Low-Intensity Extracorporeal Shock Wave as a Novel Treatment for Erectile Dysfunction

Abstract

The paradigm of erectile dysfunction (ED) treatment was fundamentally altered following the introduction of oral phosphodiesterase type 5 inhibitors. Unfortunately, a significant number of men exhibit a suboptimal response and require additional management strategies. One of the novel, minimally invasive strategies being developed is low-intensity extracorporeal shock wave therapy. Used in the hope of delaying placement of an inflatable penile prosthesis, the final phase of ED treatment, low-intensity extracorporeal shock wave therapy is a unique application of an established technology that may hopefully one day expand the medical options for patients with ED. This commentary will highlight the physiology underlying this technique and summarize the most recent studies.

Introduction

Erectile dysfunction (ED), a common disorder affecting men, is defined as the inability to achieve and maintain erections adequate for sexual intercourse (Gareri, Castagna, Francomano, Cerminara, & De Fazio, 2014). Pharmacological options such as phosphodiesterase type 5 inhibitors (PDE5i), while effective, do not produce satisfactory results in all men (Guay, Perez, Jacobson, & Newton, 2001). Given that recent studies suggest ~18% of patients do not respond to PDE5is (Guay et al., 2001), there has been an increased focus on developing novel therapies for management. Particularly, interest has centered on treatment methods that fundamentally alter spontaneous erectile function in a robust and enduring way.

Low-Intensity Extracorporeal Shock Wave Therapy (LI-ESWT)

LI-ESWT has been previously used in the treatment a wide variety of conditions (Skolarikos, Alargof, Rigas, Deliveliotis, & Konstantinidis, 2005). The theories for application are based on prior experiences with acoustic waves generating pressure impulses targeted to treat kidney stones (high-intensity waves), tendonitis (medium-intensity waves), as well as Peyronie’s disease, peripheral neuropathy, cardiac, and peripheral vascular disease (low-intensity waves; Ciccone et al., 2012; Skolarikos et al., 2005; Zuoziene, Laucevicius, & Leibowitz, 2012).

Recently, LI-ESWT (administered at 7.33 MPa at 2 Hz for 300 shocks per treatment) has been considered a potential modality for the management of ED (Liu et al., 2013). Since LI-ESWT for ED is still in its infancy, the mechanisms by which LI-ESWT acts to improve ED symptoms are incompletely understood. However, it has been postulated to be related to cell membrane microtrauma and mechanical stress. The resultant release of angiogenic factors, such as vascular endothelial growth factor (VEGF), nitric oxide synthase (NOS), von Willebrand factor (vWF), fibroblast growth factor (FGF), TLR3, and the pro-inflammatory cytokines IL-6 and IL-10, result in increased angiogenesis and vascularization of target tissues (Gruenwald, Appel, Kitrey, & Vardi, 2013; Holfeld et al., 2014; Nishida et al., 2004; Wang, Yang, & Huang, 2011). Recruitment of circulating endothelial progenitor cells through chemoattractant factors such as VEGF and stromal cell derived factor 1 has also been reported to result from LI-ESWT (Aicher et al., 2006). Based on these findings, it is suggested that LI-ESWT could increase blood flow and endothelial function in the penis thereby improving erectile function.

Based on animal studies, it is tempting to speculate that LI-ESWT may be beneficial for patients with diabetes-induced ED. This belief is founded in basic laboratory research where diabetic rats were administered LI-ESWT and noted to exhibit improvements in penile blood flow, intracavernosal pressures, as well as increased VEGF, neuronal NOS-positive neurons, alpha-smooth muscle actin (α-SMA), vWF, and endogenous mesenchymal stem cells compared with controls (Liu et al., 2013; Qiu et al., 2013). Improvements were also noted in the percentage of elastic fibers within the corpus cavernosum as well as the smooth muscle to collagen ratio. Furthermore, a decreased expression of cavernosal receptors for advanced glycosylation end-products (RAGE) was identified. Given that RAGE molecules have been attributed to a component of the vascular and neurological damage seen in diabetes, the decrease in RAGE following LI-ESWT hints at a potential to reverse and/or prevent diabetes-induced ED (Liu et al., 2013). The exact mechanism regulating diabetes-induced ED is unclear. Furthermore, the results of animal data must be tempered with the fact that similar improvements have not yet been observed, or studied, in humans.

Results of LI-ESWT in initial human trials are promising but still in the investigational stage. As such, only a few studies exist and are detailed as follows. An initial pilot study examined the responses to LI-ESWT of 20 men with vasculogenic ED (Vardi, Appel, Jacob, Massarwi, & Gruenwald, 2010). Findings were promising with improvements in the International Index of Erectile Function (IIEF) scores at both 1 and 6 months. The same group of authors then followed this initial article with an open-label, prospective study on patients with severe ED who previously failed PDE5i therapy (Gruenwald, Appel, & Vardi, 2012). In these patients (n = 29), a similar protocol was followed as to the first report. Specifically, two LI-ESWT treatment sessions were administered per week for 3 weeks, and separated by a 3-week period of no treatment. This resulted in a significant mean increase of 3.5 points in ED scores within the IIEF (Gruenwald et al., 2012). Furthermore, of those treated with LI-ESWT, 65% had a 5-point or greater increase in total IIEF score compared with only 20% in controls (Gruenwald et al., 2012; Gruenwald et al., 2013). Men treated with LI-ESWT also had significantly improved penile hemodynamics and increased blood flow by venocclusive strain gauge plethysmography. Unfortunately, both studies were limited by a very small numbers of patients, nonrandomized data, and a very short duration of follow-up (Gruenwald et al., 2012; Vardi et al., 2010).

A more recent article from the same group (Vardi, Appel, Kilchevsky, & Gruenwald, 2012) attempted to address a few of these concerns with a randomized, double-blind, sham controlled study. A total of 77 men underwent initial screening, and inclusion criteria were an IIEF-EF score of >19 while on PDE5i and a stable, heterosexual relationship for 3 months. Exclusion criteria were prior prostatectomy, pelvic radiotherapy, hormonal therapy, and current treatment for a psychiatric condition or any anatomical, neurological, or hormonal abnormalities (Vardi et al., 2010). This led to a randomization of 67 patients of which there was a 5% to 13% dropout for a final completed patient base of 20 in the sham group and 40 in the LI-ESWT group. Significant improvements were seen in multiple components of the IIEF as well as in the penile hemodynamics. A 25% sham effect was also observed, as was an unexpected (and unexplained) improvement in the Sexual Desire subdomain. Furthermore, no statistically significant improvements in the IIEF sexual satisfaction scores were noted (Vardi et al., 2010). While no patients experienced any adverse events (i.e., pain, hematoma, hematuria, and bruising) in any of the aforementioned trials, the authors did concede that the long-term risk of LI-ESWT remains unknown.

A more recent article by Yee, Chan, Hou, and Ng (2014) is the first from another group examining LI-ESWT. This study had only a 2-week washout for PDE5i (while the Vardi group discussed above chose a 4-week washout). Moreover, while Yee et al. (2014) employed a similar LI-ESWT treatment protocol based on time, intensity, and frequency as the Vardi group, follow-up was limited to 13 weeks postintervention. The Sham (n = 28 patients) and Treatment groups (n = 30 patients) did not reach statistical significance with respect to the IIEF-ED or the Erectile Hardness Score (Yee et al., 2014). When a subgroup analysis was performed, those patients with baseline “severe” ED had significantly improved IIEF-ED scores.

Conclusions

Taken together, initial reports suggest that LI-ESWT appears to be a safe and effective treatment for ED. Difficulties surrounding the treatment exist in the extensive time commitments required for the protocols as well as the cost and availability of the device. In total, 167 patients have been reported on in the literature from all of the available studies published to date (Gruenwald et al., 2012; Vardi et al., 2010; Vardi et al., 2012; Yee et al., 2014).

Improvements are postulated to be because of shockwave-induced microtrauma with subsequent angiogenic neovascularization and improvement in penile blood flow (Liu et al., 2013; Qiu et al., 2013; Vardi et al., 2012). However, further studies are needed. Randomized control trials with a greater number of patients will help determine the efficacy and safety of LI-ESWL for ED. Measurement of other parameters may also provide useful information. Similar to animal experiments, aspiration of corporal blood for VEGF levels may provide direct evidence that neovascularization also occurs after LI-ESWT in humans. Dynamic contrast-enhanced magnetic resonance imaging can also functionally characterize tissue perfusion and a biomarker for angiogenesis in tumors and may provide a way to measure the degree of neovascularization in patients after LI-ESWT (Teo, Thng, Koh, & Ng, 2014). Sampling of penile tissue after treatment for immunohistochemistry and evaluation of smooth muscle and endothelial content, although invasive, may provide further evidence of angiogenesis. As such, while still in its infancy, LI-ESWT presents an attractive, noninvasive option for the management of ED.