shock waves contacting tissues beginning with immediate release of NO, chemokine release, expression of angiogenic growth factors, stem cell activation and recruitment of endothelial progenitor cells initiating neoangiogenesis.¹ LI-ESWT is not approved by the U.S. Food and Drug Administration (FDA) for treating ED. Specific ESWT devices have been approved by the FDA for the treatment of plantar fasciitis, tennis elbow (2005) and diabetic foot ulcers (2017). Documented side effects are rare and transitory, including bruising, local swelling, petechiae, pain during treatment, numbness following treatment and sensitivity reaction to latex membrane of probes and/or coupling gels. Several clinical trials have shown benefit in ED. A recent meta-analysis that analyzed 7 randomized controlled trials using LI-ESWT for ED found improvement in International Index of Erectile Function-erectile function domain (IIEF-EF) score for the treatment group (6.4) compared to sham (1.6).² Nevertheless, heterogeneity in treatment protocols and patient populations makes broad adoption into clinical practice difficult.^3,4 At the University of Miami, we performed a phase 2 clinical trial assessing different treatment protocols (720 shocks for 5 consecutive days vs 600 shocks every other day for 2 weeks) and found that both groups improved in IIEF-EF score compared to baseline, and there was no difference between the protocols at 6 months of followup,³ suggesting the number of shocks may be more important than how they are delivered. Importantly, we did not see any adverse events. Overall, LI-ESWT appears safe and likely provides some benefit in select patients.

We invited several experts in the field of erectile dysfunction to share their clinical experience with LI-ESWT for ED, asking 1) Are you convinced current evidence on shock wave therapy for ED supports that it does no harm?, 2) Which patients in your practice are candidates? and 3) Does LI-ESWT provide durable results or will men need to have periodic therapy sessions? Here are some of their responses:

1. Dr. Mohit Khera, Baylor College of Medicine: “I am convinced that shock wave therapy does not cause any significant harm to patients. This is based on numerous years of clinical data and our own experience over the past 2 years. Adverse events tend to be very mild” (personal communication).
   Dr. Faysal Yafi, University of California Irvine: “Currently available evidence from multiple prospective randomized trials and meta-analysis clearly shows that shock wave therapy is a safe intervention with minimal risks to patients. The European Association of Urology Guidelines on Sexual and Reproductive Health–2021 Update, Male Sexual Dysfunction concludes that LI-SWT can significantly increase the International Index of Erectile Function scores and Erection Hardness scores in patients with mild vasculogenic ED, although this improvement appears modest” (Eur Urol 2021; 80: 333).
2. Dr. Yafi: “We have found that the patients who demonstrate the best clinical outcomes are those who are younger, have mild to moderate erectile dysfunction and are not diabetic” (personal communication).
   Dr. Khera: “Patients who have mild to moderate erectile dysfunction tend to respond better. I’ve also noticed patients who are younger and have less comorbid conditions also respond better” (personal communication).
3. Dr. Khera: “The effects don’t seem to be everlasting as many patients see a decline in erectile function over time. I suspect that this form of therapy will need periodic repeat treatments. However, the frequency of these repeat treatments has not yet been established” (personal communication).
   Dr. Yafi: “Data from at least 1 study with longer followup demonstrated that only 53% of patients sustained benefits 2 years after being treated. It is likely that periodic treatments (unknown frequency) will be needed for most patients” (J Urol 2018; 200: 167).

Stem Cell Therapy

Stem cells are unspecialized and undifferentiated cells found in embryonic and adult tissues. SCT for ED involves harvesting mesenchymal stem cells (MSCs) obtained from bone marrow, adipose tissue or umbilical cord, and injecting them into the penile tissue in the hope of facilitating endogenous repair, restoring erectile function. There are 2 theories on how stem cell injections improve erectile function. The first is that MSCs act to improve endothelial blood flow to the penis through chemokine signaling. The second is that MSCs directly replace the damaged corpus cavernosum.⁵ The benefits of STC for ED are still being studied, and there are limited available results to show efficacy. A recent meta-analysis found that 5 completed human clinical trials using SCT showed promise; however, limited data were presented and further investigation regarding safety, efficacy and standardization is required.⁶ Ultimately, the use of SCT for ED is a complex issue and needs further consensus on the dose, delivery and patient selection before entering routine clinical practice.

Platelet Rich Plasma

PRP is a blood product created through centrifugation and separation of whole blood and removal of the platelet rich layer. PRP is utilized in a variety of different specialties, including orthopedics, dermatology and cardiothoracic surgery.⁷ The belief is that PRP contains concentrated growth factors and when injected directly into the penis will locally increase cytokines such as vascular endothelial growth factor (VEGF), platelet-derived growth factor (PDGF), epidermal growth factor (EGF), insulin-like growth factor (IGF) and fibroblast growth factor (FGF) to recruit new blood vessels and promote healing.⁸ Specifically, VEGF can repair nerve damage and promote regeneration through the endothelial NO synthase pathway, a key mechanism to achieving and maintaining erections.⁹ PRP injection for ED is a widely available treatment in North America. The treatments are marketed under a variety of proprietary names, but it is important to acknowledge PRP is not approved by the FDA for medical treatments in any tissues at this time.

What has allowed the proliferation of PRP in the U.S.? PRP is being marketed aggressively to consumers as effective for ED, increasing penile size and correcting penile curvature. There is no evidence that PRP can work the miracle of creating a bigger penis, a straighter penis or reversing ED. The Center for Biologics Evaluation and Research is responsible for regulating the use of human cells and cellular tissue-based products. As it turns out, the infusion or injection of human blood products is exempt from FDA regulation (FDA Code of Federal Regulations Title 21, part 1271). What is tightly regulated are the safe practices for handling and centrifuging blood products. The combination of PRP with a drug or other tissue product (stem cells) would fall under current regulatory restrictions. The strategic variables in PRP administration include 1) the amount of whole blood drawn, 2) the speed of centrifugation, 3) the duration of centrifugation, 4) amount injected into the corpora (1 or both sides) and 5) how often is therapy given. Two recent clinical trials showed that 2 PRP injections can significantly improve IIEF-EF score—namely 69% improvement vs 27% in the placebo group.^9,10 ClinicalTrials.gov (September, 2021) lists 3 ongoing trials evaluating PRP in North America: University of Miami Miller School of Medicine (NCT04396795), Mayo Clinic Florida (NCT04350125) and University of Nebraska (NCT04357353).

Problems with Regenerative Therapy

Currently, none of the above treatments are approved by the FDA for the treatment of erectile dysfunction. The Sexual Medicine Society of North America (SMSNA) has issued a position statement on restorative therapies, which states, “Restorative therapies should be reserved for clinical trials and not offered in routine clinical practice.”¹¹ There remain few large, randomized, placebo-controlled trials supporting the efficacy of PRP, SCT or LI-ESWT. Additionally, the degree of heterogeneity between studies is problematic. In terms of the LI-ESWT, several different types of generators that have been reported on using differing energy flux densities and number of shocks, and often in populations of men with differing etiologies and severity of ED. For PRP, there is not a standard dosage equivalent or routine quantification of the number of platelets. Dosing protocols also differ. For SCT, the lack of standardization of which cell types are harvested and what concentrations are injected has also yielded wide variations in the clinical trial results. There is also the concern that the injected stem cells don’t take up residence in the cavernous tissues. More research is needed to optimize and standardize treatment protocols before physicians should offer these treatments as routine care for their patients

Conclusion

Current medicinal therapies like PDE5 inhibitors and injectable prostaglandin E1 are the standards of care for the medical management of ED. These therapies do not reverse the underlying pathology and must be administered as needed to promote or enhance erection. A permanent “fix” for ED requires placement of a penile implant. Although penile implants have a high degree of satisfaction among men with severe ED (eg those with diabetes mellitus, cancer survivors and those with vasculopathy), an implant requires surgery and has associated risks. As a result, there is tremendous enthusiasm for restorative technologies and regenerative medicine treatments. Initial studies of PRP, SCT and LI-ESWT appear promising. With PRP and low intensity shock waves, there is a good body of evidence that they do no major harm. However, at this time the administration of LI-ESWT, SCT or PRP remains investigational, and patients should be fully informed before treatment.