Review Article | Published:

Therapeutic areas of Li-ESWT in sexual medicine other than erectile dysfunction

Abstract

Low intensity extracorporal shock wave therapy (Li-ESWT) may induce tissue regeneration, neo-angiogenesis and improve endothelial function. This has shown promise in the treatment of erectile dysfunction (ED). The aim of this narrative review was to describe potential therapeutic areas of Li-ESWT in sexual medicine other than ED. An extensive literature search and review of the most recent guidelines revealed that Li-ESWT has been used in the treatment of Peyronie’s disease (PD) and is being investigated as a method of improving stem cell therapy. In PD, Li-ESWT has been shown to decrease pain but no clinically relevant benefits regarding plaque size or penile curvature have been shown in randomized clinical trials. For stem cell optimization, only two preclinical studies have been conducted within the realm of sexual medicine. These show that application of Li-ESWT to the tissue after stem cell transplantation may increase the erectile response following cavernous nerve or diabetes damage. More research is needed to bring this concept from bench to bedside. In addition to this, Li-ESWT has shown promise in pelvic pain and it’s effects on testicles have been preliminarily investigated in preclinical studies.

Introduction

Extracorporal shock wave therapy (ESWT) was originally introduced in a medical context when it was first used to treat kidney stones [1]. Since then, a low-intensity version of the modality (Li-ESWT) has been employed in several conditions including wound healing and musculoskeletal disorders [2, 3]. The proposed mechanism of action is the upregulation of growth factors and recruitment of progenitor cells, which in turn induce tissue regeneration, neo-angiogenesis and improved endothelial function [4,5,6,7].

From a theoretical standpoint, these cellular and tissue effects could also be of benefit in other conditions and the range of potential indications seem to be expanding. From a sexual medicine stand point, it is notable that Li-ESWT has shown promise in the treatment of erectile dysfunction (ED) in recent years [8]. The purpose of this narrative review is to summarize the evidence regarding the use of Li-ESWT in sexual medicine other than ED.

Methods

This paper represents a narrative review of Li-ESWT in sexual medicine. To identify relevant topics, a literature search of PubMed regarding Li-ESWT and sexual dysfunction was conducted on October 18th, 2018. Due to the broad subject matter of the paper, we simply searched for the term “Shock wave therapy” and included articles describing the use of Li-ESWT in sexual medicine except in the context of ED. We restricted our search to full-text English-language articles. No restrictions were placed on article type and we included both animal and humans studies. Articles were screened based on titles and abstracts. Subsequently, the literature was searched again for each identified topic relating to Li-ESWT in sexual medicine other than ED. The final articles were selected based on reviews of the full texts. Reference lists of the selected articles were searched manually.

Results

Our initial search yielded 886 papers. After screening titles and abstracts we found that 47 articles described Li-ESWT in sexual medicine or directly related topics. Thirty-six of these related to ED only, while the remaining papers dealt primarily with Peyronie’s disease (PD) and pelvic pain/prostatitis. Meanwhile, several papers reported on Li-ESWT as a method of improving stem cells, which may have an indirect impact in the future of sexual medicine. Finally, four preclinical studies described potential testicular effects of Li-ESWT and optimization of surgical results in breast implants [9] respectively. In addition to these findings, it was noted that no other indications for Li-ESWT were mentioned in the latest guidelines on neither female nor male sexual dysfunction [10, 11]. Likewise, a questionnaire-based study from 2017 among sexual medicine practitioners did not identify any other uses of Li-ESWT in sexual medicine [12]. The following text will focus on the use of Li-ESWT in PD and stem cell optimization. It will also briefly describe effects on pelvic pain and the testicles as this relates to sexual medicine. Optimization of breast implants is outside the scope of this article.

Peyronie’s disease (PD)

Peyronie’s disease is a connective tissue disorder with unknown etiology characterized by penile pain and formation of fibrous plaques in the tunica albuginea [13]. The condition typically manifests after the age of 40 and develops during an active phase over several months often with increasing penile deformity followed by stabilization [13,14,15,16]. Although the reported prevalence rates differ widely in the published literature there is no doubt that it is a common condition, affecting up to 9% in some reports [17]. For many years, surgical correction of stabilized plaques has been the gold standard in the treatment of PD, while more conservative measures have generally been disappointing [18, 19]. Therefore, such treatments have been highly sought after.

Initial studies of Li-ESWT in PD

Shock wave therapy was originally introduced in sexual medicine when Bellorofonte and co-workers attempted to use it in the treatment of penile fibrosis and Peyronie’s plaques in 1989 [20]. In this report, the authors confirmed the safety of the approach and formed the basis for further research.

Subsequent case series have generally shown excellent safety and clinically meaningful reductions in pain. More importantly, most studies have found that about 30% to 60% of treated men had reductions in penile curvatures which were deemed clinically meaningful by the investigators [21,22,23,24,25,26,27,28,29,30], while relatively few studies have been unable to find measurable benefits [31, 32]. However, when examining these encouraging results, it is important to consider the natural history of PD as the course may vary significantly between individual patients. In this context, it is well established that pain subsides with time in most patients. However, very few studies have utilized serial objective measurements in untreated PD patients. In one study, 217 men with recent onset (<6 months) PD and an initial curvature were followed for a mean of 18 months and the investigators found improvement in 12% [15] of the group. In another study, 95 patients with PD for a mean duration of 12.9 months at inclusion were followed for 12 months [16]. Here, 26% of the patients had objective reductions in their penile curvatures. Improvements were most prevalent in men with limited plaque size and smaller curvatures at baseline. Although this can hardly explain the whole apparent effect of Li-ESWT, the effects reported in uncontrolled studies may therefore, in part, reflect natural regression of the disease in some patients. In addition, measurement of objective parameters such as plaque size and curvature are prone to bias if it is known by the assessors that an entire cohort has received treatment. Therefore, it is crucial to turn our attention toward randomized placebo-controlled trials when assessing possible effects of Li-ESWT in PD.

Randomized placebo-controlled trials of Li-ESWT in PD

Currently, three randomized placebo-controlled trials investigating Li-ESWT in PD trials have been conducted (Table 1). The first one was published by Palmieri and coworkers in 2009 [33]. Here, 100 men who all suffered from limited PD in the active phase were randomized to either four weekly Li-ESWT sessions of 2000 focused shock waves with an energy flux density of 0.25 mJ/mm and an emission frequency of 4 Hz or placebo. The authors found that pain was reduced in the Li-ESWT group at both 12 and 24 weeks compared to the placebo group, while both erectile function and quality of life were improved. In addition, mean plaque size and mean curvature degree both improved with Li-ESWT compared to placebo at the 24 weeks analysis. However, when looking at the absolute values, the changes were limited as mean plaque size decreased by 0.6 mm in the treatment group and increased by 1.4 mm in the placebo group, while the mean curvature decreased by 1.43 degrees in the Li-ESWT group and increased by 1.8 degrees in the placebo group.

Table 1 Randomized, placebo-controlled trials exploring Li-ESWT in Peyronie’s disease

The second trial investigated 36 men with PD in the stable phase but without plaque calcifications who were randomized to six sessions of either Li-ESWT with 3000 shock waves or sham therapy [34]. In this study, there was no effect of Li-ESWT compared to placebo in neither subjective nor objective parameters. In fact, the mean dorsal and lateral angles showed improvements of 5.3 and 3.5 degrees respectively while there was a deterioration of 0.9 degrees in both measurements in the Li-ESWT group. However, these differences did not reach statistical significance. In addition, there were potentially important between group differences with longer disease duration and more baseline angulation in the control group and an uneven drop-out rate between the groups which makes the results difficult to interpret.

The final randomized placebo-controlled trial which compared Li-ESWT to sham treatment in PD randomized 102 men to either 6 weekly sessions with 2000 shock waves with an energy flow density of 0.29 mJ/mm2 and an emission frequency of 3 Hz or sham treatment [35]. This study also targeted men with PD in the stable phase although symptoms had to be unchanged for only ≥3 months and about half of the participants experienced pain at inclusion. The study found a significant decrease in pain at 4 weeks following Li-ESWT compared to sham as 17/20 treated patients with pain at baseline experienced an improvement in symptoms while this was only the case for 12/25 patients in the placebo group (p = 0.013). However, penile curvature did not improve with Li-ESWT compared to sham. Thus, the curvature worsened in 20/50 treated patients and in 12/49 sham patients (P = 0.133). Likewise, there was no statistically significant difference between the groups regarding the plaque size reduction and erectile function.

In addition to these trials, a fourth randomized placebo-controlled trial warrants mention [36]. Here, 100 men were randomized to either 4 weekly Li-ESWT sessions with an energy flux density of 0.25 mJ/mm2 and an emission frequency of 4 Hz plus tadalafil 5 mg once daily or 4 weekly Li-ESWT sessions only. The mean VAS score improved significantly in both groups without significant intergroup differences (from about 5 at baseline to about 0.5 at 24 weeks) and, not surprisingly, the erectile function was better in the combination group at both 12 and 24 weeks. However, there were no statistically significant changes in either plaque size or curvature after the treatment compared to baseline in either group. Importantly, no side effects, aside from limited bruising, were seen in any of the described studies.

In line with these results, a 2016 meta-analysis of 6 comparative studies including the three randomized placebo-controlled trials found that Li-ESWT could reduce (OR 4.46, 95% CI 2.29–8.68, P < 0.0001) or eliminate pain (OR 5.86, 95% CI 2.66–12.92, P < 0.0001) and increase the percentage of men with lessening of penile plaques (OR 2.07, 95% confidence interval (CI) 1.11–3.85, P = 0.02). However, there were no statistically significant improvements in penile curvature and no overall improvements in erectile function were seen [37].

Future aspects of Li-ESWT in PD

Although the possible effect of Li-ESWT in ED is still a topic of controversy, this potential application of the technology has created considerable excitement and anticipation within the field of sexual medicine [38]. Meanwhile, shock wave therapy has been used in PD for much longer. When examining the studies, there is hardly doubt that the treatment has some effects in the condition. Thus, pain universally subsides with treatment across studies and this benefit is confirmed in randomized trials. The mechanism of action behind this is unknown but animal studies exploring Li-ESWT directed at the penis have suggested that it may improve endothelial function, promote the formation of new blood vessels, and even improve the function of nerve fibers [39,40,41,42]. Previously shock waves have also been shown to induce immediate vasodilatation [43]. It may be speculated that such effects could also influence pain. Regarding plaque size and penile curvature, it has been hypothesized that Li-ESWT may cause direct physical damage to fibrotic tissue or that it may induce local inflammation leading to lysis of the plaque and removal by macrophages [24].

However, this have never been shown in neither preclinical nor clinical studies and the available high-quality studies do not point to any effect of Li-ESWT on penile morphology compared to sham treatment. Only one out of three studies found minor effects in this regard [34]. Interestingly, this was the only randomized sham-controlled study to investigate the disease in the acute phase. When viewed in this light, it is possible that Li-ESWT may help stop PD progression when applied early. However, one needs to be very careful with such speculation as the results are yet to be replicated and as the actual effects shown in the study cannot be considered clinically significant. Likewise, the clinical utility of Li-ESWT as a treatment for PD induced pain has been questioned as this subsides spontaneously in almost 90% [15, 35].

When discussing Li-ESWT in the treatment of PD it warrants mention that shock waves have been associated with the development of subsequent fibrosis in animal studies and have actually been used to induce PD in an animal model [44]. This may relate to the finding that, the development of PD is associated to elevated levels of transforming growth factor-β1, which can be up-regulated by Li-ESWT [45, 46], Therefore, there is a theoretical risk that the treatment may actually worsen fibrosis or induce new plaques in some patients. The problem has not been reported in the literature, but long-term outcomes are lacking in most studies.

Improvement of stem cells

Stem cells are expected to play an important role in a wide range of medical conditions in the future and the modality has been discussed in relation to sexual medicine for more than 10 years [47]. The focus has been on ED and PD with several animal studies exploring different stem cell types and forms of administration [48]. However, human data is limited with only a handful of small pilot studies. These show feasibility and seem to confirm safety but are insufficient to document any clinical effects [48]. Due to its potential ability to induce growth factors, Li-ESWT has been proposed to optimize stem cell treatment in two principally different ways, namely, by treating in vitro stem cell cultures and by applying Li-ESWT after injection of stem cells in the host.

Li-ESWT in general stem cell studies

In preclinical studies, the first method has shown to metabolically activate stem cells, and to increase their rate of proliferation possibly through induction of growth factors including placental growth factor and insulin-like growth factor-1 [49,50,51]. In addition, Li-ESWT has promoted differentiation into osteogenic, cartilagenic, and myogenic cell lineages, thus promoting healing of specific tissues [52,53,54,55,56,57]. Taken together, this suggests that Li-ESWT may prompt stem cells to establish themselves in a variety target tissues.

The second method has also shown promise in preclinical studies. Here, the combination of stem cell treatment and Li-ESWT has been shown to offer better tissue protection in rats compared to either one applied individually in both critical limb ischemia and ischemia-reperfusion injury [58, 59]. The method has also been applied in a randomized trial, where 63 patients with previous failed healing of long bones were subjected to either combined transplantation of autologous bone mesenchymal stems cells and Li-ESWT or Li-ESWT alone [60]. In this study, the researchers noted a superior 12-month fracture healing rate in the combined group (84.4% vs 67.7%, P < 0.05).

Li-ESWT in sexual medicine stem cell studies

To our knowledge, only two preclinical studies within the of field sexual medicine have attempted to combine Li-ESWT and stem cell therapy (Table 2). In the first study, Jeon and co-workers investigated the combined effect of human adipose-derived stem cells and Li-ESWT in a rat model of cavernous nerve injury, imitating the situation in post-prostatectomy ED [61]. For this purpose, 50 rats were divided into five groups consisting of controls, bilateral cavernous nerve injury, nerve injury plus adipose-derived stem cell, nerve injury plus Li-ESWT, and nerve injury plus both stem cells and Li-ESWT. After four weeks, the combination group showed significantly increased smooth muscle actin content, neural nitric oxide synthase of the dorsal penile nerve, endothelial nitric oxide synthase protein expression, and cyclic guanosine monophosphate compared to the stem cell or Li-ESWT only groups. In addition, the combination therapy significantly increased intracavernosal pressure compared to the other groups with nerve injury. Based on the findings of the individual groups, the authors proposed that the results of the combination treatment were due to enhanced nerve regeneration with stem cell therapy and upregulation of growth factors with subsequent neovascularization induced by Li-ESWT. In the second study Shan and co-workers used a rat model of diabetes-induced ED to investigate if Li-ESWT could improve survival and effects of bone marrow-derived mesenchymal stem cells [62]. The authors divided, 42 streptozotocin-induced diabetic rats into four groups who served as untreated controls, stem cell treatment only, Li-ESWT only, and a combination of stem cell transplantation and penile Li-ESWT. Upon subsequent evaluation, the authors found that Li-ESWT increased survival of transplanted stem cells, perhaps due to increased stromal cell-derived factor-1 expression and induced angiogenesis. Even more importantly, the combination of Li-ESWT and stem cell transplantation improved the erectile function of the rats more than either modality alone as measured by intracavernous pressure/mean arterial pressure response to electric stimulation of the cavernous nerve.

Table 2 Preclinical studies combining stem cells and Li-ESWT in sexual medicine

Future aspects of Li-ESWT in stem cell studies

It is widely believed that stem cell therapy may play an important role in the future of medicine in general and in sexual medicine in particular. So far the modality has been studied in ED and PD [48]. However, to date, stem cell therapy has not shown clear clinical effects and extensive research is ongoing [63]. Therefore, optimization of stem cells efficacy is of interest and Li-ESWT may play a role in this aspect. Only two published studies have focused on sexual medicine indicating a possible effect of combining Li-ESWT and stem cells in penile rehabilitation following radical prostatectomy and in treating diabetes-induced ED [61, 62]. Although encouraging, this needs confirmation in human studies as preclinical data on erectile function recovery has previously proven difficult to translate into a clinical setting [64].

Other conditions related to sexual medicine

In addition to PD and stem cell optimization, we identified two potential therapeutical areas for Li-ESWT related to sexual medicine, namely pelvic pain/prostatitis and effects on the testicles. For pelvic pain, Li-ESWT is hypothesized to exert positive effects by increasing blood flow and by reducing pelvic muscle tone. The first study to investigate Li-ESWT for pelvic pain was a case series conducted by Zimmermann et. al. and included 34 patients with pelvic pain and prostatitis [65]. In the initial part of the study, 14 patients received Li-ESWT treatments to the prostate of 2000 impulses, at an energy density of 0.11 mJ/mm2 and a frequency 3 Hz within 2 weeks using a the Minilith SL1 device (Storz Medical, Tägerwilen, Switzerland). Subsequently, another 20 patients received a similar treatment but with one weekly Li-ESWT session for 4 weeks at 3000 impulses and at an energy density of 0.25 mJ/mm2 with the Duolith SD1 (Storz Medical, Tägerwilen, Switzerland), which has a smaller transducer. At 12 weeks both groups experienced statistically significant reductions in their symptoms as measured by the National Institutes of Health Chronic Prostatitis Symptom Index (CPSI) and reductions in their mean Visual Analog Pain Score (VAS) of 3.1 point (from 7.0 to 3.9) and 2 points (from 5.3 to 3.3), respectively.

In a subsequent study, the same research group randomized another 60 patients with chronic pelvic pain and prostatitis to Li-ESWT or sham treatment again using the Duolith SD1 device with the 4-week protocol [66]. Here the treatment group experienced a 16.7% reduction in their CPSI score and a 50% reduction in VAS at 12 weeks. Meanwhile, there were no notable changes in symptoms for the sham group. A second sham-controlled study from China randomized 80 patients to either 10 li-ESWT sessions over a two-week period or sham treatment [67]. In this study, 29% in the Li-ESWT group exhibited clinically significant improvements in CPSI compared with 11% in the sham group (P < 0.01). Likewise, a study from 2016 (n = 60) found that the combination of Li-ESWT and triple with an α-blocker, an anti-inflammatory agent and a muscle relaxant was superior to triple therapy alone in chronic pelvic pain [68]. Two recent case series, both administering 4 weekly Li-ESWT sessions, have confirmed a possible effect in men with chronic pelvic pain who had failed other treatments [69, 70].

Regarding Li-ESWT impact on the testicles, we identified two animal studies, which investigated possible detrimental effects. In the first study, 2000 shock waves at 18 kV were applied to the testicles of 12 rabbits and on subsequent transmission electron microscopy examination, no apparent detrimental effects on sperm morphology were found [71]. In the second study, 24 male rats were divided into a control group or two treatment groups receiving 300 shock waves at 1.6 BAR and 3.2 BAR respectively three times a week for 3 weeks [72]. The treatment did not alter testosterone levels; however, the 3.2 BAR group showed a decreased sperm quality compared to the control group. In addition to these trials, a recent study in 64 male rats has suggested that Li-ESWT treatment following induction of testicular torsion could reduce germ cell loss and tissue damage from ischemia-reperfusion injury, possible through reduction in oxidative stress mediated through the PI3K/AKT/NRF2 pathway [73].

Conclusion

The current utility of Li-ESWT in sexual medicine other than erectile dysfunction is limited. Future research on Li-ESWT in the acute phase of PD would be of interest but until high-quality studies on this topic are published, the treatment cannot be recommended for this indication. Likewise, more studies on Li-ESWT for the optimization of stem cells are needed and although this aspect is promising, the required work and investments in the technology should not be underestimated. On the contrary, Li-ESWT seems like a promising option in chronic pelvic pain and could reasonably be attempted in men suffering from this condition under close observation of both short term and long term outcomes.

Finally, it should be noted that Li-ESWT is a relatively new modality with a broad potential and that the future is likely to reveal new indications for the treatment, perhaps also in sexual medicine.

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Correspondence to Mikkel Fode.

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